Medical Genetics

1. Medical Genetics

2. Imprinting • Normally at a given locus we have two alles one from mother and the other from father • Definition: At a single locus, only one allele is active, the other is inactive.

5. Why DNA methylation causes epigentic silencing • DNA methylation acts as an epigenetic modification in vertebrate DNA. Recently it has become clear that the DNA and histone lysine methylation systems are highly interrelated and rely mechanistically on each other for normal chromatin function in vivo.

6. Imprinting • Definition: At a single locus, only one allele is active, the other is inactive; • Phenotype depends on origin of mutation  paternal v. maternal • Both syndromes due to inactivation or deletion of genes on chromosome 15 q (11-13) • Can also occur as a result of uniparental disomy Deletion of normal chromosome 15q(11-13) from Paternal side: Pader Willi Deletion of normal chromosome 15q(11-13) from Maternal side: Angel Man Syndrome

7. Imprinting • Prader-Willi: Deletion of normally active PATERNAL allele • Mental retardation • Obesity • hypogonadism • Hypotonia • At birth usually demonstrates "floppy baby" with "undescended testicles"

8. Imprinting • Angelman’s syndrome “Happy Puppet Syndrome” : Deletion of normally active MATERNAL allele • Mental retardation • seizures • ataxia • innapropriate laughter • AS is named after a British pediatrician, Harry Angelman, who first described the syndrome in 1965

9. Modes of Inheritance • Autosomal Dominant: Affects both males and females in all generations. Presents clinically after puberty and FH is essential for diagnosis. • Examples: Achondroplasia, Huntington’s dz, Neurofibromatosis types 1 & 2, and many many more!

10. Autosomal Recessive • Only offspring of 2 carrier parents can be affected. Usually only seen in one generation, usually due to enzyme deficiencies. • Commonly more severe than dominant disorders, presents in childhood • Examples: Albinism, Cystic Fibrosis, PKU, Wilson’s dz, and many more!

11. X-Linked Recessive • Only sons of heterozygous mothers can be affected, no father to son transmission. • Examples: Fragile X, Lesch-Nyhan, Hemophilia A and B • Females may rarely be affected due to random inactivation of X chrom (e.g. Lyonization)

12. Lyonization X-inactivation (also called lyonization) is a process by which one of the 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.

13. X-Linked Disorders • X-Linked Recessive Inheritance: • X Inactivation or Lyonization: • One of 2 copies of X Ch inactivated in female mammals • Inactive X Ch  silenced  packaging into inactive heterochromatin  Barr Body in female cell nucleus • Reason? So that no duplication of gene products bcz of double X Ch as compared to males (dosage compensation) • Inactivation is Random but once inactivated will remain for lifetime • Applied to both homozygous and heterozygous recessive females • In heterozygotes, it’s almost always the mutant or abnormal allele that is inactivated • Remotely possible for normal allele to be deactivated in most cells to express the disease • Variable proportion of cells in which mutant X Ch is active

14. Modes of Inheritance • X-linked dominant: Transmitted through both parents, males and females can be affected, but all females of affected fathers are affected. • Example- • Hypophosphatemic rickets: increased phosphate wasting at proximal tubule

15. Modes of Inheritance • Mitochondrial: Transmission ONLY through the mother. All offspring of affected mothers are affected. • Variable expression due to heteroplasmy

16. Autosomal Dominant Dz’s • Achondroplasia • Genetics and Cell Level: • Defect in Fibroblast Growth Factor receptor 3 • Causes abnormal cartilage development • Phenotypic Traits: • Dwarfism: short limbs, head and neck normall size • Misc info: • Associated with advance paternal age • AD so if one parent affected then 50% of children affected • Homozygotes die either before or shortly after birth

17. ACHONDROPLASIA(Dwarfism)Defined as a bone growth disorder characterized by abnormal body proportions

18. Autosomal Dominant Dz’s • APKD (adult polycystic kidney dz) • Genetics and Cell Level: • 90% due to mut in APKD1 on chromosome 16 • Phenotypic Traits: • Bilateral enlargement of kidney due to multiple cysts • Clinical Presentation: • flank pain, hematuria, HTN, • progressive renal failure Usually presents in adulthood (hence the name!) • Misc info: cysts in the liver ( 30% ) berry aneurysms of the circle of Willis ( 10-15%)  mitral valve prolapse (MVP) Colonic diverticulosis

19. Autosomal Dominant Dz’s • Familial AdenomatousPolyposis • Genetics and Cell Level: • Deletion on chromosome 5q21-22 (APC gene) • Phenotypic Traits: • Colon covered with polyps after puberty that progress to 100 % cancer if not resected around 30 years • Clinical Presentation: anemia, melena, changes in bowel habits • Misc info: (Screening, Definite ? Will need yearly colonoscopies beginning age of 12 • Once you see polyps do colectomy • Also do upper GI endoscopy to rule out polyps congenital hypertrophy of retinal pigment epithelium

20. Autosomal Dominant Dz’s • Lynch Syndrome (HNPCC or hereditary nonpolyposis colorectal cancer) • Other Cancer like endometrial (2nd most common), ovarian and gastric cancers common • Genetics and Cell Level: • Due to defects in Mismatch Repair Genes • Misc info: • Three or more family members with colon cancers, one of whom is a first degree relative of the other two • Two successive affected generations • Colon cancer in one family member under age 50 years • Will need yearly colonoscopies beginning age of 20 to 25 • Endometrial sampling beginning at age of 30 • Gastric and ovarian cancer screening at age of 30

21. Autosomal Dominant Dz’s • Neurofibromatosis 1 (NF1/von Recklinghausen’s dz) • Genetics and Cell Level: • Mutation on chromosome 17q11 (long arm of 17) • This neurofibronin gene is a negative regulator of Ras oncogene (Increases incidence of cancers like Juvenile myelomonocytic leukemia and Malignant Nerve Sheet Tumor

22. Neurofibromatosis 1 (NF1/von Recklinghausen’s dz) • Clinical Presentation: café-au-lait spots • neural tumors • Lisch nodules (pigmented iris hamartomas) • Misc info: • Increased incidence of Optic Gliomas, pheochromocytomas, susceptibility to tumors, and skeletal disorders

23. NF1 Café Au lait spots Lisch Nodule

24. Autosomal Dominant Dz’s • Neurofibromatosis 2 (NF2) • MISME Multiple inherited Schwanomas, Meningeomas and Ependymomas • Genetics and Cell Level: • Mutation on chromosome 22q12 • Merlin gene

25. Autosomal Dominant Dz’s • Neurofibromatosis 2 (NF2) Clinical Presentation: • Bilateral acoustic neuromas on CN8 is the diagnostic • Tumors may cause tinnitus, hearing loss, balance problems, vertigo, etc. • Juvenile Subscapular Cataract • Brain and other crainial nerve tumors: Schwanomas, meningiomas, astrocytomas • Spine; astrocytomas and ependymomas. • If unilateral acoustic neuroma with meningioma, glioma , schwanoma, Cataract or First degree relative with NF II

26. NF-2 may be inherited in an autosomal dominant fashion, as well as through random mutation

27. Autosomal Dominant Dz’s • Tuberous Sclerosis • Genetics and Cell Level: • mutation of either of two genes, TSC1 and TSC2 • code for the proteins hamartin and tuberin, respectively. • These proteins act as tumor growth suppressors, agents that regulate cell proliferation and differentiation • causes benign tumors called as HAMARTOMAS to grow in the brain and on other vital organs such as the kidneys, heart, eyes, lungs, and skin.

28. Most common cause of Morbidity in Tuberous Sclerosis is Seizures • Mostly patient present with a type of seizures called as infantile spasm • hypsarrythmia can be seen on EEG • Rx with ACTH therapy to reduce CRH levels • CRH is known to have excitatory physiological actions on neurons and can induce seizures

30. Autosomal Dominant Dz’s • Tuberous Sclerosis

31. Tuberous Sclerosis: facial angiofibromas in characteristic butterfly pattern Ash Leaf Spot Adenoma Sebaceum

32. Autosomal Dominant Dz’s • Von Hippel-Lindau disease • Genetics and Cell Level: • Deletion of VHL gene (tumor suppressor) on chromosome 3, results in expression of  hypoxia inducible factor 1α (HIF1α) and activation of angiogenic growth factors • Phenotypic Traits: • Hemangioblastomas of retina/cerebellum/medulla • About ½ of affected develop multiple renal cell carcinomas and other tumors • Pheochromocytomas • Clinical Presentation: miscellaneous can be discomfort from growing tumors or blindness 2/2 tumors in retina

33. Autosomal Recessive Dz’s • a1-antitrypsin deficiency (14q32.1) • Genetics and Cell Level: • A1AT is Serine protease inhibitor produced by the liver and protects the lungs from Neutrophil Elastase

34. It is a genetically inherited autosomal-codominant condition with more than 120 alleles identified . •  There are several forms and degrees of deficiency; the form and degree depend on whether the sufferer has one or two copies of a defective allele. In the literature it has been described as either a recessive or co-dominant trait as there is some evidence that smoking heterozygotes are affected.

35. Autosomal Recessive Dz’s • a1-antitrypsin deficiency (14q32.1) Clinical Presentation: • Less A1AT in blood to neutralize the effect of elastase enzyme secreted by neutrophil. The elastase dissolves alveolar septae resulting in COPD • Mutant A1AT protein is not secreted into the blood stream. It accumulates in the liver cells , resulting in cirrhosis in early adulthood • High risk of hepatocellular carcinoma • Misc: • Important when presented with pt who has COPD and has only smoked for a few years

36. Autosomal Recessive Dz’s • Cystic Fibrosis: this one is important • Genetics and Cell Level: • More than 900 genetic mutations in CFTR( cystic fibrosis transmembrane conductance regulator ) gene are known to cause Cystic Fibrosis • CFTR gene mutation on chrom 7 DF508 classically ( the codon for phenylalanine at position 508 ) . • Defective Cl channel

37. In Lungs Normal Cystic Fibrosis

38. In Lungs Normal Cystic Fibrosis

39. In Lungs Normal Cystic Fibrosis

40. In Lungs Normal Cystic Fibrosis

41. In Lungs Normal Cystic Fibrosis

42. Same thing in Pancreas and Vas Deference Normal Cystic Fibrosis

43. Autosomal Recessive Dz’s • Cystic Fibrosis: this one is important • Clinical Presentation: secretion of abnl thick mucus into lungs, pancreas, and liver • Pulm infections (P. aeruginosa and S. aureus) • Chronic bronchitis, bronchiectasis, pancreatic insufficiency, male infertility (absence of vas deferens)

44. Gives rise to hypertonic sweat

45. Autosomal Recessive Dz’s • Cystic Fibrosis (cont.) • Diagnosis: • increased concentration of Cl in sweat test ( 1st test to be done ) • Genetic Testing is not sensitive (Because till now we have mapped more than 900 mutation in CFTR gene linked to cystic fibrosis and many more may be there which we don’t know) • Nasal Potential Test is confirmatory (Confirmatory test )

46. Symptoms • Symptoms respiratory symptoms are more prominent in adulthoodrecurrent pulmonary infections • Pseudomonal spp and S. aureus are most common • chronic sinusitis • chronic, productive cough • dyspnea on exertion • hemoptysis

47. Symptoms • Gastrointestinal symptoms are more prominent in infancychronic, frequent diarrhea • greasy stool with flatulence from malabsorption secondary to pancreatic insufficiency • can lead to rectal prolapse • meconium ileus( It is extremely sticky and causes the bowel to be blocked at birth) in infants (15%) • pancreatitis 

48. Symptoms • Other symptoms • calcium oxalate kidney stones • secondary to fat malabosorption • For Patients with Calcium Oxalate Kidney Stones advise decreased Calcium in Diet.

49. Autosomal Recessive Dz’s • Treatment: • N-acetylcysteine to loosen mucus plugs • Nasal Irrigation of Sinuses • Adequate hydration • Antibiotics especially against Pseudomonas Aeruginosa (inhaled Tobramycin) and others • Pancreatic Enzymes • Misc: • If presented with . . . THINK CF! • newborn with meconium ileus or failure to thrive • Fat soluble vitamin deficiency • Pancreatic insufficiency

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