The Gale Genetic Disorders of encyclopedia vol 1 - part 10 ppsx

Diagnosis The diagnosis of Kabuki syndrome relies on physical exam by a physician familiar with the condition and by radiographic evaluation, such as the use of x rays or ultra-sound to

longed QT interval Genetic testing for JLNS is ble for high-risk individuals.

possi-Individuals with JLNS sometimes have normal orborderline-normal QT intervals on an ECG/EKG.Additional ECGs/EKGs performed during exercise mayreveal an abnormal QT interval ECGs/EKGs of the par-ents may also reveal a prolonged QT interval

Treatment and management

Since JLNS can result in sudden death, includingsudden infant death syndrome (SIDS), treatment is essen-tial Beta-blockers are the most common treatment forthe ventricular arrhythmia of JLNS Treatment with thesedrugs usually continues for life Beta-blockers such aspropranolol are considered to be safe medications Anyside effects from propranolol are usually mild and disap-pear once the body has adjusted to the drug However,beta-blockers can interact dangerously with many othermedications

K E Y T E R M SAction potential—The wave-like change in the

electrical properties of a cell membrane, resulting

from the difference in electrical charge between the

inside and outside of the membrane

Arrhythmia—Abnormal heart rhythm, examples are

a slow, fast, or irregular heart rate

Autosomal recessive—A pattern of genetic

inheri-tance where two abnormal genes are needed to

dis-play the trait or disease

Beta-adrenergic blocker—A drug that works by

controlling the nerve impulses along specific nerve

pathways

Cochlea—A bony structure shaped like a snail shell

located in the inner ear It is responsible for

chang-ing sound waves from the environment into

electri-cal messages that the brain can understand, so

people can hear

Congenital—Refers to a disorder which is present at

birth

Depolarization—The dissipation of an electrical

charge through a membrane

Electrocardiogram (ECG, EKG)—A test used to

measure electrical impulses coming from the heart

in order to gain information about its structure or

function

Endolymph—The fluid in the inner ear.

Fibrillation—A rapid, irregular heartbeat.

Heterozygous—Having two different versions of the

same gene

Homeostasis—A state of physiological balance.

Homozygous—Having two identical copies of a

gene or chromosome

Ion channel—Cell membrane proteins which

con-trol the movement of ions into and out of a cell

QT interval—The section on an electrocardiogram

between the start of the QRS complex and the end

of the T wave, representing the firing or tion of the ventricles and the period of recoveryprior to repolarization or recharging for the nextcontraction

depolariza-Repolarization—Period when the heart cells are at

rest, preparing for the next wave of electrical rent (depolarization)

cur-Syncope—A brief loss of consciousness caused by

insufficient blood flow to the brain

Tachycardia—An excessively rapid heartbeat; a

heart rate above 100 beats per minute

Torsade de pointes—A type of tachycardia of the

ventricles characteristic of Jervell and Nielsen syndrome

Lange-Signs and symptoms

The deafness associated with JLNS usually is

appar-ent in infancy or early childhood Although the severity

of JLNS varies, children with acute JLNS are profoundly

deaf in both ears

Depending on the severity of the disorder, the

car-diac symptoms of JLNS may be overlooked Thus,

peo-ple with JLNS can be at serious risk for sudden death In

addition to a prolonged QT interval on an ECG/EKG,

cardiac arrhythmias, dizziness, periods of

unconscious-ness (syncopic episodes), and seizures are common

symptoms of JLNS These symptoms most often occur

upon awakening, during strenuous physical activity, or

during moments of excitement or stress

Diagnosis

Deaf children, particularly those with a family

his-tory of sudden death, syncopic episodes, or LQTS should

be screened for JLNS, using an ECG to detect a

pro-Surgery may reduce cardiac arrhythmias in people

with JLNS A mechanical device called a pacemaker or

an automatic implanted cardioverter defibrillator (AICD)

may be used to regulate the heartbeat or to detect and

cor-rect abnormal heart rhythms Sometimes a pacemaker or

AICD is used in combination with beta-blockers

In 2000, the first cochlear implant in the inner ear of

a child with JLNS was reported The child gained limited

hearing and improved speech

Preventative measures

All individuals who have been diagnosed with JLNS

must avoid reductions in blood potassium levels, such as

those that occur with the use of diuretics (drugs that

reduce fluids in the body) People with JLNS must also

avoid a very long list of drugs and medications that can

increase the QT interval or otherwise exacerbate the

syn-drome

People with JLNS usually are advised to refrain

from competitive sports and to practice a “buddy system”

during moderate exercise Family members are advised

to learn cardiopulmonary resuscitation (CPR) in case of

cardiac arrest

Prognosis

Cochlear implants may improve the hearing of

peo-ple with JLNS The cardiac abnormalities of JLNS

usu-ally can be controlled with beta-blockers However,

without treatment, there is a high incidence of sudden

death due to cardiac events

Family members of a JLNS individual should be

screened with ECGs/EKGs for a prolonged QT interval,

since they are at risk of having LQTS Genetic

counsel-ing is recommended for people with JLNS, since their

children will inherit a gene causing LQTS

Resources

PERIODICALS

Chen, Q., et al “Homozygous Deletion in KVLQT1 Associated

with Jervell and Lange-Nielsen Syndrome.” Circulation

99 (1999): 1344-47.

Schmitt, N., et al “A Recessive C-terminal Jervell and

Lange-Nielsen Mutation of the KCNQ1 Channel Impairs Subunit

Assembly.” The EMBO Journal 19 (2000): 332-40.

Steel, Karen P “The Benefits of Recycling.” Science 285

.org .

European Long QT Syndrome Information Center Ronnerweg

2, Nidau, 2560 Switzerland 04(132) 331-5835 tler@bielnews.ch
http://www.bielnews.ch/cyberhouse/

jmet-qt/qt.html .

Sudden Arrhythmia Death Syndrome Foundation PO Box

58767, 508 East South Temple, Suite 20, Salt Lake City,

UT 84102 (800) 786-7723 sads@sads.org
http://www

.sads.org .

WEBSITES

Contie, Victoria L “Genetic Findings Help Tame the Runaway

QT Syndrome).” Archives of Pediatrics and Adolescent

Medicine, 153 (4)
http://archpedi.ama-assn.org/ issues/

of the face, hands, and feet

Description

Marie Joubert (whose name is given to the tion) gave a detailed description of the syndrome in 1969.She wrote about four siblings (three brothers, one sister)

condi-in one family with abnormal breathcondi-ing, jerky eye ments (nystagmus), poor mental development, and ataxia

(staggering gait and imbalance) X ray examination

showed that a particular section of the brain, called the

cerebellar vermis, was absent or not fully formed This

specific brain defect was confirmed on autopsy in one of

these individuals Her initial report also described a

spo-radic (non-inherited) patient with similar findings, in

addition to polydactyly Another name for Joubert

syn-drome is Joubert-Bolthauser synsyn-drome

Genetic profile

There have been numerous instances of siblings

(brothers and sisters), each with Joubert syndrome The

parents were normal A few families have also been seen

where the parents were said to be closely related (i.e may

have shared the same altered gene within the family) For

these reasons, Joubert syndrome is an autosomal recessive

disorder Autosomal means that both males and females

can have the condition Recessive means that both parents

would be carriers of a single copy of the responsible gene

Autosomal recessive disorders occur when a person

inherits a particular pair of genes that do not work

cor-rectly The chance that this would happen to children of

carrier parents is 25% (1 in 4) for each pregnancy

It is known that the cerebellum and brain stem begin

to form between the sixth and twelfth week of pregnancy

The birth defects seen in Joubert syndrome must occur

during this crucial period of development As of 2001,

the genetic cause remains unknown

Demographics

Joubert syndrome affects both males and females,

although more males (ratio of 2:1) have been reported

with the condition The reason why more males have the

condition remains unknown

Joubert syndrome is found worldwide, with reports

of individuals of French Canadian, Swedish, German,

Swiss, Spanish, Dutch, Italian, Indian, Belgian, Laotian,

Moroccan, Algerian, Turkish, Japanese, and Portuguese

origin In all, more than 200 individuals have been

described with Joubert syndrome

Signs and symptoms

The cerebellum is the second largest part of the

brain It is located just below the cerebrum, and partially

covered by it The cerebellum consists of two

hemi-spheres, separated by a central section called the vermis

The cerebellum is connected to the spinal cord, through

the brain stem

The cerebellum (and vermis) normally works to

monitor and control movement of the limbs, trunk, head,

K E Y T E R M SApnea—An irregular breathing pattern character-

ized by abnormally long periods of the completecessation of breathing

Ataxia—A deficiency of muscular coordination,

especially when voluntary movements areattempted, such as grasping or walking

Cerebellum—A portion of the brain consisting of

two cerebellar hemispheres connected by a row vermis The cerebellum is involved in control

nar-of skeletal muscles and plays an important role inthe coordination of voluntary muscle movement Itinterrelates with other areas of the brain to facili-tate a variety of movements, including maintainingproper posture and balance, walking, running, andfine motor skills, such as writing, dressing, andeating

Iris—The colored part of the eye, containing

pig-ment and muscle cells that contract and dilate thepupil

Nystagmus—Involuntary, rhythmic movement of

Vermis—The central portion of the cerebellum,

which divides the two hemispheres It functions tomonitor and control movement of the limbs, trunk,head, and eyes

and eyes Signals are constantly received from the eyes,ears, muscle, joints, and tendons Using these signals, thecerebellum is able to compare what movement is actuallyhappening in the body, with what is intended to happen.Then, it sends an appropriate signal back The effect is toeither increase or decrease the function of different mus-cle groups, to make movement both accurate andsmooth

In Joubert syndrome, the cerebellar vermis is eitherabsent or incompletely formed The brain stem is some-times quite small The absence or abnormal function ofthese brain tissues causes problems in breathing andvision, and severe delays in development

One characteristic feature of Joubert syndrome isthe pattern of irregular breathing Their breathing alter-nates between deep rapid breathing (almost like pant-ing) with periods of severe apnea (loss of breathing).This is usually noticeable at birth The rate of respira-

tion may increase more than three times that of normal

(up to 200 breaths per minute) and the apnea may last up

to 90 seconds The rapid breathing occurs most often

when the infant is awake, especially when they are

aroused or excited The apnea happens when the infants

are awake or asleep Such abnormal breathing can cause

sudden death or coma, and requires that these infants be

under intensive care For unknown reasons, the

breath-ing tends to improve with age, usually within the first

year of life

Muscle movement of the eye is also affected in

Joubert syndrome It is common for the eyes to have a

quick, jerky motion of the pupil, known as nystagmus

The retina (the tissue in the back of the eye that receives

and transmits visual signals to the brain) may be

abnor-mal Some individuals (most often the males) may have a

split in the tissue in the iris of the eye Each of these

prob-lems will affect their vision, and eye surgery may not be

beneficial

The central nervous system problem affects the

larger muscles of the body as well, such as those for the

arms and legs Many of the infants will have severe

mus-cle weakness and delays in development They reach

nor-mal developmental milestones, such as sitting or

walking, much later than normal For example, some may

learn to sit without support by around 19–20 months of

age (normal is six to eight months) Most individuals are

not able to take their first steps until age four or older.Their balance and coordination are also affected, whichmakes walking difficult Many will have an unsteadygait, and find it difficult to climb stairs or run, even asthey get older

Cognitive (mental) delays are also a part of the drome, although this can be variable Most individualswith Joubert syndrome will have fairly significant learn-ing impairment Some individuals will have little or nospeech Others are able to learn words, and can talk withthe aid of speech therapy They do tend to have pleasantand sociable personalities, but problems in behavior canoccur These problems most often are in temperament,hyperactivity, and aggressiveness

syn-Careful examination of the face, especially ininfancy, shows a characteristic appearance They tend tohave a large head, and a prominent forehead The eye-brows look high, and rounded, and the upper eyelids may

be droopy (ptosis) Their mouth many times remainsopen, and looks oval shaped in appearance The tonguemay protrude out of the mouth, and rest on the lower lip.The tongue may also quiver slightly These are all signs

of the underlying brain abnormality and muscle ness Occasionally, the ears look low set on the face Asthey get older, the features of the face become lessnoticeable

weak-Less common features of the syndrome includeminor birth defects of the hands and feet Some individ-uals with Joubert syndrome have extra fingers on eachhand The extra finger is usually on the pinky finger side(polydactyly) It may or may not include bone, and couldjust be a skin tag A few of these patients will also haveextra toes on their feet

Diagnosis

The diagnosis of Joubert syndrome is made on thefollowing features First, there must be evidence of thecerebellar vermis either being absent or incompletelyformed This can be seen with a CT scan or MRI of thebrain Second, the physician should recognize the infanthas both muscle weakness and delays in development Inaddition, there may be irregular breathing and abnormaleye movements Having four of these five criteria isenough to make the diagnosis of Joubert syndrome Mostindividuals are diagnosed by one to three years of age

Treatment and management

During the first year of life, many of these infantsrequire a respiratory monitor for the irregular breathing.For the physical and mental delays, it becomes necessary

This child is diagnosed with Joubert syndrome Common

symptoms of this disorder include mental retardation, poor

coordination, pendular eye movement, and abnormal

breathing patterns.(Photo Researchers, Inc.)

to provide special assistance and anticipatory guidance.

Speech, physical, and occupational therapy are needed

throughout life

Prognosis

The unusual pattern of breathing as newborns,

especially the episodes of apnea, can lead to sudden

death or coma A number of individuals with Joubert

syndrome have died in the first three years of life For

most individuals, the irregular breathing becomes more

normal after the first year However, many continue to

have apnea, and require medical care throughout their

life Although the true lifespan remains unknown, there

are some individuals with Joubert syndrome who are intheir 30s

I Kabuki syndrome

Definition

Kabuki syndrome is a rare disorder characterized by

unusual facial features, skeletal abnormalities, and

intel-lectual impairment Abnormalities in different organ

sys-tems can also be present, but vary from individual to

individual There is no cure for Kabuki syndrome, and

treatment centers on the specific abnormalities, as well as

on strategies to improve the overall functioning and

qual-ity of life of the affected person

Description

Kabuki syndrome is a rare disorder characterized by

mental retardation, short stature, unusual facial features,

abnormalities of the skeleton and unusual skin ridge

pat-terns on the fingers, toes, palms of the hands and soles of

the feet Many other organ systems can be involved in the

syndrome, displaying a wide variety of abnormalities

Thus, the manifestations of Kabuki syndrome can vary

widely among different individuals

Kabuki syndrome (also known as Niikawa-Kuroki

syndrome) was first described in 1980 by Dr N Niikawa

and Dr Y Kuroki of Japan The disorder gets its name

from the characteristic long eyelid fissures with eversion

of the lower eyelids that is similar to the make-up of

actors of Kabuki, a traditional Japanese theatrical form

Kabuki syndrome was originally known as Kabuki

Make-up syndrome, but the term “make-up” is now

often dropped as it is considered offensive to some

families

Scientific research conducted over the past two

decades suggests that Kabuki syndrome may be

associ-ated with a change in the genetic material However, it is

still not known precisely what this genetic change may

be and how this change in the genetic material alters

growth and development in the womb to cause Kabuki

syndrome

Genetic profile

As stated above, the etiology of Kabuki syndrome isnot completely understood While Kabuki syndrome isthought to be a genetic syndrome, little or no geneticabnormality has been identified as of yet Chromosomeabnormalities of the X and Y chromosome or chromo-some 4 have occurred in only a small number of individ-uals with Kabuki syndrome, but in most cases,

chromosomes are normal.

In almost all cases of Kabuki syndrome, there is nofamily history of the disease These cases are thought torepresent new genetic changes that occur randomly andwith no apparent cause and are termed sporadic.However, in several cases the syndrome appears to beinherited from a parent, supporting a role for genetics inthe cause of Kabuki syndrome Scientists hypothesizethat an unidentified genetic abnormality that causesKabuki syndrome is transmitted as an autosomal domi-nant trait With an autosomal dominant trait, only oneabnormal gene in a gene pair is necessary to display thedisease, and an affected individual has a 50% chance oftransmitting the gene and the disease to a child

Demographics

Kabuki syndrome is a rare disorder with less than

200 known cases worldwide, but the prevalence of thedisease may be underestimated as only a handful ofphysicians have first-hand experience diagnosing chil-dren with Kabuki syndrome Kabuki syndrome appears

to be found equally in males and females Earlier caseswere reported in Japanese children but the syndrome isnow known to affect other racial and ethnic groups.Theoretical mathematical models predict that theincidence of Kabuki syndrome in the Japanese popula-tion may be as high as one in 32,000

Signs and symptoms

The signs and symptoms associated with Kabukisyndrome are divided into cardinal symptoms (i.e those

K

For children with heart defects, surgical repair isoften necessary This may take place shortly after birth ifthe heart abnormality is life threatening, but often physi-cians will prefer to attempt a repair once the child hasgrown older and the heart is more mature For childrenwho experience seizures, lifelong treatment with anti-seizure medications is often necessary.

Children with Kabuki syndrome often have ties feeding, either because of mouth abnormalities orbecause of poor digestion In some cases, a tube thatenters into the stomach, is placed surgically in theabdomen and specially designed nutritional liquids areadministered through the tube directly into the stomach.People with Kabuki syndrome are at higher risk for

difficul-a vdifficul-ariety of infections, most often involving the edifficul-ars difficul-andthe lungs In cases such as these, antibiotics are given totreat the infection, and occasionally brief hospital staysare necessary Most children recover from these infec-tions with proper treatment

Nearly half of people affected by Kabuki syndromehave some degree of hearing loss In these individuals,formal hearing testing is recommended to determine ifthey might benefit from a hearing-aid device A hearingaid is a small mechanical device that sits behind the earand amplifies sound into the ear of the affected individ-ual Occasionally, hearing loss in individuals withKabuki syndrome is severe, approaching total hearingloss In these cases, early and formal education usingAmerican Sign Language as well as involvement with thehearing-impaired community, schools, and enrichmentprograms is appropriate

Children with Kabuki syndrome should be seen ularly by a team of health care professionals, including aprimary care provider, medical geneticist familiar withthe condition, gastroenterologist, and neurologist Aftergrowth development is advanced enough (usually lateadolescence or early adulthood), consultation with areconstructive surgeon may be of use to repair physicalabnormalities that are particularly debilitating

reg-During early development and progressing intoyoung adulthood, children with Kabuki syndromeshould be educated and trained in behavioral andmechanical methods to adapt to any disabilities Thisprogram is usually initiated and overseen by a team ofhealth care professionals including a pediatrician, phys-ical therapist, and occupational therapist A counselorspecially trained to deal with issues of disabilities inchildren is often helpful is assessing problem areas andencouraging healthy development of self-esteem.Support groups and community organizations for peoplewith disabilities often prove useful to the affected indi-viduals and their families, and specially equipped

K E Y T E R M SAutosomal dominant—A pattern of genetic inher-

itance where only one abnormal gene is needed to

display the trait or disease

Cardinal symptoms—A group of symptoms that

define a disorder or disease

Gastric tube—A tube that is surgically placed

though the skin of the abdomen to the stomach so

that feeding with nutritional liquid mixtures can be

accomplished

Gastroenterologist—A physician who specializes

in disorders of the digestive system

Kabuki—Traditional Japanese popular drama

per-formed with highly stylized singing and dancing

using special makeup and cultural clothing

Neurologist—A physician who specializes in

dis-orders of the nervous system, including the brain,

spine, and nerves

that are almost always present) and variable symptoms

(those that may or may not be present) The cardinal and

variable signs and symptoms of Kabuki syndrome are

summarized in the table below

Diagnosis

The diagnosis of Kabuki syndrome relies on physical

exam by a physician familiar with the condition and by

radiographic evaluation, such as the use of x rays or

ultra-sound to define abnormal or missing structures that are

consistent with the criteria for the condition (as described

above) A person can be diagnosed with Kabuki

syn-drome if they possess characteristics consistent with the

five different groups of cardinal symptoms: typical face,

skin-surface abnormalities, skeletal abnormalities, mild

to moderate mental retardation, and short stature

Although a diagnosis may be made as a newborn,

most often the features do not become fully evident until

early childhood There is no laboratory blood or genetic

test that can be used to identify people with Kabuki

syn-drome

Treatment and management

There is no cure for Kabuki syndrome Treatment of

the syndrome is variable and centers on correcting the

different manifestations of the condition and on strategies

to improve the overall functioning and quality of life of

the affected individual

enrichment programs should be sought Further, because

many children with Kabuki syndrome have poor speech

development, a consultation and regular session with a

speech therapist is appropriate

Prognosis

The abilities of children with Kabuki syndrome vary

greatly Most children with the condition have a mild to

moderate intellectual impairment Some children will be

able to follow a regular education curriculum, while

oth-ers will require adaptations or modifications to their

schoolwork Many older children may learn to read at a

functional level

The prognosis of children with Kabuki syndrome

depends on the severity of the symptoms and the extent

to which the appropriate treatments are available Most

of the medical issues regarding heart, kidney or

intes-tinal abnormalities arise early in the child’s life and are

improved with medical treatment Since Kabuki

syn-drome was discovered relatively recently, very little is

known regarding the average life span of individuals

affected with the condition, however, present data on

Kabuki syndrome does not point to a shortened life

Kawame, H “Phenotypic Spectrum and Management Issues in

Kabuki Syndrome.” Journal of Pediatrics 134(April

1999): 480-485.

Mhanni, A.A., and A.E Chudley “Genetic Landmarks Through

Philately—Kabuki Theater and Kabuki Syndrome.”

Clinical Genetics 56(August 1999): 116-117.

“Entry 147920: Kabuki Syndrome.” OMIM—Online Mendelian

Inheritance in Man ⬍http://www.ncbi.nlm.nih.gov/

in three separate families Hence, the syndrome ofhypogonadotropic hypogonadism and anosmia wasnamed Kallmann syndrome (KS)

Kallmann syndrome (KS) is occasionally called plasia olfactogenitalis of DeMorsier Affected peopleusually are detected in adolescence when they do notundergo puberty The most common features are HH andanosmia, though a wide range of features can present in

dys-an affected person Other features of KS may include asmall penis or undescended testicles in males, kidneyabnormalities, cleft lip and/or palate,clubfoot, hearing

problems, and central nervous system problems such assynkinesia, eye movement abnormalities, and visual andhearing defects

Genetic profile

Most cases of Kallmann syndrome are sporadic.However, some cases are inherited in an autosomal dom-inant pattern, an autosomal recessive pattern, or an X-linked recessive pattern In most cells that make up aperson there are structures called chromosomes.Chromosomes contain genes, which are instructions forhow a person will grow and develop There are 46 chro-mosomes, or 23 pairs of chromosomes, in each cell Thefirst 22 chromosomes are the same in men and womenand are called the autosomes The last pair, the sex chro-mosomes, are different in men and women Men have an

X and a Y chromosome (XY) Women have two mosomes (XX) All the genes of the autosomes and theX-chromosomes in women come in pairs

X-chro-Autosomal dominant inheritance occurs when onlyone copy of a gene pair is altered or mutated to cause thecondition In autosomal dominant inheritance, the secondnormal gene copy cannot compensate, or make up for, thealtered gene People with autosomal dominant inheri-tance have a 50% chance of passing the gene and the con-dition onto each of their children

mann syndrome The gene instructs the body to make aprotein called anosmin-1 When this gene is altered in amale, Kallmann syndrome occurs Of those families whohave an X-linked recessive form of KS, approximately1/2 to 1/3 have identifiable alterations in their KAL gene.

Demographics

Kallmann syndrome is the most frequent cause ofhypogonadotropic hypogonadism and affects approxi-mately 1/10,000 males and 1/50,000 females Kallmannsyndrome is found in all ethnic backgrounds Because theincidence of KS in males is about five times greater than

KS in females, the original belief was that the X-linkedform of Kallmann syndrome was the most common.However, as of 2001, it is now assumed that the X-linkedrecessive form is the least common of all KS The reasonfor Kallmann syndrome being more frequent in males isnot known

Signs and symptoms

Embryology

Normally, a structure in the brain called the amus makes a hormone called gonadotrophin releasinghormone (GnRH) This hormone acts on the pituitarygland, another structure in the brain, to produce the twohormones: follicle stimulating hormone (FSH) andluteinizing hormone (LH) Both of these hormones travel

hypothal-to the gonads where they stimulate the development ofsperm in men and eggs in women FSH is also involved inthe release of a single egg from the ovary once a month.Hypogonadotropic hypogonadism results when there is analteration in this pathway that results in inadequate pro-duction of LH or FSH In Kallmann syndrome, the alter-ation is that the hypothalamus is unable to produce GnRH.How hypogonadotropic hypogonadism and theinability to smell are related can be explained during thedevelopment of an embryo The cells that eventuallymake the GnRH in the hypothalamus are first found inthe nasal placode, part of the developing olfactory system(for sense of smell) The GnRH cells must migrate, ormove, from the nasal placode up into the brain to thehypothalamus These GnRH cells migrate by followingthe path of another type of cell called the olfactory neu-rons Neurons are specialized cells that are found in thenervous system and have long tail-like structures calledaxons The axons of the olfactory neurons grow from thenasal placode up into the developing front of the brain.Once they reach their final destination in the brain, theyform the olfactory bulb, the structure in the brain thathelps process odors allowing the sense of smell TheGnRH cells follow the pathway of the olfactory neurons

up into the brain to reach the hypothalamus

K E Y T E R M SHormone—A chemical messenger produced by

the body that is involved in regulating specific

bodily functions such as growth, development,

and reproduction

Hypothalamus—A part of the forebrain that

con-trols heartbeat, body temperature, thirst, hunger,

body temperature and pressure, blood sugar

lev-els, and other functions

Neuron—The fundamental nerve cell that

con-ducts impulses across the cell membrane

Pituitary gland—A small gland at the base of the

brain responsible for releasing many hormones,

including luteinizing hormone (LH) and

follicle-stimulating hormone (FSH)

Puberty—Point in development when the gonads

begin to function and secondary sexual

character-istics begin to appear

Synkinesia—Occurs when part of the body will

move involuntarily when another part of the body

moves

Autosomal recessive inheritance occurs when both

copies of a gene are altered or mutated to cause the

con-dition In autosomal recessive inheritance, the affected

person has inherited one altered gene from their mother

and the other altered gene from their father Couples who

both have one copy of an altered autosomal recessive

gene have a 25% risk with each pregnancy to have an

affected child

X-linked recessive inheritance is thought to be the

least common form of inheritance in KS, but is the most

well understood at the genetic level With X-linked

reces-sive inheritance, the altered gene that causes the

condi-tion is on their X chromosome Since men have only one

copy of the X chromosome, they have only one copy of

the genes on the X chromosome If that one copy is

altered, they will have the condition because they do not

have a second copy of the gene to compensate Women,

however, can have one altered copy of the gene and not

be affected as they have a second copy to compensate In

X-linked recessive conditions, women are generally not

affected with the condition Women who are carriers for

an X-linked recessive condition have a 25% chance of

having an affected son with each pregnancy

Though all three patterns of inheritance have been

suggested for Kallmann syndrome, as of 2001 only one

gene has been found that causes Kallmann syndrome

The gene, KAL, is located on the X chromosome and is

responsible for most cases of X-linked recessive

Kall-In Kallmann syndrome, the olfactory neurons are

unable to grow into the brain Hence, the GnRH cells can

not follow their pathway As a result, the olfactory bulb

does not form, resulting in the inability to smell The

GnRH cells can not follow the pathway of the axons and

do not reach their final destination in the hypothalamus

Hence, no GnRH is made to stimulate the pituitary to

make FSH and LH, resulting in hypogonadotropic

hypogonadism

In X-linked recessive KS, the KAL gene instructs

the body to make the protein anosmin-1 This protein is

involved in providing the pathway in the brain for which

the olfactory axons grow If it is altered in any way, the

axons will not know where to grow in the brain and the

GnRH cells will be unable to follow The protein

anos-min-1 is also found in other parts of the body, possibly

explaining some of the other symptoms sometimes seen

in Kallmann syndrome

Other features

The features of Kallmann syndrome can vary among

affected individuals even within the same family The

two features most often associated with Kallmann

syn-drome are HH and the inability to smell Males can also

have a small penis and undescended testicles at birth

(tes-ticles are still in body and have not dropped down into the

scrotal sac) Clubfoot, cleft lip and/or cleft palate can also

be present at birth Clubfoot occurs when one or both feet

are not properly placed onto the legs and can appear

turned Cleft lip and/or cleft palate occur when the upper

lip and/or the roof of the mouth fail to come together

dur-ing development Kidney abnormalities, most often

uni-lateral renal agenesis (one kidney did not form) are

especially common in those males with X-linked

reces-sive KS Choanal atresia (pathway from the nose is

blocked at birth) and structural heart defects have also

been seen in KS

Central nervous system problems can also occur in

Kallmann syndrome These can include nystagmus

(involuntary eye movement), ataxia (involuntary body

movement), hearing loss and problems with vision

Synkinesia is especially common in men with the

X-linked recessive form of KS Some people with KS are

also mentally retarded Holoprosencephaly, when the

brain fails to develop in two halves, can also be seen in

some individuals with KS

Diagnosis

Individuals with Kallmann syndrome are usually

diagnosed when they do not undergo puberty Hormone

testing shows that both LH and FSH are decreased

Affected individuals often do not realize they cannotsmell MRI can often detect the absence of the olfactorybulb in the brain Renal ultrasound can determine if a kid-ney is missing

As of 2001, genetic testing for alterations in the

KAL gene is the only genetic testing available Even withfamilies with clear X-linked recessive inheritance,genetic testing does not always detect an alteration in theKAL gene Hence, diagnosis is still very dependent uponclinical features

Treatment and management

When a child with KS is born with structural malities such as cleft lip and/or palate, clubfoot or heartdefects, surgery is often required to fix the defect Takingsex hormones treats delayed puberty; women take estro-gen and men take testosterone Once puberty is com-pleted, taking GnRH or both LH and FSH can treathypogonadism For most affected individuals, treatment

abnor-is successful and infertility abnor-is reversed However, a smallportion of people will not respond to treatment

When an isolated case of Kallmann syndrome isdiagnosed, evaluation of first-degree family members,such as parents and siblings, should be completed Thisshould include a detailed family history, measuring hor-mone levels, assessing sense of smell, and renal ultra-sound to look for kidney abnormalities This informationmay help to diagnosis previously unrecognized cases ofKallmann syndrome Furthermore, this information may

be important for genetic counseling and determiningwhom in the family is at risk for also having Kallmannsyndrome

Prognosis

For individuals with the most common features ofKallmann syndrome, hypogonadism and the inability tosmell, prognosis is excellent In most cases, hormonetreatment is able to reverse the delayed puberty andhypogonadism For those individuals with other symp-toms of Kallmann syndrome, prognosis can depend onhow severe the defect is For example, structural heartdefects can be quite complex and sometimes surgery cannot fix them Furthermore, no treatment is available forthe mental retardation in the portion of affected individu-als with this symptom

Resources

PERIODICALS

Rugarli, Elena, and Andrea Ballabio “Kallmann Syndrome:

From Genetics to Neurobiology.” JAMA 270, no 22

(December 8, 1993): 2713–2716.

American Society for Reproductive Medicine 1209

Montgomery Highway, Birmingham, AL 35216-2809.

Kartagener (pronounced KART-agayner) syndrome

refers to a condition that involves difficulty with clearing

mucus secretions from the respiratory tract, male

infertil-ity, and situs inversus The defining characteristic of this

syndrome is the situs inversus, which is a reversal of

abdominal and thoracic organs

Description

This syndrome is named after Kartagener, a

physi-cian from Switzerland In the 1930’s, Kartagener and a

colleague described a familial form of bronchiectasis

with situs inversus and nasal polyps This came to be

known as Kartagener syndrome Kartagener syndrome is

also known as the Siewert syndrome, after another

physi-cian, Siewert, who described the syndrome in the early

1900’s

Individuals who have Kartagener syndrome form a

subset of the disorder called primary ciliary dyskinesia

Originally, primary ciliary dyskinesia was known as

immotile cilia syndrome The name, immotile cilia

syn-drome, is no longer used since the discovery that the

cilia are actually not immotile, but rather, abnormal in

movement Individuals who have Kartagener syndrome,

basically have primary ciliary dyskinesia, plus partial

or complete situs inversus The situs inversus is what

sets Kartagener syndrome apart from primary ciliary

dyskinesia

Kartagener syndrome is caused by abnormalities of

the cilia that line the respiratory tract and also form the

flagella of sperm Cilia are tiny hair-like structures that

contain a bundle of small parallel tubes that form a

cen-tral core This core is called the axoneme Ciliary

move-ment is accomplished by the bending of the axoneme

One of the most important associated structures that

enable ciliary movement to occur are sets of tiny armsthat project from each tubule These tiny arms are calleddynein arms

Cilia line the cells of the lungs, nose and sinuses.Before reaching the lungs, air travels through the airwaywhere it is moistened and filtered The nasal passages andairway are lined with mucus membranes The mucus cov-ering the mucus membrane traps dirt and other foreignparticles that have been breathed in The cilia, lining themembranes, beat in a wavelike manner moving the layer

of mucus and carrying away the dirt and debris that hasbeen trapped This mucus can then be coughed out orswallowed into the stomach

In Kartagener syndrome, the cilia do not move,move very little, or move abnormally Because the cilia

do not function properly, the mucus is not cleared fromthe respiratory tract, which leads to sinus infection(sinusitis) and chronic changes of the lung (bronchiecta-sis), which make it difficult to exhale Mucus clearancefrom the middle ear can also be affected and over timecan lead to hearing loss

The male infertility in Kartagener syndrome is alsocaused by abnormal cilia movement One spermatozoonconsists of a head, midpiece, and a tail or flagellum Thetail of a spermatozoon is a long flagellum consisting of acentral axoneme This axoneme enables the movement ofthe flagellum so that the spermatozoon can propel its way

to the fallopian tube and burrow through the egg coat tofertilize the egg In Kartagener syndrome, these cilia areeither immotile, or are not able to move normally to com-plete the journey to the fallopian tubes, nor may they beable to burrow through the egg coat This results in maleinfertility

As stated above, situs inversus is what setsKartagener syndrome apart from primary ciliary dyski-nesia Complete situs inversus involves reversal of boththe abdominal and thoracic organs so that they form amirror image of normal In partial situs inversus, the tho-racic organs may be reversed, while the abdominalorgans are normally positioned, or vice versa.Approximately one in 10,000 adults have situs inversus.Only about 20% of individuals who have complete situsinversus are diagnosed to have Kartagener syndrome Ofthose with complete situs inversus who are diagnosed tohave Kartagener syndrome, there is only a small risk forassociated cardiac defects Partial situs inversus mayoccur in individuals who have Kartagener syndrome aswell Partial situs inversus has a higher association withother abnormalities, including polysplenia or asplenia(extra or absent spleen) and cardiac defects

One theory behind the association of situs inversuswith the underlying cause of Kartagener syndrome is thatthe lack of ciliary movement in the developing embryo

may result in incorrect organ rotation in approximately

50% of affected individuals In fact, 50% of patients with

PCD will have situs inversus and thus be diagnosed to

have Kartagener syndrome However, this is a theory

supported only by some researchers

Genetic profile

Kartagener syndrome is an autosomal recessive

con-dition This means that in order to have the condition, an

individual needs to inherit two copies of the gene for the

condition, one from each parent Individuals who carry

only one gene for an autosomal recessive syndrome are

called heterozygotes Heterozygotes for Kartagener

syn-drome have normal ciliary function and do not have any

clinical features of the condition If two carriers of

Kartagener syndrome have children, there is a 25%

chance, with each pregnancy, for having a child with

Kartagener syndrome

The components that form the cilium contain several

hundred different proteins Each is coded for by different

DNA sequences, potentially on different chromosomes.

A defect in any of these codes could produce an

abnor-mal or missing protein that is a building block for the

cilium and thus could cause abnormal ciliary structure

and movement, resulting in Kartagener syndrome

When the same condition can be caused by different

genetic abnormalities, this is known as genetic

hetero-geneity In fact, several different defects in cilia have

been seen in association with Kartagener syndrome,

including; overly long cilia, overly short cilia, absent cilia

and randomly oriented cilia, suggesting genetic

hetero-geneity Studies have suggested that the most common

defect of cilia in Kartagener syndrome is the lack of

dynein arms There have been rare cases in which

indi-viduals have Kartagener syndrome, yet have no

detectable abnormality of the cilia, even though the

cil-iary function is abnormal Results of one study involving

a genome-wide linkage search performed on 31 families,

with multiple individuals affected with either PCD or

Kartagener syndrome, strongly suggested extensive

het-erogeneity Potential regions involving genes responsible

for PCD or Kartagener syndrome were localized on

chro-mosomes 3, 4, 5, 7, 8, 10, 11, 13, 15, 16, 17 and 19

Demographics

Kartagener syndrome occurs in approximately one in

32,000 live births, which is half the incidence of primary

ciliary dyskinesia (one in 16,000 live births) Kartagener

syndrome is not found more commonly in any particular

sex, ethnic background or geographic region Males,

however, may be diagnosed more often than females

because of infertility investigation

K E Y T E R M SBronchiectasis—An abnormal condition of the

bronchial tree, characterized by irreversiblewidening and destruction of the bronchial walls ofthe lungs

Cystic fibrosis—A respiratory disease

character-ized by chronic lung disease, pancreatic ciency and an average age of survival of 20 years.Cystic fibrosis is caused by mutations in a gene onchromosome 7 that encodes a transmembranereceptor

insuffi-Dyskinesia—Impaired ability to make voluntary

movements

Tympanoplasty—Any of several operations on the

eardrum or small bones of the middle ear, torestore or improve hearing in patients with con-ductive hearing loss

Signs and symptoms

Newborns who have Kartagener syndrome maypresent with neonatal respiratory distress Often whenindividuals are diagnosed to have Kartagener syndrome

in later childhood, problems such as neonatal respiratorydistress may be identified in their history Symptoms thatmay present in childhood include; recurrent ear infec-tions (otitis media) that can lead to hearing loss, chronicproductive cough, reactive airway disease, pneumonia,chronic bronchitis, runny nose (rhinitis) with a thin dis-charge, and sinus infection (sinusitis) Situs inversus usu-ally does not present symptomatically, unless it isassociated with a congenital heart defect

The most common clinical expression ofKartagener syndrome in adults includes chronic upperand lower airway disease presenting as sinusitis andbronchiectasis Clubbing of the digits (fingers) mayoccur as the result of chronic hypoxia (lack of oxygen)from bronchiectasis In males of reproductive age, maleinfertility is almost universal In females who haveKartagener syndrome, infertility is not usually a charac-teristic This suggests that the egg transport down thefallopian tube is associated more with muscle contrac-tions than with ciliary movement

Several other conditions should be considered whenthe aforementioned symptoms present, including; Cystic

fibrosis (CF), immune deficiencies and severe allergies.

Although the causes of Kartagener syndrome and CF arecompletely different, the symptoms of these two diseases

are very similar Often when the symptoms present,

chil-dren with Kartagener syndrome are tested for CF first

because the incidence of CF is much higher (one in

2,400) than the incidence of Kartagener syndrome CF is

also associated with male infertility

Diagnosis

Diagnosis of Kartagener syndrome is confirmed by

identifying the ciliary abnormalities of structure and

movement This is accomplished by biopsy of the mucus

membranes of the respiratory tract and/or by examination

of sperm, looking for ciliary dyskinesia Situs inversus

can be identified by x ray or ultrasound examination

Infertility investigation may elicit the possibility of

Kartagener syndrome in a patient previously

undiag-nosed After a diagnosis is made, genetic counseling

should be provided to discuss the inheritance pattern, to

help identify other possible affected family members and

to discuss reproductive options

As Kartagener syndrome is an autosomal

reces-sive disorder, individuals who have had a child with

Kartagener syndrome have a 25% chance, with each

future pregnancy, of having another child with

Kartagener syndrome Prenatal diagnosis may be

pos-sible for a couple with a previously affected child, by

performing ultrasound examination to identify a fetus

who has situs inversus Although, if the fetus does not

exhibit situs inversus, it is still possible for the fetus to

have PCD Also, it is important to remember that

iden-tifying a fetus who has situs inversus in a family not

known to be at an increased risk for Kartagener

syn-drome, does not mean that the fetus has Kartagener

syndrome as only 20% of individuals who have situs

inversus have Kartagener syndrome As of January

2001, DNA testing for Kartagener syndrome is not

possible

Treatment and management

Treatment for Kartagener syndrome involves

treat-ment of the symptoms Treattreat-ment for sinusitis includes

the use of antibiotics to treat and prevent recurrent

infec-tion Occasionally, surgery to relieve the sinusitis and

remove nasal polyps that may be present is necessary

Daily chest physiotherapy to loosen mucus secretions is

a common therapy as well, and if started early in life can

help to prevent or delay development of bronchiectasis

Tympanoplasty in children with recurrent ear infections

is often necessary

Advances in reproductive technology allow for men

who have Kartagener syndrome to have the opportunity

to have children A procedure called intracytoplasmic

sperm injection or ICSI, now allow immotile or

dys-motile sperm to fertilize an egg ICSI involves injection

of a single sperm into single eggs in order for fertilization

to occur This procedure first involves ovulation tion and egg retrieval to obtain eggs for attempt at fertil-ization by ICSI In Vitro Fertilization (ICSI) pregnancyrates vary from center to center Overall pregnancy rates

induc-of 10%-40% have been quoted worldwide, utilizing theseprocedures

The chance for an affected male and his unaffectedpartner to have a child who has Kartagener syndrome issmall If the disease incidence is one in 32,000, then thechance for the unaffected woman to be a carrier ofKartagener syndrome is approximately one in 100 andthe chance for having an affected child would beexpected to be approximately one in 200 (0.5%).However, all children of affected males or females will becarriers for Kartagener syndrome

Prognosis

The severity of Kartagener syndrome is variable.With the advent of antibiotic use for infection control, thelife expectancy of a patient with Kartagener syndrome isclose to or within the normal range, if there are no imme-diate problems in the newborn period

Resources

BOOKS

Jones, Kenneth Lyons Smith’s Recognizable Patterns of

Human Malformation. Philadelphia: W.B.Saunders Company, 1997.

PERIODICALS

Guichard, Cècile, et al “Axonemal Dynein Intermediate-Chain Gene (DNAI1) Mutations Result in Situs Inversus and Primary Ciliary Dyskinesia (Kartagener Syndrome).”

American Journal of Human Genetics (April 2001): 1030.

I Karyotype

Definition

Karyotype refers to the arrangement of

chromo-somes in their matched (homologous) pairs For the

pur-poses of this definition, we will be referring to human

chromosomes, although there is a karyotype

characteris-tic for each species The human chromosomes are

arranged and numbered according to the International

System for Human Cytogenetic Nomenclature (ISCN)

The most recent recommendations of the ISCN are from

1995 Karyotype either refers to the actual composition

of the chromosomes in a body cell of an individual or

species, or to the actual diagram or photograph of those

chromosomes, arranged in their pairs

Description

The normal human karyotype consists of 23 pairs of

chromosomes There are 22 pair of autosomes, which are

the chromosomes that are not the sex chromosomes The

genes on these chromosomes instruct our bodies as to

how they look and function The 23rd pair of

chromo-somes are the sex chromochromo-somes Typically, females have

two X sex chromosomes and males have one X sex

chro-mosome and one Y sex chrochro-mosome

Karyotype construction

In the construction of the karyotype, the

chromo-somes are numbered 1 to 22 from longest to shortest The

last pair are the sex chromosomes and are placed on the

karyotype after the 22nd pair The chromosomes can be

separated into groups, based on their length and the

posi-tion of the centromere Group A consists of chromosome

pairs 1, 2 and 3 They are the longest chromosomes and

their centromeres are in the center of the chromosomes

(metacentric) Group B consists of chromosome pairs 4

and 5 They are long; however, their centromeres lie

toward the top of the chromosomes (submetacentric)

Group C consists of chromosome pairs 6, 7, 8, 9, 10, 11

and 12 and also includes the X chromosome They are

medium-sized and their centromeres either lie in the

mid-dle or toward the top of the chromosomes Group D

con-sists of chromosome pairs 13,14 and 15 They are

medium-sized and their centromeres lie at the top of the

chromosomes (acrocentric) Additionally, the D group

chromosomes have satellites Group E consists of

chro-mosome pairs 16, 17 and 18 They are relatively short

chromosomes and their centromeres lie in the center or

towards the top of the chromosomes Group F consists of

chromosomes 19 and 20 They are short chromosomes

with centromeres that lie in the center of the

K E Y T E R M SAcrocentric—A chromosome with the centromere

positioned at the top end

Centromere—The centromere is the constricted

region of a chromosome It performs certain tions during cell division

func-Homologous chromosomes—func-Homologous

chro-mosomes are two chrochro-mosomes of a doublet setthat are identical, particularly for the genes thatare on them

Metacentric—When a chromosome has the

cen-tromere in the middle of the chromosome it iscalled a metacentric chromosome

Satellites of chromosomes—Small segments of

genetic material at the tips of the short arms ofchromosomes 13, 14, 15, 21, and 22

Submetacentric—Positioning of the centromere

between the center and the top of the some

chromo-some Lastly, group G consists of chromosome pairs 21,

22 and the Y chromosome These are short chromosomeswith their centromeres at the top Chromosome pairs 21and 22 have satellites The Y chromosome does not havesatellites

The actual chromosomes are only individually tinguishable during a certain stage of cell division Thisstage is called the metaphase stage Chromosome prepa-rations are made from pictures of the chromosomes dur-ing the metaphase stage of division The metaphasespread is what the technician sees in one cell under themicroscope and what the photograph of that one cell isreferred to Usually, the chromosomes in a metaphasepreparation are banded by special staining techniquesused in the laboratory Each numbered chromosome isunique in its banding pattern so that all number 1s lookthe same and all number 2s look the same, etc Although,there can be small normal familial variations in chromo-somes Because of banding, the chromosomes are moreeasily distinguishable from each other and the bandingmakes it is easier to see differences or abnormalities Forexample, if a chromosome is missing a piece, or twochromosomes are attached to each other (translocation),

dis-it is much easier to see wdis-ith banded chromosomes thanwith unbanded chromosomes

Chromosome preparations can be made from anypotentially dividing cells, including; blood cells, skincells, amniotic fluid cells (the fluid surrounding an

unborn baby), placental tissue or chorionic villi (tissue

that forms the placenta and can be used in prenatal

diag-nosis)

ISCN formulas exist to describe any chromosome

complement The basic formula for writing a karyotype

is as follows The first item written is the total number of

chromosomes, followed by a comma The the second

item written is the sex chromosome complement The

typical female karyotype is written as 46,XX and the

typ-ical male karyotype is written as 46,XY

Formulas for abnormal karyotypes

Many formulas for writing abnormal karyotypes

have been determined Some common examples follow

A plus or a minus sign before a chromosome number is

used to show that the entire chromosome is extra or

miss-ing Also, the total number of chromosomes will be

dif-ferent than 46 For example, the condition Down

syndrome occurs when an individual has an extra

num-ber 21 chromosome For a male, this karyotype is written

as 47,XY,⫹21 An individual may also have extra or

missing parts of chromosomes The short arm of a

chro-mosome is called the p arm and the long arm is called the

q arm For example, the condition Wolf-Hirschhorn

syndrome is caused by a missing part of the top arm of

chromosome 4 For a female, this karyotype would be

written as 46,XX,del(4)(p16) The chromosome that is

involved in the change is specified within the first set of

parentheses and the breakpoint for the missing material is

defined in the second set of parentheses A final example

is a balanced translocation karyotype A balanced cation means that there is no missing or extra geneticmaterial as the result of the translocation There are manytypes of translocations One type is called a robertsoniantranslocation A robertsonian translocation occurs whentwo acrocentric chromosomes are attached together Onecommon example is a translocation involving chromo-somes 13 and 14 If a male has a balanced robertsoniantranslocation of chromosomes 13 and 14, this is written

translo-as 45,XY,der(13;14) The “der” stands for derivative, translo-asthe new 13;14 chromosome is considered a derivative.There are only 45 separate chromosomes now, which iswhy 45 is the number written in the karyotype There aremany more formulas for the abundant abnormal chromo-some findings in individuals For further detailed infor-mation, please refer to the resource listed below

Resources

BOOKS

Mitelman, Felix, ed An International System for Human

Cytogenetic Nomenclature (1995) Farmington, CT: S.

Karger AG, 1995.

Renee A Laux, MS

Karyotype analysis see Karyotype

Keller syndrome see FG syndrome

Definition

Kennedy disease (KD) is a disorder characterized bydegradation of the anterior horn cells of the spinal cordresulting in slow progressive muscle weakness and atro-phy Men with Kennedy disease often have breastenlargement (gynecomastia), testicular atrophy, and mayhave infertility

Description

Kennedy disease, also referred to as spinobulbarmuscular atrophy (SBMA), arises primarily from degra-dation of the anterior horn cells of the spinal cord, result-ing in proximal weakness and atrophy of voluntaryskeletal muscle Anterior horn cells control the voluntarymuscle contractions from large muscle groups such as thearms and legs For example, if an individual wants tomove his/her arm, electrical impulses are sent from thebrain to the anterior horn cells to the muscles of the arm,which then stimulate the arm muscles to contract, allow-

Karyotype showing three copies of chromosome 21 This

indicates Down syndrome.(Custom Medical Stock Photo, Inc.)

ing the arm to move Degradation is a rapid loss of

func-tional motor neurons Loss of motor neurons results in

progressive symmetrical atrophy of the voluntary

mus-cles Progressive symmetrical atrophy refers to the loss of

function of muscle groups from both sides of the body

For example, both arms and both legs are equally

affected by similar degrees of muscle loss and the

inabil-ity to be controlled and used properly Progressive loss

indicates that muscle loss is not instantaneous, rather

muscle loss occurs consistently over a period of time

These muscle groups include those skeletal muscles that

control large muscle groups such as the arms, legs and

torso The weakness in the legs is generally greater than

the weakness in the arms

Proximal weakness is in contrast to distal weakness,

and indicates that muscles such as the arms and the legs

are affected rather than the muscles of the hands, feet,

fingers, and toes However, the motor neuron of the

brainstem and sensory neurons of the dorsal root ganglia

are also affected in KD Motor neurons are the neurons

that control large muscle groups (arms, legs, torso) of

which anterior horn cells are a subgroup Sensory

neu-rons are a distinct class of neuneu-rons that control an

indi-vidual’s senses An example would be pain receptors that

cause an involuntary reaction to a stimuli such as when a

person accidentally grasps a boiling hot kettle and

imme-diately releases the kettle Dorsal root ganglia are

analo-gous to a headquarters for neurons, through which

essentially all neuronal stimuli are processed

Diagnosis

Kennedy disease is suspected clinically in a male

with an early adulthood onset of proximal muscle

weak-ness of the limbs, fasticulations (small local contractions

of the musculature that is visible through the skin) of the

tongue, lips or area around the mouth, absence of

hyper-active reflexes and spasticity, and often evidence of

enlarged breasts and/or small testes with few or no sperm

The diagnosis is made by a specific molecular

genetic test that measures the number of “repeats” in a

particular part of the androgen receptor (AR) gene The

alteration of the AR gene that causes Kennedy disease is

an expansion of a CAG trinucleotide repeat in the first

PART of the gene In unaffected individuals, between 11

to 33 copies OF the CAG trinucleotide are present In

patients with Kennedy disease, this number rises to 40 to

62 The greater the number of expanded repeats, the

ear-lier the age of onset

Genetic profile

Kennedy disease is an X-linked recessive disease,

meaning the abnormal gene is found on the X

K E Y T E R M SAnterior horn cells—Subset of motor neurons

within the spinal cord

Atrophy—Wasting away of normal tissue or an

organ due to degeneration of the cells

Degradation—Loss or diminishing.

Dorsal root ganglia—The subset of neuronal cells

controlling impulses in and out of the brain

Intragenic—Occuring within a single gene.

Motor neurons—Class of neurons that specifically

control and stimulate voluntary muscles

Motor units—Functional connection with a single

motor neuron and muscle

Sensory neurons—Class of neurons that

specifi-cally regulate and control external stimuli (senses:sight, sound)

Transcription—The process by which genetic

information on a strand of DNA is used to size a strand of complementary RNA

synthe-Voluntary muscle—A muscle under conscious

control, such as arm and leg muscles

some and two copies of the abnormal gene must be ent for the disorder to occur Since males only inherit one

pres-X chromosome (the other is the Y chromosome) they willalways express an X-linked disorder if the abnormal gene

is on the X chromosome they receive Females on theother hand inherit two X chromosomes Even if one Xchromosome contains the abnormal gene, the second Xchromosome with a normal functioning gene can usuallycompensate for the other Males lack the second X chro-mosome that may be able to mask the effect of the abnor-mal gene

The disease was first characterized in 1968 The determining gene, androgen receptor (AR), maps to theproximal long arm of the X-chromosome

KD-The AR protein is a member of the steroid-thyroidhormone receptor family and is involved in transcriptionregulation Transcription regulation is the molecularprocess that controls the “reading” of the genetic DNAinformation and turning it into RNA which is the mate-rial which generates proteins

Demographics

Because of the X-linked inheritance pattern ofKennedy disease, only males are affected by this disor-

der Females may be carriers of the disease if they

pos-sess an abnormal gene on one of her X chromosomes

Due to the rare nature of this disease, and the fact that it

may frequently be misdiagnosed as another form of

neu-romuscular disease, no particular race or ethnicity

appears to be at greater risk than another

Kennedy disease is primarily an adult disease, with

an onset between the third and fifth decade of life Once

symptoms present, the disease is slowly progressive In

addition to neuronal cell loss, breast enlargement

(gynecomatia), reduced fertility and testicular atrophy

have also been reported in affected males

Treatment and management

To date, there is not treatment for SBMA However,

there are possible mechanisms through which treatment

could be developed Gene therapy could be used for

SBMA to replace the abnormal gene associated with

SBMA with a copy carrying fewer CAG repeats

Currently this is not possible or available

As the bulbar muscles of the face are affected, eating

and swallowing can become difficult Due to the

weak-ening of the respiratory muscles, breathing can also be

labored It is therefore essential for patients to undergo

chest physiotherapy (CPT) CPT is a standard set of

pro-cedures designed to trigger and aid coughing in patients

Coughing is important as it clears the patient’s lungs and

throat of moisture and prevents secondary problems,

such as pneumonia

As symptoms progress, patients may require a

venti-lator to aid breathing

Prognosis

The majority of patients with SBMA have a normal

life span About 10% of older, severely affected patients

with SBMA may die from pneumonia or asphyxiation

secondary to weakness of the bulbar muscles

Resources

BOOKS

Zajac, J.D., and H.E MacLean “Kennedy’s Disease: Clinical

Aspects.” In Genetic Instabilities and Hereditary

Neurological Diseases, edited by R.D Wells and S.T.

Warren New York: Academic Press, 1998, pp 87-100.

PERIODICALS

Crawford, T.O., and C.A Pardo “The Neurobiology of

Childhood Spinal Muscular Atrophy.” Neurobiology of

Disease 3 (1996): 97-110.

Ferlini, A., et al “Androgen Receptor CAG Repeat Analysis in

the Differential Between Kennedy’s Disease and Other

Motoneuron Disorders.” American Journal of Human

Families of Spinal Muscular Atrophy ⬍http://www.fsma.org⬎.

The Andrew’s Buddies web site FightSMA.com

⬍http://www.andrewsbuddies.com/news.html⬎.

Muscular Dystrophy Association.⬍http://www.mdausa.org⬎.

Philip J YoungChristian L Lorson, PhD

Ketotoic hyperglycinemia see Propionic acidemia

Kinky hair disease see Menkes syndrome

Klein-Waardenburg syndrome, see

Description

Klinefelter syndrome is a condition where one ormore extra X-chromosomes are present in a male Boyswith this condition appear normal at birth They enterpuberty normally, but by mid-puberty have low levels oftestosterone causing small testicles and the inability tomake sperm Affected males may also have learning dis-abilities and behavior problems such as shyness andimmaturity and are at an increased risk for certain healthproblems

Genetic profile Chromosomes are found in the cells in the body.

Chromosomes contain genes, structures that tell the bodyhow to grow and develop Chromosomes are responsiblefor passing on hereditary traits from parents to child.Chromosomes also determine whether the child will be

male or female Normally, a person has a total of 46

chro-mosomes in each cell, two of which are responsible for

determining that individual’s sex These two sex

chromo-somes are called X and Y The combination of these two

types of chromosomes determines the sex of a child

Females have two X chromosomes (the XX

combina-tion); males have one X and one Y chromosome (the XY

combination)

In Klinefelter syndrome, a problem very early in

development results in an abnormal number of

chromo-somes Most commonly, a male with Klinefelter

syn-drome will be born with 47 chromosomes in each cell,

rather than the normal number of 46 The extra

chromo-some is an X chromochromo-some This means that rather than

having the normal XY combination, the male has an

XXY combination Because people with Klinefelter

syn-drome have a Y chromosome, they are all male

Approximately one-third of all males with

Kline-felter syndrome have other chromosome changes

involv-ing an extra X chromosome Mosaic Klinefelter

syn-drome occurs when some of the cells in the body have an

extra X chromosome and the other have normal male

chromosomes These males can have the same or milder

symptoms than non-mosaic Klinefelter syndrome Males

with more than one additional extra X chromosome, such

as 48,XXXY, are usually more severely affected than

males with 47,XXY

Klinefelter syndrome is not considered an inherited

condition The risk of Klinefelter syndrome reoccurring

in another pregnancy is not increased above the general

population risk

Demographics

Klinefelter syndrome is one of the most common

chromosomal abnormalities About one in every 500 to

800 males is born with this disorder Approximately 3%

of the infertile male population have Klinefelter

syn-drome

Signs and symptoms

The symptoms of Klinefelter syndrome are variable

and not every affected person will have all of the features

of the condition Males with Klinefelter syndrome appear

normal at birth and have normal male genitalia From

childhood, males with Klinefelter syndrome are taller

than average with long limbs Approximately 20–50%

have a mild intention tremor, an uncontrolled shaking

Many males with Klinefelter syndrome have poor upper

body strength and can be clumsy Klinefelter syndrome

does not cause homosexuality Approximately one-third

of males with Klinefelter syndrome have breast growth,

some requiring breast reduction surgery

K E Y T E R M SChromosome—A microscopic thread-like struc-

ture found within each cell of the body and sists of a complex of proteins and DNA Humanshave 46 chromosomes arranged into 23 pairs.Changes in either the total number of chromo-somes or their shape and size (structure) may lead

con-to physical or mental abnormalities

Gonadotrophin—Hormones that stimulate the

ovary and testicles

Testosterone—Hormone produced in the testicles

that is involved in male secondary sex tics

characteris-Most boys enter puberty normally, though some can

be delayed The Leydig cells in the testicles usually duce testosterone With Klinefelter syndrome, the Leydigcells fail to work properly causing the testosterone pro-duction to slow By mid-puberty, testosterone production

pro-is decreased to approximately half of normal Thpro-is canlead to decreased facial and pubic hair growth Thedecreased testosterone also causes an increase in twoother hormones, follicle stimulating hormone (FSH) andluteinizing hormone (LH) Normally, FSH and LH helpthe immature sperm cells grow and develop InKlinefelter syndrome, there are few or no sperm cells.The increased amount of FSH and LH cause hyalinizationand fibrosis, the growth of excess fibrous tissue, in theseminiferous tubules where the sperm are normallylocated As a result, the testicles appear smaller and firmerthan normal With rare exception, men with Klinefeltersyndrome are infertile because they can not make sperm.While it was once believed that all boys withKlinefelter syndrome were mentally retarded, doctorsnow know that the disorder can exist without retardation.However, children with Klinefelter syndrome frequentlyhave difficulty with language, including learning tospeak, read, and write Approximately 50% of males withKlinefelter syndrome are dyslexic

Some people with Klinefelter syndrome have culty with social skills and tend to be more shy, anxious,

diffi-or immature than their peers They can also have podiffi-orjudgement and do not handle stressful situations well As

a result, they often do not feel comfortable in large socialgatherings Some people with Klinefelter syndrome canalso have anxiety, nervousness, and/or depression

The greater the number of X-chromosomes present,the greater the disability Boys with several extra X-chro-mosomes have distinctive facial features, more severe

retardation, deformities of bony structures, and even

more disordered development of male features

Diagnosis

Diagnosis of Klinefelter syndrome is made by

exam-ining chromosomes for evidence of more than one X

chromosome present in a male This can be done in

preg-nancy with prenatal testing such as a chorionic villus

sampling or amniocentesis Chorionic villus sampling is

a procedure done early in pregnancy (approximately

10–12 weeks) to obtain a small sample of the placenta for

testing An amniocentesis is done further along in

preg-nancy (from approximately 16–18 weeks) to obtain a

sample of fluid surrounding the baby for testing Both

procedures have a risk of miscarriage Usually these

pro-cedures are done for a reason other than diagnosing

Klinefelter syndrome For example, a prenatal diagnostic

procedure may be done on an older woman to determine

if her baby has Down syndrome If the diagnosis of

Klinefelter syndrome is suspected in a young boy or adult

male, chromosome testing can also be on a small blood

or skin sample after birth

Treatment and management

There is no treatment available to change mal makeup Children with Klinefelter syndrome maybenefit from a speech therapist for speech problems orother educational intervention for learning disabilities.Testosterone injections started around the time of pubertymay help to produce more normal development includingmore muscle mass, hair growth, and increased sex drive.Testosterone supplementation will not increase testicularsize, decrease breast growth, or correct infertility

chromoso-Prognosis

While many men with Klinefelter syndrome go on tolive normal lives, nearly 100% of these men will be ster-ile (unable to produce a child) However, a few men withKlinefelter syndrome have been reported who havefathered a child through the use of assisted fertility serv-ices Males with Klinefelter syndrome have an increasedrisk of several conditions such as osteoporosis, autoim-mune disorders such as lupus and arthritis, diabetes, andboth breast and germ cell tumors

BOOKS

Bock, R Understanding Klinefelter’s Syndrome: A Guide for

XXY Males and Their Families National Institutes of

Health, USA, 1993.

Probasco, Teri, and Gretchen A Gibbs Klinefelter Syndrome.

Richmond, IN: Prinit Press, 1999.

PERIODICALS

Smyth, Cynthia M., and W.J Bremner “Klinefelter Syndrome.”

Archives of Internal Medicine 158 (1998): 1309–1314.

Smyth, Cynthia M “Diagnosis and Treatment of Klinefelter

Syndrome.” Hospital Practice (September 15, 1999):

111–120

Staessen, C., et al “Preimplantation Diagnosis for X and Y

Normality in Embryos from Three Klinefelter Patients.”

Human Reproduction 11, no 8 (1996): 1650–1653.

ORGANIZATIONS

American Association for Klinefelter Syndrome Information

and Support (AAKSIS) 2945 W Farwell Ave., Chicago, IL

Individuals with Klippel-Feil sequence (KFS) were

originally described as having a classic triad of webbed

neck (very short neck), low hairline, and decreased

flex-ibility of the neck More commonly, abnormal joining or

fusion of two or more vertebrae (bones) of the cervical

spine (neck bones) characterizes Klippel-Feil sequence

Description

Klippel-Feil sequence is extensive fusion of multiple

cervical vertebrae (the uppermost bones of the spine)

There may be complete fusion or multiple irregular bony

segments in the bones of the upper back (cervical and

often upper thoracic spine) Premature and extensive

arthritis and osseous (bony) spurring affecting the joints

of the spine (facet joints) are common in individuals withKlippel-Feil sequence

There are three classifications of Klippel-Feilsequence

• Group 1 exhibits fusion of the lower skull (head) andthe first bone of the spine (the first cervical vertebrae(C1)) The second and third spinal bones (cervical ver-tebrae C2 and C3) are also usually fused together inGroup 1 The normal cervical spine has seven bones orvertebrae Normally half of the ability of humans tobend their heads forward (flexion) and backwards(extension) occurs in the joints between the base of theskull and the uppermost spinal bone The other half ofthe motions of flexion and extension occur in the rest ofthe upper spine Therefore, the danger is due to theexcessive motion of the neck between the joints that arefused

• Group 2 has fusion of bones (vertebrae) below the ond cervical bone (C2) Group 2 also has an abnormalskull and upper spinal bone connection

sec-• Group 3 has an open space between two fused segments

of spinal bones

Genetic profile

Although this is usually a sporadic occurrence, anabnormal gene responsible for Klippel-Feil sequence hasbeen found on the q (long) arm of chromosome 8 Thehuman cell contains 46 chromosomes arranged in 23pairs Most of the genes in the two chromosomes of eachpair are identical or almost identical with each other.However, with KFS individuals, there appears to be areversal or inversion on part of chromosome 8

Demographics

Approximately one out of every 42,000 people hasKlippel-Feil sequence The classic triad is seen in 52% ofindividuals with the syndrome Men and women areaffected equally, however, some studies have shownslightly higher numbers for women There have beensome reports of Klippel-Feil sequence being more com-mon among infants born with fetal alcohol syndrome(FAS) because FAS affects bone development of thefetus However, there is a genetic component that passesthe syndrome on through the generations in a dominant

inheritance pattern.

Signs and symptoms

The first clinical signs are the classic triad of webbedneck, low hairline, and decreased flexibility of the neck.However, the presence of abnormalities of the cervical

anomalies of the upper neck (cervical vertebrae).Anomalies of the genital areas and urinary system arealso common.

Individuals diagnosed with Klippel-Feil sequencefrequently have problems with cervical nerves and nervesthat go from the neck to the arms and hands Individualscan have pain that starts in their neck and travels into thearms if the nerve roots coming off of the spinal cord areirritated or pinched

Diagnosis

Klippel-Feil sequence is usually diagnosed in earlychildhood or adolescence Observing the clinical signs ofhaving the classic triad of webbed neck, low hairline, andlimited cervical ranges of motion initiates the diagnosis.When further testing is done such as x ray, the diagnosis

is confirmed by the fusion of multiple cervical vertebrae

Treatment and management

If the individual has a very mild case of Klippel-Feilsequence, then the person can lead a normal life withonly minor restrictions These restrictions, such as avoid-ing contact sports that would place the neck at risk, arenecessary because of the instability of the cervical spine.This is due to the increased motion between the fusedcervical vertebrae

Symptoms, such as pain, that occur with the arthritisand degeneration of the joints may also result The indi-viduals should be treated with pain medication and pos-sible cervical traction If neurological symptoms occur,the treatment of choice is fusion of the symptomatic area.However, due to the severe consequences of not havingthe preventive surgery, surgery is still the treatment mostperformed

Prognosis

There have been reports of death following minortrauma because of injuries to the spinal cord in the cervi-cal spine Most commonly, individuals with Klippel-Feilwill develop pain Some diseases are acquired or occurbecause of the increased motion of the vertebrae.Degenerative disc disease, or destruction of the cushionlike disc between the vertebrae is very common Themost common findings were degenerative disc diseasethat affected the entire lower cervical spine Spondyloticosteophytes, or bone spurs in the spine, form as a result

of this degeneration This laying down of new bone maylead to narrowing of the canal through which the spinalcord travels (spinal stenosis)

Surgery may prevent a dangerous and fatal accidentbecause of the instability of the spinal cord Pain that

K E Y T E R M SDegenerative disc disease—Narrowing of the disc

space between the spinal bones (vertebrae)

Fetal alcohol syndrome—Syndrome characterized

by distinct facial features and varying mental

retar-dation in an infant due to impaired brain

develop-ment resulting from the mother’s consumption of

alcohol during pregnancy

Hypoplasia—Incomplete or underdevelopment of

a tissue or organ

Microtia—Small or underdeveloped ears.

Ossicles—Any of the three bones of the middle

ear, including the malleus, incus, and stapes

Radiculopathy—A bulging of disc material often

irritating nearby nerve structures resulting in pain

and neurologic symptoms A clinical situation in

which the radicular nerves (nerve roots) are

inflamed or compressed This compression by the

bulging disc is referred to as a radiculopathy This

problem tends to occur most commonly in the

neck (cervical spine) and low back (lumbar spine)

Scoliosis—An abnormal, side-to-side curvature of

the spine

Torticollis—Twisting of the neck to one side that

results in abnormal carriage of the head and is

usually caused by muscle spasms Also called

wry-neck

spine found with x rays is the hallmark diagnosis Other

signs and symptoms may be found, but vary from person

to person

Some patients may exhibit wryneck or Torticollis,

which is a twisting of the neck to one side that results in

abnormal carriage of the head The individual may have

differences between the two sides of his face, known as

facial asymmetry They may also have scoliosis

(abnor-mal curves of the spine)

A variety of miscellaneous abnormalities may

clini-cally manifest themselves in Klippel-Feil sequence

Deafness occurs in about 30% of the cases Ear

abnor-malities such as very small ear lobes (microtia), or

deformed bones within the ear (ossicles) may be present

Patients may even have a small or absent internal ear

Abnormalities of the blood vessels such as a missing

radial artery in the forearm may decrease the size of the

thumbs (thenar hypoplasia) Anomalies of the right

sub-clavian artery (artery under the clavicle or collar bone)

have been reported as well as higher incidences of artery

originates in the neck and travels into the arms

(radicu-lopathy) is common near the sites of the surgical fusion of

vertebrae One study found that 25% of the individuals

who had surgery would have had neurological problems

within ten years, therefore requiring additional surgery

Resources

BOOKS

Guebert, Gary M., et al “Congenital Anomalies and Normal

Skeletal Variants.” In Essentials of Skeletal Radiology,

edited by Terry Yochum and Lindsay Rowe 2nd ed.

Baltimore: Williams & Wilkins, 1996.

Juhl J.H., A.B Crummy, and J.E Kuhlman, eds Paul and

Juhl’s Essentials of Radiologic Imaging 7th ed.

Philadelphia: Lippencot-Raven, 1998.

PERIODICALS

Clarke, Raymond A., et al “Familial Klippel-Feil Syndrome

and Paracentric Inversion inv(8)(q22.2q23.3).” American

Journal of Human Genetics 57(1995): 1364–1370.

Clarke, Raymond A, et al “Heterogenectiy in Klippel-Feil

Syndrome: A New Classification.” Pediatric Radiology

28(1998): 967–974.

Hilibrand, A.S., et al “Radiculopathy and Myelopathy at

Segments Adjacent to the Site of a Previous Anterior

Cervical Arthrodesis.” Journal of Bone and Joint Surgery

81-A, no 4 (1999): 519–528.

Nagashima, Hideki “No Neurological Involvement for More

Than 40 Years in Klippel-Feil Syndrome with

Hypermobility of the Upper Cervical Spine.” Archives of

Orthopedic Trauma and Surgery 121(2001): 99–101.

Thomsen, M.N., et al “Scoliosis and Congenital Anomalies

Associated with Klippel-Feil Syndrome Types I-Ill.” Spine

Knobloch syndrome see Encephalocele

Konigsmark syndrome see Hereditary

hearing loss and deafness

Kowarski syndrome see Pituitary dwarfism syndrome

Definition

Krabbe disease is an inherited enzyme deficiencythat leads to the loss of myelin, the substance that wrapsnerve cells and speeds cell communication Most affectedindividuals start to show symptoms before six months ofage and have progressive loss of mental and motor func-tion Death occurs at an average age of 13 months Otherless common forms exist with onset in later childhood oradulthood

Description

Myelin insulates and protects the nerves in the tral and peripheral nervous system It is essential for effi-cient nerve cell communication (signals) and bodyfunctions such as walking, talking, coordination, andthinking As nerves grow, myelin is constantly beingbuilt, broken down, recycled, and rebuilt Enzymes breakdown, or metabolize, fats, carbohydrates, and proteins inthe body including the components of myelin

cen-Individuals with Krabbe disease are lacking theenzyme galactosylceramidase (GALC), which metabo-lizes a myelin fat component called galactosylceramideand its by-product, psychosine Without GALC, thesesubstances are not metabolized and accumulate in largegloboid cells For this reason, Krabbe disease is alsocalled globoid cell leukodystrophy Accumulation ofgalactosylceramide and psychosine is toxic and leads tothe loss of myelin-producing cells and myelin itself Thisresults in impaired nerve function and the gradual loss ofdevelopmental skills such as walking and talking

Genetic profile

Krabbe disease is an autosomal recessive disorder.Affected individuals have two nonfunctional copies ofthe GALC gene Parents of an affected child are healthycarriers and therefore have one normal GALC gene andone nonfunctional GALC gene When both parents arecarriers, each child has a 25% chance to inherit Krabbedisease, a 50% chance to be a carrier, and a 25% chance

to have two normal GALC genes The risk is the same formales and females Brothers and sisters of an affectedchild with Krabbe disease have a 66% chance of being acarrier

Symptoms are more general including weakness, culty walking, vision loss, and diminished mentalabilities.

diffi-Diagnosis

There are many tests that can be performed on anindividual with symptoms of Krabbe disease The mostspecific test is done by measuring the level of GALCenzyme activity in blood cells or skin cells A person withKrabbe disease has GALC activity levels that are zero tofive percent of the normal amount Individuals with lateronset Krabbe disease may have more variable GALCactivity levels This testing is done in specialized labora-tories that have experience with this disease

The fluid of the brain and spinal cord (cerebrospinalfluid) can also be tested to measure the amount of pro-tein This fluid usually contains very little protein but theprotein level is elevated in infantile Krabbe disease.Nerve-conduction velocity tests can be performed tomeasure the speed at which the nerve cells transmit theirsignals Individuals with Krabbe disease will haveslowed nerve conduction Brain imaging studies such ascomputerized tomography (CT scan) and magnetic reso-nance imaging (MRI) are used to get pictures from insidethe brain These pictures will show loss of myelin in indi-viduals with Krabbe disease

DNA testing for GALC mutations is not generallyused to make a diagnosis in someone with symptoms but

it can be performed after diagnosis If an affected personhas identifiable known mutations, other family memberscan be offered DNA testing to find out if they are carri-ers This is helpful since the GALC enzyme test is notalways accurate in identifying healthy carriers of Krabbedisease

If an unborn baby is at risk to inherit Krabbe disease,prenatal diagnosis is available Fetal tissue can beobtained through chorionic villus sampling (CVS) or

amniocentesis Cells obtained from either procedure can

be used to measure GALC enzyme activity levels If bothparents have identified known GALC gene mutations,DNA testing can also be performed on the fetal cells todetermine if the fetus inherited one, two, or no GALCgene mutations

Some centers offer preimplantation diagnosis if bothparents have known GALC gene mutations In-vitro fer-tilization (IVF) is used to create embryos in the labora-tory DNA testing is performed on one or two cells takenfrom the early embryo Only embryos that did not inheritKrabbe disease are implanted into the mother’s womb.This is an option for parents who want a biological childbut do not wish to face the possibility of abortion of anaffected pregnancy

K E Y T E R M SGloboid cells—Large cells containing excess toxic

metabolic “waste” of galactosylceramide and

psy-chosine

Motor function—The ability to produce body

movement by complex interaction of the brain,

nerves, and muscles

Mutation—A permanent change in the genetic

material that may alter a trait or characteristic of

an individual, or manifest as disease, and can be

transmitted to offspring

The GALC gene is located on chromosome 14 Over

70 mutations (gene alterations) known to cause Krabbe

disease have been identified One specific GALC gene

deletion accounts for 45% of disease-causing mutations

in those with European ancestry and 35% of

disease-causing mutations in those with Mexican ancestry

Demographics

Approximately one in every 100,000 infants born in

the United States and Europe will develop Krabbe

dis-ease A person with no family history of the condition has

a one in 150 chance of being a carrier Krabbe disease

occurs in all countries and ethnic groups but no cases

have been reported in the Ashkenazi Jewish population

A Druze community in Northern Israel and two Moslem

Arab villages near Jerusalem have an unusually high

incidence of Krabbe disease In these areas, about one

person in every six is a carrier

Signs and symptoms

Ninety percent of individuals with Krabbe disease

have the infantile type These infants usually have normal

development in the first few months of life Before six

months of age, they become irritable, stiff, and rigid

They may have trouble eating and may have seizures

Development regresses leading to loss of mental and

muscle function They also lose the ability to see and

hear In the end stages, these children usually cannot

move, talk, or eat without a feeding tube

Ten percent of individuals with Krabbe disease have

juvenille or adult type Children with juvenile type begin

having symptoms between three and ten years of age

They gradually lose the ability to walk and think They

may also have paralysis and vision loss Their symptoms

usually progress slower than in the infantile type Adult

Krabbe disease has onset at any time after age 10

Treatment and management

Once a child with infantile Krabbe disease starts to

show symptoms, there is little effective treatment

Supportive care can be given to keep the child as

com-fortable as possible and to counteract the rigid muscle

tone Medications can be given to control seizures When

a child can no longer eat normally, feeding tubes can be

placed to provide nourishment

Affected children who are diagnosed before

devel-oping symptoms (such as through prenatal diagnosis) can

undergo bone marrow transplant or stem cell transplant

The goal of these procedures is to destroy the bone

mar-row which produces the blood and immune system cells

After the destruction of the bone marrow, cells from a

healthy donor are injected If successful, the healthy cells

travel to the bone marrow and reproduce Some children

have received these transplants and had a slowing of their

symptom’s progression or even improvement of their

symptoms However, these procedures are not always

successful and research is being done in order to reduce

complications

Scientists are also researching gene therapy for

Krabbe disease This involves introducing a normal

GALC gene into the cells of the affected child The goal

is for the cells to integrate the new GALC gene into its

DNA and copy it, producing functional GALC enzyme

This is still in research stages and is not being performed

clinically

Prognosis

Prognosis for infantile and juvenile Krabbe disease

is very poor Individuals with infantile type usually die at

an average age of 13 months Death usually occurs within

a year after the child shows symptoms and is diagnosed.Children with juvenile type may survive longer afterdiagnosis but death usually occurs within a few years.Adult Krabbe disease is more variable and difficult topredict but death usually occurs two to seven years afterdiagnosis

Resources

BOOKS

Wenger, D.A., et al “Krabbe Disease: Genetic Aspects and

Progress Toward Therapy.” Molecular Genetics and

Lamellar ichthyosis see Ichthyosis

Definition

Langer-Giedion syndrome (LGS) is a rare genetic

disorder characterized by skeletal abnormalities and

dys-morphic (distinctive) facial features Most people with

LGS also have mental retardation

Description

LGS affects mostly the skeletal system and facial

structure Since the features include abnormalities in the

hair (tricho), nose shape (rhino), and fingers and toes

(phalangeal), another name for LGS is

tricho-rhino-pha-langeal syndrome, type II

Genetic profile

LGS is not usually passed through generations in a

family However, the condition is considered a

contigu-ous-gene syndrome This means that it is caused by the

loss of functional copies of two genes near each other on

chromosome 8 Research suggests that another gene may

be involved Genetic counseling is suggested for

any-one considering pregnancy who has a relative with this

condition

Demographics

About 50 cases of Langer-Giedion syndrome have

been reported in the literature Males are affected three

times more often than females

Signs and symptoms

Craniofacial features associated with

Langer-Giedion syndrome include a bulbous, pear-shaped nose;

a small jaw; a thin upper lip; and large ears The hair isusually sparse, and the head is small in 60% of individu-als with LGS Mild to severe mental retardation is pres-ent in 70% of people; it often affects speech more thanother skills

Skeletal features include exostoses—spiny growths

on the bone—which occur before age five and usuallyincrease in number until the skeleton matures.Compression of nerves or blood vessels, asymmetriclimb growth, and limitation of movement are problemsthat can result from the exostoses Scoliosis—a curvature

of the spine—is found in some people, as well as thinribs Short stature is often seen as a result of epiphyses—cone-shaped bone ends Longitudinal bone growthappears to be slowed Short and/or curved fingers arecommon Loose skin often occurs, but that tends toimprove with age

Features of LGS that are less commonly seeninclude loose joints and low muscle tone Others are wan-dering eye (exotropia), droopy eyelid, widely spacedeyes, fractures in the bones, birthmarks that increase withage, hearing loss, heart or genito-urinary abnormalities,and webbing of the fingers

Diagnosis

The criteria for diagnosis of LGS are a bulbous,pear-shaped nose, and epiphyses and exostoses Thesesigns are probably all related to abnormal bone growth,but researchers do not yet understand the link to mentalretardation and hair abnormalities The distinctive facialfeatures may be recognized at birth Changes in the epi-physes are recognizable through x ray by age three, andexostoses are visible by age five Chromosome analysiswill likely reveal an abnormality in a certain region ofchromosome 8

There are no reports of prenatal diagnosis of thiscondition To provide accurate genetic counseling regard-ing prognosis and risk of recurrence, it is important todistinguish this condition from others that are similar to

it, such as tricho-rhino-phalangeal syndrome, type 1

L

Goodman, Richard M., and Robert J Gorlin “Langer-Giedion

Syndrome.” In The Malformed Infant and Child, by New

York: Oxford University Press, 1983.

PERIODICALS

Moroika, D., and Y Hosaka “Aesthetic and Plastic Surgery for

Trichorhinophalangeal Syndrome.” Aesthetic Plastic

Surgery 24 (2000): 39-45.

ORGANIZATIONS

Langer-Giedion Syndrome Association 89 Ingham Ave., Toronto, Ontario M4K 2W8, Canada (416) 465-3029 kinross@istar.ca.

National Institute on Deafness and Other Communication Disorders 31 Center Dr., MSC 2320, Bethesda, MD

character-Description

This condition was first described in 1950 by Larsen,Schottstaedt, and Bost, who compiled information on sixpeople with sporadic cases of Larsen syndrome

Larsen syndrome has been called both a skeletaldysplasia (a condition caused by abnormalities of bonestructure), and a hypermobility syndrome (a conditioninvolving abnormally loose joints) It is most likelycaused by inherited abnormalities of connective tissuethat affect both bone and joint structure

Present at birth are multiple dislocations of theelbows, hips, and most commonly the knees Personswith Larsen syndrome have other distinctive physicalfeatures that can include a prominent forehead, widelyspaced eyes, long cylindrical fingers, and short bones of

K E Y T E R M SContiguous gene syndrome—A genetic syndrome

caused by the deletion of two or more genes

located next to each other

Craniofacial—Relating to or involving both the

head and the face

Epiphysis—The end of long bones, usually

termi-nating in a joint

Exostose—An abnormal growth (benign tumor) on

a bone

Mental retardation—Significant impairment in

intellectual function and adaptation in society

Usually associated with an intelligence quotient

(IQ) below 70

Philtrum—The center part of the face between the

nose and lips that is usually depressed

Short stature—Shorter than normal height, can

include dwarfism

Treatment and management

The treatment for LGS is tailored to each person

Exostoses may need to be surgically removed if they are

causing problems with nerves or blood vessels If the two

leg lengths are different, corrective shoes may be helpful

Orthopedic devices such as braces or, more rarely,

sur-gery may be indicated in severe cases of skeletal

abnor-mality Plastic surgery to alter specific features, such as

the ears or nose, has been chosen by some people

The risk of cancer at the site of the exostoses is not

known but may be higher

Special education for mentally retarded individuals

is indicated A focus on speech development may be

appropriate

Prognosis

Langer-Giedion syndrome does not alter lifespan

Complications from associated abnormalities such as

mental retardation, however, can cause problems

Asymmetry of the limbs can interfere with their function

and cause pain Psychological effects due to physical

abnormalities may also be experienced

Resources

BOOKS

“Tricho-rhino-phalangeal Syndrome, Type II.” In Birth Defects

Encyclopedia, ed Mary Louise Buyse Boston: Blackwell

Scientific Publications, 1990.

the hand Sometimes present are other birth defects such

as structural heart defects, cleft palate, cataracts, extra

bones of the wrist, and abnormalities of the vertebrae

Most people have moderate symptoms that can be

treated, allowing for a relatively normal life span

However, a small number of babies have a severe form of

the condition and die at birth

Genetic profile

There are likely to be multiple different causes for

Larsen syndrome Both recessive and dominant patterns

of inheritance have been described thus far

Some cases are sporadic, meaning the affected

per-son is the first in the family to have the condition Many

sporadic cases are though to be cause by new dominant

mutations (spontaneous changes in the genetic material)

A person with sporadic Larsen syndrome has a change in

the genetic material that is not present in either parent but

can be passed on, with 50/50 odds in each child, to his or

her offspring

Patients have been reported who have affected

broth-ers or sistbroth-ers but unaffected parents Most of these cases

probably represent a recessive form of Larsen syndrome

in which a person must have two copies of a genetic

change in order to be affected The parents of a person

with a recessive condition must each have one copy of

the genetic change in order to have an affected child

There are rare instances in which a person with

Larsen appears to have the recessive form but then gives

birth to an affected child These cases are most likely

dominant rather than recessive It can be difficult to be

certain of the inheritance pattern in some families and

genetic counselors must be careful to address both forms

of inheritance when discussing chances of recurrence

The autosomal dominant form of Larsen syndrome

is thought to be due to mutations in a gene called LAR1,

on the short arm of chromosome 3 The exact structure

and function of this gene is not yet known There may be

other genes responsible for a proportion of cases of

dom-inant Larsen syndrome; however, as of 2001, no other

candidate genes have been located

Another dominantly inherited condition called

Atelosteogenesis Type III (AOIII) has features which

overlap with Larsen syndrome, and may, in fact, be a

variant of Larsen caused by mutations in the same gene

Demographics

Larsen syndrome is an extremely rare genetic

condi-tion that occurs in about one in every 100,000 births

A variant of Larsen syndrome is found in high

fre-quency on La Reunion island near East Africa Over 40

K E Y T E R M SArthrogryposis—Abnormal joint contracture.

Carrier—A person who possesses a gene for an

abnormal trait without showing signs of the der The person may pass the abnormal gene on tooffspring

disor-Clubfoot—Abnormal permanent bending of the

ankle and foot Also called talipes equinovarus.

Congenital—Refers to a disorder that is present at

birth

Connective tissue—A group of tissues responsible

for support throughout the body; includes lage, bone, fat, tissue underlying skin, and tissuesthat support organs, blood vessels, and nervesthroughout the body

carti-Contrature—A tightening of muscles that prevents

normal movement of the associated limb or otherbody part

Deformation—An abnormal form or position of a

part of the body caused by extrinsic pressure ormechanical forces

Epiphysis—The end of long bones, usually

termi-nating in a joint

Hypermobility—Unusual flexibility of the joints,

allowing them to be bent or moved beyond theirnormal range of motion

Joint dislocation—The displacement of a bone

from its socket or normal position

Kyphosis—An abnormal outward curvature of the

spine, with a hump at the upper back

Magnetic resonance imaging (MRI)—A technique

that employs magnetic fields and radio waves tocreate detailed images of internal body structuresand organs, including the brain

Scoliosis—An abnormal, side-to-side curvature of

the spine

Skeletal dysplasia—A group of syndromes

consist-ing of abnormal prenatal bone development andgrowth

affected children have been reported, with an incidence

of 1/1500 births This variant is thought to be recessivebut the responsible gene has not yet been located

Signs and symptoms

The symptoms of Larsen syndrome are widely able from person to person and can range from lethal tovery mild, even among members of the same family

vari-Typical characteristics at birth are multiple joint

dis-locations that can include hips, elbows, wrists, and knees

Babies can be born with their knees in hyperextension

with their ankles and feet up by their ears, a deformation

called genu recurvatum Clubfoot is common and

per-sistent flexion, or contractures, of other joints, such as the

wrist and fingers, can also occur

Persons with Larsen syndrome often have distinctive

facial features Common findings, in addition to a large

forehead and wide spaced eyes, are flat cheekbones and

a flat bridge of the nose, which is sometimes indented

and called “saddle nose” The hands are often short but

the fingers are long and lack the normal tapered ends

Other birth defects can occur but are not present in

all people Cleft palate, cataracts, and heart defects of the

valves or between the upper or lower chambers occur

occasionally

Often, babies have floppy muscle tone giving them a

“rag doll” appearance Respiratory problems are

fre-quently seen at birth because of laxity of the trachea

Feeding and swallowing difficulties are common

Abnormalities of the bones are frequent

Under-development and abnormal shape of some of the

verte-bral bones can lead to problems such as scoliosis or

kyphosis Abnormalities of the epiphyses (centers of

bone growth) can develop in childhood Height is often

reduced, and an adult height of four to five feet is not

uncommon The joints between the bones of the ear may

be abnormal and may cause conductive hearing loss

Hypermobility of joints lasts throughout life and

may lead to early-onset arthritis, recurrent dislocations,

and may necessitate joint replacement at an early age

Cervical spine instability is a very serious complication

of Larsen syndrome as it can cause compression of the

spinal cord and lead to paralysis or death

The condition does not affect intelligence and

chil-dren can expect to have normal school experiences, with

the exception of physical education, which will need to

be adapted to each child’s needs

Diagnosis

Larsen syndrome should be suspected in any baby

having multiple joint dislocations at birth As of 2001,

there is no genetic test to confirm the diagnosis and, thus,

diagnosis must be based on clinical and x ray findings

Babies suspected to have the condition warrant a

com-plete evaluation by a medical geneticist (a physician

spe-cializing in genetic syndromes)

Larsen syndrome is sometimes misdiagnosed as

another condition called arthrogryposis, which involves

multiple joint contractions Larsen syndrome can be

dis-tinguished from this and other syndromes involving jointdislocations or contractions because of the unusual con-stellation of features found in the face and hands Extrabones of the wrist, often seen in Larsen syndrome, areextremely rare in other syndromes

Some people have very mild symptoms and may nothave joint dislocations or other problems at birth Thediagnosis can be missed in these people unless they arecarefully evaluated

A person with dominantly inherited Larsen drome has a 50% chance with each pregnancy of having

syn-a child with the ssyn-ame disorder Genetic counseling csyn-anhelp couples sort out their options for parenthood Somecouples would choose to adopt rather than take thechance of an affected child, others would go ahead with

a pregnancy, and others would choose to have prenataldiagnosis The only form of prenatal diagnosis available

to date is ultrasound

Fetal ultrasound performed by a specialist at 18-20weeks of pregnancy can sometimes reveal signs ofLarsen syndrome Knee dislocations and hyperextension,club feet, fixed flexion of elbows, wrists, and fingers, andsome of the characteristic facial features can sometimes

be noted by ultrasound in affected fetuses Physical ings from ultrasound can suggest but do not confirm thediagnosis of Larsen syndrome in a fetus

find-Treatment and management

Treatment will vary according to the symptoms of aparticular child Joint problems require long-term ortho-pedic care Dislocations, clubfeet, and joint contracturesare treated with intensive physical therapy, splints, cast-ing, and/or surgery Physical therapy is also importantafter joint surgery to build up muscles around the jointand preserve joint stability Occupational therapy may behelpful for children with wrist and finger contractures.Respiratory problems at birth may necessitate oxy-gen or assistive breathing devices If not alleviated bymedication or special feeding techniques, eating andswallowing problems may require tube feeding Heartproblems, cleft palate, and cataracts often warrant surgi-cal correction Special care is needed if laxity of the tra-chea is present because of an increased risk forrespiratory problems during and after surgery

People with chronic pain associated with bile joints often can be helped by techniques taught in apain management clinic

hypermo-Magnetic resonance imaging (MRI) of the neck isrecommended in childhood to screen for cervical verte-bral problems Early diagnosis and surgical stabilization

of the spine can help patients avoid paralysis and death

from spinal cord compression Scoliosis is usually treated

by bracing, or by a surgically placed metal rod Artificial

hip and knee replacements may be needed in

early-to-mid adulthood because of degeneration of unstable

joints

Regular medical examinations are crucial to assess

the condition of the bones, joints, spine, heart, and eyes

Hearing should be evaluated on a periodic basis,

espe-cially in children, because of the potential for conductive

hearing loss Ophthalmologic examinations are

recom-mended periodically to screen for cataracts

Prognosis

The effects of the syndrome vary markedly from

person to person Therefore, prognosis is based on the

findings in a given individual The usual causes of early

death are either severe respiratory problems or

compres-sion of the cervical spine from vertebral instability

If careful and consistent orthopedic treatment is

ini-tiated early, prognosis can be good, with a normal life

span Weak and unstable joints and limited range of

motion from contractures may cause walking difficulties

and restrict other physical activities Contact sports and

heavy lifting should be avoided as anything that puts

extra strain or pressure on the joints can cause harm

Swimming is a good activity because it helps strengthen

muscles without joint strain

Resources

PERIODICALS

Becker, R., et al “Clinical Variability of Larsen Syndrome:

Diagnosis in a Father after Sonographic Detection of a

Severely Affected Fetus.” Clinical Genetics 57 (2000):

148-150.

Tongsong, T., et al “Prenatal Sonographic Diagnosis of Larsen

Syndrome.” Journal of Ultrasound Medicine 19 (2000):

Late onset multiple carboxylase deficiency

see Biotinidase deficiency

Laurence-Moon-Bardet-Biedel syndrome

see Bardet-Biedel syndrome

Description

Vision is an important and complex sense by whichthe qualities of an object, such as color, shape, and size,are perceived through the detection of light For propervision, a critical series of biological steps must occur; ifany of the steps in the process is abnormal, visual impair-ment or blindness may occur

The process of vision begins with light that bouncesoff an object and passes through the outer coverings andlens of the eye and projects onto a layer of cells at theback of the eye called the retina The retina contains twokinds of specialized cells types, called the rods andcones, that are responsible for sensing visual stimuli.When rods and cones are stimulated by light, impulsesare conducted through the optic nerve to a region in theback of the brain known as the occipital lobe The occip-ital lobe contains the visual cortex, the area of the brainthat processes visual stimuli and integrates signals sent

by the retina to obtain a composite image of an object.Leber congenital amaurosis (LCA) is term for agroup of inherited conditions in which the rod and conereceptors in the retina are defective or missing Withoutthe proper function of these specialized cells, light can-not be sensed normally

LCA is often referred to by other names, such as:congenital absence of the rods and cones, congenital reti-nal blindness, congenital retinitis pigmentosa, Leber’scongenital tapetoretinal degeneration, or Leber’s congen-ital tapetoretinal dysplasia The disorder was firstdescribed by the German ophthalmologist, TheodorLeber, in 1869, who subsequently showed that it was aninherited defect Although similarly named, LCA should

visual cortex of the brain The different types of LCA andthe corresponding genetic abnormality is described in thetable below These six identified mutations likely accountfor less than half of all diagnosed cases of LCA, and thus,there are additional mutations resulting in LCA thatremain to be discovered.

LCA is a genetic condition and can be inherited orpassed on in a family The genetic defects for the disor-der are all inherited as autosomal recessive traits, mean-ing that two mutant genes of the same group are needed

to display the disease A person who carries one mutantgene does not display the disease and is called a carrier

A carrier has a 50% chance of transmitting the gene totheir children, who must inherit the same defective genefrom each parent to display the disease Since there aredifferent genes that are responsible for causing LCA, twoindividuals with different types of LCA will have anunaffected child, as it is impossible for the child toinherit two of the same type of defective genes from theparents

Demographics

LCA has been reported to account for at least 5% ofall cases of inborn blindness, but several reports suggestthat is an underestimation In 1957, scientific investiga-tors reported that one form of LCA was responsible for10% of blindness in Sweden Several years later, similarrates of LCA were found in people living in theNetherlands While this suggests that the geographicaldistribution of LCA is not uniform and may be higher incertain ethnic groups, a comprehensive study has neverbeen performed

Signs and symptoms

Because there are different types of LCA, there isconsiderable variation in the symptoms experienced by

an affected infant Most infants with LCA are often blind

at birth or lose their sight within the first few years of life,however some people with LCA may have residualvision In these patients, visual acuity is usually limited

to the level of counting fingers or detecting hand motions

or bright lights, and patients are extremely farsighted.There may be some small improvement in vision duringthe first decade of life as the visual system reaches matu-rity, but it is uncommon for children to be able to navi-gate without assistance or to be able to read print.Other symptoms of LCA may include crossed eyes,sluggish pupils, rapid involuntary eye movements,unusual sensitivity to light, and the clouding of the lenses

of the eyes Many children with LCA habitually press ontheir eyes with their fists or fingers This habitual press-ing on the eyes is known as an oculo-digital reflex and

K E Y T E R M SAutosomal recessive—A pattern of genetic inheri-

tance where two abnormal genes are needed to

display the trait or disease

Braille—An alphabet represented by patterns of

raised dots which may be felt with the fingertips It

is the main method of reading used by the blind

today

Carrier—A person who possesses a gene for an

abnormal trait without showing signs of the

disor-der The person may pass the abnormal gene on to

offspring

Computed tomography (CT) scan—An imaging

procedure that produces a three-dimensional

pic-ture of organs or strucpic-tures inside the body, such as

the brain

Electroretinography (ERG)—A diagnostic test that

records electrical impulses created by the retina

when light strikes it

Mutation—A permanent change in the genetic

material that may alter a trait or characteristic of

an individual, or manifest as disease, and can be

transmitted to offspring

Occipital lobe—An anatomical subdivision,

located at the back of the brain, that contains the

visual cortex

Oculo-digital reflex—A reflex causing an

individ-ual to press on their eyes with their fingers or fists

Retina—The light-sensitive layer of tissue in the

back of the eye that receives and transmits visual

signals to the brain through the optic nerve

Visual cortex—The area of the brain responsible

for receiving visual stimuli from the eyes and

inte-grating it to form a composite picture of an object

not be confused with another disorder of sight, Leber

optic atrophy, that was also discovered by Theodor

Leber

Genetic profile

Mutations in any one of at least six different gene

groups may result in LCA Each of the known genes

pro-duce proteins, which are located within the retinal rod

and cone cells These proteins participate in the detection

of an incoming stimulus of light and the subsequent

transmission of signals out of the retinal cells to the

may represent an instinctual attempt to provide the

evel-oping visual cortex of the brain with a stimulus to replace

the loss of normal visual stimuli As a result of this

behavior, the eyes may become thin and conical in shape

and appear sunken or deep In some cases, LCA is

asso-ciated with hearing loss, epilepsy, decreased

coordina-tion, kidney problems, or heart abnormalities Mental

retardation may be present in approximately 20% of

indi-viduals affected with LCA

Diagnosis

Infants are usually brought to medical attention

within the first six months of life when parents note a

lack of visual responsiveness and the unusual roving eye

movements characteristic of the disease As with any

evi-dence of loss of vision, a prompt and thorough evaluation

is initiated to determine the cause of the visual defect,

and steps may include physical tests designed to measure

brain and eye function, CT scans (a method using x rays

controlled by a sophisticated computer) of the brain and

eye, and even tests to look for genetic and metabolic

causes of blindness

Eye examinations of infants with LCA usually reveal

a normal appearing retina By early adolescence,

how-ever, various changes in the retinas of patients with LCA

become readily apparent; blood vessels often become

narrow and constricted, and a variety of color changes

can also occur in the retina and its supportive tissue

One of the most important tests in diagnosing LCA

is called electroretinography (ERG) This test measures

electrical impulses which are produced in the retina when

light is sensed by the rod and cone cells It is useful in

distinguishing whether blindness is due to a problem in

the retina versus a problem in the visual cortex of the

brain When ERG tests are performed on people with

LCA, there is no recordable electrical activity arising

from the eye, indicating the problem is based in the retina

rather than in the brain

Thus, an absence of activity on ERG, combined with

the absence of diagnostic signs of other conditions which

result in blindness, point to a diagnosis of LCA Although

several abnormal genes have been identified which are

responsible for LCA, genetic analysis and prenatal

diag-nosis is rarely performed outside of research studies

Treatment and management

Currently, there is no treatment for LCA, and thus,

patient and family education and adaptive assistance is

critical Some people with remaining vision may benefit

from vision-assistance technology such as electronic,

computer-based, and optical aids, but severely

visually-impaired individuals often utilize traditional resourcessuch as canes and companion-guide dogs Orientationand mobility training, adaptive training skills, job place-ment and income assistance are available through hospi-tal physical and occupation therapy programs and variouscommunity resources It should be noted that up to 20%

of patients with LCA may have associated mental dation and will require additional adaptive and vocationalassistance

retar-Most people with LCA are unable to read print andinstead utilize braille, an alphabet represented by raiseddots that can be felt with the fingertips People withLCA often attend schools specially designed to meet theneeds of visually-impaired students and may requiremodifications to their home and work environments inorder to accommodate their low or absent vision Asalmost all patients with LCA are legally blind, they willnot be able to drive or operate heavy machinery

Genetic counseling may assist affected individuals

with family planning

Scientists have isolated several mutant genes thatcan each cause LCA Ongoing scientific research isdirected toward understanding how these genes function

in the retina and toward locating the remaining genes thatcause LCA With this information, scientists can betterdevelop a means of prevention and treatment A dramaticexample of this principle was provided in 2000, whenresearchers were able to restore vision in mice withLCA2 By giving oral doses of a chemical compoundderived from vitamin A, the scientists were able to restorethe animals’ visual functions to almost normal levelsafter just two days The researchers report that they willattempt the same experiments in dogs with LCA2 beforetrying the treatment in humans It should be noted thatLCA2 causes only 10% of the known cases of LCA, andthe treatment in this experimental study does not workfor other types of LCA

Location of genetic abnormality for specific types of Leber congenital amaurosis

Gene Type Abnormal Mutant gene location

LCA1 Retinal-specific

guanylate cyclase

RETGC/GUC2D 17p13.1 LCA2 Retinal pigment

epithelium-specific protein

RPE65 1p31 LCA3 Unknown Unknown 14q24 LCA4 Arlhydrocarbon-interacting

protein-like 1

AIPL1 17p13.1 LCA5 Unknown Unknown 6q11–q16 LCA due to Cone-rod homeobox

CRX defect protein

CRX 19q13.3

TABLE 1

While children born with LCA may have variable

symptoms and differing levels of visual acuity, they can

lead productive and healthy lives with adaptive training

and assistance In those patients who do not have

associ-ated problems with their brain, heart, or kidney, lifespan

is approximately the same as the general population,

oth-erwise the prognosis is variable and depends on the

extent of the complication

Resources

BOOKS

“Disorders of Vision” In Nelson Textbook of Pediatrics, edited

by R E Behrman Philadelphia: W B Saunders, 2000, pp.

1900-1928.

PERIODICALS

Dharmaraj, S R., et al “Mutational Analysis and Clinical

Correlation in Leber Congenital Amaurosis.” Ophthalmic

Genetics 21 (September 2000): 135-150.

Gamm, D M., and A.T Thliveris “Implications of Genetic

Analysis in Leber Congenital Amaurosis.” Archives of

Ophthalmology 119 (March 2001): 426-427.

Lambert, S R., A Kriss, and D Taylor “Vision in Patients with

Leber Congenital Amaurosis.” Archives of Ophthalmology

11 (February 1997): 293- 294.

Perrault, I “Leber Congenital Amaurosis.” Molecular Genetics

and Metabolism 68 (October 1999): 200-208.

ORGANIZATIONS

Foundation Fighting Blindness Executive Plaza 1, Suite 800,

11350 McCormick Rd., Hunt Valley, MD 21031-1014.

(888) 394-3937 ⬍http://www.blindness.org⬎.

WEBSITES

“Entry 20400: Leber Congenital Amaurosis, Type 1.” OMIM—

Online Mendelian Inheritance in Man.⬍http://www.ncbi

.nlm.nih.gov/entrez/dispomim.cgi?id ⫽20400⬎.

Leber’s Links: Leber’s Congenital Amaurosis. ⬍http://www

.freeyellow.com/members4/leberslinks/index.html ⬎.

Oren Traub, MD, PhD

Lebers hereditary optic neuropathy see

Lebers hereditary optic atrophy

optic atrophy

Definition

Lebers hereditary optic atrophy is a painless loss of

central vision (blurring of objects and colors appearing

less vivid) that usually begins between the ages of 25 and

35 (but can occur at any age) and leads to legal blindness.Other minor problems may be present such as tremors,numbness or weakness in arms and legs, or loss of anklereflexes It was first described in 1871 by Theodore Leberand is the most common cause of optic atrophy

Description

Lebers hereditary optic atrophy is also called Lebershereditary optic neuropathy or LHON The beginning ofvisual blurring in both eyes is called the acute phase ofLHON In about half the patients, both eyes are affected

at the same time In the remainder of patients, centralvision is lost in one eye over a period of a few weeks,then a month or two later, the second eye is affected.Once both eyes are affected, a few weeks usually passbefore the eyesight stops getting worse Other less com-mon patterns of central vision loss in LHON can be verysudden loss in both eyes, or very gradual loss occuringover several years After the acute phase, there is rarelyany significant change in eyesight during the remainder

of the person’s life People with LHON are usually leftwith some peripheral vision, which is seeing around theedges, or out of the corner of the eye This final phase iscalled the atrophic phase because the optic discs areatrophic (cells have wasted away) and rarely change.The optic disc is the center part of the retina (back ofthe eye) and is where the clearest vision—both in detailand color—comes from The retina is what interpretswhat a person sees and sends this message to their brain,along the pathway known as the optic nerve In LHON,both the retina and the optic nerve stop working properly.The rest of the eye works normally, so that light entersthe eye through the pupil (black circle in the center of theiris, the colored part of the eye) as it should However,even though the light is focused on the retina properly, inLHON, this information isn’t converted into signals forthe brain to process When a person wears prescriptionglasses, the purpose is to help focus light properly on theretina In LHON, light is already focused as it should be,

so glasses will not improve vision Magnifying glassesand telescopes do help, however, because they makethings look bigger When a person looks through a mag-nifier or telescope they use more of their retina to see,and some undamaged cells of the retina may be able toprovide some information to the brain

Suddenly losing vision is a shock Patients nosed with LHON may feel they have no useful sight left,and often, their family and friends treat them as thestereotypic blind person In reality, LHON usually leaves

diag-an affected person with some useable vision A variety ofvisual aids are available to enhance this

Genetic profile

In 60% of patients with LHON, there is a positive

family history of LHON, while the remaining cases are

considered sporadic (occur by chance), where only one

person in the family has LHON In 1988 it was

discov-ered that LHON is caused by a mutation in a

mitochon-drial gene Mitochondria are the energy producing

organelles (structures) of cells They have their own

genetic material called mitochondrial DNA, which is

separate from the usual genetic material contained in the

center of the cell (or nucleus) Each mitochondria has

several copies of its’ circular DNA DNA is the chemical

that makes up genes Genes code for certain traits, and in

some cases, can code for disease Mutations in the DNA

of a mitochondria may be present in all copies (called

homoplasmy), or may be present in a portion of the

mito-chondria’s DNA (called heteroplasmy) About 15% ofindividuals with LHON are heteroplasmic, which meanssome of their mitochondrial DNA has a mutation, andsome does not This may have a bearing on the chance todevelop symptoms, and on the risk of transmission

There are three specific DNA changes or mutationsthat are found in the majority (90-95%) of LHON cases.The remaining LHON patients have other various mito-chondrial mutations In genetics, mutations are desig-nated in such a way as to tell a scientist where they arelocated in the mitochondrial DNA and what the DNAalteration is:

• G11778A (i.e., mutation is located at position 11778;DNA change is G [guanine] to A [adenine]—a change

in the base pairs that make up DNA)

• T14484C

K E Y T E R M SAcute phase—The initial phase of LHON where

visual blurring begins in both eyes, and central

vision is lost

Atrophic phase—The final phase of LHON where

cells in the optic disc and optic nerve have

atro-phied, resulting in legal blindness Peripheral vision

remains

Central vision—The ability to see objects located

directly in front of the eye Central vision is

neces-sary for reading and other activities that require

people to focus on objects directly in front of them

Heteroplasmy—When all copies of mitochondrial

DNA are not the same, and a mix of normal and

mutated mitochondrial DNA is present

Homoplasmy—When all copies of mitochondrial

DNA are the same, or have the same mutation

Lebers hereditary optic atrophy or Lebers

heredi-tary optic neuropathy (LHON)—Discovered in

1871 by Theodore Leber, the painless loss of central

vision in both eyes, usually occurring in the second

or third decade of life, caused by a mutation in

mitochondrial DNA Other neurological problems

such as tremors or loss of ankle reflexes, may also

be present

Lifetime risk—A risk which exists over a person’s

lifetime; a lifetime risk to develop disease means

that the chance is present until the time of death

Mitochondria—Organelles within the cell

responsi-ble for energy production

Mitochondrial inheritance—Inheritance associated

with the mitochondrial genome which is inheritedexclusively from the mother

Multiple sclerosis (MS)—A progressive

degenera-tion of nerve cells that causes episodes of muscleweakness, dizziness, and visual disturbances, fol-lowed by periods of remission

Mutation—A permanent change in the genetic

material that may alter a trait or characteristic of anindividual, or manifest as disease, and can be trans-mitted to offspring

Ophthalmologist—A physician specializing in the

medical and surgical treatment of eye disorders

Optic disc—The region where the optic nerve joins

the eye, also refered to as the blind spot

Optic nerve—A bundle of nerve fibers that carries

visual messages from the retina in the form of trical signals to the brain

elec-Peripheral vision—The ability to see objects that

are not located directly in front of the eye.Peripheral vision allows people to see objectslocated on the side or edge of their field of vision

Pupil—The opening in the iris through which light

enters the eye

Retina—The light-sensitive layer of tissue in the

back of the eye that receives and transmits visualsignals to the brain through the optic nerve

Sporadic—Isolated or appearing occasionally with

no apparent pattern

• G3460A

Not all persons who have one of these mutations

will develop LHON, since it is thought that additional

genetic or environmental factors are necessary to

develop central vision loss In general, males with one of

these mutations have a 40% lifetime risk to develop

symptoms of LHON, while females have a 10% risk,

although the actual risk varies slightly from mutation to

mutation In addition, the older a person in whom a

mutation has been identified becomes without

symp-toms, the less likely they will lose their vision at all If a

person is going to experience vision loss from LHON,

the majority of people with a mutation will express

symptoms by the age of 50 years

Environmental factors that can reduce the blood

sup-ply to the retina and optic nerve, and ‘trigger’ the vision

loss in LHON to begin, include heavy drinking or

smok-ing, exposure to poisonous fumes such as carbon

monox-ide, high levels of stress, and certain medications A

person in whom a mutation has been identified is

consid-ered more susceptible to some of these exposures and are

advised not to smoke and to moderate their alcohol intake

if they are asymptomatic

The other important concept to understand in

rela-tion to mitochondrial disease is that mitochondria are

only inherited from the mother Therefore, a woman with

a mitochondrial mutation (whether she has symptoms or

not) will pass it to all of her offspring Sons who inherit

the mutation will not pass it to any of their children,

while daughters who inherit the mutation will pass it to

all of their children This is in contrast to nuclear DNA,

where half the genetic material is inherited from each

parent

Demographics

Males have LHON more often than females,

how-ever, females may develop LHON at a slightly older age

and may have more severe symptoms, including a

multi-ple sclerosis-like illness Multimulti-ple sclerosis is a

progres-sive degeneration of nerve cells that causes episodes of

muscle weakness, dizziness, and visual disturbances,

fol-lowed by remission The onset of LHON usually occurs

by 50 years if a mitochondrial DNA mutation is present,

although it can present as late as the sixth or seventh

decade of life

Signs and symptoms

Symptoms of LHON include a painless sudden loss

of central vision, both in visual detail and color, in both

eyes over a period of weeks to months Peripheral vision

(seeing out of the corner of the eye) remains Additional

symptoms involving the neurological system may bepresent such as tremors, numbness or weakness in arms

or legs, or loss of ankle reflexes Symptoms vary by der and type of mutation present The following muta-tions are frequently identified and well understood:

gen-• G11778A—the most common mutation and usually themost severe vision loss

• T14484C—usually has the best long term prognosis oroutcome

• G3460A—has an intermediate presentationPersons who have a multiple sclerosis-like illnesscan have any of the three mutations Thisphenomena–where different mutations give differentclinical outcomes–is called a genotype-phenotype corre-lation The word genotype describes the specific findings

in DNA, while the word phenotype is used to describe theclinical presentation

Diagnosis

Suspicion of LHON is usually made by an lamologist after a complete eye examination Genetic

ophth-testing for the presence/absence of mitochondrial

muta-tions can then be performed from a small blood sample.After a symptomatic person with LHON in a family hasbeen identified to have a mitochondrial mutation, otherasymptomatic at-risk relatives can also be tested At-riskrelatives would include the affected persons’ mother, sib-lings, and the offspring of any females found to have themutation Testing for asymptomatic children who are at-risk is not currently offered since no treatment is avail-able for LHON; these individuals could opt for testingupon becoming a legal adult (i.e reaching 18 years ofage) Prenatal diagnosis for LHON is presently not avail-able in the United States, but may be offered elsewhere.With genetic testing for LHON, it is important to remem-ber that the presence of a mitochondrial mutation doesnot predict whether the condition will occur at all, the age

at which it will begin, the severity, or rate of progression

Treatment and management

There is no proven treatment available for LHON,although some studies report benefit from various vita-min therapies or other medications Management ofLHON is supportive, utilizing visual aids such as magni-fiers

Prognosis

The loss of central vision tends to remain the same(legally blind) over a lifetime once a person with LHONhas reached the atrophic phase