Ebook Escourolle poirier’s manual of basic neuropathology Part 2

(BQ) Part 2 book Escourolle poirier’s manual of basic neuropathology presentation of content: Acquired metabolic disorders, hereditary metabolic diseases, congenital malformations and perinatal diseases, pathology of skeletal muscle, pathology of peripheral nerve, diseases of the pituitary gland.

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9

L E I L A C H I M E L L I A N D F R A N Ç O I S E   G R AY

A WIDE range of systemic acquired metabolic

diseases can also aff ect the central and/or

periph-eral nervous system (e.g hypoxia, hypoglycemia,

disorders of serum electrolytes, vitamin defi

cien-cies, and exogenous intoxications) By and large,

the morphologic manifestations of most of these

diseases in the various organs of the body are

non-specifi c In the central nervous system (CNS), on

the other hand, lesions may fi nd expression via

selective involvement of some brain regions with

simultaneous complete preservation of others, a

phenomenon oft en referred to as selective

vulnerabil-ity Th e pathogenesis of the predisposition to injury

of some anatomical areas and/or of some specifi c,

largely neuronal, cell types varies considerably from

one disease to another and is undoubtedly

multifac-torial in all Diff erences in the vascular patt erns of

irrigation and resulting alterations in regional

perfu-sion may explain, at least partly, the phenomenon of

selective vulnerability in some disorders Regional

variations in the biochemical characteristics of

neu-ronal populations or, most likely, in the distribution

of receptors for various excitatory amino acids may also play a role in some others

1 CEREBRAL HYPOXIA

The brain normally receives about 15% of the cardiac output, consumes about 20% of the blood oxygen, and consumes about 10% to 20%

of the blood glucose Different states of deficient oxygen supply and utilization or deficient sub-strate may produce prominent cerebral hypoxic changes:

• Anoxic or hypoxic hypoxia results from decreased

pulmonary access to oxygen Th is may be due

to insuffi cient oxygen in the inspired air It also may result from upper airway obstruction or may accompany pulmonary disorders that impede the uptake of oxygen In rare instances (i.e., hyper-thermia) it may be due to increased metabolic demand

206 • E S C O U R O L L E & P O I R I E R ’ S M A N U A L O F B A S I C N E U R O P AT H O L O G Y

Th e hippocampus (Ammon’s horn) oft en shows

selective involvement by hypoxia Th is is most dent in the CA1 sector (an area that corresponds

evi-to what is anaevi-tomically defi ned as Sommer’s tor) ( Fig. 9 2 A, B ) Th e CA3 area (also referred to

sec-as the endplate) is oft en less severely aff ected Th e CA2 area tends to be relatively resistant to hypoxic changes Th e regional variation in the susceptibil-ity of the pyramidal hippocampal neurons is now best explained by implicating the distribution of excitotoxic receptors as an important pathogenetic factor

Among the basal ganglia , the pallidum

(espe-cially the medial portion) ( Fig.  9 3 ) , the striatum, especially the lateral half of the putamen, and the thalamus are selectively vulnerable to hypoxia Th e mammillary bodies may be especially vulnerable when hypoxia occurs in infancy

In the cerebellum , cortical involvement is frequent

and aff ects chiefl y the Purkinje cells with secondary proliferation of Bergmann glia Th e dentate nucleus

is also frequently involved

In the brainstem , the medullary olives are

vulner-able areas In children, the brainstem is sometimes severely damaged, especially the medial and lateral reticular formations and the adjacent cranial nerve nuclei

Various types of white matt er lesions may be

seen in isolation in response to anoxia or in ciation with gray matt er damage Some white mat-ter lesions consist predominantly of extravasation

asso-of edema fl uid due to increased vascular ability but with preservation of endothelial cells

perme-Th ese lesions currently are designated as reversible

• Anemic hypoxia results from decreased oxygen

transport, either from reduced hemoglobin levels

or reduced capacity of the hemoglobin molecule

to transport oxygen, as occurs in carbon

monox-ide poisoning

• Stagnant hypoxia results from reduction or

ces-sation of blood fl ow Th is can be the result of

impaired cardiac output producing global

isch-emia, or can be localized as is the case in brain

infarcts Th e cerebral lesions that result from

stagnant hypoxia are due to a combination of an

inadequate supply of oxygen and glucose and an

accumulation of lactic acid

• Histotoxic hypoxia results from exposure to

intoxi-cants, such as cyanide or hydrogen sulfi de, which

render the neural parenchyma incapable of

utiliz-ing oxygen and substrates

• Oxyachrestic hypoxia results from severe

hypogly-cemia, where oxygen is not utilized because of the

severe metabolic substrate defi ciency

1.1 Basic Cellular Reactions

to Injury

Th e basic cellular reactions to injury (see Chapter 1)

seen in cerebral hypoxia mostly involve neurons

(ischemic nerve cell change); glial cells may also be

aff ected and this may be manifest, for example, as

glial necrosis, reactive gliosis, or rod-shaped

microg-lia and macrophage proliferation

1.2 Selective Tissue Lesions

Th e cellular changes resulting from hypoxia are

maximal in those areas of the brain that are regarded

as showing selective vulnerability

In the cerebral cortex , the neuronal changes are

more pronounced in the third, fi ft h, and sixth layers

of the neocortex In addition, the changes are more

severe in the depths of sulci than along the banks or

the apices of the gyri Widespread, severe

destruc-tion of the deeper layers of the cortex leads to

lami-nar (or pseudo-lamilami-nar) necrosis ( Fig.  9 1 ) Th is

descriptive term applies to a phenomenon whereby

the distribution of the necrosis is confi ned to one or

more layers of the isocortex and may be especially

evident in the parietal and occipital lobes, where

impaired perfusion may exacerbate the eff ects of

hypoxia In the most severe cases, the cortical

necro-sis is not selective

FIGURE 9.1 Laminar cortical necrosis Th is is oft en most severe in the posterior frontal and parietal lobes

Chapter 9 Acquired Metabolic Disorders • 207

that interval, a variable degree of cerebral ing may be observed In cases of sudden death

swell-or where only moderate cerebral hypoxia has occurred, unquestionable signs of hypoxia may

be discerned solely on histological examination; these changes consist of ischemic neurons in the most vulnerable areas, where they are difficult to detect before 4 to 12 hours of survival beyond the insult

Depending on the mechanism of cerebral anoxia, separate and distinctive patt erns of ischemic changes are recognized

leukoencephalopathy and may be seen in hypoxia and

other acquired metabolic disturbances or

intoxica-tions Other white matt er lesions, oft en designated

collectively as hypoxic encephalopathy , consist of

varying proportions of demyelination and white

matt er necrosis Th e degree of severity of these

lesions ranges from small, perivascular foci of

demy-elination, to focal plaque-like areas of demyelination

and necrosis, and up to large confl uent areas of

demyelination and necrosis Th e lesions tend to be

most severe deep in the white matt er and are oft en

associated with relative preservation of the

subcorti-cal “U” fi bers (Fig. 9.4)

1.3 Variation of Lesions

According to Etiology

A survival time of approximately 48 hours is

necessary for macroscopically visible lesions of

cerebral hypoxia to become apparent Before

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carboxyhemoglobin; that hue is also imparted to the external and cut surface of the brain ( Fig. 9 6 ) Scatt ered petechial hemorrhages also may be pres-ent With prolonged formalin fi xation, the red dis-coloration becomes less prominent

Some individuals who seem to recover clinically from acute toxic exposure to CO may, some days to

weeks later , develop a neurological syndrome that

includes neuropsychiatric manifestations ing personality changes, parkinsonism, dementia, incontinence, and frank psychosis In these cases, diff erent combinations of the neuropathological abnormalities described below may be found

Pallidal necrosis is most oft en observed in fatal

cases of CO intoxication occurring aft er some delay aft er the insult (6 or more days) Microscopic foci

of ischemic or hemorrhagic necrosis may develop even sooner Th e pallidal lesions are usually bilat-eral but are oft en asymmetrical Th e necrosis usually involves the anterior portion and inner segment of the pallidum but may extend into the outer segment

or dorsally into the internal capsule Although lidal necrosis is characteristic of and frequently seen

pal-in delayed deaths from CO, it may also be seen pal-in other conditions associated with hypoxia or anoxia ( Fig s 9 3 , 9.7, and 9.8 ) Th e selective involvement

of the globus pallidus in CO poisoning has been

1 3 1 C E R E B R A L I N FA R C T S

Cerebral infarcts are the result of localized ischemic

hypoxia due to vascular occlusion (see Chapter 4)

Infarcts and/or ischemic lesions in the boundary

zone areas are the result of global oligemic hypoxia,

especially in the sett ing of low cerebral blood fl ow of

sudden onset, even of short duration Th ese lesions

are one of the possible consequences of acute heart

failure (cardiogenic shock), drug-induced

hypoten-sion, or general anesthesia

1 3 2 C A R D I O VA S C U L A R   A R R E S T

Cardiovascular arrest exceeding three to four

min-utes at normal temperature ordinarily causes diff use

cortical lesions and Ammon’s horn involvement; the

distribution and extent of damage in the basal

gan-glia and in the brainstem vary ( Fig 9.5 ) Comparable

lesions are caused by profound hypoglycemia ( vide

infr a ) and status epilepticus

1 3 3 C A R B O N M O N O X I D E P O I S O N I N G

Carbon monoxide (CO) is produced by

incom-plete combustion of carbon-containing substances

Humans are exposed to CO mainly through

auto-mobile exhaust, improperly ventilated stoves or

heaters, and tobacco smoke Th e toxic eff ects of

CO result primarily from the decreased capacity of

blood to transport oxygen

At autopsy examination, the brain of an

indi-vidual who dies within a few hours of intoxication

is diff usely swollen and congested Th e blood within

vessels has the characteristic cherry-red color of

FIGURE 9.5 Diff use cortical and basal ganglia

lesions in a case of delayed death following

cardiovas-cular arrest

FIGURE 9.6 Macroscopic image of the brain from patient with acute CO poisoning Th e postmortem blood CO saturation was 60%.Th e cherry-red color

of the carboxyhemoglobin imparts a red hue to the entire brain

Chapter 9 Acquired Metabolic Disorders • 209

develop If death occurs some time later, the brain may show foci of necrosis in the basal ganglia and white matt er and loss of Purkinje cells

1 3 5 H Y P O G LY C E M I A

Glucose is the principal source of energy in the CNS Neuronal stores of glucose and glycogen are relatively small and need practically continuous replenishment A  decrease of glucose level under 1.5mmol/L (25 to 30mg/100mL) leads to brain damage within one to two hours

Th e most common cause of hypoglycemia is an excess of exogenous insulin Th e eff ects of hypo-glycemia are not due just to the energy defi cit Releases of aspartate and to a lesser extent release of glutamate probably contribute to neuronal damage through excitotoxic mechanisms

In acute hypoglycemia, the lesions are similar to those of acute hypoxia but not identical In general, the patt ern of injury is that of selective degeneration

of neurons rather than frank necrosis of all other lular components Aff ected neurons are shrunken with hypereosinophilic cytoplasm Initially, the nucleus is pyknotic, as seen in anoxia, but later may become eosinophilic and appears to blend in with the cytoplasm (nuclear dropout) Th e topography of the lesions is roughly similar to that in hypoxia, but Purkinje cells may be relatively spared

cel-att ributed to selective vulnerability of pallidal

neu-rons, the result of hypotension and impaired

circu-lation through the pallidal branches of the anterior

choroidal arteries, or the relatively high iron content

of this portion of the brain, which somehow renders

the structure especially susceptible

Other gray matt er regions involved include the

neocortical and hippocampal neurons, and the

cer-ebellar Purkinje cells and granule cells, where there

may be focal neuronal loss

Lesions of the white matt er are also encountered

in individuals who die some time aft er CO

poi-soning Th ese lesions consist of varying degrees of

demyelination and associated necrosis Th ere may

be small perivascular foci found in the deep white

matt er, large confl uent areas that extend from the

frontal to occipital poles in the periventricular white

matt er, or sharply demarcated foci of demyelination

with relative sparing of axons in the deep white

mat-ter (“Grinker’s myelinopathy”) (Fig. 9.8 ) All these

lesions tend to spare the arcuate fi bers

1 3 4 C YA N I D E S

Cyanides are histotoxic or cytotoxic agents, the

tox-icity of which is due to bonding between the cyanide

ion and the ferric iron of intracellular cytochrome

oxidase Th is reaction leads to cessation of cellular

respiration Acute intoxication can result from either

ingestion or inhalation of cyanides and causes

respi-ratory arrest Rarely, survivors of cyanide

intoxica-tion may develop parkinsonism or dystonia

When death is acute, the brain may be edematous

and in some cases focal subarachnoid hemorrhages

FIGURE 9.7 Coronal section showing bilateral

pallidal necrosis Th is can be seen following delayed

death from CO or other hypoxic conditions

FIGURE 9.8 CO poisoning Necrosis of the lidum and white matt er necrosis in a case of Grinker myelinopathy (Loyez stain)

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complication of the rapid rise in osmolality that accompanies excessively rapid correction or over-correction of chronic hyponatremia Th e clini-cal manifestations vary according to the size of the lesion—from asymptomatic to coma In life, the diagnosis can be made by MRI

At autopsy, the typical CPM lesion appears as a discolored, destructive area in the basis pontis that may be centrally cavitated ( Fig.  9 9 ) Th e lesions are oft en triangular, T-shaped, or diamond-shaped and vary from a few millimeters across ( Fig.  9 10 )

to lesions that involve nearly the entire basis pontis Even when the lesion is extensive, generally at least

a thin rim of intact tissue with myelin preservation

In long-term survivors of severe hypoglycemia

who then come to postmortem examination, the

cerebral cortex may appear thinned and the

hippo-campi shrunken and discolored Th e white matt er is

reduced in bulk and the ventricles are dilated Th ere

may be marked atrophy of the caudate nucleus and

putamen On microscopic study, the cerebral cortex

shows laminar neuronal loss and gliosis associated

with capillary proliferation Th ere is oft en dense

subpial gliosis Th e hippocampal pyramidal cell

layer and subiculum are replaced by a loose

mesh-work of glial tissue Th e white matt er is usually

rar-efi ed and gliotic Th e caudate nucleus and putamen

are diff usely gliotic Th e globus pallidus is relatively

spared Moderate neuronal loss and gliosis may be

evident in the thalamus As in acute hypoglycemia,

the cerebellar cortex, including the Purkinje cells, is

relatively spared

1 3 6 H Y P E R T H E R M I A

Acute hyperthermia or heat stroke is a thermal

insult to the cerebral thermoregulatory system

con-trolling heat production and heat dissipation Th e

thermal insult may be endogenous in “exertional

heat stroke” or environmental “classic heat stroke.”

It is also a feature of malignant hyperthermia, an

autosomal dominant disorder of the skeletal muscle

characterized by a hypermetabolic response to

com-monly used inhalation anesthetics and depolarizing

muscle relaxants Clinically heat stroke is defi ned as a

syndrome characterized by elevated core body

tem-perature over 40° Celsius and neurological

dysfunc-tion Neuropathological studies are relatively few

Abnormalities similar to those of hypoxic–ischemic

damage, probably resulting from a combination of

cardiovascular collapse and an increased metabolic

rate, have been described Severe diff use loss of

Purkinje cells with consequent degeneration of the

cerebellar eff erent pathways is known to occur, but

oft en in the absence of injury to Ammon’s horn and

other areas susceptible to hypoxia

2 ELECTROLYTIC

DISTURBANCES

2.1 Central Pontine Myelinolysis

Central pontine myelinolysis (CPM) is a

mono-phasic demyelinating disease that predominantly

involves the basis pontis It usually occurs as a

FIGURE 9.9 Cross-section of pons from patient with CPM Note the ill-defi ned brown discoloration

of the demyelinative lesion

FIGURE 9.10 Triangular lesion of limited CPM (Loyez stain)

Chapter 9 Acquired Metabolic Disorders • 211

anatomically by close apposition of gray and white matt er structures

2.2 Disorders of Iron Metabolism

In primary or secondary hemochromatosis , the

blood–brain barrier provides eff ective protection against the diff usion of protein-bound iron into the CNS Th erefore, hemosiderin iron deposits are limited to regions of the CNS devoid of the blood–brain barrier, including the choroid plexuses, the area postrema, the pineal gland, adenohypophy-sis, dorsal root ganglia, and a number of vestigial remnants such as the paraphysis and the subforni-cal organ Th ese regions have a gross rusty appear-ance and show marked Prussian blue reaction with ferrocyanide

2.3 Disorders of Calcium Metabolism

Massive perivascular deposits including calcium ( Fig.  9 13A ) but also iron ( Fig.  9 13B ) and other minerals may be observed in the basal ganglia and sometimes in the dentate nucleus, the white mat-ter, and Ammon’s horn (so-called Fahr syndrome)

in a variety of circumstances, including parathyroidism and conditions accompanied by hypercalcemia

3 VITAMIN DEFICIENCY DISORDERS

3.1 Thiamine Defi ciency

Th e Wernicke-Korsakoff syndrome is caused by thiamine (vitamin B1) defi ciency from inadequate intake (beriberi, prolonged intravenous therapy without vitamin supplementation), signifi cant nutritional defi cit as in fasting or famine, gastric

absorption defect such as in hyperemesis gravidarum ,

gastrointestinal neoplasms, and gastric plication for morbid obesity

Th e distribution of the lesions of Wernicke encephalopathy is characteristic ( Figs 9.14 and 9.15] and accounts for the symptoms, which include disturbances of wakefulness, hypertonia, and ocular palsies Th ey are found in the periventric-ular areas, including the medial aspect of the thala-mus, hypothalamus, and mammillary bodies, the

is present at the lateral and ventral margins of the

basis pontis ( Fig.  9 11 ) Demyelination is usually

maximal in the middle and rostral portions of the

pons Lesions may extend to the middle cerebellar

peduncles

Histologically, the CPM lesion is

character-ized by demyelination with relative preservation

of axons and neuronal perikarya ( Fig 9 12 ) Acute

lesions contain numerous lipid-laden

macro-phages but few or no infl ammatory cell infi ltrates

Occasionally foci of necrosis and cavitation are

present in the center of the more severe lesions

Sometimes, especially in more severe cases, CPM

is accompanied by extrapontine demyelinated

lesions Th ese may involve the subcortical white

matt er, striatum, anterior commissure, internal and

external capsules, lateral geniculate bodies, and

cerebellar folia As is the case in the pons, these

extrapontine sites of involvement are characterized

FIGURE 9.11 Large section of pons from a patient

with extensive CPM (Loyez stain for myelin)

FIGURE 9.12 Microscopic section of pons from a

patient with CPM Note the intact neuron in the midst

of an area of demyelination (Klüver-Barrera stain)

Th e perivascular spaces may contain lipid-laden macrophages Extravasated erythrocytes and hemosiderin-laden macrophages are seen in the cases with grossly discernible petechial hemor-rhages In the chronic stages of the disease and in treated patients the aff ected regions may show litt le more than mild loss of neurons and gliosis Central chromatolysis of neurons may result from associated niacin defi ciency (see below)

Korsakoff psychosis is defi ned clinically as rograde amnesia and an impaired ability to acquire new information and is usually encountered in alcoholic patients with chronic Wernicke encepha-lopathy Th e pathological basis of that syndrome is debated It does not seem to result from the lesions

ret-of the mammillary bodies only Involvement ret-of the medial dorsal nuclei ( Fig s 9 15A and 9 19 ) and/or midline region of the thalamus plays an important causative role, according to some authors

Th iamine defi ciency also produces peripheral ropathy, including beriberi neuropathy and at least some cases of so-called alcoholic polyneuropathy

3.2 Pellagra

Pellagra is clinically manifest typically by dermatitis, diarrhea, and dementia Th e disease has long been recognized among malnourished individuals who depended on corn as a major part of their diet It

periaqueductal region at the level of the third cranial

nerve, the reticular formations of the midbrain,

cau-dal portion of the corpora quadrigemina, and the

fl oor of the fourth ventricle Th e mammillary bodies

are the most frequently aff ected structures and are

involved in virtually all cases

Th e changes vary with the stage and severity of

the disease At gross examination, when patients

die during the acute stages of the disease, petechial

hemorrhages involve predominantly the

mammil-lary bodies ( Fig. 9 16 ) and sometimes may be more

extensive ( Fig.  9 15 ) In contrast, the lesions may

be inconspicuous grossly Patients with less severe,

chronic, or previously treated disease may have

mildly atrophic mammillary bodies that are gray to

brown in color as a result of hemosiderin deposition

( Fig.  9 17 ) A  narrow band of tissue immediately

FIGURE 9.13 (A) Massive perivascular mineral deposits in a case of Fahr disease (H&E) (B) Iron lar deposits in the same patient revealed by Perl’s method for iron

FIGURE 9.14 Topographical distribution of the

lesions in Wernicke encephalopathy

Chapter 9 Acquired Metabolic Disorders • 213

FIGURE 9.15 Wernicke encephalopathy: topographical distribution of the lesions (Loyez stain)

(A) Periventricular hemorrhagic thalamic lesions (B) Lesions in the tegmentum of the midbrain at the level of the third cranial nerve nuclei (C) Hemorrhages in the tegmentum of the upper pons (D) Hemorrhagic lesions

in the medullary fl oor of the fourth ventricle

FIGURE 9.16 Acute Wernicke encephalopathy

Note the petechial hemorrhages in the mammillary

bodies and, to a lesser extent, the walls of the third

ventricle

FIGURE 9.17 Shrunken, discolored mammillary bodies in a patient who had been treated for previous episodes of Wernicke encephalopathy

214 • E S C O U R O L L E & P O I R I E R ’ S M A N U A L O F B A S I C N E U R O P AT H O L O G Y

dorsal nucleus of the vagus, the gracile and cuneate nuclei, the nucleus ambiguus, the trigeminal nerve nuclei, the oculomotor nuclei, the reticular forma-tions, and the anterior horn motor neurons of the spinal cord In some cases of niacin defi ciency there may be degeneration of the posterior columns and corticospinal tracts

3.3 Vitamin B12 defi ciency

Vitamin B12 is obtained primarily from meat and dairy products Th e vitamin must be bound to

“intrinsic factor,” a glycoprotein produced by the gastric parietal cells, prior to being absorbed by the body through the ileum Most cases of vitamin B12 defi ciency actually result from inadequate produc-tion of intrinsic factor In pernicious anemia, this is due to autoimmune atrophic gastritis, more rarely to gastric neoplasms or gastrectomy Vitamin B12 defi -ciency also can result from impaired ileal absorp-tion, in individuals with malabsorption syndromes, intestinal tuberculosis, regional enteritis, or lympho-mas Rarely the cause of the defi ciency is the result

of competitive utilization of the vitamin within the

intestine by the fi sh tapeworm ( Diphyllobothrium latum ) or bacterial overgrowth in intestinal blind

loops or diverticula Very similar changes olar myelopathy”) have been observed in AIDS patients, resulting from abnormalities of vitamin B12 metabolism

Vitamin B12 defi ciency aff ects the etic (megaloblastic anemia), gastrointestinal (glossi-tis, anorexia, diarrhea, and weight loss), and nervous systems Neurological complications develop in 40%

hematopoi-of untreated cases and can occur in the absence hematopoi-of hematological abnormalities Th e neuroanatomical/clinical syndrome of nervous system involvement

has been termed subacute combined degeneration of the spinal cord

Th e spinal cord from patients with ing severe vitamin B12 defi ciency may be mildly shrunken, with discolored posterior and lateral col-umns Histologically, the earliest lesions consist of vacuolar distention of myelin sheaths, resulting in

longstand-a chlongstand-arlongstand-acteristic spongy longstand-appelongstand-arlongstand-ance of the longstand-aff ected white matt er With further demyelination, lipid-laden macrophages become scatt ered throughout the lesions Some of the axons traversing the lesions undergo Wallerian degeneration Initially astrocyto-sis is not marked, but dense gliosis may be seen in patients who have had the disease for a protracted

results from lack of P-P (pellagra preventive) factor

(nicotinic acid or niacin) It is now known that defi

-ciency of niacin itself, or of tryptophan, an amino

acid precursor of niacin that is defi cient in corn,

leads to pellagra Th e disease has become very rare

as the result of enriching common foods, such as

bread, with niacin Th is vitamin defi ciency is now

encountered most oft en in patients with chronic

alcoholism In these patients the disease may be

clin-ically atypical, lacking the characteristic skin lesions

Th e neuropathological changes resulting from

niacin defi ciency consist of isolated neuronal

changes of central chromatolysis type ( Fig.  9 20),

without associated glial or vascular alterations Th ey

aff ect, in decreasing order of frequency, the Betz cells

of the cerebral motor cortex, the pontine nuclei, the

FIGURE 9.18 Microscopic appearance of the

mammillary bodies from a patient with Wernicke

encephalopathy Note the petechial hemorrhages and

the swelling of the endothelial cells

FIGURE 9.19 Petechial hemorrhages and myelin

loss in the thalamus from a patient with Korsakoff

syndrome

Chapter 9 Acquired Metabolic Disorders • 215

also determine the extent and severity of the toxic insult Accordingly, the neuropathological picture is highly variable, refl ecting the selective vulnerability

of some of the neural structures and the diversity of the underlying mechanisms (e.g., energy defi ciency, excitotoxicity) Some lesions may also result from visceral disturbances caused by the intoxication In some toxic encephalopathies the peripheral nervous system may also be aff ected

Here we describe the most widely recognized toxic substances that are known to produce lesions

of the CNS

4.1 Ethanol

Ethanol has many eff ects upon the CNS It is well known that alcoholism potentiates infections, con-tributes to traumatic injuries, and may increase the risk of stroke, especially hemorrhagic stroke

4 1 1 A C U T E A L C O H O L I N T O X I C AT I O N

Ingestion of large quantities of alcohol can lead directly to death from cardiorespiratory paralysis Blood alcohol levels over 450 to 500 mg/dL are generally considered as potentially lethal, although there is considerable individual variation Autopsy examination of the brain in fatal cases of acute alco-hol intoxication usually shows only cerebral edema

4 1 2 C E R E B R A L L E S I O N S I N C H R O N I C

A L C O H O L I S M

Whereas a direct neurotoxic eff ect of excessive hol consumption on the nervous system remains

alco-period Th e distribution of the lesions is

remark-ably constant Th ey are bilateral and symmetrical

and involve chiefl y the long tracts of the spinal cord

Initial lesions are found in the central part of the

pos-terior column of the thoracic cord, from where they

extend peripherally and aff ect the corticospinal and

spinocerebellar tracts in the lateral columns In severe

cases, the lesions may involve virtually all the white

matt er, including the anterior columns, only sparing

the fi bers adjacent to the gray matt er Th e severity

of the lesions usually decreases toward the cervical

and lumbar levels, in which they are restricted to

the dorsal and lateral columns, oft en sparing a small

peripheral zone ( Fig. 9 21] However, changes of

sec-ondary ascending and descending tract degeneration

may be associated at those levels Rarely, the lesions

extend rostrally into the medulla Occasionally,

simi-lar mixed demyelinative and destructive lesions may

be seen in the optic nerve and cerebral white matt er

4 TOXIC

ENCEPHALOPATHIES

Th e nervous system is particularly susceptible to

noxious agents Th ere are several reasons for this

Neurons are continually active and are highly

suscep-tible to energy deprivation; also, they are post-mitotic

cells and cannot divide as a response to toxic insults

It is also important to recognize that the

suscepti-bility of cells of the CNS to toxic substances in

dif-ferent anatomical regions is quite variable Th ese

diff erences are att ributable in part to the anatomical

blood–brain barrier’s diff erential susceptibility to

some toxic substances Th e type of exposure, dose,

age, gender and inherent, probably genetic factors

FIGURE 9.20 Pellagra encephalopathy Microscopic picture of cell chromatolysis (H&E) (A) In nuclei tis (B) In the gracile nucleus

pon-216 • E S C O U R O L L E & P O I R I E R ’ S M A N U A L O F B A S I C N E U R O P AT H O L O G Y

Th e clinical manifestations evolve slowly over months to years and include truncal instability, a wide-based stance, and an ataxic gait Th e vermal atrophy can be demonstrated by CT and MRI, but the degree of atrophy does not correlate well with the severity of the clinical manifestations Th e lesions involve the rostral vermis ( Fig. 9 2 2 ) and

to a lesser extent the superior surface of the ebellar hemispheres ( Fig. 9 2 3 ) Th e folia are pale, sclerotic, and separated by widened inter-folial sulci Th e atrophy aff ects the crests of the folia more severely than the depths of the inter-folial sulci Microscopically, the lesions consist of loss of Purkinje cells with proliferation of Bergmann glia and variable depopulation of the internal granular cells Th ey are associated with lesions of the dorsal laminae of the inferior olives Th e cerebellar white matt er remains relatively unaff ected

• Central pontine myelinolysis was fi rst described

in individuals with chronic alcoholism but may also be seen in other conditions in which severe

controversial, patients suff ering from chronic

alco-holism develop a wide range of visceral lesions that

have a serious impact on the nervous system:

• Hepatic encephalopathy may result from

decom-pensated cirrhosis leading to hepatic coma and/or

occurring in the sett ing of a portocaval shunt (see

below)

• Cerebral lesions due to vitamin defi ciency include

Wernicke-Korsakoff encephalopathy secondary to

defi ciency of vitamin B1 absorption due to

alco-holic gastritis and pseudopellagra encephalopathy,

with which it is frequently associated (see above)

• Alcoholic cerebellar degeneration may occur as

an isolated lesion or in association with other

alcohol-related lesions, such as Wernicke

encephalopathy Its pathogenesis is unclear

Morphologically similar but generally milder

cerebellar vermal atrophy can also occur as

an age-related phenomenon independent of

Chapter 9 Acquired Metabolic Disorders • 217

commissure ( Fig   9 24B ), centrum semiovale ( Fig 9 24A ), and middle cerebellar peduncles Histologically, the lesions show loss of myelin with abundant lipid-laden macrophages and relative spar-ing of axons

• Morel’s laminar sclerosis is known to occur in

chronic alcoholism It is characterized by a glial astrocytic band-like proliferation localized to the third cortical layer, especially in the lateral frontal cortex Th is disease is usually associated with, and probably secondary to, the callosal lesions of Marchiafava-Bignami disease

4.2 Methanol

Methanol poisoning resulting from oral intake, most oft en as a substitute for ethanol, may cause acute cere-bral and ocular lesions Methanol itself is neurotoxic; its catabolites, including formaldehyde and formic acid, are even more toxic Formic acid and formates block cellular respiration and contribute to the meta-bolic acidosis that is characteristic of this intoxication

Th e ocular pathology of the blindness has been investigated extensively Th e lesions include princi-pally optic disc edema and retrolaminar and optic nerve necrosis

Pathological changes in the brain include cerebral edema, demyelination, and necrosis of the subcorti-cal white matt er, the lateral aspect of the putamen, and the claustrum ( Fig 9 25 ) Th e putaminal necro-sis is oft en hemorrhagic and may evolve into a mas-sive hematoma Th e necrosis of the claustrum is generally non-hemorrhagic Th e white matt er lesions and the retrolaminar demyelination of the optic nerves are believed to be due to histotoxic myelinoc-lastic damage caused by formates Th e pathogenesis

of the putaminal lesions remains unclear

4.3 Ethylene glycol

Ethylene glycol is a dihydroxy alcohol that is widely used as a solvent and a component of certain anti-freezes and coolants Intoxication with this compound

is encountered most oft en when it is consumed as a substitute for ethanol or with suicidal intent Ethylene glycol is progressively oxidized to more toxic com-pounds, including glycoaldehyde, glycolic acid, and glyoxylic acid A  small proportion is also oxidized

to oxalic acid Th e clinical manifestations include encephalopathy, severe metabolic acidosis, cardiopul-monary failure, and acute renal failure

metabolic or electrolytic disturbances are present

(see Section 2.1)

• Marchiafava-Bignami disease is a rare disorder,

the pathophysiology of which is unknown It

is observed in the sett ing of chronic

alcohol-ism of long duration and great severity Rarely,

Marchiafava-Bignami disease has been described

in association with Wernicke encephalopathy or

CPM Th e disease is usually diagnosed at autopsy,

but the lesions may be seen by CT and MRI

Grossly and macroscopically the lesions are

demyelinated or partially necrotic regions in the

interior of the corpus callosum, with relative

pres-ervation of a thin strip of myelinated fi bers on its

dorsal and ventral surfaces Th e involvement is

maximal in the genu and body of the corpus

cal-losum ( Fig 9 24 ) and may be accompanied by

similar involvement of the optic chiasm, anterior

FIGURE 9.22 Superior vermal atrophy from a

patient with chronic alcoholism

FIGURE 9.23 Atrophy of the rostral vermis and

superior surface of the cerebellar hemispheres in a

patient with chronic alcoholism

218 • E S C O U R O L L E & P O I R I E R ’ S M A N U A L O F B A S I C N E U R O P AT H O L O G Y

around intraparenchymal blood vessels Deposits of calcium oxalate may be seen in and around blood vessels in the meninges, neural parenchyma, and choroid plexus Th ese crystals are birefringent under polarized light ( Fig. 9 26 A, B )

4.4 Phenytoin

Patients with seizure disorders who have been treated with phenytoin for prolonged periods may develop cerebellar cortical atrophy, which can

be documented by CT and MRI during life or at autopsy Histopathological studies have shown folial atrophy, loss of Purkinje cells throughout the cerebellum, and mild loss of internal granular layer cells ( Fig. 9 2 7 ) Whether the drug itself is the sole factor that causes toxic damage to Purkinje cells has been diffi cult to establish since loss of Purkinje cells may also be the result of hypoxia during sei-zures or from preexisting brain damage Reports

of patients with seizure control under long-term

Macroscopic examination of the brain in fatal cases

shows edema, meningeal congestion, and,

occasion-ally, petechial hemorrhages Microscopicoccasion-ally, acute

infl ammatory cells may be seen in the meninges and

C

FIGURE 9.24 Marchiafava-Bignami disease (A) Gross appearance showing necrosis of the interior of the corpus callosum Note involvement of the adjacent white matt er Whole-brain sections showing necrosis and demyelination

of the corpus callosum and anterior commissure (B) and splenium of corpus callosum (C) (Loyez myelin stain)

FIGURE 9.25 Methanol intoxication Note the

bilateral necrosis of the putamen and claustrum

Chapter 9 Acquired Metabolic Disorders • 219

the morphologic changes that may be seen include edematous or hemorrhagic lesions In the majority

of cases, the brain lesions are secondary to the ple visceral disturbances caused by the intoxication

4 5 1 A L U M I N U M

Th e neurotoxicity of this element is controversial Various aluminum compounds, applied directly onto or injected into the cerebral cortex of certain laboratory animals, produce seizures and neurofi bril-lary tangles, but these lesions are diff erent from the Alzheimer neurofi brillary tangles seen in humans Aluminum toxicity was described most com-monly in patients undergoing chronic hemodialysis and is due to exposure to aluminum in the dialysate and the use of oral phosphate binding compounds that contain aluminum

Dialysis dementia is a syndrome now largely appeared through the purifi cation, of the water used

dis-in dialysis, characterized cldis-inically by dyspraxia, asterixis, myoclonus, and dementia In fatal cases the brain aluminum content may become elevated

to levels even greater than reported in Alzheimer disease but neurofi brillary tangles are not present

4 5 2 A R S E N I C

Arsenic intoxication is encountered most oft en as the result of occupational exposure or aft er inges-tion with homicidal or suicidal intent Acute triva-lent arsenic poisoning is characterized by abdominal pain, nausea, vomiting, and diarrhea followed by renal failure Death may occur in severe cases

phenytoin treatment, and who develop cerebellar

atrophy, support the view that phenytoin itself may

be neurotoxic

4.5 Intoxication by Heavy

Metals and Certain Metalloids

Many diff erent metals and certain metalloids, in

suffi cient concentration and determined

chemi-cal form, are toxic to humans It is usually diffi cult

to correlate a particular type of lesions with a

spe-cifi c etiology In some hyperacute fatal forms of

intoxication, the clinical course may be so rapid

that, at the time of autopsy examination,

histologi-cal changes have not yet become evident Some of

FIGURE 9.26 Microscopic sections showing cerebellar cortex and leptomeninges from a patient with ene glycol intoxication (A) Note the refractile calcium oxalate crystals in the vessel walls (H&E) (B) Note the birefringence of the same crystals when viewed with polarized light

FIGURE 9.27 Microscopic section of cerebellar

folium from a patient who had been on long-term

treatment with high-dose phenytoin Note the loss of

Purkinje cells and the mild loss of internal granular

cell layer neurons

220 • E S C O U R O L L E & P O I R I E R ’ S M A N U A L O F B A S I C N E U R O P AT H O L O G Y

4 5 5 M E R C U RY

Acute poisoning from inorganic mercury pounds is manifest clinically predominantly by gastrointestinal tract and renal tubular injury Pulmonary injury is caused by inhalation of metallic mercury vapors Neurotoxicity is also a prominent manifestation of chronic inorganic mercury poison-ing, and patients present with behavioral changes, intention tremor, and movement disorders; periph-eral neuropathy may also develop

Organic mercury intoxication is usually caused

by ingestion of contaminated food Some years ago, reports from Japan described a large number

of patients who developed chronic organic cury intoxication by eating fi sh contaminated by methyl mercury (Minamata disease) Other large outbreaks have resulted from the consumption of grain treated with an organic mercury fungicide Th e clinical manifestations in these cases included corti-cal blindness, impaired proprioception, movement disorders, mental retardation, and quadriparesis

Th e neuropathology of organic and inorganic mercury poisoning is essentially indistinguishable

Th e slight diff erences that may exist possibly refl ect variations in the rate of entry of mercury into the nervous system Th e lesions observed involve the neurons predominantly Th ere is cerebral atrophy involving mainly the anterior portions of the cal-carine fi ssures with loss of neurons, especially the outer cortical layers, and gliosis Cerebellar atrophy

is also frequent, notably with loss of granule cell neurons, mild loss of Purkinje cells, and prolifera-tion of Bergmann glia

4 5 6 T H A L L I U M

Most cases of thallium intoxication result from dental or deliberate ingestion of thallium pesticides used for insect and rodent control Th e clinical pic-ture resembles that of trivalent arsenical poisoning

acci-Th e only consistent abnormalities in the CNS are chromatolysis of spinal motor neurons and degen-eration of the posterior columns, related to the sen-sorimotor distal axonopathy

4 5 7   T I N

Inorganic tin is not neurotoxic, but two organic tin compounds, triethyl-tin and trimethyl-tin, are Triethyl-tin causes striking white matt er edema due to accumulation of fl uid in vacuoles within

Chronic arsenic intoxication is manifest by

gastro-intestinal and dermatological symptoms A  mixed

sensory and motor neuropathy is a well-known and

oft en disabling sequela of both acute and chronic

arsenical intoxication Encephalopathy also has been

reported with acute and chronic arsenic

intoxica-tion Acute hemorrhagic leukoencephalopathy has

been reported in patients treated with organic

pen-tavalent arsenicals Th is may have been the result of

a hypersensitivity reaction to the drug, rather than

arsenic intoxication

4 5 3 L E A D

Lead can enter the body through the

gastrointes-tinal and respiratory tracts and, when in organic

compounds, through the skin Lead

encephalopa-thy is now encountered predominantly in young

children who chew on items coated with lead paint

Acute encephalopathy produces irritability, seizures,

altered consciousness, and evidence of increased

intracranial pressure Th e intoxication usually

responds to sedation and chelation therapy but can

lead to permanent damage Many authors att ribute

the encephalopathy to vascular injury, which seems

to be more severe in the immature nervous system

At gross examination, the brains are diff usely

swollen Th e histological changes include

conges-tion, petechial hemorrhages, and foci of necrosis

Intraparenchymal capillaries may show necrosis,

thrombosis, and swelling of endothelial cells Th ere

is a proteinaceous exudate in the perivascular space

extending into the adjacent brain tissue Periodic

acid-Schiff –positive globules may be seen within

the exudates and in astrocytes Diff use astrocytosis

has been reported even in the absence of capillary

changes

4 5 4 M A N G A N E S E

Manganese exposure may result from inhaling dust

in manganese mines or vapor released during

fer-romanganese smelting Th e clinical manifestations

include headaches, transient psychiatric

distur-bances, and a hypokinetic extrapyramidal

dysfunc-tion that resembles Parkinson disease but is not

responsive to L-dopa

Pathological studies in humans are limited but

document degenerative lesions in the pallidum and

subthalamic nucleus and, to a lesser extent, the

stria-tum Th e substantia nigra is involved in some cases

Chapter 9 Acquired Metabolic Disorders • 221

Wilson hepatolenticular degeneration It is terized by the presence of Alzheimer type II glia (see Chapter 1 and Fig. 1 20 ) Th e lesions predominate

charac-in the pallidum but may also charac-involve the cerebral cortex and the dentate nuclei

5.3 Multifocal Necrotizing Leukoencephalopathy

Th is condition is characterized by the ment of multiple, usually microscopic foci of necro-sis in the white matt er It oft en aff ects the basis pontis (focal pontine leukoencephalopathy) Th e pathogenesis of the lesions observed is unclear Aff ected individuals are predominantly those who are found to have increased levels of circulating pro-infl ammatory cytokines (e.g., patients with AIDS, neoplasms treated with radiotherapy and oft en intrathecal chemotherapy, sepsis) In most cases it is discovered at autopsy

By and large, the lesions are only visible on scopic examination and consist of well-demarcated areas of necrosis disseminated in the white matt er, but particularly involving the transverse pontine

micro-fi bers ( Fig. 9 29 A ) Th ere is loss of myelin staining, proliferation of macrophages, and lesions of axons, which appear swollen and fragmented and tend to calcify ( Fig. 9 29 B )

5.4 Paraneoplastic Encephalomyelopathies

Paraneoplastic CNS syndromes are neurological disorders that are associated with systemic malig-nancies and that are unlikely to be the direct result

of involvement by the neoplasm, say by sion, invasion, or metastasis Excluded, by defi ni-tion, are iatrogenic complications of radiotherapy or chemotherapy and opportunistic infections related

compres-to immunodepression secondary compres-to the neoplastic process itself, to treatment, or to both Also set apart are the metabolic or defi ciency disorders and vas-cular disorders associated with the development of malignant disease

Paraneoplastic syndromes can aff ect the tral, peripheral, or autonomic systems Th e neuro-logical symptoms may be the initial manifestation

cen-of the neoplastic process and can be multifocal Comparable idiopathic autoimmune disorders of the CNS in which no systemic cancer is found have also been described

the myelin sheaths, which are separated along the

intra-periodic lines (see Chapter 1 and Fig. 1 24C )

Trimethyl-tin does not cause intra-myelinic edema

but is toxic to neurons in the hippocampus, the

entorhinal cortex, and the amygdala

Th e neuropathology of respiratory encephalopathy,

secondary to chronic bronchopulmonary disease

and essentially due to hypoxia and hypercapnia, is

characterized by diff use vasodilatation, microscopic

perivascular hemorrhages, and anoxic neuronal

changes of variable intensity

At postmortem examination, the brain of patients

with who die soon aft er acute asphyxia shows

con-gestion of the meninges and cortex due to venous

and capillary dilatation (“lilac brain”) ( Fig.  9-2 8 )

Perivascular hemorrhages predominating in the

white matt er may be seen

5.2 Hepatic Encephalopathy

Hepatic encephalopathy occurs in the course

of severe hepatic insuffi ciency in cases of severe

hepatic cirrhosis or hepatitis, in association with

portocaval anastomosis and in individuals with

FIGURE 9.28 “Lilac brain” in a patient who died

from acute asphyxia Note petechial hemorrhages and

laminar necrosis

222 • E S C O U R O L L E & P O I R I E R ’ S M A N U A L O F B A S I C N E U R O P AT H O L O G Y

In recent decades, specifi c autoantibodies (IgGs) and their target antigens have been identifi ed that are oft en but not exclusively associated with specifi c neoplasms and neurological syndromes ( Tables 9.1 and 9.2 )

By and large, many paraneoplastic syndromes have

been shown to develop in the sett ing of autoimmune

mechanisms directed against an oncoantigen aberrantly

expressed by the systemic tumor, which cross-react with

antigens normally present in the nervous system

FIGURE 9.29 Multifocal necrotizing leukoencephalopathy (A) Whole-brain section of the pons showing disseminated necrotic foci in the transverse pontine fi bers (Klüver-Barrera) (B) Microscopic section showing a necrotic lesion with vacuolation and central calcifi cation (H&E)

Table 9.1 Paraneoplastic Antibodies, Antigens, Associated Neoplasm and

VGK-complex Ab LGI1, CASPR2 Small cell lung carcinoma Limbic encephalitis

neuropathy   Carcinoma of breast, prostate Myoclonus NMDA receptor Ab NR1 Ovarian teratoma Limbic encephalitis AMPA receptor Ab GluR1,2 Th ymic tumors Limbic encephalitis

Carcinoma of breast, lung GABA-B receptor Ab GABA-B Small cell lung carcinoma Limbic encephalitis

Other neuroendocrine tumor P/Q and N-type P/Q and N-type Small cell lung carcinoma Paraneoplastic

encephalomyelopathy Calcium channel Ab Calcium channel Gynecological or breast carcinoma Neuropathies,

Lambert-Eaton syndrome Muscle AChR Ab Muscle AChR Th ymoma, thymic or Myasthenia gravis

lung carcinoma Neuronal ganglionic Neuronal Adenocarcinoma, thymoma Peripheral and autonomic

neuropathy AChR Ab Ganglionic AChR Small cell lung carcinoma Paraneoplastic

encephalomyelopathy

Chapter 9 Acquired Metabolic Disorders • 223

degeneration is then mediated by cytotoxic T cells

Th ese disorders, accompanied by autoantibody markers of neural peptide-specifi c cytotoxic eff ec-tor T cells, are generally poorly responsive to immunotherapy

Th e main neuropathological entities tered in CNS paraneoplastic syndromes are para-neoplastic cerebellar degeneration, paraneoplastic

In some of these syndromes, the patient

devel-ops antibodies against neural cell surface receptors

or channels, the antibodies have a pathogenic role,

and there can be a clinical improvement aft er early

immunotherapy In other conditions, the antigens

are not superfi cial but intracellular, and the immune

reaction is cellular, through MHC class 1

mol-ecules and cytotoxic T-cell mechanisms Neuronal

Table 9.2 Paraneoplastic Antibodies, Antigens, Associated Neoplasm and Clinical/

(Ri)

Small cell lung carcinoma, breast carcinoma

Cerebellar degenerationParaneoplastic encephalomyelopathy ANNA-3 Unknown Lung or esophageal

carcinomas Small cell lung carcinoma

Paraneoplastic encephalomyelopathy Cerebellar degeneration

Peripheral neuropathy AGNA SOX-1 Small cell carcinoma Lambert-Eaton syndrome

Mal, Ma2 PNMA1,

PNMA2

Testicular (Ma2) Cerebellar degeneration

Breast, colon, testicular (Ma1)

Brainstem encephalitis PCA-1 CDR2 (Yo) Müllerian adenocarcinoma Cerebellar degeneration

Breast carcinoma Paraneoplastic encephalomyelopathy

Peripheral neuropathy PCA-2 Unknown Small cell carcinoma Paraneoplastic encephalomyelopathy

Peripheral and autonomic neuropathy Lambert-Eaton syndrome

PCA-Tr Unknown Hodgkin lymphoma Cerebellar degeneration

CRMP-5 IgG CRMP-5 Small cell carcinoma Cerebellar degeneration

Th ymoma Paraneoplastic encephalomyelopathy

Peripheral and autonomic neuropathy Amphiphysin

IgG

Amphiphysin Small cell carcinoma Stiff ness

Breast adenocarcinoma Paraneoplastic encephalomyelopathy

Peripheral neuropathy GAD65 Ab GAD65 Th ymoma, renal, breast, Stiff ness

or colon adenocarcinoma Paraneoplastic myelopathy

B cells may predominate in disorders accompanied

by neural plasma membrane-reactive ies Th e lesions have a characteristic distribution and show a predilection for the medial temporal cortex (limbic encephalitis), the rhombencephalon (medullary pontine encephalitis), the cerebellum, the gray matt er of the spinal cord (poliomyelitis), and the spinal root ganglia In some patients, lesions

autoantibod-in these diff erent anatomical locations may ist; they may also be associated with infl ammatory

coex-encephalomyelitis, and the opsoclonus-myoclonus

syndrome

5 4 1 PA R A N E O P L A S T I C C E R E B E L L A R

D E G E N E R AT I O N

Th e clinical course of the disease is generally

sub-acute and manifests as gait ataxia, incoordination,

dysarthria, and oft en nystagmus Th e cerebellum may

be atrophic but is usually macroscopically normal

Histologically, there is massive, diff use loss of the

Purkinje cells with proliferation of the Bergmann glia

( Fig. 9 30A ) and sparing of the basket fi bers and to

a lesser extent of the granular neurons ( Fig. 9 30B )

Th e degeneration of Purkinje cells axons oft en

pro-duces myelin pallor of the amiculum of the dentate

nucleus ( Fig. 9 3 1 ) Microglial nodules and

perivas-cular mononuclear cuff s in the leptomeninges and

parenchyma are frequent, but infl ammation may be

prolifera-Chapter 9 Acquired Metabolic Disorders • 225

cere-226 • E S C O U R O L L E & P O I R I E R ’ S M A N U A L O F B A S I C N E U R O P AT H O L O G Y

manifest by numbness, paresthesias, dysesthesias, and reduced or absent refl exes Th e peripheral nerves show axonal degeneration with varying degrees of secondary segmental demyelination Additional pathological changes include degenera-tion of posterior roots, degeneration and demyelin-ation of the posterior columns of the spinal cord, and degeneration of dorsal root ganglia ( Fig. 9 34 A ) Mild perivascular and intraparenchymal infi ltrates

of mononuclear infl ammatory cells are oft en ent In the sensory ganglia, infl ammatory cell infi l-trates may be especially prominent Th e number of ganglion cells is reduced and nodules of Nageott e are found where the ganglion cells have been lost ( Fig.  9 34 B ) Autonomic ganglia may be involved

pres-as well pres-as dorsal root ganglia but show less severe changes

5 4 3 PA R A N E O P L A S T I C

O P S O C L O N U S - M Y O C L O N U S S Y N D R O M E

Th e opsoclonus-myoclonus syndrome is rare but

is best known in association with neuroblastomas

in children Even more rarely, the syndrome also occurs in adults, in association with small cell car-cinoma of the lung or breast carcinoma Autopsy examination of the brain of aff ected individuals may show no histopathological abnormalities or may show Purkinje cell loss and/or mild periaqueductal infi ltrates of infl ammatory cells

lesions in the myenteric plexuses, the peripheral

nerves, and/or the skeletal musculature

Patients with paraneoplastic limbic encephalitis

display behavioral changes, memory loss, and

hal-lucinations Limbic structures including the

hip-pocampi, cingulate gyri, insular cortex, amygdala,

and parts of the temporal lobe may be aff ected

( Fig.  9 32A , B, C ) Th e midbrain ( Fig.  9 3 3 ) and

thalamus may also show similar changes

Sensory neuropathy is a frequent component

of an encephalomyeloneuropathy Clinically it is

FIGURE 9.33 Medullary pontine paraneoplastic

encephalitis Microscopic section showing nodules of

neuronophagia, proliferation of rod-shaped microglia,

astrocytic gliosis, and mononuclear infi ltration in the

medullary olive

FIGURE 9.34 Paraneoplastic sensory neuropathy (A) Note demyelination of the posterior columns (Loyez myelin stain) (B) Spinal ganglion: note loss of ganglion cells, proliferation of satellite cells, and interstitial lym-phocytic infi ltration

Hereditary metabolic diseases were originally

identi-fi ed based on the absence of speciidenti-fi c enzyme activities

within distinct metabolic pathways Identifi cation of

defi ciency of enzymatic activity, oft en with

accumu-lation of an intermediate metabolite within the

path-way, eventually led to identifi cation of the involved

gene Th erefore, the original classifi cation of

heredi-tary metabolic disease was based on enzyme defi

cien-cies More recently, pedigrees with inherited diseases

have been linked to specifi c genetic loci and, by

iden-tifying the involved gene, the protein sequences and

putative protein functions have been established,

without understanding the metabolic pathways that

may be involved Th is “reverse” genetics,

includ-ing fi ndinclud-ings from more recent methods such as full

exome or whole genome sequencing, has

consider-ably increased the speed of discovery of inherited

metabolic diseases and expanded the categories of

disease that are recognized As a result, the classifi

ca-tion of inherited metabolic diseases is in fl ux

One approach is the identifi cation of two major categories of disorders based on intracellular or extracellular abnormalities in metabolites Th e

fi rst is a group of disorders in which the bolic derangements are most prominent inside the cell and oft en are linked to the dysfunction

meta-of a single cellular organelle Th ese disorders may have increased intracellular levels of an interme-diate metabolite and may have intracellular accu-mulation of the metabolite, resulting in a so-called

“storage” disease Th e organelles most commonly involved in these disorders are lysosomes, per-oxisomes, mitochondria, and the cytoplasmic compartment In the second group of hereditary metabolic disorders, no intracellular accumulation

is identifi ed Instead, these disorders are viewed

as systemic biochemical disorders in which chemical abnormalities are most prominent in the circulation or in the urine Th ese are classifi ed by the biochemical pathways involved and are oft en identifi ed by the presence of circulating small mol-ecules or by genetic testing

bio-228 • E S C O U R O L L E & P O I R I E R ’ S M A N U A L O F B A S I C N E U R O P AT H O L O G Y

A  past history of prolonged neonatal jaundice is suggestive of disorders of cholesterol and bile acid metabolism Splenomegaly is highly suggestive of some lipid storage diseases, such as Gaucher disease, Tangier disease, and Niemann-Pick disease (either type A, B or C) Other presentations are less specifi c for lipid metabolism disorders:  cerebellar ataxias, dementia, psychiatric disorders, epilepsy, and spas-tic paraparesis A  slow progression of symptoms, which corresponds to progressive lipid storage, is highly suggestive of these disorders

1 1 3 I N T O X I C AT I O N S Y N D R O M E S

Some metabolic disorders are associated with able clinical symptoms that correlate with the serum levels of a small molecule or metabolite Th ese include porphyrias, urea cycle defects, organic acid-urias, and amino acidopathies Th e onset of acute symptoms that accompany the metabolic crisis is characteristic of these disorders and has led to their designation as “intoxication” syndromes However,

vari-in mild adult forms, symptoms can be progressive, giving rise to leukoencephalopathies, epilepsy, psy-chiatric disorders, or spastic paraparesis

1 1 4 D I S O R D E R S O F

N E U R O T R A N S M I T T E R M E TA B O L I S M

Disorders of neurotransmitt er metabolism are mostly represented by defects in the synthesis of serotonin and dopamine Clinical signs are related

to dopamine defi ciency (dystonia, parkinsonism, oculogyric crisis), noradrenergic defi ciency (ptosis, myosis, hypotension), or serotonin defi ciency (sleep disturbance, dysthermia, behavioral disturbance) Dopa-responsive dystonia or parkinsonism is highly suggestive Diurnal fl uctuations of symptoms are also characteristic, with improvement in the morning and worsening during the day Diagnosis of these disor-ders relies on analysis of neurotransmitt er metabolism

in the cerebrospinal fl uid Cerebral folate defi ciency can be added to this group because it shares several clinical features and diagnostic methods, although this syndrome is still highly heterogeneous

1 1 5 D I S O R D E R S O F M E TA L

M E TA B O L I S M

Metal storage disorders include Wilson disease, ferritinopathy, aceruloplasminemia, PANK2-associated neurodegeneration, PLA2G6 mutations, and a recently

1.1 Biochemical abnormalities

According to the metabolic pathway involved,

inher-ited metabolic diseases involving the nervous system

can be divided into several categories of biochemical

abnormality, many of which display some

similari-ties in clinical presentation, diagnostic methods, and

treatment strategies

1 1 1 A B N O R M A L I T I E S I N E N E R G Y

M E TA B O L I S M

Energy metabolism disorders include some that

directly aff ect the respiratory chain and others that

involve metabolic pathways required for energy

production Th ese defects include respiratory chain

disorders (that can be primary or secondary, as can

occur in organic acidurias), pyruvate dehydrogenase

defi ciency, Krebs cycle defi ciencies, glucose

trans-port (GLUT1) defi ciency, and β-oxidation defects, as

well as disorders involving co-factors such as electron

transfer fl avoprotein defi ciency, vitamin E defi ciency,

biotinidase defi ciency, biotin-responsive thiamine

metabolism dysfunction, creatine defi ciency

syn-dromes, and coenzyme Q synthesis defects Th is

group includes the disorders of mitochondrial

func-tion (mitochondriopathies) Acute manifestafunc-tions

are oft en triggered by infections and include Leigh

syndrome, acute optic neuropathy, acute

cerebel-lar ataxia, or pseudo-strokes Chronic presentations

oft en involve muscles, cerebellum, basal ganglia

(parkinsonism), cortex (epilepsy, myoclonus), or the

peripheral nervous system (axonal polyneuropathy)

In adults, these diseases rarely involve the brain white

matt er, and spastic paraparesis is very uncommon

1 1 2 D I S O R D E R S O F L I P I D

M E TA B O L I S M

Lipid metabolism disorders include some lysosomal

diseases, mainly sphingolipidoses (Krabbe disease,

metachromatic leukodystrophies, Niemann-Pick A,

B, and C, Fabry disease, Gaucher disease),

peroxi-somal disorders (adrenomyeloneuropathy, Refsum

disease, disorders of pristanic acid metabolism,

per-oxisome biogenesis disorders), Tangier disease, and

cerebrotendinous xanthomatosis

Given the high content of lipids in the nervous

system, these diseases can produce severe

neuro-logical symptoms Leukodystrophies and

demyelin-ating polyneuropathies are hallmarks of disorders

interfering with myelin formation or maintenance

Chapter 10 Hereditary Metabolic Diseases • 229

“leukodystrophies.” Th e latt er disorders are terized by loss of myelin (demyelination) or abnor-mal myelin formation (hypomyelination), which is oft en evident on MRI of the brain Hereditary leu-kodystrophies, in which the production of myelin may be impaired due to abnormalities in the struc-ture of myelin or in myelin metabolism, are oft en considered “dysmyelinating” disorders rather than

charac-“demyelinating” diseases Pathologically, however, the process is characterized by the absence of myelin with a relative preservation of axons

As a consequence of the many metabolic ways involved and the diff erent structures and regions aff ected, the clinical presentation of heredi-tary metabolic disease is highly variable However, starting from the regions of the brain involved cer-tain types of metabolic disease are more likely and specifi c metabolic testing can be performed

1 Involvement of white matt er is particularly mon in leukodystrophies, and diff erential diag-nostic considerations include Krabbe disease, metachromatic leukodystrophy, cerebrotendi-nous xanthomatosis, Zellweger disease, adre-noleukodystrophy, polyglucosan body disease, Canavan disease, and phenylketonuria

2 Progressive involvement of the basal glia, especially when mineral deposits are detected by MRI, is common in disorders of metal metabolism, and diff erential diagnos-tic considerations include Wilson disease, Hallervorden-Spatz disease, aceruloplasmin-emia, phospholipase A2 group VI (PLA2G6) mutation, neuroferritinopathy, and also disor-ders of dopamine synthesis

3 Degeneration of the cerebellar or hemispheric cortex implies a neuronal storage disease or neuronal metabolic disorder; diff erential diag-nostic considerations include gangliosidoses, neuronopathic Gaucher disease, Niemann-Pick disease, neuronal ceroid lipofuscinoses, or mucopolysaccharidoses

4 Predominant involvement of the peripheral nervous system is common in a subset of dis-orders: Tangier disease, Refsum disease, or the porphyrias

5 Predominant involvement of the vascular system may be seen in Fabry disease and homocystinuria

6 Weakness and muscle atrophy are common in metabolic myopathies and may be seen in glyco-genoses or mitochondrial myopathies

identifi ed disorder of manganese metabolism Th e

hallmark of these diseases is an abnormality in metal

metabolism that may result in metal deposits, oft en

in the basal ganglia, sometimes visible on brain MRI

Th e main presentations are movement disorders

because of the primary involvement of the basal

gan-glia Treatments, when they exist, are mainly based on

metal chelators

1.2 Morphological classifi cation

Many of the biochemical pathways involved in

inherited metabolic diseases are associated with a

specifi c cellular organelle Th ere are three

organ-elles commonly associated with the metabolic

disorders:  lysosomes, peroxisomes, and

mitochon-dria As a general rule, disorders involving lysosomal

proteins tend to involve catabolic pathways, and

the lack of a lysosomal enzymatic function is oft en

associated with the accumulation of a metabolite

for which the catabolic pathway is defective Th e

accumulation of the nondegraded metabolite in

lysosomes is oft en referred to as a “storage” disease

and may lead to distention of nerve cell bodies and

their processes, glia, blood vessel walls, or cells

out-side the nervous system In particular, the liver and

spleen are involved in some storage diseases, with

the presence of hepatosplenomegaly

Other disorders involve a separate cellular

organ-elle, the peroxisome Like the lysosome, the

peroxi-some is involved in specifi c catabolic pathways, and

serum levels of metabolites from these pathways are

oft en increased in peroxisomal disorders However,

in contrast to lysosomal disorders, intracellular

stor-age of the metabolite is not usually present

Mitochondria are the third major organelle

asso-ciated with specifi c metabolic disorders Serum

lev-els of intermediary metabolites are oft en normal,

although impairment of oxidative phosphorylation

may lead to elevations of lactic acid In addition, the

inheritance has a Mendelian patt ern for the

mito-chondrial proteins encoded in nuclear DNA but a

maternal patt ern of inheritance for genes encoded in

mitochondrial DNA (mtDNA)

1.3 Clinical Findings

Some hereditary metabolic disorders tend to aff ect

neurons and may do so within certain regions

or nuclei Disorders that involve gray matt er, or

neurons, have been termed “poliodystrophies,”

while those involving white matt er are called

is present, the metabolite is a sulfatide, and when multiple sugar moieties, are present, including sialic acid (N-acetylneuraminic acid), the metabolites are gangliosides

2 1 1 G A U C H E R D I S E A S E ( G L U C O C E R E B R O S I D A S E

D E F I C I E N C Y )

Gaucher disease (or glucocerebrosidase defi ciency)

is an autosomal recessive disease due to a defi ciency

of acid beta-glucosidase (beta-glucocerebrosidase), which catabolizes glucosylceramide into ceramide and glucose Th e disease is characterized by the accu-mulation of glucosylcerebroside within lysosomes and involves the bone marrow, liver, and spleen

Th e most common form (type I) has an onset in adults and the central nervous system (CNS) is not aff ected Involvement of the nervous system occurs only in the infantile severe (neuronopathic) form

Th e gene (GBA; glucosidase, beta acid) is located

on chromosome 1q21, and mutations in this gene are responsible for all clinical forms of the disease Although specifi c mutations are associated with spe-cifi c clinical phenotypes, there is no correlation with

enzyme activity measured in vitro

In the typical form (type I  Gaucher disease), hepatosplenomegaly is common, and pancytope-nia results from replacement of the marrow with storage cells Th e storage cells are predominantly macrophages and are known as Gaucher cells Th ey are found in large numbers outside the nervous sys-tem, sometimes appearing to have almost replaced the normal parenchyma of the liver, lymph nodes, marrow, and spleen Th ese large (30 to 40  μm) Gaucher cells are distended with cerebrosides, and the parallel cleft ed vacuoles give the cells a distinct appearance that has been described as resembling crumpled tissue paper By electron microscopy, the cells contain tubular, sickle-shaped profi les measur-ing 12 to 30 nm

In the neuronopathic form (type II Gaucher disease) and in the rare juvenile form with a pro-longed course characterized by dementia (type III), Gaucher cells are present in the brain, where they are distributed chiefl y around blood vessels

7 Acute encephalopathy is an uncommon

pre-sentation in hereditary metabolic diseases but

may occur in mitochondrial encephalopathy

with lactic acidosis and stroke (MELAS), Leigh

disease, urea cycle disorders, or nonketotic

hyperglycinemia

2 LYSOSOMAL

DISORDERS (LYSOSOMAL

STORAGE DISEASES)

Th ese diseases are due to a defi ciency of a specifi c

lysosomal enzyme required for the lysosomal

catab-olism of a particular metabolite, usually a complex

lipid or sphingolipid, and are oft en accompanied by

the accumulation of the lipid (“storage disease”)

Current classifi cations most oft en refer to the lipid

involved or to the enzyme defi ciency responsible for

their accumulation rather than to clinical features

However, distinct clinical syndromes are recognized

and oft en carry the eponyms of the author of the

fi rst clinical description

Th e abnormalities commonly involve both the

cerebrum and cerebellum; they oft en consist of

neu-ronal storage, with enlargement of the neuneu-ronal cell

body initially but ultimately neuronal loss and

glio-sis When involvement of white matt er is the

pre-dominant abnormality, the disorder may be referred

to as a leukodystrophy In some lipid disorders,

espe-cially those involving myelin lipids, the brain lesions

are accompanied by peripheral nerve disease due to

involvement of Schwann cells and peripheral myelin

sheaths Storage of the metabolic product in

lyso-somal storage diseases also oft en occurs in the heart,

liver, kidney, spleen, or eye Ocular storage may be

seen on ophthalmic examination as a “cherry red”

spot, due to storage within retinal ganglion cells;

involvement of viscera may be detected as

hepato-splenomegaly or cardiomyopathy

Defi ciencies in specifi c lysosomal proteins cause

the accumulation of sphingolipids (gangliosides,

cerebrosides, and sulfatides), mucopolysaccharides,

and complex neutral lipids

2.1 Sphingolipidoses

Sphingolipidoses represent the most common

group of neuronal lysosomal storage disease Th e

catabolic enzyme defect impairs the lysosomal

catabolism of the sphingolipid, and accumulation

of the sphingolipid is the most common result

Chapter 10 Hereditary Metabolic Diseases • 231

osmiophilic limiting membrane; they are variably needle- or splinter-shaped or gently curved, 10 to

100 nm wide, and of indeterminate length

Involvement of the peripheral nervous system may also be found Th e clinical manifestation refer-able to the peripheral nervous system is hyporefl exia, particularly in the childhood variants of the disease Loss of myelinated fi bers and relative preservation

of unmyelinated axons are the outstanding fi ndings, although segmental demyelination and remyelin-ation also occur By electron microscopy, inclusions similar to those seen in globoid cells may be seen in histiocytes and Schwann cells ( Fig. 10 1C )

Th ere is no storage of galactocerebroside in the liver or spleen and no visceral enlargement or dysfunction

2 1 3 N I E M A N N - P I C K D I S E A S E ( S P H I N G O M Y E L I N L I P I D O S I S )

Niemann-Pick disease is an autosomal recessive multiorgan storage disease with several forms, each form sharing the defi ning feature of accumu-lation of sphingomyelin (sphingomyelin lipidosis) Sphingomyelinase is the enzyme that catalyzes the breakdown of sphingomyelin to phosphocho-line and ceramide Th ere are at least three distinct genetic loci and multiple distinct clinical forms

of the disease at the diff erent loci Clinical forms

A and B involve the gene for acid sphingomyelinase (chromosome 11p15.4-p15.1) and are the forms of

“classic” Niemann-Pick disease with elinase defi ciency However, there are two forms

sphingomy-of the disease, types C and D (Nova Scotia ant), which involve a separate gene, NPC1 (chro-mosome 18q11.2) In both of these forms, there

vari-is sphingomyelin storage (sphingomyelin sis), but the sphingomyelinase enzyme activity is normal

Th e nervous system is prominently involved in the acute infantile form (type A), which is most common in Ashkenazi Jewish populations Th ere is severe hepatosplenomegaly, a cherry red spot of the retina, a diff use reticular infi ltration of the lungs, and

a rapidly progressive encephalopathy Hypotonia may be present in the early course, but there is grad-ual loss of motor function and intellectual deteriora-tion Death usually occurs by 3 years of age

Type B is more variable in presentation and progression but much less severe than Type A. Th e patients do not have neurological involvement but present with massive hepatosplenomegaly, oft en

Accumulation of glucocerebroside within the

neu-rons themselves is variable and usually discrete

Survival in type 1 Gaucher disease is variable,

usu-ally depending on the severity of liver and bone

mar-row involvement Type 2 neuronopathic Gaucher

disease has a severe and rapidly progressive course,

with death usually occurring before the age of 2

2 1 2 K R A B B E D I S E A S E

( G A L A C T O C E R E B R O S I D A S E

D E F I C I E N C Y )

Krabbe disease (globoid-cell leukodystrophy;

galactosyl-ceramide-beta-galactosidase defi ciency)

is an autosomal recessive leukodystrophy due to

a defi ciency of the enzyme galactosyl ceramidase

(galactosyl-ceramide-ß-galactosidase, or

galacto-cerebrosidase [GALC]), which is necessary for

the catabolism of galactosylceramide

(galactocer-ebroside), an integral component of myelin Th e

gene, GALC, is located on chromosome 14q31.3

and encodes the enzyme It is a rare condition and

is the only sphingolipidosis in which accumulation

of the metabolite (galactocerebroside) does not

occur Rather, the block in catabolism of

galactocer-ebroside leads to shunting of galactocergalactocer-ebroside to

psychosine (galactosylsphingosine), with elevated

levels of psychosine Th e elevated levels of

psycho-sine have a toxic eff ect on oligodendrocytes in

tis-sue culture experiments, and it has been postulated

that psychosine impairs the maintenance of myelin

Instead of neuronal storage, there is destruction of

white matt er, resulting in an infantile

leukodystro-phy Th e onset is usually before the age of 6 months,

and the clinical course is usually rapidly

progres-sive, with death usually occurring before the age of

2 years

Demyelination is widespread, resulting in

atro-phy of the white matt er of the cerebrum and

cer-ebellum and marked fi brillary gliosis A  common

feature of the disease is the presence of rounded

macrophages with a large amount of cytoplasm,

known as “globoid” cells Th ey may measure up to

40  μm, with more irregular outlines, and are oft en

multinucleated Globoid cells occur throughout

the white matt er of the CNS (but are not

pres-ent in the peripheral nervous system) and may be

found singly but are more oft en grouped to form

perivascular collections ( Fig.  10 1A , B) By

elec-tron microscopy, globoid cells contain

intracy-toplasmic inclusions, which appear as elongated

cleft -like empty spaces, sometimes bordered by an

232 • E S C O U R O L L E & P O I R I E R ’ S M A N U A L O F B A S I C N E U R O P AT H O L O G Y

of the brain with severe gliosis Types C and D may show atrophy, but the fi nding is more variable In all three forms (types A, C, and D), there are abundant large neurons with distended cytoplasm and many small round clear vacuoles Histochemical studies performed on frozen sections may demonstrate the presence of neutral lipids Patients with onset of the disease in infancy, who have severe involvement of

detected on routine physical examination Survival

into adulthood is common

Type C is less common and has a slower

clini-cal course; it may also involve the nervous system

However, the neurological manifestations appear

later in the course of the disease Type D (Nova

Scotia variant), which may also involve the CNS, has

been reported as a separate type, but many sources

now consider it a syngenic variant of type C that was

discovered in pedigrees from Nova Scotia Type E

had been distinguished as an adult-onset disorder

but is now viewed as type B with late onset

All of the forms of Niemann-Pick disease,

regard-less of the gene involved are characterized by the

presence of large macrophages with distended

cyto-plasm Th ese large cells have round clear vacuoles by

light microscopy and electron microscopy and have

been called “foam cells” ( Fig.  10 2 ) , regardless of

location Th ey are oft en detected on bone marrow

biopsy but also occur in the liver, spleen, and lymph

nodes Involvement of the nervous system occurs in

types A, C, and D.  Type A  shows marked atrophy

Chapter 10 Hereditary Metabolic Diseases • 233

(cornea verticillata) Th e disease commonly results

in life-threatening pathological changes in the kidneys, heart, and cerebral blood vessels, lead-ing to renal or cardiac failure or multiple strokes Gastrointestinal dysfunction is likewise frequent; this has been att ributed to lipid inclusions in the myenteric plexus Common symptoms suggesting involvement of the peripheral nervous system are recurrent att acks of severe pain in the hands or feet, especially in the presence of heat, and absence of sweating

Foam cells are found in the liver, spleen, and lymph nodes as well as in renal and cutaneous epi-thelial cells Th e storage material is sudanophilic, PAS-positive, and birefringent under polarized light, with a Maltese-cross shape By electron microscopy, the inclusions oft en have a myelin-like lamellated structure, sometimes in parallel arrays, sometimes in concentric layers, with a periodicity of 5 nm Some

of them are membrane-bound, others not Some, instead of being lamellated, are in the form of dense osmiophilic aggregates

CNS involvement is apparently limited to the amygdala, hypothalamus, hippocampus, entorhi-nal cortex, and brainstem nuclei Neurons in these areas have reticular foam cytoplasm with abundant storage material Storage is also seen in astrocytes, endothelial cells, and smooth muscle cells around blood vessels In peripheral nerves, inclusions may

be found in the cytoplasm of perineurial cells, lar endothelial cells, and smooth muscle cells in the tunica media of arteries

2 1 6 G A N G L I O S I D O S E S

Th e gangliosidoses are characterized by the mulation of gangliosides, which are composed of ceramide linked to an oligosaccharide (up to four hexose saccharides, either galactose or glucose) and one or more sialic acids (N-acetylneuraminic acid, or NANA) Gangliosides stain intensely with myelin stains in histological sections (such as LFB) but do not stain appreciably with routine H&E, so swollen neurons usually appear to have clear vacu-oles on H&E-stained sections ( Fig.  10 3A ) By electron microscopy, the perikarya of neurons con-tain membranous cytoplasmic bodies, which may have two appearances:  circular concentric profi les formed by alternating concentric electron-lucent and electron-dense bands 5 to 6 nm wide, known as membranous concentric bodies (MCBs), or oblong profi les with alternating linear electron-lucent

accu-the CNS, sometimes show evidence of peripheral

nervous system involvement When peripheral

ner-vous system involvement is present, it is

character-ized morphologically by the presence of lamellated

inclusions and empty vacuoles in the cytoplasm of

Schwann cells and in endoneurial and perineurial

fi broblasts

2 1 4 FA R B E R L I P O G R A N U L O M AT O S I S

( C E R A M I D A S E D E F I C I E N C Y )

Farber lipogranulomatosis (ceramidase defi ciency;

Farber disease) is an autosomal recessive

disor-der resulting from defi ciency of acid ceramidase, a

lysosomal enzyme required for the catabolism of

ceramide into sphingosine and fatt y acids Ceramide

accumulates in various tissues, including the central

and peripheral nervous system Th e gene, located

on chromosome 8p22, encodes the acid ceramidase

protein

Th e characteristic feature of the disease is the

development of periarticular and perivascular

nod-ules that are composed of lipid-fi lled macrophages,

typically accompanied by a granulomatous infl

am-matory reaction Th e nodules are oft en fi rst detected

within the skin, where they form readily visible

sub-cutaneous nodules Similar lipogranulomas may also

involve the joints, bones, and kidneys In the CNS,

the large neurons of the anterior horns of the spinal

cord and their homologues in the brainstem are the

main structures aff ected, and they appear distended

with lipid inclusions Peripheral (sensory and

auto-nomic) ganglion cells are also aff ected Characteristic

inclusions (curvilinear tubular structures) are also

seen in capillary endothelial cells in the CNS

2 1 5 FA B RY D I S E A S E

( A L P H A - G A L A C T O S I D A S E A   D E F I C I E N C Y,

A N G I O K E R AT O M A C O R P O R I S D I F F U S U M )

Fabry disease is a rare X-linked disorder due to a

defi ciency of the hydrolase enzyme α-galactosidase

Th is enzyme is encoded on the long arm of the X

chromosome (Xq22.1) Alphagalactosidase A defi

-ciency results in the accumulation of

glycosphingo-lipids, particularly globotriaosylceramide, forming

abnormal intracellular lipid inclusions (foam cells),

especially in vascular endothelial and smooth

muscle cells

Clinically, Fabry disease is characterized by

the development of angiokeratomas of the skin

and mucous membranes and by corneal changes

234 • E S C O U R O L L E & P O I R I E R ’ S M A N U A L O F B A S I C N E U R O P AT H O L O G Y

life It presents with poor head control and other symptoms of psychomotor decline In the early stages, the head and brain are enlarged, but there

is no hepatosplenomegaly Gradual decline occurs, and death usually occurs within 2  years Th e neu-ropathology is that of a neuronal storage disease, with greatly enlarged neurons with distended cyto-plasm and large clear vacuoles on H&E Th e micro-scopic features are the same as other gangliosidoses (PAS-positive on frozen sections, PAS-negative on routine sections, strongly LFB-positive, membra-nous concentric bodies on electron microscopy) 2.1.6.2 GM2 gangliosidosis type II (Sandhoff disease) and GM2 gangliosidosis AB variant Sandhoff disease (GM2 gangliosidosis type II)

results from mutations involving the HEXB gene

(chromosome 5q13.3), causing defi ciency of osaminidase A  and B activities; hexosaminidase

hex-S activity is preserved hex-Sandhoff disease does not show any particular ethnic predominance and is clinically indistinguishable from Tay-Sachs disease

and electron-dense bands, known as zebra bodies

( Fig. 10 3 B, C)

2.1.6.1 Tay-Sachs disease (hexosaminidase

A  defi ciency, GM2-gangliosidosis B variant)

Tay-Sachs disease is an autosomal recessive disease,

formerly known as amaurotic idiocy (to

empha-size the blindness and intellectual deterioration)

It is caused by mutations in the α subunit gene of

hexosaminidase A  (HEXA, chromosome 15q23),

with defi ciencies in hexosaminidase A and S

activi-ties Hexosaminidase A  is composed of α and β

subunits (encoded by the HEXA and HEXB genes,

respectively) Hexosaminidase B is composed of

two β subunits ( HEXB gene), and hexosaminidase

S is composed of two α subunits ( HEXA gene)

Mutations of the α gene, therefore, lead to defi

cien-cies of both hexosaminidase A and S activities

Tay-Sachs disease occurs predominantly in

Ashkenazi Jews, with a high mutation frequency

in that population Th e onset is in infancy,

usu-ally aft er birth but within the fi rst few months of

C

FIGURE 10.3 Tay-Sachs disease (A) Swollen neurons with clear peripheral vacuoles (H&E) (B, C)

Membranous cytoplasmic bodies on electron microscopy

Chapter 10 Hereditary Metabolic Diseases • 235

of onset are thought to be related to residual enzyme activity associated with the two mutations aff ecting each allele, with the least enzyme activity associated with the late infantile form of the disease Th e onset

of symptoms in the disease may be during the tile or juvenile periods, or in adulthood In the late infantile form, clumsiness and spasticity are oft en early fi ndings, with onset between 2 and 3  years

infan-of age Progression is relentless, and death usually occurs in early childhood

Sulfatides accumulate in many tissues, and the deposits may be up to 20 or 30  μm in diameter

Th ey are PAS-positive and metachromatic (stain brown with acidic cresyl violet [ Fig. 10 4B ] and pink with toluidine blue) By electron microscopy, these lysosomal inclusions have a lamellar structure with

a periodicity of 5.8 nm Th ey may be arranged centrically, but parallel prismatic bodies or rectilin-ear “tuff stone” bodies ( Fig. 10 4C ) are characteristic

On gross examination, the brain may be atrophic, especially in longstanding cases Th e entire white matt er shows loss of myelin, with sparing of the sub-cortical fi bers ( Fig.  10 4A ) Myelin is largely absent throughout the entire centrum semiovale, and gliosis

is severe, with scatt ered macrophages Metachromasia

is identifi ed in the macrophages, which tend to have a perivascular location In the peripheral ner-vous system, there is demyelination and there may

be some onion bulb formation Schwann cells and macrophages, and occasionally axons, may contain metachromatic material Electron microscopy in peripheral nerve shows the characteristic inclusions Two important variants are known that involve separate genetic loci: activator protein saposin B and sulfatase-modifying factor-1 Mutations involving the activator protein, saposin B (prosaposin gene,

PSAP located on chromosome 10q22.1), lead to a

clinical appearance that is indistinguishable from arylsulfatase A defi ciency, but in which arylsulfatase activity is normal (metachromatic leukodystrophy due to saposin B defi ciency) Multiple sulfatase defi ciency (Austin disease) is caused by mutations

in the sulfatase-modifying factor 1 gene and leads

to an absence of arylsulfatases A, B, and C activity

Th e sulfatide accumulation is accompanied by an accumulation of mucopolysaccharides, and patients have some facial and bony features that resemble Hurler disease Th ere are also benign mutations in the arylsulfatase A gene, which lead to pseudodefi -ciency of arylsulfatase A  activity Th ese mutations, although characterized biochemically by greatly reduced enzyme activity, are not associated with

GM2 gangliosidosis AB variant, which is rare, is

clinically and histologically identical to Tay-Sachs

disease, but there is normal hexosaminidase A and

B activity Th e disease is caused by mutations in

the GM2 activator protein ( GM2A ; chromosome

5q33.1)

2.1.6.3 GM1 gangliosidosis type I

(beta-galactosidase-1 defi ciency) GM1

gangliosi-dosis type I is an autosomal recessive neuronal

stor-age disease caused by a defi ciency of β-galactosidase

( GLB1 , chromosome 3p22.3) Similar to Tay-Sachs

disease, the onset is in infancy and there is early onset

of hypotonia and cherry red spots However, there

are also signs of systemic involvement, including

corneal opacities, depression of the nasal bridge, and

hepatomegaly, features similar to Hurler disease, a

mucopolysaccharide storage disorder Th e disorder

is, therefore, sometimes known as pseudo-Hurler

disease Th e staining properties of the gangliosides

are similar to Tay-Sachs; however, storage material

may also be found in the liver, spleen, kidney, and

Metachromatic leukodystrophy (MLD) is an

auto-somal recessive disorder resulting from a defi ciency

of lysosomal arylsulfatase A  activity, which

cata-lyzes the catabolism of the sphingolipid,

galactocer-ebroside sulfate (a sulfatide), to the corresponding

nonsulfated sphingolipid Th ese lipids are integral

components of myelin sheaths, both in the central

and peripheral nervous systems; defi ciency of the

enzyme activity creates an excessive accumulation

of sulfatides, which in turn results in breakdown

of myelin and phagocytosis of its disintegration

products

Th ese sulfatides have an unusual staining

prop-erty, known as metachromasia When certain dyes

bind to sulfatides, the absorption spectrum of the

dye shift s to a diff erent color Th is chemical

prop-erty led to the distinction between this disorder, a

metachromatic leukodystrophy, and the majority

of leukodystrophies, which are “orthochromatic” or

“sudanophilic” leukodystrophies

Th e disease most oft en occurs due to mutations

in the arylsulfatase gene ( ARSA ), located on

chro-mosome 22q13.33 Diff erences in severity and age

The histopathological findings consist of

an association of nervous system changes with alterations in the blood vessel walls In the cere-bral cortex and cerebellum, the appearance of the swollen neurons is comparable to that seen in gangliosidoses, with the presence of zebra bodies ( Fig.  10 5A ) and other structures that are inter-mediary to the membranous cytoplasmic bodies

of Tay-Sachs disease Capillary pericytes may show marked vacuolation ( Fig.10 5B ) , which cor-responds to the excessive accumulation of glycos-aminoglycans Vacuolization is found in the CNS,

in various visceral organs (including the liver, myocardium, and bone marrow), and in lympho-cytes The vacuoles appear to be of lysosomal origin, as suggested by the demonstration of acid phosphatase

neurological disease, and pseudodefi ciency of

aryl-sulfatase activity may be present in up to 2% of some

populations

2.2 Mucopolysaccharidoses

Th e nervous system and especially neurons are

involved only in certain forms of

mucopolysac-charidosis In such cases, a systemic disturbance of

acid mucopolysaccharides, or glycosaminoglycans

(which are excreted in the urine), is accompanied

by a neuronal lipid storage disorder that closely

resembles the gangliosidoses Because of the

sec-ondary nature of the gangliosidosis, this group of

diseases is not a form of neurolipidosis, but it should

be stressed that in some forms the neuronal changes

dominate the pathological fi ndings

C

FIGURE 10.4 Metachromatic leukodystrophy (A) Massive demyelination of the white matt er sparing the U

fi bers in the right parieto-occipital region (Loyez) (B) Metachromasia of the white matt er, which stains brown with acidic cresyl violet (C) Sulfatide inclusion by electron microscopy

Chapter 10 Hereditary Metabolic Diseases • 237

and lymph nodes Th e foam cells are derived from macrophages and have large clear vacuoles In the CNS, choroid plexus, leptomeninges, and Purkinje cells are oft en aff ected Death usually occurs before the age of 1 year

2 3 2 TA N G I E R D I S E A S E

Tangier disease (high-density lipoprotein defi ciency type I, analphalipoproteinemia) is an autosomal recessive multiorgan disease aff ecting cells of the lymphoreticular type, cornea, and the peripheral nervous system due to mutations in the ATP-binding

cassett e 1 ( ABCA1 ) gene Th e gene is located on chromosome 9q31.1 and encodes an ATP-binding cassett e transporter, an important protein involved in regulating the intracellular transport of cholesterol

Th e disease is characterized by near or total absence of circulating alpha lipoproteins Histiocytes, which may be encountered in lymphoid tissues and bone marrow, transform to “foam cells” due to cholesterol ester accumulation Tonsil hypertrophy, hepatomegaly, and splenomegaly are common, and nearly all patients have some degree of neuromus-cular dysfunction during the course of the illness About one third of patients come to medical att en-tion because of peripheral neuropathy

Neuropathological features vary with each of three fairly distinct clinical syndromes Sural nerve biopsies from patients with peripheral neuropathy, characterized by remitt ent and relapsing asymmetri-cal polyneuropathy, have shown striking evidence

of segmental demyelination and remyelination and very litt le overall fi ber loss Patients with a dis-tal symmetrical polyneuropathy have loss of large myelinated fi bers and a relative increase in very small fi bers, with evidence of remyelination and

Th e mucopolysaccharidoses that involve the

CNS to the greatest extent are:

• Hurler syndrome (type IH

mucopolysaccharido-sis, α-L-iduronidase defi ciency; dermatan sulfate

and heparan sulfate storage; gene locus 4p16.3)

with facial and skeletal deformities (gargoylism),

corneal opacities, and nervous system lesions

• Hunter syndrome (type II

mucopolysaccharido-sis; iduronate-2-sulfatase defi ciency; dermatan

sulfate and heparan sulfate storage; gene locus

Xq28), similar to Hurler disease, with similar

deposition of glycosaminoglycans, but with

X-linked inheritance and absence of corneal

opacities

• Type III A mucopolysaccharidosis (Sanfi lippo

disease; heparan sulfate storage; heparan sulfate

N-sulfatase defi ciency; gene locus 17q25.3),

which is histologically similar to types I and II,

but in which only heparan sulfate accumulates in

excessive amounts

2.3 Enzymes involved in metabolism of

cholesterol, other lipids, and lipoproteins

2 3 1 W O L M A N D I S E A S E ( LY S O S O M A L

A C I D L I PA S E D E F I C I E N C Y )

Wolman disease (lysosomal acid lipase defi ciency)

is an autosomal recessive infantile disease with

hepa-tosplenomegaly, gastrointestinal signs, and

progres-sive neurological deterioration caused by mutations

of the lysosomal acid lipase gene (LIPA,

chromo-some 10q23.31) and accumulation of cholesterol

and triglycerides Calcifi cation of the adrenals is

accompanied by lesions in the intestinal mucosa and

by the presence of “foam cells” in the liver, spleen,

FIGURE 10.5 Mucopolysaccharidosis (A) Zebra body in Hurler disease (B) Vacuoles in a pericyte

young adult life and progresses slowly Th e disease is

caused by mutations of the CYP27A1 gene or

chro-mosome 2q35, which encodes polypeptide 1 of the cytochrome P450, subfamily XXVIIA, required for sterol 27-hydroxylase activity Th is enzyme activity

is required for hydroxylation of a variety of sterols at the 27position In a few cases of cerebrotendinous xanthomatosis, there has been evidence of a periph-eral neuropathy clinically and pathologically on nerve biopsy Th e changes in the nerves have been those of relative loss of large myelinated fi bers and segmental demyelination and remyelination with some onion bulb formation

2 3 5 C E R O I D L I P O F U S C I N O S I S ,

N E U R O N A L ( C L N , B AT T E N D I S E A S E ,

K U F S D I S E A S E )

Th e neuronal ceroid lipofuscinoses are now classifi ed

as ceroid lipofuscinosis, neuronal (CLN), and are the most frequent type of neurodegenerative disease

in children Th ese disorders are marked by neuronal loss and ubiquitous accumulation of intracellular lipopigments Juvenile and late infantile forms of the disease are the most common, but there is also a rare adult form (Kufs disease) Th e frequency is 0.1 to 7/100,000 live births Th ey are autosomal recessive progressive disorders of uniformly fatal outcome and are characterized by lysosomal accumulation of lipid pigments that are positive for acid phosphatase and autofl uorescent by light microscopy

Infantile, late-infantile, juvenile, and adult forms are defi ned based on the age of onset of clinical symptoms While the juvenile form is the most fre-quent one in Northern Europe and North America, the late infantile form is the most frequent one in Southern Europe and South America Th e infantile form, however, predominates in Finland as one of the hereditary diseases of Finnish heritage and, though more rarely, may be encountered worldwide Th e former classifi cation of the neuronal ceroid lipofus-cinoses, according to clinical subtypes, has recently been replaced by one based on genetic defects, now numbering CLN1 to CLN10 ( Table  10.1) In the three early childhood forms (CLN1, CLN2, and CLN10), three diff erent proteases (palmitoyl pro-tein thioesterase 1 [PPT1], tripeptidyl peptidase

1 [TPP1], and cathepsin D) are the defi cient gene products, respectively Th e other genetically identi-

fi ed forms (CLN3, CLN5, CLN6, and CLN8) are marked by defi ciencies of structural transmem-brane proteins, perhaps of lysosomal location; the

fi ber regeneration (sprouting) In patients with a

syringomyelia-like syndrome, mostly middle-aged

adults, there has been severe loss of small

myelin-ated and unmyelinmyelin-ated fi bers, with a tendency for

the large myelinated fi bers to be relatively spared

Accumulation of lipid droplets in Schwann cells is

a constant feature

2 3 3 A B E TA L I P O P R O T E I N E M I A

( B A S S E N - K O R N Z W E I G D I S E A S E )

Th is rare autosomal recessive syndrome is

character-ized by a combination of malabsorption of lipids, a

chronic progressive peripheral neuropathy,

pigmen-tary degeneration of the retina, and acanthocytosis

(burr cells) aff ecting red blood cells Signs of

cer-ebellar dysfunction (intention tremor, nystagmus)

are frequently seen in association with peripheral

neuropathy characterized by prominent sensory

impairment, muscular weakness, and atrophy

(lead-ing to kyphoscoliosis and pes cavus in some cases)

Th e disease results from mutations of a gene on

chromosome 4q23 that encodes the microsomal

tri-glyceride transfer protein (MTP) Th is protein

cata-lyzes transport of lipids between membrane surfaces

and is required for assembly of very-low-density

lipoprotein (VLDL) particles in the liver, and in the

absence of functional MTP, the apolipoprotein is

never assembled and released from the liver

Th e peripheral neuropathy is characterized by

marked loss of myelinated axons, especially large

ones, and involvement of the posterior horns of the

spinal cord Retinal pathology entails loss of

photo-receptors and pigmentary retinopathy with

mobili-zation of retinal pigment epithelial cells, which enter

the sensory retina to produce brownish

pigmenta-tion Th e formation of fi nely granular lipopigments

in peripheral nerve and skeletal muscle fi bers

resembles that seen in vitamin E or alphatocopherol defi

-ciencies, and tocopherol therapy has been found

benefi cial for Bassen-Kornzweig disease patients

2 3 4 C E R E B R O T E N D I N O U S

X A N T H O M AT O S I S

Cerebrotendinous xanthomatosis is an autosomal

recessive disorder of sterol metabolism that results

in extensive lipid deposition, mainly in large

ten-dons (Achilles tenten-dons and elbow regions) and in

the CNS, where it is associated with ataxia,

spastic-ity, accelerated atherosclerosis, and impaired

intel-lect Th e disease generally becomes manifest in

Table 10.1 Current Classifi cation of the Neuronal Ceroid Lipofuscinoses (CLN)

Kufs (autosomal-recessive)

Parry (autosomal-dominant)

CLN4, CLN1

CLN5, CLN6 DNAJC5

CLN4 :

unknown20q13.33

UnknownCysteine string protein alpha

Granular, CP, FPGranular

SCMASSAPs

Finnish variant CLN CLN5 13q-22 Soluble CLN5 protein in

lysosomes

RP, CP, FP SCMAS Early-juvenile Indian/Czech

of ER and ER-Golgi complexes

Granular, CP, FP SCMAS

Congenital + juvenile CLN CLN10/CTSD 11p15.5 Cathepsin D in lysosomes Granular SAPs

RP, rectilinear profi les; CP, curvilinear profi les; FP, fi ngerprint profi les; ER, endoplasmic reticulum; GROD, granulo-osmiophilic deposits; SAPs, sphingolipid activator proteins; SCMAS, subunit C of mitochondrial ATP synthase

phosphatase Th ey are PAS-positive and are stained

by Luxol fast blue ( Fig. 10 6C ) Varying in degree, the lipopigments may also contain the subunit C of mitochondrial ATP synthase and sphingolipid acti-vator proteins that are demonstrable by immunohis-tochemistry Immunohistochemical absence of the genetically defi cient tripeptidyl peptidase (TPP) enzyme protein in late-infantile CLN/CLN2 has been documented

As the lipopigments in CLN show diff erent ultrastructural patt erns, conventional diagnosis of individual CLN forms may be achieved by electron microscopic examination of circulating lympho-cytes in which, among numerous other cell types (skin biopsies, appendectomy specimens, muscle biopsies), lipopigments accrue A  granular pat-tern may be seen in infantile CLN ( Fig.  10 6E ) ; curvilinear bodies are a hallmark of late-infantile CLN ( Fig.  10 6F ); fi ngerprint profi les within membrane-bound lysosomal vacuoles are indica-tive of juvenile CLN ( Fig.  10 6G ) ; and genetic late-infantile variants show a granular matrix and fi n-gerprint profi les within the circulating lymphocytes

In adult CLN, lymphocytes have not been found aff ected by lipopigment formation Apart from gran-ular material, fi ngerprint profi les have been identi-

fi ed in neuronal lipopigments ( Fig.  10 6H ) and curvilinear/rectilinear lipopigment profi les within skeletal muscle fi bers in Kufs disease Prenatal elec-tron microscopy may reveal granular lipopigments

in the infantile type and lamellar inclusions in nile CLN within mural cells of chorionic vessels, whereas late-infantile CLN is prenatally marked by curvilinear bodies within amniotic fl uid cells

3 PEROXISOMAL DISORDERS

Peroxisomes are intracellular organelles with a single membrane and a granular matrix by electron microscopy Initially identifi ed as “microbodies”

by electron microscopy, peroxisomes contain lase, and their ability to cleave hydrogen peroxide via the enzymatic activity of catalase allowed their initial localization and is the basis for their name

cata-Th ey are involved in a number of metabolic ways, including the initial pathway for breakdown

path-of very-long-chain fatt y acids (VLCFAs), and the catabolism of several organic acids (phytanic acid, glutaric acid, pipecolic acid) Defects in the biogen-esis of the entire organelle may lead to defi ciencies

of all of the enzymatic functions of the peroxisome

CLN3 protein has been named batt enin For in vivo

and prenatal diagnoses, biochemical activities of

PPT1 and TPP1 may be measured and are severely

reduced or absent in CLN1 and CLN2, respectively

CLN9 is a putative juvenile form, but without a

disease-specifi c gene or protein known Th e gene

for CLN4, an adult-onset phenotype, is also not yet

known However, several adult CLN patients have

been found to have autosomal recessive mutation

in genes associated with childhood onset (CLN1,

CLN5, and CLN6) Recently, mutations in a new

gene have been identifi ed in a few families with

adult autosomal dominant CLN, also named Parry

disease ( Table 10.1)

CLN are uniformly fatal disorders, the late-infantile

form resulting in death during the second decade of

life Patients with juvenile CLN may survive to the

third or even fourth decade of life Patients who have

adult CLN usually succumb within less than 10 years

aft er onset In aff ected children, the clinical tetrad

of visual disturbance (ending in blindness owing to

retinal degeneration), ataxia, seizures, and

demen-tia may be encountered in each form, although with

a diff erent onset of fi rst symptoms and sequence of

subsequent clinical fi ndings Th e ocular fundi show

thinning of the degenerating retina and brownish

pig-mentation However, visual disturbances or blindness

are not a clinical component of the adult form and the

electroretinogram is largely normal

Lesions in CLN involve predominantly the cortex

(cerebral and cerebellar), resulting in almost

com-plete depletion of nerve cells in the infantile form at

autopsy, lesser depletion in the late-infantile form,

and some neuronal depletion in the juvenile form,

while there relatively litt le neuronal loss in the adult

form Macroscopically, there is variable brain

atro-phy, which correlates with onset and duration of the

disease It is particularly severe in the infantile and

late infantile forms ( Fig. 10 6A ) , whereas the juvenile

CLN cortex may display a brownish hue Secondary

loss of axons and myelin, shrinkage of the white

mat-ter, and dilatation of the ventricles and the

subarach-noid space are also common

Two microscopic features defi ne CLN: (1) loss

of nerve cells followed by cellular and fi brillar

astrocytosis and proliferation of macrophages and

(2) the intracellular, especially intraneuronal,

accu-mulation of lipopigments Th is may lead to

enlarge-ment of nerve cell perikarya ( Fig.  10 6C , D) and

proximal segments, albeit usually not to the degree

as seen in the gangliosidoses Th e lipopigments

are autofl uorescent ( Fig.  10 6B ) and rich in acid

Chapter 10 Hereditary Metabolic Diseases • 241

which is located in the peroxisome and is involved

in transporting VLCFA into the peroxisome for catabolism In the absence of functional ABCD1, VLCFAs accumulate in the blood and brain Accumulation is also evident in the adrenal and may lead to functional hypoadrenalism

In the classic juvenile form, young males oft en present with behavioral problems or adrenal insuffi -ciency (Addison disease) Th e adrenal insuffi ciency oft en includes hyperpigmentation of the skin

Th e disorder is rapidly progressive; initial elination is detected by MRI in the occipital lobes ( Fig. 10 7B ) but progresses to eventually involve the entire cerebral hemispheres Demyelination in the CNS is the predominant neuropathological fi nding and is extensive and symmetrical Midline struc-tures (corpus callosum, fornix) and the optic nerves and tracts are severely aff ected ( Fig. 10 7A ) , and at late stages, the demyelination may be accompanied

demy-by axonal loss and cavitary leukomalacia with ondary degeneration of the descending pathways Myelin stains show the complete absence of myelin

sec-in the areas of chronic sec-involvement, and the older central portion of the demyelinated lesion shows severe fi brillary gliosis Scatt ered macrophages con-tain myelin degradation material, which stains with neutral lipid stains and is PAS-positive In chronic lesions, macrophage infi ltration is intense and is accompanied by a marked infl ammatory infi ltrate ( Fig. 10 7C )

Th e pathology in peripheral nerve is nantly a demyelinating neuropathy, with thin myelin sheaths and segmental demyelination on teased

predomi-fi bers By electron microscopy, membrane-bound cleft -like intracytoplasmic inclusions are seen, usu-ally in cells of the adrenal cortex, interstitial cells of the testis, and Schwann cells

By electron microscopy, storage material forms cleft -like inclusions composed of two lamellae that measure 2.5 to 3.5 nm in thickness and are separated

by a clear space measuring 4 to 10 nm ( Fig. 10 7D )

Th ese inclusions are sometimes associated with lipid droplets Th ey are most readily identifi ed in cells of the adrenal cortex but may also be found in macro-phages in the CNS, in Schwann cells in peripheral nerves, and in interstitial cells of the testis

Adrenomyeloneuropathy is the adult form of the disease and occurs in the same families with adreno-leukodystrophy Th ese patients present with clumsi-ness and ataxia, which results from involvement of the long tracts of the spinal cord and peripheral nerve It may aff ect either hemizygous males or heterozygous

(Zellweger disease, neonatal Refsum disease, and

neonatal adrenoleukodystrophy); involvement of

a single gene product results in the defi ciency of a

single enzymatic function of the peroxisome

3.1 Zellweger Syndrome

(cerebrohepatorenal syndrome)

Zellweger syndrome is an autosomal recessive

sys-temic syndrome caused by mutations in any of at

least eight genes involved in the biogenesis of the

peroxisome Th e eight genes identifi ed so far have

all been named “peroxins,” or peroxisome

biogen-esis factors, and mutations in peroxins 1, 3, 5, 10,

13, 14, 19, 26 (PEX1–PEX26) have all been

iden-tifi ed in Zellweger disease Patients are

symptom-atic at birth, with dysmorphic features and severe

hypotonia (“fl oppy baby”), and oft en have cataracts,

retinitis pigmentosa, deafness, hepatomegaly, small

renal cysts, pulmonary hypoplasia, and cerebral

mal-formations Death usually occurs before the age of

6 months

Electron microscopy of cells from patients with

Zellweger syndrome has demonstrated an absence

of peroxisomes, usually identifi ed by special

tech-niques that localize catalase in the peroxisome of

control patients Absence of peroxisomal function is

identifi ed by elevated serum levels of VLCFA,

pipe-colic acid, and phytanic acid

Th e neuropathological fi ndings in patients

with Zellweger syndrome are principally those

of a neuronal migration disorder Th e cortex may

show polymicrogyria, pachygyria, or

subcorti-cal neuronal heterotopias, all fi ndings that are

associated with abnormalities of neuronal

migra-tion Closely related, but less severe, disorders

are neonatal adrenoleukodystrophy and

infan-tile Refsum disease Th ese disorders share the

early onset and cerebral malformation fi ndings of

Zellweger disease but are less severe phenotypes

with longer survival Neonatal

adrenoleukodys-trophy also has the infl ammatory demyelination of

adrenoleukodystrophy

3.2 Adrenoleukodystrophy (and

adrenomyeloneuropathy)

Adrenoleukodystrophy is an X-linked recessive

leukodystrophy with a defect in the catabolism

of VLCFA Th e aff ected gene ( ABCD1 ), located

on chromosome Xq28, encodes a member of the

ATP-binding cassett e, subfamily D, member 1,

Chapter 10 Hereditary Metabolic Diseases • 243

abnormalities, nystagmus, ichthyosis, skeletal deformities, and a cardiomyopathy that can lead to arrhythmias, cardiac failure, and early death Th e dis-ease makes its appearance in late childhood, adoles-cence, or early adult life, and, untreated, progresses gradually, though with occasional remissions

Th e biochemical abnormality is a marked increase in the serum levels of phytanic acid, a branched 20-carbon fatt y acid Accumulation of phytanic acid is due to the defi ciency of phytanoyl CoA hydroxylase, the enzyme responsible for the

fi rst step in the catabolism of phytanic acid via alpha-oxidation within the peroxisome

Th e peripheral nervous system shows a severe demyelinating neuropathy Th e nerves (including the spinal nerve roots) are considerably enlarged as compared with normal Microscopically, there are

females in families with ABCD1 gene mutations

Adrenal insuffi ciency is also common and may be

associated with slowly progressive spastic paraplegia

3.3 Refsum disease (phytanic acid

oxidase defi ciency)

Refsum disease is an autosomal recessive disease

caused by a mutation in the gene ( PHYH ,

chromo-some 10p13) encoding the peroxisomal enzyme,

phytanoyl-CoA hydroxylase (phytanic acid

oxi-dase) Th e disease is characterized by progressive

distal motor and sensory impairment, ataxia of

trunk and limb movements, blindness (from

pig-mentary degeneration of the retina), and deafness

of sensorineural type Additional clinical

manifesta-tions, of varying degrees, include anosmia, pupillary

Th e condition is characterized by the presence of symmetrical spongy necrotizing lesions that aff ect both the gray and the white matt er; the lesions are predominantly located near midline structures Basal ganglia (especially the putamen), thala-mus ( Fig.  10 8A ) , substantia nigra, subthalamic nucleus, tegmentum of the midbrain ( Fig.  10 8B ) , inferior olives, and posterior columns of the spi-nal cord may be involved Th e relative sparing of the neurons, the presence of gliosis, and especially the endothelial proliferation ( Fig.  10 8C ) closely resemble the lesions of Wernicke encephalopathy (see Chapter 9) Sponginess and demyelination are subsequently replaced by cystic cavitation, necrosis, and cortical pseudolaminar destruction Sensory neuropathy is seldom recognized Ultrastructural studies show alterations of mitochondria, but only

in a few cases Th e same abnormalities may or may not be present in skeletal muscle

Recent data have demonstrated extensive genetic heterogeneity of the disease, which may

be related to mutations of mitochondrial genes, nuclear autosomal genes, and an X-linked gene (pyruvate dehydrogenase complex, subunit E1α, defi ciency) Among the nuclear autosomal genes, there are abnormalities of the nuclear genes of com-plex I, II, and IV (mutations of assembly genes of

cytochrome C oxidase, such as SURF1 ) Among

the mitochondrial-encoded genes are genes ing for ATPase 6 and tRNA (Lys) Enzyme defects have been demonstrated in muscle biopsy material

cod-in a low percentage of cases and fewer cod-in the bracod-in Congenital lactic acidosis may likewise cause necro-tizing lesions in the hemispheric white matt er

4.2 Mitochondrial encephalopathy with lactic acidosis and stroke (MELAS)

MELAS is defi ned by the association of chondrial encephalomyopathy, lactic acidosis, and stroke-like episodes Other CNS signs include dementia, seizures, and deafness Pathologically, infarcts are present in the cerebral cortex and subcortical white matt er, oft en located in the parieto-occipital lobes, the cerebellum, and rarely

mito-in the bramito-instem Th e spinal cord may be involved Calcifi cations of basal ganglia are common Enlarged mitochondria, present in pericytes, smooth muscle cells, and endothelial cells of the terminal arterioles, have been considered responsible for the recurrence

of transient cerebral ischemia Ragged-red fi bers

prominent concentrically arranged Schwann cells

interspersed with collagen fi bers, creating a

strik-ing onion bulb patt ern Th ere is also an increase of

perineurial and interstitial connective tissue Axons,

myelinated and unmyelinated, are decreased in

numbers In the CNS, cerebellar system

degenera-tion is oft en present, with neuronal loss in the

infe-rior olivary nucleus and dentate nucleus and loss of

fi bers in the cerebellar peduncles Posterior column

degeneration and loss of neurons in the gracile and

cuneate nuclei also have been observed

4 MITOCHONDRIAL DISEASES

(MITOCHONDRIAL ENCEPHA -

LOMYELOMYOPATHIES)

Th e mitochondrial encephalomyelomyopathies are

a group of clinically heterogeneous disorders with

multiorgan involvement caused by dysfunction of

the mitochondrial respiratory chain Most of them

involve muscle, of which the morphological and the

biochemical analysis oft en allow the diagnosis (see

Chapter 12) But abnormalities are not always

pres-ent in skeletal muscle, especially when the CNS is

predominantly involved

Mitochondria contain their own DNA which

encodes 13 polypeptides, including subunits of

the respiratory chain (complexes I, III, IV, V) and

also 22 tRNAs and 2 rRNAs Th e remainder of the

mitochondrial proteins is encoded by nuclear genes

Mitochondrial disorders may thus be caused by

mutations either in the mitochondrial or the nuclear

genome; defects of intergenomic signaling may

also interfere Th ere are two main types of mtDNA

mutations:  those that aff ect mitochondrial protein

synthesis in toto and those that aff ect protein-coding

genes Disorders related to mtDNA mutations are

sporadic or due to maternal transmission Mendelian

transmission characterizes nuclear DNA mutations

and defects of intergenomic signaling

Histologically most of the mitochondrial

enceph-alomyelomyopathies are characterized by sponginess

aff ecting gray and white matt er, capillary

prolifera-tion, and some degree of neuronal loss and gliosis

Some of the diseases may overlap

4.1 Leigh disease (subacute necrotizing

encephalopathy, infantile)

Leigh disease is seen most oft en in early childhood,

but variants with late onset have been described