J a v a d J a m s h i d i

F a s a U n i v e r s i t y o f M e d i c a l S c i e n c e s , D e c e m b e r 2 0 1 5

S e s s i o n 11Medical Genetics

Single-Gene

Disorders

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Single-gene Traits

To date, more than 10,000 single-gene traits and disorders have been identified

Individually are rare, affect between 1% and 2% of the general population

The management of these disorders presents the major workload challenge in clinical genetics

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Huntington Disease (HD)

Derives its name from Dr George Huntington, who described it in 1872

Progressive neurological disability one of the worst hereditary disorders in man, no effective treatment or cure

The prevalence is approximately 1:10,000

The onset is mostly between 30 and 50 years, but it can start at virtually any age

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Clinical Features of HDSlowly progressive movement disorder and insidious impairment of intellectual function with psychiatric disturbance

The mean start age is about 40, duration is approximately 15 to 20 years

Chorea is the most common

5Image from: Netter's Neurology, Second Edition

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Clinical Features of HDSlowly progressive movement disorder and insidious impairment of intellectual function with psychiatric disturbance

The mean start age is about 40, duration is approximately 15 to 20 years

Chorea is the most common

As disease progresses the gait becomes unsteady and speech unclear

Intellectual changes in the early stages include memory impairment and poor concentration span

Anxiety and panic attacks, mood changes and depression

Aggressive behavior, paranoia, irrationality

Gradual deterioration in intellectual function, leading eventually to total incapacitation and dementia.

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Genetics of HDAutosomal dominant, variable age of onset, close to complete penetrance

Often shows anticipation, particularly when transmitted by a male

Codes for a protein known as huntingtin, 4p16.3, contain CAG repeats at 5´end

Huntingtin is expressed in many different cells throughout the central nervous system, as well as other tissues

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CAG Repeats and HD

Normal Alleles 26 or fewer CAG

Mutable Alleles 27 to 35 CAG

Reduced Penetrance Alleles 36 to 39 CAG

Disease Alleles 40 or more CAG

Predictive genetic test is available but…

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Myotonic Dystrophy (MD)

The most common form of muscular dystrophy seen in adults, overall incidence of approximately 1: 8000

Autosomal dominant inheritance, can be congenital

Anticipation with mother transmission

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Clinical Features of MDusually present in adult life with slowly progressive weakness and myotonia

Other clinical features include:CataractsCardiac conduction defectsDisturbed gastrointestinal peristalsis (dysphagia, constipation, diarrhea)Increased risk of diabetes mellitus and gallstonesSomnolence, frontal balding

As the age of onset becomes earlier, so the clinical symptoms increase in severity and more body systems are involved

From Dubowitz V: Muscle disorders in childhood, London, 1995, Saunders12

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Genetics of MD

Instability in a CTG repeat, present in the 3' UTR of dystrophia myotonica protein kinase gene (DMPK), 19q13.3

Normally the CTG consists of up to 37 repeats, affected individuals have an expansion of at least 50 copies

Correlation between disease severity and the size of the expansion, which can exceed 2000 repeats

Pre-symptomatic genetic testing and prenatal diagnosis are available…..

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Increasing repeats and severity of Myotonic Dystrophy

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Marfan Syndrome (MFS)

MFS is a disorder of fibrous connective tissue, specifically a defect in type I fibrillin, encoded by the FEN I gene

In the classic presentation affected individuals are:

Taller compared with unaffected family membersJoint laxityReduced upper to lower segment body ratioPectus deformity, and scoliosisConnective tissue defect gives rise to ectopia lentisDilatation of the ascending aorta (some families)

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Scoliosis

Marfan Syndrome17

Marfan Syndrome

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Genetics of MFS

Autosomal dominant and the majority of cases are linked to the large FEN I gene on 15q21

Most mutations are missense and have a dominant-negative effect

Resulting in less than 35% of the expected amount of fibrillin

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Cystic Fibrosis

One of the most common autosomal recessive disorders

Individuals of western european origin, incidence varies from 1 in 2000 to 1 in 3000

Much lower in African Americans (1 in 15,000) and Asian Americans (1 in 31,000)

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Clinical FeaturesThe organs most commonly affected in CF are the lungs and the pancreas

Chronic lung disease caused by recurrent infection eventually leads to fibrotic changes in the lungs with secondary cardiac failure

In 85% of people with CF, pancreatic function is impaired

Cirrhosis, and diabetes mellitus are common

Almost all males with CF are sterile because of congenital bilateral absence of the vas deferens (CBAVD).

CFTR Gene and Protein

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Duchenne Muscular Dystrophy (DMD)

The most common and most severe form of muscular

dystrophy.

A similar but milder condition, Becker muscular

dystrophy (BMD), is caused by mutations in the same

gene.

The incidences of DMD is approximately 1:3500 and

BMD 1:20,000 males

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Clinical FeaturesUsually present between the ages of 3 and 5 years with slowly progressive muscle weakness resulting in:

An awkward gait, inability to run quicklyDifficulty in rising from the floorMost affected boys have to use a wheelchair by the age of 11 years

Subsequent deterioration leads to lumbar lordosis, joint contractures, and cardiorespiratory failure, resulting in death at a mean age of 18 years

One-third of boys with DMD show mild-moderate intellectual impairment

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Genetics Both DMD and BMD show X-linked recessive inheritance, males with DMD rarely, if ever, reproduce

The dystrophin gene is huge in molecular terms, consisting of 79 exons and 2.3 Mb of genomic DNA

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HemophiliaThere are two forms of hemophilia: A and B.

Hemophilia A is the most common severe inherited coagulation disorder, with an incidence of 1:5000 males.

Deficiency of factor VIII, which, plays a critical role in the pathway activation of prothrombin to thrombin.

Hemophilia B affects approximately 1: 40,000 males and is caused by deficiency of factor IX.

It is also known as Christmas disease

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Clinical Features

Vary from mild bleeding following major trauma or surgery to spontaneous hemorrhage into muscles and joints

The degree of severity shows a close correlation with the reduction in factor VIII or IX activity

Levels below 1% are usually associated with a severe hemorrhagic tendency from birth.

Hemorrhage into joints causes severe pain and swelling

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The effect of recurrent hemorrhage into the knees

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Hemophilia A

X-linked recessive inheritance, Xq28

Factor VIII levels are about half normal in carrier females and many are predisposed to a bleeding tendency.

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Hemophilia B

A rare variant, hemophilia B Leyden shows the characteristic of age-dependent expression.

During childhood the disease is very severe, with factor IX levels of less than 1 %. After puberty the levels rise to around 50% of normal and the condition resolves to become asymptomatic.

Hemophilia B Leyden has been shown to be caused by mutations in the promoter region.

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Treatment

Protein Substitution

Using plasma-derived factor VIII or factor IX

Factor VIII has a half-life of 8 h

Transmission of viral infection such as hepatitis B and

HIV

10% of patients develop inhibitory antibodies

Gene TherapyExcellent candidates for gene therapy as only a slight increase in the plasma level of the relevant factor is of major clinical benefit.