Autosomal dominant diseases

Autosomal dominant diseases

1. Autosomal Dominant Diseases Ekbal Mohamed Abo- Hashem -MD Professor of Clinical Pathology Mansoura University-Egypt

2. An individual with an autosomal dominant disease may have inherited an abnormal allele from an affected parent, or alternatively the mutant allele may have risen de novo as a new mutation during gametogenesis in an unaf­fected parent. AUTOSOMAL DOMINANT DISEASES

3. An affected individual possesses a 50% risk of donating the mutant allele to an offspring. Different mutations within the gene have varying effects on the protein so that affected patients can have variability in clinical expression of the disease.

4. In some instances, known mutant gene carriers have no clinical symptoms of the disease, a phenomenon referred to as reduced penetrance, yet possess a 50% chance of having an affected child. Differences in phenotypic expression of the disease are most likely explained by the effect of other genes (modifier genes) and/or environmental influences.

5. Autosomal Dominant Disorders include : -Familial polyposis coli - von Willibrand disease -Polycystic kidney disease -Acute intermittent porphyria -* Achondroplasia -*Charcot-Marie-Tooth disease - *Huntington disease -Neurofibromatosis - Myotonic dystrophy -Familial hypercholesterolemia - Hereditery spherocytosis

6. 1. Achondroplasia

7. Achondroplasia is the most common form of human genetic dwarfism and is inherited as an autosomal dominant trait with complete penetrance. It is characterized by short-­limbed dwarfism ( rhizomelic form), macrocephaly, frontal and biparietal bossing, bowing of the lower extremities, and normal intelligence. Infants with this disease can die within the first year of life from central apnea caused by compression at the craniocervical junction; homozygous disease is most often lethal. a . Phenotype

8. Children undergoing surgical decompression of the craniocervical junction have decreased mortality and demonstrate improvement in neurological function. The mean and standard deviation adult height is (131 -+5.6 ) cm for men and (124_ + 5.9 ) cm for women. The life expectancy is about 10 years less than that for the general population.

9. During the first 5 years of life, affected children are at risk of death from compression of the brainstem and/or the upper cervical spinal cord. Deaths in adults between 25 and 54 years of age are most often attributed to cardiovascular problems. Achondroplasia has an incidence of about 0.5 to 1.5 per 10,000 births and has been reported in individuals from different races and ethnic groups.

10. More than 90% of patients are born to parents of normal height. These patients represent sporadic cases arising from new mutations, a phenomenon associated with advanced paternal age. b . Mutation

11. This "paternal effect" has been thought to occur because of lifelong spermatogonial stem cell divisions and thus an increase in production of mutant sperm as the male grows older. However , recent data generated from exam­ining sperm DNA from donors of different ages did not illustrate an exponential increase in mutation with age, indicating that sperm mutation frequency cannot explain an effect of paternal age in achondroplasia .

12. The gene for achondroplasia is mapped to the telo­meric region of chromosome 4p (4p16.3). T he fibroblast growth factor receptor 3 gene (FGFR3), mapped to this region and previously considered as a candidate gene for Huntington's disease (HD), is known as a candidate gene for achondroplasia and is reported to have mutations in patients with achondroplasia . c . FGFR3 Gene and Protein

13. FGFR3 is a tyrosine kinase receptor, which when bound to 1 of 23 fibroblast growth factors (FGFs) coupled with heparin sulfate-bearing proteoglycans on the cell surface, induces dimerization of receptor monomers, activates tyro­sine kinase activity, and promotes phosphorylation of key tyrosine residues in the cytoplasmic domain, which in turn induces multiple signaling pathways . The target genes for FGFR3 are not well characterized, but FGFR3 is thought to negatively regulate chondrocyte proliferation and differentiation.

14. The FGFR3 protein product, FGFR3, contains three extracellular immunoglobulin-like domains, a single transmembrane domain, and an intracellular tyrosine kinase domain.

15. The primary mutation in achondroplasia results in a defect in internalization and degradation of the mutant receptor. Thus it is retained on the cell surface and has uncontrolled and prolonged activation in chondrocytes. Hence, chondrocyte maturation and terminal differentiation are inhibited. d . Gene Mutation

16. In the original report identifying the FGFR3 gene as the cause of achondroplasia , most patients had a G-to-A tran­sition mutation at nucleotide 1138 (G1138A), and the only patient that did not have this mutation instead had a G-to-­C transversion mutation at the same position (G1138C). Both mutations result in a glycine-to-arginine substitution in the transmembrane domain of FGFR3 at codon 380 .

17. Since >98% of FGFR3 mutations causing achondroplasia are G 1138A, and about I % are G 1138C, DNA testing includes direct mutation analysis for both mutations.

18. Testing can be performed postnatally to confirm the diagnosis of achon­droplasia . In addition, prenatal DNA testing may be requested by unaffected couples with an affected child rep­resenting a sporadic case Pre­natal DNA testing can be requested by these couples who have a 25% chance of having a child homozygous for this condition e . DNA Testing

19. 2. Charcot-Marie-Tooth Disease

20. Charcot-Marie-Tooth (CMT) disease, sometimes referred to as hereditary motor and sensory neuropathies (HMSN), refers to a genetically heterogeneous group of hereditary neuropathies characterized by chronic motor and sensory polyneuropathy and demonstrating all patterns of mendelian inheritance. a . Phenotype

21. The most common form of CMT, type l A, is one of the most common autosomal dominant disorders in man, with an estimated incidence of 1 in 2500. This disease is charac­terized by progressive distal muscle atrophy and weakness, depressed or absent deep tendon reflexes, high-arched feet, decreased nerve conduction velocity (generally <35 to 40 m/s), and nerve demyelination as visualized on biopsy specimens.

22. The age of onset is within the first decade of life in 50% of patients and before the age of 20 in 70% of patients. However, despite a common genetic abnormality, phenotypic manifestations of the disease are variable even within the same family, suggesting the influence of environ­mental factors or modifier genes at other loci.

23. The gene was mapped to the short arm of chromosome 17 and specifically localized to 17p11.2-p12 (short arm of chromosome 17 between banding regions 11.2 and 12). Further , some DNA markers in this region detected a duplication in the DNA of affected individuals within families and in unre­lated CMT patients. b . Gene and Mutation

24. The peripheral myelin protein gene, PMP22, was identified as a candidate gene for CMT type l A in 1992. PMP22 is contained within a 1.5Mb monomer unit that is flanked by several low-copy repeat sequences. A duplication of the gene is associated with disease and results from unequal meiotic crossing over caused by misalignment of homologous sequences.

25. A duplication of PMP22 results in an extra copy of the gene (altered gene dosage) and overexpression of the PMP22 protein, which is considered the causative event for disease. Interestingly , patients with trisomy 17p (three copies of the short arm of chromosome 17), who would have an altered PMP22 copy number, also have clinical features consistent with CMT .  

26. PMP22 is a 160-amino acid transmembrane glycoprotein that contains four transmembrane hydropho­bic regions and two extracellular domains with the amino and C termini exposed to the cytosol. It is predominantly localized in the compact portion of myelin. c . PMP22 Protein

27. PMP22 is pre­dominantly expressed in myelinating Schwann cells of the peripheral nervous system where it is important in myelina­tion and myelin stability and acts as a negative modulator of Schwann cell growth.

28. From studies on transgenic mice, it has been proposed that when overexpressed, PMP22 accumulates in a late-Golgi and/or plasma-membrane com­partment and uncouples myelin assembly from the underly­ing program of Schwann cell differentiation

29. The PMP22 gene duplication associated with CMT type IA can be detected by use of Southern blot analysis, fluores­cence in situ hybridization (FISH) on interphase cells, or PCR. d . DNA Testing

30. 3. Huntington's Disease

31. HD is an autosomal dominant, late-onset neurodegenerative disorder with an incidence of about 1 in 10,000 in most populations of European origin. The disease is progressive and characterized by frequent involuntary, rapid movements (chorea) and dementia with a median survival time of 15 to 18 years after the onset of symptoms. a . Phenotype

32. The mean age of onset is in the decade between 35 and 44 years, but approx­imately 25% of patients first display symptoms after the age of 50, and about 10% of patients have juvenile HD with the age of onset before 20 years. . In the first few years of the disease, symptoms include mood disturbances, cognitive deficits, clumsiness, and impairment of voluntary movement.

33. The next stage of the disease is associated with slurred speech (dysarthria), hyperreflexia , chorea, gait abnormalities, and behavioral disturbances including intermittent explosiveness, apathy, aggression, alcohol abuse, sexual dysfunction and deviations, and increased appetite. As the disease advances, bradykinesia , rigidity, dementia, dystonia, and dysphagia are present. In the late stages of HD, weight loss, sleep disturbances, and inconti­nence occur.

34. A linkage between DNA marker D4Sl0 on the short arm of chromosome 4 and HD was reported. Subsequently, more DNA markers were identified, and the region of the genome containing the HD gene was narrowed to 4p16.3 (short arm of chromosome 4 band 16.3). 10 years after its initial localization, the HD gene, IT15, was cloned. b . Gene Mutation, CAG Trinucleotide Repeat Expansion

35. The molecular basis of HD was determined to be expansion of a glutamine-encoding CAG trinucleotide repeat and was subsequently confirmed in a worldwide study by the identi­fication of expanded CAG repeat alleles in HD patients.

36. The median CAG-repeat length was reported to be 44 in affected patients and 18 in controls. Normal CAG repeats range from 10 to 27, repeats of 28 to 35 are considered "mutable," repeats of 36 to 39 are associated with reduced penetrance of the disease, and repeats of 40 or greater are associated with HD.

37. The number of CAG repeats is inversely correlated with the age at onset of the disease. Patients with onset as early as 2 years of life have a repeat number approaching 100 or greater and late-onset-disease patients have repeat numbers of 36 to 39. The onset of symptoms occurs at progressively younger ages in successive generations of affected families, a pattern called anticipation. Anticipation is explained by meiotic expansion of the unstable CAG repeat during transmission by the affected parent, resulting in an even higher CAG ­repeat number in the offspring and an earlier age of onset. An increase in the CAG-repeat number is also associated with more rapid progression of disease and greater neuropathological severity in the striatum.

38. The HD gene protein, huntingtin ( htt ), consists of 3144 amino acids, is expressed in all tissue, and pre­dominantly resides in the cytoplasm with lesser amounts in the nucleus. In neurons, htt is associated with synaptic vesicles and microtubules and is abundant in den­drites and nerve terminals. c . HD Gene Protein

39. Huntingtin interacts with multi­ple proteins functioning in intracellular trafficking and cytoskeletal organization, thereby suggesting its role in these activities. Expansion of the CAG repeats results in elonga­tion of the N-terminal glutamine tract and triggers the pref­erential loss of striatal neurons.

40. The precise mechanism of disease progression has not been elucidated. However, expanded alleles are effectively transcribed and translated, but as a result of the increase in glutamine residues, the protein is misfolded . Thus abnor­mal folding may result in aberrant protein-protein interac­tion of mutant htt with any of its protein partners and could contribute to the pathogenesis of HD. d . Disease Mechanism

41. In addition, truncated fragments of mutant htt , containing the amino terminus with expanded polyglutamine repeats, accumulate to form large aggregates in the nucleus (nuclear inclusions) and in other subcellular compartments. The aggregates are thought to be toxic to the cell and may also sequester pro­teins essential for cell viability (e.g., transcription factors) or may trigger degradation of specific factors through the ubiq­uitin- proteasome-dependent pathway.

42. DNA testing for HD is performed by use of PCR so that the exact CAG-repeat number can be determined. a new primer pair was identified that flanked the CAG repeat, yet excluded the problematic polymorphic CGG repeat and provided accu­rate assessment of the CAG-repeat number. currently the most common methodology for this assay involves the use of PCR with fluorescently labeled primers. e . DNA Testing

43. Deferential Diagnosis

44. THANK YOU