Single Gene Disorders: Molecular Pathology, Prevalence and Diagnosis

1. Single Gene Disorders: Molecular Pathology, Prevalence and Diagnosis Dr Maha Al-Sulaimani Department of Biochemistry College of Sciences

2. Single Gene Disorders • Examples of single gene disorders include cystic fibrosis, sickle cell anemia, Tay-Sachs disease, myotonic dystrophy, Duchenne and Becker muscular dystrophies, Fragile X syndrome and spinal muscular atrophy, to name a few.

3. Tay-Sachs Disease • Is an autosomal recessive genetic disorder. • In its most common variant, known as infantile Tay–Sachs disease, it causes a relentless deterioration of mental and physical abilities that commences around six months of age and usually results in death by the age of four.

4. Tay-Sachs Disease • The disease occurs when harmful quantities of cell membrane components known as gangliosides (glycosphingolipids) accumulate in the nerve cells of the brain, eventually leading to premature death of those cells. • There is no cure or treatment.

5. Gangliosides

6. Tay-Sachs Disease • The frequency of the condition is much higher in certain ethnic groups than in others. • There is a noticeable incidence of TSD in non-Jewish French Canadians living near the St. Lawrence River and in the Cajun community of Louisiana.

7. Tay-Sachs Disease • By contrast, the carrier rate in the general population is about one in every 250. • Also, individuals with ancestry from Ireland are at increased risk for the Tay-Sachs gene. • Current research indicates that among Irish Americans, the carrier rate is about one in 50.

8. Tay-Sachs Disease • Diagnosis and prognosis: The diagnosis can be made via a blood test in which the Hex A enzyme can be measured in either the serum, WBCs, or in skin fibroblast. • Beta-hexosaminidase A plays a critical role in the brain and spinal cord (central nervous system).

9. Tay-Sachs Disease • This enzyme is found in lysosomes. • Within lysosomes, beta-hexosaminidase A forms part of a complex that breaks down GM2 gangliosides.

10. Tay-Sachs Disease • Over the past 25 years, carrier screening and genetic councelling within high-risk populations have greatly reduced the number of children born with TSD in these groups. • Therefore, a great percentage of the babies born with Tay-Sachs Disease today are born to couples who were not previously thought to be at significant risk.

11. Tay-Sachs Disease • Prenatal tests that can diagnose Tay-Sachs in the fetus before birth are available. • These procedures are referred to as Amniocentesis and Chorionic Villus Sampling. • Amniocentesis sampling is performed between the 15th and 16th week of pregnancy.

12. Tay-Sachs Disease • The procedure involves inserting a needle into the mother's abdomen and obtaining a sample of the fluid that surrounds the baby. • In Chorionic Villus Sampling a sample of cells from the placenta is retrieved by the doctor during the 10th and 12th week of pregnancy, and tested for the level of Hex A (deficiency).

13. Duchenne and Becker Muscular Dystrophies (x-linked recessive) • Are a group of genetic conditions characterized by progressive muscle weakness and wasting (atrophy). • The Duchenne and Becker types of muscular dystrophy primarily affect the skeletal muscles, which are used for movement, and the muscles of the heart. • These conditions predominantly affect males.

14. Duchenne and Becker Muscular Dystrophies (DBMD) • DBMD have similar signs and symptoms and are caused by different mutations in the same gene. • The two conditions differ in their severity, age of onset, and rate of progression.

15. Duchenne and Becker Muscular Dystrophies (DBMD) • In people with Duchenne muscular dystrophy, muscle weakness tends to appear in early childhood and progresses rapidly. Affected children may have delayed motor skills, such as sitting, standing, and walking. • They are usually wheelchair-dependent by adolescence.

16. Becker Muscular Dystrophy • Becker muscular dystrophy is very similar to Duchenne muscular dystrophy, except that it gets worse at a much slower rate. • Having a family history of the condition raises your risk.

17. Duchenne and Becker Muscular Dystrophies (DBMD) • Prevalence is 1 in 4000 newborn males. • Diagnosis: Creatine Phosphokinase assay. • DNA testing: The disorder is caused by a mutation in the dystrophin gene, located on the X chromosome (Xp21).

18. Dystrophin Gene and Protein • The dystrophin gene codes for dystrophin, an important structural component within muscle tissue. • Dystrophin is a rod-shaped cytoplasmic protein, and a vital part of a protein complex that connects the cytoskeleton of a muscle fiber to the surrounding extracellular matrix through the cell membrane.

19. Dystrophin

20. Dystrophin and DBMD Treatment • Dystrophinprovides structural stability to the dystroglycan complex (DGC), located on the cell membrane. • In skeletal muscle, the dystroglycan complex works as a transmembrane linkage between the extracellular matrix and the cytoskeleton. • There is no treatment for DBMD.

21. Fragile X Syndrome • The Fragile X syndrome is caused by a "fragile" site at the end of the long arm of the X-chromosome. • It is a genetic disorder that manifests itself through a complex range of behavioral and cognitive phenotypes.

23. Fragile X Syndrome • It is the result of a genetic mutation which varies considerably in severity among patients. • Fragile X syndrome is the most common cause of inherited mental retardation. • Although it is an X-linked recessive trait with variable expression and incomplete penetrance, 30% of all carrier women are affected.

24. Fragile X Syndrome • Penetrance is expressed as the percentage of those who carry the variant who show any effect of it (small or large). • Is a genetic syndrome that is the most common known single-gene cause of autism.

25. Fragile X Syndrome • It results in a spectrum of intellectual disability ranging from mild to severe as well as physical characteristics such as an elongated face, large or protruding ears, and larger testes, behavioral characteristics such as stereotypic movements (e.g. hand-flapping), and social anxiety.

26. Fragile X Syndrome • Prevalence: Fragile X syndrome is the single most common inherited cause of mental impairment affecting 1 in every 2000 males and 1 in every 4000 females with full mutation worldwide.

27. Fragile X Syndrome • Studies have also revealed that 1 in 259 women of all races carry fragile X and could pass it to their children. • The number of men who are carriers is thought to be 1 in 800 of all races and ethnicity. • Carrier females have a 30% to 40>% chance of giving birth to a retarded male child and a 15 to 20% chance of having a retarded female.

28. Fragile X Syndrome • Diagnosis and prognosis: The diagnosis is made through the detection of errors in the FMR1 gene that codes for a protein called fragile X mental retardation protein, or FMRP. • This protein, most commonly found in the brain, is essential for normal cognitive development and female reproductive function.

29. Fragile X Syndrome • Over 99% of affected individuals have a full mutant FMR1 gene. • Tests used for diagnosis include chromosome analysis and various protein tests. • Diagnosis is usually made when young, and there is no current cure for this illness.

30. Fragile X Syndrome • Early diagnosis of the syndrome allow for therapeutic interventions like speech therapy, occupational therapy, psychotherapy and special education, that can considerably improve the quality of the patients' life