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Javad Jamshidi Fasa University of Medical Sciences, December 2014 Session 11 Medical Genetics Single-Gene Disorders.

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Presentation on theme: "Javad Jamshidi Fasa University of Medical Sciences, December 2014 Session 11 Medical Genetics Single-Gene Disorders."— Presentation transcript:

1 Javad Jamshidi Fasa University of Medical Sciences, December 2014 Session 11 Medical Genetics Single-Gene Disorders

2 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 2

3 3 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

4 4 Slowly 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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6 6 Autosomal 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

7 7 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…

8 8 The most common form of muscular dystrophy seen in adults, overall incidence of approximately 1: 8000 Autosomal dominant inheritance, with anticipation, and an congenital form Anticipation with mother transmission

9 9 usually present in adult life with slowly progressive weakness and myotonia Other clinical features include: Cataracts Cardiac conduction defects Disturbed gastrointestinal peristalsis (dysphagia, constipation, diarrhea) Increased risk of diabetes mellitus and gallstones Somnolence, frontal balding As the age of onset becomes earlier, so the clinical symptoms increase in severity and more body systems are involved

10 A mother and child with myotonic dystrophy 10

11 11 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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13 13 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 members Joint laxity Reduced upper to lower segment body ratio Pectus deformity, and scoliosis Connective tissue defect gives rise to ectopia lentis Dilatation of the ascending aorta (some families)

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15 Marfan Syndrome 15

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17 17 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

18 18 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)

19 19 The 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).

20 CFTR Gene and Protein20

21 21 French neurologist Guillaume Duchenne, who described a case in 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

22 22 Usually present between the ages of 3 and 5 years with slowly progressive muscle weakness resulting in: An awkward gait, inability to run quickly Difficulty in rising from the floor Most 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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24 24 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

25 25 There 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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27 27 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

28 28 X-linked recessive inheritance, Xq28 The factor VIII comprises 26 exons and spans 186 kb with a 9-kb mRNA transcript. Factor VIII levels are about half normal in carrier females and many are predisposed to a bleeding tendency.

29 29 The factor IX gene comprised 8 exons and is 34 kb long 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.

30 30 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 Therapy Excellent candidates for gene therapy as only a slight increase in the plasma level of the relevant factor is of major clinical benefit.


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