Simple and Complex Genetic Diseases

1. Simple and Complex Genetic Diseases • Simple: One gene -> one disease • Example: sickle-cell anemia • Complex: Many genes interacting with • other and the environment -> one disease • Examples: MS, Types I, II diabetes

2. Single Gene Disorders Autosomal recessive • Albinism • Cystic fibrosis • Phenylketonurea

3. Galactosemia Metabolic disorder defect in galactose meatbolism, • The problem in the enzyme galactose 1- phoshate uridyl transferese, Which breakdown glucose. • This leads to accumulation of galactose in blood, leads to blood poisoning which cause: • 1- Hepatomegaly • 2- Cirrrhosis • 3- Renal failure • 4- Cataracts • 5- Brain damage

4. Mucopolysaccharidosis • Absence of lysosomal enzymes (α-L-iduronidase) which digest Mucopolysaccharide (also named Glycosaminoglycans) • This sugar is found in the liquid between joints and act as lubricant.

5. Autosomal dominant Achondroplasia • Askeletal disorder causeing dwarfism, shortening in limbs and digits, enlargement in skull. • Caused as a defect in Fibroblast Growth factor Receptor Gene3 (FGFR3) • This leads to a defect in cartilage and bone growth.

6. Marfan syndrome • 15q 15-21 • Affect c.t • Defect in FBN1 gene

7. Neurofibromatosis • 17q11 • Swallow sacs under skin affect skin, bone and nerves • Caused as a defect in the Neurofibromin gene.

8. Brachydactyly 5p13 and 2q33 • Problem in fingers Noonan syndrome • Defect in PTPN11 gene which encode • Protain Tyrosine Phosphatase, which play a role in embryonic development, Differentiation and migration

9. Huntington's disease • 4p16 • Trinucleotide repeat expansion in the gene which encode Huntington protein. • This leads to defect in the produced protein, degeneration in neurons, and chorea.

10. 1 Glucose-6-ph. Dehydrogenase deficiency • X-Linked r • Deficiency in • Glucose-6-ph. dehydrogenase enzyme ( G6PDH) • This enzyme is related to Pentose phosphorylation Pathway • This enzyme converts Glucose-6-ph to 6- Phosphogluconate delta-lactone

11. Duchenne muscular dystrophy • Defect in the gene which encode Dystrophin Haemophilia A • Defect in the gene which encode Factor VIII

12. Hypophosphatemia • X-linked dominant disorders • a form of vitamin D- resistant rickets

13. Y-linked genes • Sex determining gene (SRY) encodes SDF which important in sex determination by playing a role in early stages of testis differentiation. • Any defect cause XY female (Swyer syndrome) • Translocation of part Y chromosome which contain SRY gene to X chromosome give XX male syndrome

14. ANT3 (adenine nucleotide translocase) • Produce enzyme change and transfer ADP from internal mitochondria to ouside as ATP

15. CSF2RA • Colony stimulating factor 2 receptor α • Produce cell surface receptor for growth factor • Control production, differentiation of granulocytes and macrophages.

16. H-Y gene • Plasma membrane protein • Play a role in testis differentiation

17. ZFY • Zinc finger protein • DNA binding protein that regulate gene expression

18. Mitochondrial disorders • Mitochondrial myopathy • neurodegenerative disorder • seizures, diabetes mellitus, hearing loss, short stature, and exercise intolerance are clearly part of the disorder.

19. MERRF syndrome • muscular disorders • cause a dysfunction of the brain and muscles (encephalomyopathies).

20. The most characteristic symptom of MERRF syndrome is seizures that are usually sudden, brief, jerking, spasms that can affect the limbs or the entire body. • Impairment of the ability to coordinate movements (ataxia), as well as an abnormal accumulation of lactic acid in the blood (lactic acidosis) may also be present in affected individuals. • Difficulty speaking (dysarthria), optic atrophy, short stature, hearing loss, and involuntary jerking of the eyes (nystagmus)

21. Leigh syndrome • progressive neurodegenerative disorder in one or more areas of the central nervous system, including the brainstem, thalamus, basal ganglia, cerebellum, and spinal cord. • The lesions are areas of demyelination, gliosis, necrosis, spongiosis, or capillary proliferation. Clinical symptoms depend on which areas of the central nervous system are involved. • The most common underlying cause is a defect in oxidative phosphorylation

22. Sideroblastic anemia • abnormal production of RBCs which can evolve into leukemia. • Thus, the body has iron available, but cannot incorporate it into hemoglobin • The common feature of these causes is a failure to completely form heme- whose biosynthesis takes place partly in the mitochondria. This leads to deposits of iron in the mitochondria that form a ring around the nucleus of the developing RBCs. This leads to a stage in bone marrow disorder that leads to acute leukemia.

23. Myoclonus • involuntary twitching of muscles. • The myoclonic twitches or jerks are usually caused by sudden muscle contractions; Contractions are called positive myoclonus; relaxations are called negative myoclonus. • myoclonic jerks are also a sign of a number of neurological disorders. • Hiccups are also a kind of myoclonic jerk specifically affecting the diaphragum.

24. myoclonus is one of several signs in a wide variety of nervous system disorders such as Parkinson’s disease, Alzheimer’s disease, and some forms of epilepsy

25. Myopathies • affect muscles connected to bones (called skeletal muscles), such as the biceps in the upper arm and the quadriceps in the thigh. • Myopathies can be caused by inherited genetic defects (e.g., muscular dystrophies), and endocrine, inflammatory , and metabolic disorders.

26. Cardiomyopathy • the heart muscle becomes inflamed and doesn't work as well as it should. • There may be multiple causes including viral infections. • Cardiomyopathy can be classified as primary or secondary. • Primary cardiomyopathy can't be attributed to a specific cause, such as high blood pressure, heart valve disease, artery diseases or congenital heart defects. • Secondary cardiomyopathy is due to specific causes. It's often associated with diseases involving other organs as well as the heart.

27. Renal tubular acidosis (RTA) • is a disease that occurs when the kidneys fail to excrete acids into the urine, which causes a person's blood to remain too acidic. • Without proper treatment, chronic acidity of the blood leads to growth retardation, kidney stones, bone disease, and progressive renal failure. • The word acidosis refers to the tendency for RTA to lower the blood's pH. When the blood pH is below normal (7.35), this is called acidemia. • Its causes are diverse, and its consequences can be serious, including coma and death.

28. Variation in chromosome number • Trisomy 18 (47,XY,+18) – Edward • Syndrome

29. Trisomy 18• Incidence 1:3333 live births• Most common abnormality in stillbirths with multiple congenital abnormalities• Prenatal growth deficiency resulting in a small for gestational age infant (SGA)•90% congenital heart defect VSD• 10% alive at one year• Marked developmental disability

30. Trisomy 18 -Physical Features • • Prominent occiput • • Micrognathia • • Microcephaly • • Low set malformed ears • • Characteristic clenched fists • • Rocker-bottom feet • • Short big toe that is dorsiflexed

31. Trisomy 18 –Edward Syndrome • Trisomy 18 • • Prominent Occiput • • Low-set malformed ears • • Small chin • • Clenched fists

32. Trisomy 18 • • Ocular manifestations in 10% • • Low-arch dermal ridge pattern • • Underdeveloped nails • • Congenital anomalies of lungs,diaphragm, and • kidneys • • Hernias, cryptorchidism, rectus muscle separation

33. Trisomy 13 (47,XY,+13) – Patau • Syndrome

34. Trisomy 13 • • Incidence 1:5,000 births • • Distinctive malformation pattern • (Craniofacial and Central Nervous System) • • 95% spontaneously aborted • • Survival rate and development similar to Trisomy 18

35. Trisomy 13 PatauSyndrome • • Microcephalywith sloping forehead • • Holoprosencephaly • • Ophthalmologic abnormalities microphthalmiaor anophthalmia Colobomataof iris and ciliarybody • • Cleft lip +/-palate • • Low set ears with abnormal helices

36. Trisomy 13 PatauSyndrome • • Cardiac defects: ASD, PDA, VSD • • Males: cryptorchidism ; Females: Bicornuateuterus • • Polycystic kidneys • • Aplasiacutis congenita • • Polydactylyof hands +/-feet • • Rockerbottomfeet

37. Turner syndrome • SHORT STATURE • OVARIAN DYSGENESIS • INFERTILITY • LEARNING DISABILITIES • SPATIAL PERCEPTION

38. XXX females • About one woman in 1000 has an extra X chromosome. It • seems to do little harm, individuals are fertile and do not • transmit the extra chromosome.

39. XYY males • XYY males Incidence 1 in 1000 male births. • May be without any symptoms. Males are tall but normally proportioned.

40. Glu • Ab 5i GTG CAC CTG ACT CCT GAG GAG AAG TCT O O O 3i • Sb 5i GTG CAC CTG ACT CCT GTG GAG AAG TCT O O O 3i • Val