Basic-Clinical-Science-for-MRCP1-by-Al-Mansour

Tumour suppressor genes  Genes which normally control the cell cycle  Loss of function results in an increased risk of cancer  Both alleles must be mutated before cancer occurs recess

By

Ali N Al-Mansour

organization [Insert Date]

Cell biology and molecule

Cell organelles

The table below summarizes the main functions of the major cell organelles:

Endoplasmic reticulum Rough endoplasmic reticulum

 translation and folding of new proteins

 manufacture of lysosomal enzymes

 site of N-linked glycosylation

 examples of cells with extensive RER include pancreatic cells, goblet cells, plasma cells

Smooth endoplasmic reticulum

 steroid, lipid synthesis

 examples of cells with extensive SER include those of the adrenal cortex, hepatocytes, testes, ovaries

Golgi apparatus Modifies, sorts, and packages these molecules that are destined for cell secretion

Site of O-linked glycosylation Mitochondrion Aerobic respiration Contains mitochondrial genome as circular DNA

Nucleus DNA maintenance and RNA transcription

Lysosome Breakdown of large molecules such as proteins and polysaccharides

Nucleolus Ribosome production

Ribosome Translation of RNA into proteins - intimately associated with the rough endoplasmic

reticulum and are responsible for protein translation Peroxisome Catabolism of very long chain fatty acids and amino acids

Results in the formation of hydrogen peroxide Proteasome Along with the lysosome pathway involved in degradation of protein molecules that

have been tagged with ubiquitin Lysosomes (lysis- breakage, soma- body) carry

hydrolases that degrade:

 Nucleotides

 Proteins

 Lipids, and

 Phospholipids

They also remove carbohydrate, sulfate, or

phosphate groups from molecules

The Golgi apparatus is part of the cellular

endomembrane system, which packages proteins

inside the cell prior to secretion

Both eukaryotes and prokaryotes have a ribosome,

significantly larger in eukaryotes

Histones allow DNA to twirl round it to form stable

nucleoprotein (nucleosomes) complexes

Chromosomes

The human karyotype: consists of 22 pairs of

autosomes and 1 pair of sex chromosomes totaling

23 pairs altogether

Normal male and female karyotypes are 46, XY and

46, XX

Telomere are DNA sequence at distal extremities of

chromosomal arms, Become progressively shorter

with each cell division when it is reduced to a critical

length; the cell is not capable of dividing

The enzyme telomerase lengthen it. Thus preventing the limitation towards cell division.

It will affect the number of potential cell divisionsCentromeres provide a point of attachment for the

mitotic spindle Divide the chromosome into short (p) arm and long (q) arm

X-inactivation (also called lyonization) is a process

by which one of the two copies of the X chromosome present in female mammals is inactivated The inactive X chromosome is silenced

by its being packaged in such a way that it has a transcriptionally inactive structure called heterochromatin (inactivated genes)

A Barr body is the inactive X chromosome in a

female somatic cell, rendered inactive in a process called lyonization, in those species in which sex is determined by the presence of the Y (including humans) or W chromosome rather than the diploid

of the X or Z

• Haploid= cell with 23 chromosome as gametes

• Diploid= cell with 46 chromosome

• Triploid= cell with 3 copies of each Chr

• Aneupoid= contain a number of Chr not a multiple of 23

• Trisomy results in 47 chromosomes

Transcription of eukaryotic genes requires coding sequences (introns) in the mRNA to be spliced out before translation at the ribosome NUCLEIC ACID STRUCTURE

non-All nucleic acids are polynucleotides A nucleotide consists of three components A base, A pentose sugar, 1-3 phosphate groups There are two kinds of nucleic acids : • (DNA) • (RNA)

DNA

 It is a double helix molecule, Each strand

consists of a chain of nucleotides

 Each nucleotide consists of a deoxyribose

sugar, a phosphate group and a nitrogenous

base

 Four nitrogenous bases, which occur in

DNA: adenine (A), thymidine (T), guanine

(G), cytosine (C)

 (A) & (G) are purines, whilst (T) and (C) are

pyrimidines

 There is specific base pairing:

o A with T, two hydrogen bonds

o G with C, three hydrogen bonds

RNA

Single stranded nucleic acid molecule involved with

the synthesis of proteins

 RNA: nucleotides, which consist of

phosphate, ribose and nitrogen base

 RNA polymerase is the enzyme that is

responsible for synthesing RNA molecules

 mRNA has codons, which are bound by the

anticodons on tRNA during translation of

protein synthesis

 Exons are coding sequences in the mRNA

and introns are areas of unknown function



 Core structure is pentose sugar ribose

linking the purine bases – (A) and (G) - with

the pyrimidines - uracil and (C)

Types of RNA involved in gene transcription and

translation:

 messenger RNA

 Ribosomal RNA

 Transfer RNA

During translation of mRNA, the bases are ‘read’ in a

3 base pair or triplet code, each 3-base pair unit

being referred to as a codon

Transfer RNA

 Made within the nucleus

 Functions within the cytoplasm

 It attaches the correct amino acid to the protein chain being synthesized according

to the codon sequence on messenger RNA,

which it encounters - translation

Ribosomal RNA

 Manufactured in the nucleolus

 Main constituent of ribosomes within the

cytoplasm

Messenger RNA

 A polynucleotide subtype of RNA, which is produced by the transcription of DNA

within the nucleus

 It passes out of the nucleus to the

ribosomes within the cytoplasm Here, the

precise sequence is translated into protein

RNA splicing Coding sequence is interrupted by non-coding

sequences

Removal of the introns in RNA transcript

modification is called RNA splicing

Splicing occurs in the nucleus before transport to the cytoplasm

Exons are expressed sequences: these sequences are those present in mature mRNA

Gene

 A gene is a length of DNA or RNA with a

suitable number of base sequences to code

for the production of a single polypeptide

chain In Man, genes exist in homologous

pairs within an allele

 It consists of exons and introns

Gene mutations;

 Mismatch: change in the nucleotide

 Inversion: nucleotide base removed,

reverse directed & reinserted

 Point mutation; single base pair

substitution

Genome

• DNA

• Only about 5% of DNA codes for proteins

• Human genome: 30.000 genes

• Each cell expresses 16.000 genes

• Housekeeping genes: genes expressed in all

cells to provide basic function for cell

survival (constitutive)

• Southern blotting detects DNA

Transcriptome

• mRNA

• Microarray analysis of transcriptome 

identify the expressed genes

• Northern blotting detects RNA

Proteome

• Protein

• Analysis of the proteome is better as it

detects changes at the protein level, not

reflected at transcriptome level due to Post

translation processing (Bioinformatics)

• Western blotting can be used to detect and

quantify proteins

Molecular biology techniques

The following table shows a very basic summary of molecular biology techniques

Technique Description Southern

blotting

Detects DNA Northern

blotting

Detects RNA Western

blotting

Detects proteins Uses gel electrophoresis to separate native proteins by 3-D structure Examples include the confirmatory HIV test

Molecular biology techniques

 SNOW (South - NOrth - West)

 DROP (DNA - RNA - Protein)

Enzyme-linked immunosorbent assay (ELISA)

 A type of biochemical assay used to detect antigens and antibodies

 A colour changing enzyme is attached to the antibody if looking for an antigen and to an antigen if looking for an antibody

 The sample therefore changes colour if the antigen or antibody is detected

 An example includes the initial HIV test

DNA analysis Direct testing;

 Identify abnormality within a well-known specific gene

 Restriction enzymes digestion

 Southern blotting

Indirect testing; (linkage analysis)

Used when the gene in question has not been identified before It involves tracing DNA markers in more than generation within a family

This is used to determine the rough location of the

gene responsible for disease, relative to another

DNA sequence which has its position already known

(a 'genetic marker') Disease genes are mapped by

measuring recombination against a panel of

different markers This can identify the region of the

genome in which the disease gene lies, then allowing

more detailed investigation of this region

Southern blotting is a laboratory procedure in which

DNA fragments that have been electrophoresed

through a gel are transferred to a solid membrane

such as nitrocellulose The DNA can then be

hybridized with a labelled probe and exposed to X

ray film

'In situ hybridization' It uses a labelled

complementary DNA or RNA probe to localise a

specific sequence within a tissue Firstly, the tissues

are treated to fix the target, and then the probe is

added This then hybridises to the target, following

which excess probe is washed away In the classical

form, the probe is labelled with radiolabelled bases,

which can then be identified using plain film

FISH is a form of in situ hybridisation in which the

probe is labelled with fluorescent bases, which can

then be visualised under a fluorescent microscope

Somatic cell hybridisation is a physical gene

mapping technique in which somatic cells from two

different species are fused and allowed to undergo

cell division Chromosomes from one species are

selectively lost, resulting in clones with only one or a

few chromosomes from one of the species

SSCP is a technique for detecting variation in DNA

sequence by running single-stranded DNA fragments

through a non-denaturing gel Fragments with

differing secondary structure (conformation) caused

by sequence variation will migrate at different rates

Occurs in gametes Results in 2 diploid

Daughter cells contain one homologue of each chromosome pair and are therefore genetically different

Mitosis

Mitosis occurs during the M phase of the cell cycle It describes the process in which somatic cells divide and replicate producing genetically identical diploid daughter cells This allows tissue to grow and renew itself

During the S phase of the cell cycle the cell prepares itself for division by duplicating the chromosomes The table below shows the phases of mitosis itself: Prophase Chromatin in the nucleus

condenses Prometaphase Nuclear membrane breaks down

allowing the microtubules to attach

to the chromosomes Metaphase Chromosomes aligned at middle of

cell Anaphase The paired chromosomes separate

at the kinetochores and move to opposite sides of the cell Telophase Chromatids arrive at opposite poles

of cell Cytokinesis Actin-myosin complex in the centre

of the cell contacts resulting in it being 'pinched' into two daughter cells

• Cell division results in 2 daughter cells, each

of which can

– Enter its own G1 phase

– Become an inactive resting (G0) or

– Die (cell loss fraction)

Cell cycle

G0  'resting' phase

 quiescent cells such as hepatocytes

and more permanently resting cells such as neurons

G1  Gap 1, cells increase in size

 determines length of cell cycle

M  Mitosis - cell division

 Cyclins: are proteins key regulators of cell cycles

which can bind to enzymes known as cyclin

dependent kinases These regulate the

progression of the cell cycle

 Different cyclins are expressed at different

stages of the cell cycle

Exons: segment of the gene transcripted into mRNA

then translated into proteins

Introns: segment of the gene transcripted then

removed by splicing (not translated)

Promotor elements: binding sites for initiation of

 Not obligatory for initiation

 But ↑ gene expression

Transcription factor is a protein that binds to

specific DNA sequences, thereby controlling the rate

of transcription of genetic information from DNA to messenger RNA

 Basal = constitutive - Housekeeping genes

 Inducible = temporal, spatial expression of genes for tissue phenotype

Application of Transcription factor;

 Many congenital malformations are due to inherited mutation of TF

 Can be oncogenic e.g cMyC, P53

 Steroids affect TF

Protein synthesis consists of two phases

Transcription is where one strand of (DNA) double

helix is used as a template by (RNA) polymerase to

synthesise mRNA from RNA nucleotides

The mRNA then migrates into the cytoplasm

maturing, for example, by the splicing of non-coding

sequences

 Transposons are genetic sequences that

have been transposed from one part of

DNA to another

Translation occurs when the ribosome binds to

mRNA at the start codon and tRNA brings amino

acids into position along the mRNA template

Ribosomal RNA interacts with tRNA during

translation by providing peptidyl transferase activity

 The ribosome moves from codon to codon

along the mRNA producing a polypeptide

sequence

Translation always begins with a methionine residue

The mRNA is translated in the 5’ to 3’ direction and

is read in groups of 3 bases, which are known as

codons New amino acids are added to the carboxyl

terminus of the growing peptide chain

Plasmids

Are circular molecules of bacterial (DNA) separate

from the bacterial chromosome

They usually:

 are small

 consist of a few thousand base pairs

 carry one or a few genes, and

 Have a single origin of replication

Genes on plasmids with multiple copies are usually

expressed at higher levels

In nature these genes often encode for proteins such

as those needed for bacterial resistance

Plasmids can be used to clone genes by splicing a

particular gene into a plasmid and then allowing the

bacteria to multiply - this is then called recombinant

Bacteria develop resistance to antibiotics by gaining genes that encode for particular proteins that offer protection to the organism

Sometimes this is by mutation and at other times the gene may be acquired from another bacterial species

The genes are usually found in plasmids - circular segments of DNA separate from the bacterial chromosome

Plasmids can easily spread from one bacteria to another - a sort of resistance package that bacteria can share

Restriction enzymes cut DNA at sequences specific

for each restriction enzyme HindIII and EcoRI are examples of restriction enzymes

DNA ligase and polymerase are involved in joining

and linking DNA together

EX: Two strains of Staph aureus are isolated and both are resistant to ampicillin Strain 1 retains its resistance to amplicillin when grown from multiple generations in the absence of ampicillin However strain 2 loses its resistance when grown in the absence of ampicillin Which of the following best explains the loss of antibiotic resistance in strain 2?

Answer: e) Loss of a plasmid containing the resistance gene Bacteria develop resistance to antibiotics by gaining genes which encode particular proteins which offer protection organism

Sometimes this occurs by mutation but at other times gene may be acquired from another bacterial species The genes are contained in plasmids (circular segments of DNA) separate from bacterial chromosome Plasmids can easily spread from one bacteria or equally lost Transfer, loss and gain of plasmids are relatively common compared to single mutations

PCR

PCR is a molecular genetic investigation technique

The main advantage of PCR is its sensitivity

Only one strand of sample DNA is needed to detect a

particular DNA sequence

It now has many uses including prenatal diagnosis,

detection of mutated oncogenes and diagnosis of

infections

PCR is also extensively used in forensics

Prior to the procedure it is necessary to have two

DNA oligonucleotide primers These are

complimentary to specific DNA sequences at either

end of the target DNA

Initial prep:

 Sample of DNA is added to test tube along

with two DNA primers

 a thermostable DNA polymerase (Taq) is

added

The following cycle then takes place

Mixture is heated to almost boiling point causing denaturing (uncoiling) of DNA

Mixture is the allowed to cool: complimentary strands of DNA pair up, as there is an excess of the primer sequences they pair with DNA preferentially The above cycle is then repeated, with the amount

of DNA doubling each time

Reverse transcriptase PCR

 used to amplify RNA

 RNA is converted to DNA by reverse transcriptase

 gene expression in the form of mRNA (rather than the actually DNA sequence) can therefore

be analyzed Using the enzyme reverse transcriptase, the cDNA is then amplified by conventional polymerase chain reaction (PCR)

Apoptosis

 Physiological process of programmed cell

death (in contrast to necrosis which is

pathological)

 A key event to initiation of apoptosis is the

activation of a cascade of

cysteine-aspartate specific proteases known as

caspases

 Cell shrinkage, compaction of chromatin,

nuclear & cytoplasmic apoptotic bodies’

phagocytised by MQ,

 Laddering of DNA on electrophoresis gel by

activation of intracellular nucleases

 Programmed cell death: naturally

occurring cell death due to activation of a

set of genes in response to external signals

e.g from neighbour or extracellular matrix

 Apoptosis webbed fingers, selection of

neurons after maturation of (normal Apoptosis in embryo)

 Apoptosis of excess or auto-reactive T

lymphocytes (normal Apoptosis in

adult)

 Removal of virally infected cells

 Removal of cells that have undergone DNA damage

Disease of excess and insufficient apoptosis:

 Excess:

o Neurodegenerative dis Alzheimer,

Parkinson’s

o HIV (CD4 cells die through

programmed cell death)

 Insufficient

o Cancer

o Autoimmune Factors that + apoptosis;

 P53,

 Fas, CD95 (receptor for TNF),

Factors that - apoptosis;

 Bcl2 (survival signals), Bcl-2 inhibits

apoptosis; preventing p53 mediated cell destruction and prevents cell death

 B catenin accumulation adenoma

Apoptosis occur through proteases called caspases

(e.g ICE= IL-1B converting enzyme) that + endonucleases

Caspases = cysteine aspartate specific proteases Cancer resists apoptosis by;

 Mutation of P53

 Over-expression of Bcl2

 Causing apoptosis of cytotoxic T cells (TNF

like + Fas)

Oncogenes:

Are endogenous human (DNA) sequences that arise

from normal genes called proto-oncogenes

Proto-oncogenes: are

 Normally expressed in many cells,

particularly during fetal development,

 Play an important regulatory role in cell

growth and development

Alterations in the proto-oncogene can activate an

oncogene, which produces unregulated gene

activity, contributing directly to tumourogenesis

Oncogene alterations are important causes of:

Ras is the commonest oncogene is involved in

sporadic tumours (colon and lung) and

rhabdomyosarcomas

C-myc: Burkitt's lymphoma (C-myc is translocated

intact from its normal position on chromosome 8 to

chromosome 14)

Philadelphia Chr.bcr + abl (9; 22)  fusion protein 

tumour growth

N-myc: Neuroblastoma

SRC oncogene is associated with sarcoma

Tumour suppressor genes

 Genes which normally control the cell cycle

 Loss of function results in an increased risk

of cancer

 Both alleles must be mutated before cancer occurs (recessive)

Examples

Gene Associated cancers

Li-Fraumeni syndrome

BRCA1 Breast and ovarian cancer BRCA2 Breast and ovarian cancer

Multiple tumor suppressor 1 (MTS-1, p16)

Melanoma

Colorectal, pancreatic

or oesophageal cancers

DCC

Tumour suppressor genes - loss of function results in

an increased risk of cancer

Oncogenes - gain of function results in an increased risk of cancer

P53

P53 is a tumour suppressor gene located on chromosome 17p It is the most commonly mutated gene in breast, colon and lung cancer

p53 is thought to play a crucial role in the cell cycle, preventing entry into the S phase until DNA has been checked and repaired It may also be a key regulator

of apoptosis Li-Fraumeni syndrome is a rare autosomal dominant disorder characterised by the early onset of a variety

of cancers such as sarcomas and breast cancer It is caused by mutation in the p53 gene

P27

Tumor suppressor gene through down regulation of

cell cycle (cyclin dependent kinase inhibitor), if

downregulated sporadic Cancer colon

BRCA 1

Lifetime Breast Cancer Risk 60%

Lifetime Ovarian Cancer Risk 40%

BRCA 2

Lifetime Breast Cancer Risk 45%

Lifetime Ovarian Cancer Risk 15%

NOTE Lifetime risk means the chance of developing

cancer by the age 70 and the above figures are

applied to females

Nitric oxide

Previously known as endothelium derived relaxation

factor, nitric oxide (NO) has emerged as a molecule,

which is integral to many physiological and

pathological processes It is formed from L-arginine

and oxygen by nitric oxide synthetase (NOS) An

inducible form of NOS has been shown to be present

in macrophages Nitric oxide has a very short half-life

(seconds), being inactivated by oxygen free radicals

Effects

 Acts on guanylate cyclase leading to raised

intracellular cGMP levels and therefore

decreasing Ca2+ levels

 vasodilation, mainly venodilation

 Inhibits platelet aggregation

Clinical relevance

 Underproduction of NO is implicated in

hypertrophic pyloric stenosis

 lack of NO is thought to promote

atherosclerosis

 in sepsis increased levels of NO contribute to

septic shock

 organic nitrates (metabolism produces NO) is

widely used to treat cardiovascular disease

(e.g angina, heart failure)

 sildenafil is thought to potentiate the action

of NO on penile smooth muscle and is used in

the treatment of erectile dysfunctions

Atrial natriuretic peptide

 Secreted mainly from myocytes of right atrium and ventricle in response to increased blood volume

 secreted by both the right and left atria (right >> left)

 28 amino acid peptide hormone, which acts via cGMP

 degraded by endopeptidases Actions

 natriuretic, i.e promotes excretion of sodium

in response to strain

Whilst heart failure is the most obvious cause of raised BNP levels any cause of left ventricular dysfunction such as myocardial ischaemia or valvular disease may raise levels Raised levels may also be seen due to reduced excretion in patients with chronic kidney disease Factors which reduce BNP levels include treatment with ACE inhibitors, angiotensin-2 receptor blockers and diuretics Effects of BNP

 vasodilator

 diuretic and natriuretic

 Suppresses both sympathetic tone and the renin-angiotensin-aldosterone system

BNP synthesis is increased by thyroid hormones as well as glucocorticoids, endothelin-1, angiotensin-II and tachycardia, independent of the haemodynamic effects of these factors

Clinical uses of BNP

diagnosing patients with acute dyspnoea

 a low concentration of BNP(< 100pg/ml)

makes a diagnosis of heart failure unlikely,

but raised levels should prompt further

investigation to confirm the diagnosis

 NICE currently recommends BNP as a

helpful test to rule out a diagnosis of heart

failure

Prognosis in patients with chronic heart failure

 Initial evidence suggests BNP is an

extremely useful marker of prognosis

Guiding treatment in patients with chronic heart

failure

 effective treatment lowers BNP levels

Screening for cardiac dysfunction

 not currently recommended for population

screening

Prostacyclin

Prostacyclin is mainly synthesized by vascular

endothelium and smooth muscle Effects include:

 Inhibitor of platelet aggregation - does not

influence platelet degranulation

 Relaxation of smooth muscle

 Reduction of systemic and pulmonary

vascular resistance by direct vasodilation

 Natriuresis in kidney

Endothelin Endothelin is a potent, long-acting vasoconstrictor and bronchoconstrictor It is secreted initially as a prohormone by the vascular endothelium and later converted to ET-1 by the action of endothelin converting enzyme It acts via interaction with a G-protein linked to phospholipase C leading to calcium release Endothelin is thought to be important in the pathogenesis of many diseases including primary pulmonary hypertension (endothelin antagonists are now used), cardiac failure, hepatorenal syndrome and Raynaud's

 Primary pulmonary hypertension

Vasodilatation & vasoconstriction:

 Calcitonin-gene related peptide causes vasodilatation

 ANB & ANP causes vasodilatation

 ADH acts on the vasopressor receptors to cause vasoconstriction

 Endothelin is also a vasoconstrictor as is renin

 Somatostatin is also recognised to produce vasoconstriction of the splanchnic system

Pro-inflammatory cytokines

A proinflammatory cytokine is a cytokine, which

promotes systemic inflammation

Il-1, TNF, TGF-B, Heat shock protein, free radicals

 etanercept: fusion protein that mimics the

inhibitory effects of naturally occurring

soluble TNF receptors, subcutaneous

administration

 adalimumab: monoclonal antibody,

subcutaneous administration

 adverse effects of TNF blockers include

reactivation of latent tuberculosis and

o Tissue repair (initiate and terminate)

o Increase extracellular matrix

o Fibrosis

 Tissue injury  + plat release of TGF-B 

chemotaxis  monocytes, neutrophils and

t cell and fibroblast

 It induce monocytes to (+ fibroblast GF,

TNF, IL-1)

 Involved in glomerulosclerosis, hep fibrosis,

pulm fibrosis, bleomycin lung

HSPs (Heat shock proteins)

• Heat, chemicals, free radicals  ↑ damage

of intracellular proteins  ↑ HSP  ↑ cell resistance to stress through;

- protein folding & unfolding

- Degradation of protein (by ubiquitination)

• Dis associated; if mutated cataract, motor neuron deg

Free radicals

Any molecule with 1 or more unpaired electron (more reactive); peroxide –HCOO, superoxide O2, hydroxyl-O, nitric oxide NO

• NB; hydroxyl is the most reactive

• Action;

- lysosomes

- Lipid peroxidation of membrane

- Mutations (by attaching purines &

pyrimidine)

• Diseases athero, cancer, neurodeg (MND)

• Free radical scavengers;

- α tocopherol (Vit E)

• Immunoglobulin superfamily (CD2, CD3, NCA (neural cell adh), ICAM (intercellular) bind to LFA (lymph funct ass Ag) to recruit lymphocytes

• Integrin (cell to matrix) Integrins are surface receptors by which cells are attached to extracellular matrix

• Cadherins (Nerve &Muscle) in embryo

• Selectins (leukocytes to endoth in inflam, over expressed in autoimmune viral hepatitis, organ rejection)

Stem cells

• Progenitor cells

• Present in certain tissues e.g BM,

embryonic

• Embryonic totipotent (any tissue)

• BM  Bl cells only, can be recruited by Ag

sorting with CD34 Ab & undergo trans

• differentiation to non-hematologic cells

Membrane receptors There are four main types of membrane receptor: ligand-gated ion channels, tyrosine kinase receptors, guanylate cyclase receptors and G protein-coupled receptors

Ligand-gated ion channel receptors

 Generally mediate fast responses

 e.g nicotinic acetylcholine, GABA-A & GABA-C, glutamate receptors

Guanylate cyclase receptors

 Contain intrinsic enzyme activity

 e.g atrial natriuretic factor, brain natriuretic peptide

Tyrosine kinase receptors

 Intrinsic tyrosine kinase: insulin, insulin-like growth factor (IGF), epidermal growth factor (EGF)

 Receptor-associated tyrosine kinase: growth hormone, prolactin, interferon, interleukin

 The bcr-abl fusion protein is the oncogene from the Philadelphia chromosome found in CML It is a potent tyrosine kinase which stimulates signal transduction and hence mitosis

 7-helix membrane-spanning domains

 Consist of 3 main subunits: alpha, beta and gamma

 The alpha subunit is linked to GDP.Ligand binding causes conformational changes to receptor, GDP is phosphorylated to GTP,and the alpha subunit is activated

 G proteins are named according to the alpha subunit (Gs, Gi, Gq)

Gs Gi Gq Mechanism Activates adenylate cyclase →

increases cAMP → activates

protein kinase A

Inhibits adenylate cyclase → decreases cAMP → inhibits protein kinase A

Activates phospholipase C → splits PIP2 to IP3 & DAG → activates protein kinase C Examples • Beta-1 receptors

• D2 receptors (dopamine)

• GABA-B receptor

• Alpha-1 receptors (epinephrine, norepinephrine)

• H1 receptors (histamine)

• V1 receptors (vasopressin)

• M1, M3 receptors (acetylcholine)

Second messengers

Overview

 many different types

 allow amplification of external stimulus

cAMP system Phosphoinositol system cGMP

system

Tyrosine kinase system Ligand:

Neurotransmitters

(Receptor)

Epinephrine (α2, β1, β2) Acetylcholine (M2)

Epinephrine (α1) Acetylcholine (M1, M3)

angiotensin II, GnRH, GHRH*, Oxytocin, TRH , ADH

ANP, Nitric oxide

insulin, growth hormone, IGF, PDGF

Primary effector Adenylyl cyclase Phospholipase C Guanylate

cyclase

Receptor tyrosine kinase

cGMP Protein

phosphatase

*the cAMP pathway is the most important

Insulin acts through mitogen-activated protein

(MAP) kinase pathway, as does growth hormone

(GH) and prolactin

Nitric oxide: (cGMP) as the second messenger

Pioglitazone acts through: (PPAR) gamma receptor

GH like TNF alpha: via the janus kinases/signal

transducers and activators of transcription

(JAK-STAT) pathway

Cholera toxin activates adenylate cyclase with

generation of cyclic adenosine monophosphate

(cAMP) which leads to the activation of luminal

sodium pumps and the secretory diarrhoea

Phosphorylation of specific tyrosine residues of

components of cell signalling pathways is often a

key event in the activation of the pathway

Receptors

Cell membrane surface receptors;

 Ligand-gated ion channel receptors

 Tyrosine kinase receptors

The complex travel to the nucleus & bind to

hormone responsive elements

When it binds T3 it is able to bind to the thyroid

hormone response element (TRE) in the promoter

region of thyroid hormone responsive genes and

initiates transcription

Chemical classes of hormones

 Amino acid derived –

o Melatonin and

o Thyroxin,

o Catecholamine ,

o Serotonin

 Polypeptide and proteins

o Small peptide hormones: TRH and

TSH

 Eicosanoids – hormones derive from lipids such

as arachidonic acid, lipoxins and prostaglandins

 Steroid –the sex hormones estradiol and

testosterone , cortisol , aldosterone ,

progesterone and vitamin D Hormones that are glycoproteins include:

Mechanism of resistance

 Penicillin is a bactericidal antibiotic which acts

by inhibiting cell wall synthesis

Mutations in penicillin binding proteins - PBPs

(enzymes required for cell wall synthesis) result

in penicillin resistance

 Rifampicin is a bacteriostatic antibiotic which

acts by inhibiting protein synthesis

Mutations in rpoB gene cause alterations in the

bacterial DNA dependent RNA transcriptase

which prevents the binding of rifampicin

 Gentamicin is synergistic to the action of

benzylpenicillin Benzylpenicillin is bactericidal,

inhibiting cell wall synthesis, enabling

gentamicin to enter the bacterial cell

It acts at the level of the ribosome, inhibiting

protein synthesis.(translation)

 Glycopeptides inhibit cell wall synthesis through

steric hindrance of peptidoglycans, components

of the bacterial cell wall

 Trimethoprim interferes with the action of

dihydrofolate reductase (DHFR)

DHFR is an enzyme that converts dihydrofolic to

tetrahydrofolic acid, an essential stage in

bacterial purine and, ultimately DNA synthesis

 Ciprofloxacin interferes with DNA synthesis by

disrupting the function of DNA gyrase

Therapeutic drug monitoring

 trough levels immediately before dose

Erythrocyte sedimentation rate (ESR)

The ESR is a non-specific marker of inflammation and depends on both the size, shape and number of red blood cells and the concentration of plasma proteins such as fibrinogen, alpha2-globulins and gamma globulins

Causes of a high ESR

The anion gap is calculated by:

(sodium + potassium) - (bicarbonate + chloride)

A normal anion gap is 8-14 mmol/L

It is useful to consider in patients with a metabolic acidosis:

Causes of a normal anion gap or hyperchloraemic metabolic acidosis

 gastrointestinal bicarbonate loss: diarrhoea, ureterosigmoidostomy, fistula

 renal tubular acidosis

 drugs: e.g acetazolamide

 ammonium chloride injection

 Addison's disease

Causes of a raised anion gap metabolic acidosis

 lactate: shock, hypoxia

 ketones: diabetic ketoacidosis, alcohol

 urate: renal failure

 acid poisoning: salicylates, methanol

Botulinum toxin

As well as the well publicised cosmetic uses of

Botulinum toxin ('Botox') there are also a number of

licensed indications:

 blepharospasm

 hemifacial spasm

 focal spasticity including cerebral palsy

patients, hand and wrist disability

associated with stroke

 spasmodic torticollis

 severe hyperhidrosis of the axillae

 achalasia

Concerning the respiratory cell biology of

an
asthmatic individual, which of the following is

true ===
T cells are mobile and contribution to

asthma is via cytokine Production

Causes of a raised amylase are:

Meralgia paraesthetica

Basics

 Caused by compression of lateral

cutaneous nerve of thigh

 Typically burning sensation over

antero-lateral aspect of thigh

 Trauma around the inguinal ligament

can lead to damage in the lateral cutaneous nerve supplying the anterolateral portion of the thigh It is a purely sensory nerve, which travels lateral to the psoas muscle

EX: A 50-year-old woman has right-sided

weakness, headache and vomiting On

examination she has a hemiplegia affecting the

right face, arm and leg She also has unilateral

internuclear ophthalmoplegia with failure of

adduction to the left and nystagmus to the left

Fundoscopy reveals papilloedema In this

patient, the papilloedema is due to obstruction

at : The aqueduct of the midbrain (the aqueduct

of Sylvius) runs in the tegmentum of the

midbrain and joins the third and fourth

ventricles Compression of the aqueduct can

result in obstructive hydrocephalus and

papilloedema

Headache and vomiting can occur because of

raised intracranial pressure Malignant or benign

intracranial tumors, colloidal cysts, arachnoid

cysts, and neurocysticercosis can also cause

compression and need to be ruled out

Most noradrenaline is taken up back into

neurosecretory granules MAO and COMT

metabolise NA in small amounts

The cord is tapered at the lower end to form the

EX: Which one of the following features is consistent with higher cortical involvement rather than a diagnosis of a subcortical lacunar stroke? Answer: c) dysphasia Evidence of higher cortical involvement, for example - dysphasia, dyscalculia or or disturbance of consciousness, would not be consistent with a lacunar syndrome

EX: A 40 year old man has an anterior mediastinal mass seen on CT scan Which of the following is likely to be a cause for the mass?

The four Ts for mediastinal masses (anterior) are thyroid, thymoma, teratoma and tumour (lymphomas)

Caudate nucleus, putamen and globus pallidus

are areas within the basal ganglia which, when

impaired, can lead to

 Wernicke and Korsakoff syndrome

Striatum (caudate nucleus) of the basal ganglia :

 Huntington chorea

Hippocampus pathology is associated with

short-term memory impairment (for

example, Alzheimer's disease)

Substantia nigra of the basal ganglia:

Parkinson's disease

Amygdala: Kluver-Bucy syndrome

(hypersexuality, hyperorality, hyperphagia,

visual agnosia

Lateral geniculate nucleus pathology causes a

visual field defect

Red nucleus is associated with tremor, which is

present both at rest and during action (for

example, multiple sclerosis tremor)

Oxygen Dissociation Curve

Acidosis raised 2,3 DPG, raised temperature, hypoxia and anaemia all shift the O2-Hb dissociation curve to the right, leading to reduced affinity to O2

B cells are not only produced in the bone

marrow but also mature in thymus However, the precursors of T cells leave the bone marrow

and mature in the thymus

EX: A postgraduate student is studying HIV replication Which of the following is important

in the replication or transmission of HIV-1?

Answer: c) GP 120 HIV reverse transcriptase, integrase and protease are key enzymes essential for HIV replication The HIV genome contains the genes: tat and rev along with nef, env, gag and pol The GP 120 is the major protein on the surface of HIV that interacts with host cells HIV binds to cell surface CD4 but enters cells through chemokine receptors including CXCR4 and CCR5 Thymidine kinase is produced by the herpes simplex virus

Lung anatomy

The lower parts of the lung and pleura overlap

the right surface of the liver The apical pleura

and lung project about 3–4 cms above the inner

aspect of the clavicle The horizontal fissure

demarcates the middle lobe from the upper lobe

on the right side The lower margin of the pleura

is about two ribs below the lower margin of the

lung

Behind (posterior to) the left main bronchus

 The descending aorta lies behind

(posterior to) the left main bronchus

 The ascending aorta is anterior to the

pulmonary trunk

 The left pulmonary artery is anterior to

the left main bronchus

 The right main bronchus should be

beside the left following bifurcation of the trachea

 The superior vena cava can be found

next to the ascending aorta

 The oesophagus is also a posterior

structure to the left main bronchus

In human anatomy, an azygos lobe is a

congenital variation of the upper lobe of the

The left atrial appendage is not readily seen on transthoracic echocardiography and requires transoesophageal echocardiography

Hand action:

Flexion of the fingers and thumb abduction is

supplied by the median nerve

Extension of the fingers are supplied by radial nerve

Adduction of thumb is supplied by ulnar nerve

Global muscle wasting of the hand indicates damage to both the median and ulnar nerves

Types of Cervical Radiculopathy

Symptoms differ depending on which nerve is affected For example, if the nerve root that runs above the C6 vertebra is affected, a physician will use the term “C6 radiculopathy”

 C5 radiculopathy can cause pain

and/or weakness in the shoulders and upper arms Especially may cause discomfort around the shoulder blades

It rarely causes numbness or tingling Weakness: shoulder abduction

 C6 radiculopathy (one of the most

common) causes pain and/or weakness along the length of the arm, including the biceps, wrists, and the thumb and index finger

- Weakness: elbow flexion, wrist extension

 C7 radiculopathy (the most common)

causes pain and/or weakness from the neck to the hand and can include the triceps and the middle finger

Weakness: elbow extension, wrist

 C8 radiculopathy causes pain from the

neck to the hand Patients may experience weakness in hand grip, and pain and numbness can radiate along the inner side of the arm, ring, and little fingers

- Weakness: thumb extension, wrist ulnar deviation

Sensory

 On sensory examination, patients with

a clear-cut radiculopathy should demonstrate a decrease in or loss of sensation in a dermatomal distribution

 In addition, patients with radiculopathy

may have hyperesthesia to light touch and pinprick examination

 The sensory examination can be quite

subjective because it requires a response by the patient

Extensor pollicis brevis and extensor carpi

ulnaris are supplied by C7/8

A pattern of rapidly recruited low amplitude

short duration motor units on the

electromyogram (EMG) would be considered to

represent myopathic changes rather than

de-innervation

The combination of diplopia, hemiparesis and a

lower motor neurone facial nerve lesion should

lead you to consider a pontine stroke

Primarily retroperitoneal organs are those that

develop and remain behind (outside) the peritoneum (kidneys, aorta, pancreas)

Secondarily retroperitoneal organs are those that develop within the peritoneal sac but are pushed behind it during growth (e.g ascending colon, most of duodenum)

The lateral pontine syndrome classically consists

of:

 Contralateral loss of pain and

temperature sensation in the trunk and extremities - lateral spinothalamic tract

 Ipsilateral paralysis of the upper and

lower face (lower motor neurone lesion), ipsilateral loss of lacrimation and reduced salivation, ipsilateral loss

of taste from the anterior two thirds of the tongue, loss of the corneal reflex (efferent limb) - facial nucleus and nerve (VII)

 Ipsilateral loss of pain and temperature

sensation of the face - spinal trigeminal nucleus and tract

 Nystagmus, nausea, vomiting, vertigo -

vestibular nuclei

 Ipsilateral central deafness - cochlear

nuclei

 Ipsilateral limb and gait apraxia -

middle and inferior cerebellar peduncle

 Ipsilateral Horner's syndrome -

descending sympathetic tract

Nerve lesions of upper limb:

lower brachial plexus injury; sudden upward movement of the abducted arm This causes features of an ulnar nerve palsy which is supplied by the lower brachial plexus roots C8 and T1 (Klumpke's paralysis)

The median and radial nerves can be excluded because of the typical ulnar nerve findings

The ulnar nerve can be damaged at the elbow from chronic pressure, leaning on the elbows, and direct trauma However, this injury is a stretching injury of the arm

A cervical spine injury would be expected to have other associated neurological signs

Nerve lesions of upper limb

 Total ulnar nerve paralysis === Inability to grip a sheet of Paper between his fingers when the hand is placed flat on the table fanning of fingers

 A 78-year-old man had poliomyelitis as a child, which left him with total paralysis of the left deltoid muscle.
Which feature is most likely to bepresent on clinical Examination ===== Detectable weakness in drawing the arm forward and internally rotating the shoulder when this is compared with the right side

The musculocutaneous nerve supples the

biceps, coracobrachialis and brachialis

muscles It also supplies sensation over the

lateral aspect of the forearm

Nerve lesios:

 The lacrimal gland is supplied by the facial

nerve

 The glossopharyngeal nerve supplies the

parotid salivary gland controlling salivary

secretions

 The oculomotor nerve carries

parasympathetic efferents to the sphincter

pupillae muscle

 The optic nerve carries sympathetic

postganglionic fibres to the dilator pupillae

The brachial artery bifurcates into the ulnar

and radial arteries at the level of

The head of the radius

The subclavian vein is a continuation of the

axillary vein, beginning at the lateral border of

the first rib

It passes anterior to scalenus anterior

The subclavian and internal jugular vein unite to

form the brachiocephalic vein, subsequently the

left and right brachiocephalic veins unite to

form the superior vena cava

The thoracic duct enters the left subclavian

The brachiocephalic trunk is a branch of the

aortic arch, which divides to form the right

subclavian and right common carotid arteries

The internal jugular vein

The internal jugular vein originates at the jugular foramen

It begins posterior to the internal carotid artery and then passes to its lateral side

As it descends in the carotid sheath it lies lateral first to the internal then the common carotid artery within the carotid sheath

It then passes anterior to the subclavian artery

to join the subclavian vein to form the brachiocephalic vein

The internal jugular vein receives a lymphatic trunk at its union with the subclavian vein

The internal jugular vein is usually of considerable size, and the right internal jugular

is usually larger than the left

The external jugular vein drains into the subclavian vein

It passes anterior to the subclavian artery to join the subclavian vein and then form the

brachiocephalic vein; the left and right brachiocephalic veins unite to form the superior vena cava

The internal jugular vein receives a lymphatic trunk at its union with the subclavian vein

The external jugular vein drains into the

subclavian vein

Body mass index (BMI) of 38, where is

the
correct position for central venous

cannulation ==== 2 cm under the mid-point of

the clavicle and 1 cm laterally

BLOOD SUPPLY UPPER LIMB

The internal thoracic artery arises from the

subclavian artery

The inferior and superior ulnar collateral

arteries and the profundabrachii are branches of

the brachial artery

The subscapular artery arises from the axillary

and is its largest branch, eventually

anastomosing with the lateral thoracic and

intercostal arteries

Mallet finger

The x ray demonstrates a small avulsion fracture

from the base of the distal phalanx where the

extensor tendon attaches Given the clinical

findings and x ray the diagnosis is mallet finger

A flexion force on the tip of the extended finger

jolts the DIPJ into flexion This may result in a

stretching or tearing of the tendon substance or

an avulsion of the tendon's insertion on the

dorsal lip of the distal phalanx base

The central slip is part of the extensor expansion

on the dorsal aspect of the finger The central

slip inserts onto the middle phalanx as is causes

extension at the proximal interphalangeal joint

(PIPJ) Hence, this option is incorrect

A DIPJ dislocation is not likely as the joint moves

freely on examination and is congruent on the x

Skier's thumb

Was formerly known as gamekeeper's thumb, and it relates to injury to the base of the thumb, resulting in damage or rupture of the ulnar collateral ligament

Once acute swelling has subsided, then gross instability of the thumb may result

Where a complete tear of the ligament is suspected, MRI may be valuable in confirming the diagnosis, as surgical repair is required

In cases of a partial rupture, immobilisation in a thumb spica is the standard therapy

General notes

 A 78-year-old man had poliomyelitis as a child, which left him with total paralysis of the left deltoid muscle.
Which feature is most likely to be present on clinical Examination = Detectable weakness in drawing the arm forward and internally rotating the shoulder when this is compared with the right side

 A posterior gastric ulcer if led to bleeding mostly from Splenic artery

 Which of the following stems best describes

a property of hyaline cartilage === It is avascular



Renal anatomy

The tables below show the anatomical relations

 The right and left renal arteries lie in the

trans pyloric plane at the level of the first

 Unconventional myosins do not form filaments and perform varied functions

in a broad range of cells (for example, organelle transport, endocytosis)

Myosin contains adenosine triphosphate (ATP) and actin-binding sites

Other myosin related genetic disorders besides the heavy chain mutations in cardiomyopathy include Carney's complex (trismus-

pseudocamptodactyly), type 1b Usher syndrome and non-syndromic deafness

Troponin

is a component of thin filaments (along with actin and tropomyosin), and is the protein to which calcium binds to accomplish this regulation

Troponin has three subunits, TnC, TnI, and TnT

When calcium is bound to specific sites on TnC, the structure of the thin filament changes in such a manner that myosin (a molecular motor organised in muscle thick filaments) attaches to thin filaments and produces force and/or movement

In the absence of calcium, tropomyosin interferes with this action of myosin, and therefore muscles remain relaxed

Common sex chromosome aneuploidies

All Diagnosis is by chromosomal analysis

Turner's syndrome: 45, XO or 45, X

It is caused by either the presence of only one sex

chromosome (X) or a deletion of the short arm of

one of the X chromosomes Turner's syndrome is

 Bicuspid aortic valve (15%),

coarctation of the aorta (5-10%)

 Primary amenorrhea (streak ovaries), low

estrogen with high gonadotrophins and infertility

 Cystic hygroma (often diagnosed

prenatally)

 High-arched palate

 Short fourth metacarpal

 Multiple pigmented naevi

 lymphoedema in neonates (especially

feet)

 Renal dysfunction due to horseshoe

kidney

 Hypertension is quite common in Turner

syndrome (10%) and is typically idiopathic - essential Or possibly by coarcitation of aorta and renal dysfunction

There is also an increased incidence of

autoimmune disease (especially autoimmune

thyroiditis) and Crohn's disease

Noonan's syndrome: 45 XY 'male Turner's',

Noonan’s, autosomal dominant condition

associated with a normal karyotype It is thought

to be caused by a defect in a gene on chromosome

Triple x (karyotype 47, XXX) (FOR READ)

Chromosomal analysis is useful for Turner's

(XO), Down's (trisomy 21) and Klinefelter's (XXY)

In Fragile X, Huntington’s disease (Trinucleotide repeat disorders), DNA analysis is useful to determine trinucleotide repeats (CGG repeats)

Common autosomal chromosome aneuploidies

Down's syndrome: Trisomy 21, mongolism

Risk of Down's syndrome with increasing

maternal age

One way of remembering this is

by starting at 1/1,000

at 30 years and then dividing the

denominator by 3 (i.e 3 times more common) for

every extra 5 years of age

translocation

(usually onto 14)

5% 10-15% if mother is

translocation carrier 2.5% if father is translocation carrier Mosaicism 1% An individual has 2 or

more genetic cell lines

The chance of a further child with Down's

syndrome is approximately 1 in 100 if the mother

is less than 35 years old If the trisomy 21 is a

result of a translocation the risk is much higher

Clinical features

 Face: upslanting palpebral fissures,

epicanthic folds, Brushfield spots in iris, protruding tongue, small ears, round/flat face

 Flat occiput

 Single palmar crease, pronounced 'sandal

gap' between big and first toe

 Multiple cardiac problems may be present

 Endocardial cushion defect (c 40%, also known as atrioventricularseptal canal defects)

 Ventricular septal defect (c 30%)

 Secundum atrial septal defect (c 10%)

 Tetralogy of Fallot (c 5%)

 Isolated patent ductus arteriosus (c 5%)

Defects, in order of decreasing frequency, are: (OnExamination)

1 Atrioventricularseptal defect

2 Ventricular septal defect

3 Patent ductusarteriosus

4 Tetralogy of Fallot, and

5 Atrial septal defect

Syndrome Key features

Patau syndrome

(trisomy 13) Microcephalic, small eyes

Cleft lip/palate Polydactyly Scalp lesions Edward's syndrome

(trisomy 18) Micrognathia Low-set ears

Rocker bottom feet Overlapping of fingers

Is a primary immunodeficiency disorder caused

by T-cell deficiency and dysfunction?

It is an example of a microdeletion syndrome

Features

 At risk of viral and fungal infections

 Parathyroid gland hypoplasia →

syndrome Short stature Learning difficulties

Friendly, extrovert personality Transient neonatal

hypercalcaemia Supravalvular aortic stenosis

Note Dominant vs Recessive

• A dominant allele is expressed even if it is paired with a recessive allele

• A recessive allele is only visible when paired with another recessive allele – Recessive alleles are not expressed in the presence of a dominant allele

Expression

• Homozygous: Both alleles alike AA or aa

• Heterozygous: Alleles are different Aa

• Codominant: Two different alleles are both dominant

• A = allele for type A blood

• B = allele for type B blood

• AB = results in type AB blood

No linkage has been established for a particular gene in manic depressive disorder

Autosomal dominate:

In autosomal dominant:

 Both homozygotes and heterozygotes

manifest disease (there is no carrier state)

 Both males and females affected

 Only affected individuals can pass on

disease

 Disease is passed on to 50% of children

 Normally appears in every generation

(although see below)

 Risk remains same for each successive

pregnancy

 Only one copy of the faulty gene is

required in the genotype for the patient to be a sufferer

Complicating factors:

 Non-penetrance: lack of clinical signs and

symptoms (normal phenotype) despite abnormal gene E.g 40% otosclerosis

 Spontaneous mutation: new mutation in

one of gametes e.g 80% of individuals with achondroplasia have unaffected parents

Autosomal recessive:

In autosomal recessive:

 Only homozygotes are affected

 Both males and females affected

 Not manifest in every generation - may 'skip a generation'

If two heterozygote parents

 25% chance of having an affected (homozygote) child

 50% chance of having a carrier (heterozygote) child

 25% chance of having an unaffected (i.e genotypical) child

If one affected parent (i.e homozygote for gene) and one unaffected (i.e not a carrier or affected)

 All the children will be carriers

Autosomal recessive disorders are often metabolic

in nature and are generally more life-threatening compared to autosomal dominant conditions

Autosomal dominant conditions

Autosomal recessive conditions are often thought

to be 'metabolic' as opposed to autosomal

dominant conditions being 'structural', notable

exceptions:

 Some 'metabolic' conditions such as

Hunter's and G6PD are X-linked recessive whilst others such as hyperlipidaemia type II and hypokalaemic periodic paralysis are autosomal dominant

 Some 'structural' conditions such as

ataxia telangiectasia and Friedreich's ataxia are autosomal recessive The following conditions are autosomal dominant:

 Achondroplasia

 Acute intermittent porphyria (metab)

 Adult polycystic disease (renal)

 Antithrombin III deficiency (haem)

 Ehlers-Danlos syndrome

 Familial adenomatous polyposis (GIT)

 Familial hypercholesterolaemia (metab)

 Hereditary haemorrg Telangiectasia

 Hereditary spherocytosis (haem)

 Hereditary nonpolyposis colorectal canc

 Hereditary angio-oedema, (immune.)

 Osteogenesis imperfect (rheum)

 Peutz-Jeghers syndrome (GIT)

 Retinoblastoma

 Romano-Ward syndrome

 Tuberose sclerosis

 Von Hippel-Lindau syndrome

 Von Willebrand's disease*

*Type 3 von Willebrand's disease (most severe

form) is inherited as an autosomal recessive trait

Around 80% of patients have type 1 disease

Autosomal recessive conditions

Autosomal recessive conditions are often thought

to be 'metabolic' as opposed to autosomal dominant conditions being 'structural', notable exceptions:

 Some 'metabolic' conditions such as Hunter's and G6PD are X-linked recessive whilst others such as hyperlipidemia type

II and hypokalemic periodic paralysis are autosomal dominant

 Some 'structural' conditions such as ataxia telangiectasia and Friedreich's ataxia are autosomal recessive The following conditions are autosomal recessive:

 Albinism (oculocutanous albinism)

 Alpha 1-Antitrypsin deficiency

autosomal dominant although the infantile form is autosomal recessive

Sickle cell disease is inherited in an autosomal recessive manner (sickle cell trait is inherited in

an autosomal dominant manner)

Achondroplasia:

An autosomal dominant disorder associated with

short stature It is caused by a mutation in the

fibroblast growth factor receptor 3 (FGFR-3) genes

This results in abnormal cartilage giving rise to:

 Short limbs (rhizomelia) dwarfism with

shortened fingers (brachydactyly) but spinal length is maintained

 Large head with frontal bossing

 Mid face hypoplasia with a flattened nasal

bridge

 'Trident’ hands

 Limited elbow extension

 Exaggerated lumbar lordosis,

Incidence increases with paternal age

Epiphyseal growth cartilage fails, but there is

normal bone formation and repair There is

therefore no increased risk of fracture The

homozygous form is usually fatal

It may be diagnosed radiographically at birth, or

becomes obvious within the first year with

disparity between a large skull, normal trunk

length and short limbs X Rays show metaphyseal

irregularity, flaring in the long bones, and late

appearing irregular epiphyses The pelvis is

narrow in anteroposterior diameter with deep

sacroiliac notches and short iliac wings The spine

shows progressive narrowing of the

interpedicular distance from top to bottom

(reverse of normal)

Ehler-Danlos syndrome is an autosomal dominant

connective tissue disorder that mostly affects type III

collagen This results in the tissue being more elastic

than normal leading to joint hypermobility and

increased elasticity of the skin

Features and complications

 Elastic, fragile skin

 Angioid retinal streaks

(FGFR) gene mutations can be associated with

skeletal dysplasias

Marfan's syndrome: an autosomal dominant

connective tissue disorder

It is caused by a defect in the fibrillin-1 gene on

chromosome 15 and affects around 1 in 3,000 people

 Lungs: repeated pneumothoraxes

 Eyes: upwards lens dislocation (superotemporal ectopia lentis), blue sclera, retinal detachment, early glaucoma, and early cataracts

 Myopia

 Dural ectasia (ballooning of the dural sac

at the lumbosacral level) The life expectancy 40-50 years With the advent

of regular echocardiography monitoring and blocker/ACE-inhibitor therapy this has improved significantly over recent years Aortic dissection and other cardiovascular problems remain the leading cause of death however

beta-Patients with the rarer form of Marfan syndrome, which is characterized by contractural

arachnodactyly instead of loose joints, can usually

be identified by detection of a mutation in the fibrillin-2 gene that is similar in structure to the gene for fibrillin-1

Preliminary data suggest that patients with mutations in the fibrillin-2 gene are not prone to develop aneurysms

As well as features similar to Turner's syndrome

(webbed neck, widely-spaced nipples, short

stature, pectus carinatum and excavatum), a

number of characteristic clinical signs may also be

 Cause by excessive release of Ca2+ from the

sarcoplasmic reticulum of skeletal muscle

 Associated with defects in a gene on

chromosome 19 encoding the ryanodine

receptor, which controls Ca2+ release from

the sarcoplasmic reticulum

Neuroleptic malignant syndrome may have a

 Due to defect in huntingtin gene on chromosome 4

Features typical develop after 35 years of age

 Chorea

 Personality changes (e.g irritability, apathy, depression) and intellectual impairment

 Dystonia

 Saccadic eye movements Treatment is with phenothiazines (haloperidol) for symptomatic control

Hypokalaemic periodic paralysis:

A rare autosomal dominant disorder characterized by episodes of paralysis, typically occur at night The underlying defect is a mutation

in muscle voltage-gated calcium channels Attacks may be precipitated by carbohydrate meals , onset most commonly in childhood and adolescents Attacks last hours and neurological examination is normally unremarkable in between attacks The average K+ on diagnosis is 2.4 mmol/L1

Diagnosis is often made clinically in association with low potassium but genetic testing can help if known mutations are present Management- lifelong potassium supplementation

This disorder is commonly caused by medication,

especially diuretics There is also an inherited

membrane disorder that predisposes patients to

episodes of hypokalaemic periodic paralysis In

the inherited cases, the condition often occurs

during a period of rest after exercise or a meal

Management: Avoiding heavy carbohydrate meals

a very low sodium diet and spironolactone may

prevent attacks

X-linked dominant

The conditions are inherited in a X-linked dominant fashion*:

Alport's syndrome (in around 85% of cases -

10-15% of cases are inherited in an autosomal recessive fashion with rare autosomal dominant variants existing) Features of Alport's syndrome (hereditary nephritis, hematuria, progressive renal failure and high frequency nerve deafness)

is usually more marked in in males

Rett syndrome in girls (regressive progressive

microcephaly, stereotypical hand movement and irregular breath pattern) defect in MeCP 2

Vitamin D resistant rickets

*pseudohypoparathyroidism was previously classified as an X-linked dominant condition but has now been shown to be inherited in an autosomal dominant fashion in the majority of cases

X linked dominant conditions are transmitted by a father to all his daughters and that, on balance, this is a better explanation of the genetics than the tenuous assertion that an autosomal dominant condition has by chance affected three daughters but neither of two sons

They affect both sexes but females more than males

All children of a homozygous mother are affected Half the sons and half the daughters inherit the disorder from an affected mother with the trait

An affected father passes the disease to all his daughters but none of his sons, as in this example

X-linked recessive

In X-linked recessive inheritance only males are

affected An exception to this seen in examinations

is patients with Turner's syndrome, who are

affected due to only having one X chromosome

 Transmitted by heterozygote females

(carriers)

 Male-to-male transmission is not seen

 Affected males can only have unaffected sons

and carrier daughters

Each male child of a heterozygous female carrier

has a 50% chance of being affected whilst each

female child of a heterozygous female carrier has a

50% chance of being a carrier

The possibility of an affected father having

children with a heterozygous female carrier is

generally speaking extremely rare However, in

certain Afro-Caribbean communities G6PD

deficiency is relatively common and homozygous

females with clinical manifestations of the enzyme

defect are seen

The abnormal gene is carried on the X

chromosome, and in the carrier female, the

normal allele on her other X chromosome protects

her from the disease Since the male does not have

this protection, he manifests the disease

In X linked inheritance therefore:

 Males are all affected

 Females only occasionally show mild sign of

disease

 Each son of a female carrier has a 1:2 chance

of being affected

 Each daughter of a female carrier has a 1:2

risk of being a carrier

 Daughters of affected males will all be

carriers, but sons of affected males will not be

affected since the Y chromosome is derived

example, creatine kinase in Duchenne muscular dystrophy

X-linked recessive conditions

The following conditions are inherited in a linked recessive fashion:

X- Androgen insensitivity syndrome

 Becker muscular dystrophy

 Duchenne muscular dystrophy

 Chronic granulomatous disease (in > 70%)

X linked recessive diseases can occur with the

same severity in females in certain situations having

 An affected father and carrier mother (seen