بسم الله الرحمن الرحيم

1. بسم الله الرحمن الرحيم

2. Single Gene Disorders Dr. Nasser Elhawary Prof. of Medical Genetics

3. Definitions … • Human Genetics:is the science of biological variations in humans. • Medical Genetics:is the science of human biologic variations as it relates to health and disease. • Clinical Geneticsis the science and art of diagnosis, prevention &treatment of genetic disease.

4. Genetic Disorder • Genetic disorder: is a condition caused by abnormalities in genes or chromosomes. • Genetic disease: refers to diseases present in all cells of the body and present since conce-ption (cancer excluded).

5. How to search for a genetic condition? • www.google.com (search text; ‘images’; ‘videos’, etc) • www.download.com (download software) • www.youtube.com (videos) • www.pubmed.com • OMIM from www.pubmed.com • List of Genetic disorders at Wikipedia (encyclopedia) • Center for Inherited Disease Research (CIDR) • National Organization for Rare Disorders

6. Genetic disorders… 1- Dominant 2- Recessive

7. A- Chromosomal Abnormalities • Down syndrome (47,+21) • Turner syndrome (45,X0) • Klinefelter syndrome (47,XXY, …) • XYY syndrome (47,XYY; 48,XXYY) (arise from meiotic non-disjunction in the father)

8. Down Syndrome (DS)… • Down-slanting palpebral fissure and a slightly protruding tongue. • The prominent epicanthal fold of a child with DS is shown. • The pupil demonstrates a light smudge opacity called a Brush-field spot. • A simian crease is seen on the hand of this child with DS.

9. Down Syndrome… Frontal (a) and lateral (b) appearance of a patient with DS Typical Down’s syndrome foot Typical Down’s syndrome hand

10. Cytogenetics of DS… Trisomy 21 FISH karyotype GTG-banding of a trisomy 21 patient

11. Maternal nondisjunction in DS

13. Hope … associated with Early Intervention • Development of communication. • Social development. • Motor Development

14. Turner Syndrome … • Turner syndrome(45,X0) is characterized by a phenotypic female with gonadal dysgenesis & sexual immaturity: - 1ry Amenorrhea & Infertility associated with: - short stature (< 5 feet) - webbing of the neck - increased carrying angle at elbow - cardiovascular abnormality. - renal abnormality.

16. Turner Syndrome …

17. Klinefelter Syndrome… • Incidence 1/1000 male births • Karyotype with 47,XXY (with Barr body). • No. of Barr bodies inform of the no. of X-chromosomes. • Characterized by postpubertal testicular failure. • Phenotype male with small testes, hyalinized testicular tubules, azoospermia (result in infertility) Barr body: A condensed, inactivated X chromosome present in most female mammals in all somatic cells, but not in germ cells

18. Murray Barr (1948) Karyotype with a male having Klinefelter syndrome (47,XXY) The Barr, or sex chromatin, body is an inactive X-chromosome (Lyon’s hypothesis). It appears as a dense, dark-staining spot at the periphery of the nucleus of each somatic cell in the human female.

19. Genetic disorders… 1- Recessive 2- Dominant

20. B. Trinucleotide repeats • Refers to a specific DNA sequence of 3 nucleotides (e.g. CGG) that is repeated along the human genome • No. of the polymorphic repeats varies from one to another (two to several hundreds). • Trinucleotide repeat sequences are stable, and inherit from parents to children with the same no. of repeats. • Polymorphic repeat regions are the basis of fingerprinting (forensics, … etc).

21. Fragile X Syndrome … • Most common form of inherited mental retardation. • Incidence of ~1/4000 male and ~1/8000 females. • Due to expansion of trinucleotide repeats (CGG)n at X27.3. • Mutation in the FMR1 gene due to expansion CGG repeats. • Large ears, prominent jaws, joint laxity and macroorchidism

22. George Huntington (1872) Huntington’s disease (H. chorea)… • It is AD neurodegenerative disease (incidence 1/10,000) that affects muscle coordination and leads to cognitive decline and dementia. • HD typically becomes noticeable in mid-adult life (35-44 y). • HD is the most common genetic cause of abnormal involuntary writhing movements called chorea. • HD characterized by slowly progressive selective cell death in the CNS. • no effective treatment or cure.

23. Huntington’s disease… • An expansion due to (CAG)n repeats located in coding region of the Huntingtin gene (located at chromosome 4p16.3) (1993). • In Huntington’s disease: - N < 26rpts→normal individual - N = 27-35rpts → mutable alleles don’t cause disease, but show meiotic instability. - N = 36-39rpts→reduced pentrance (late-onset) or non-pentrance. - N ≥ 40-100rpts→ mutant

24. Genetic disorders… 1- Recessive 2- Dominant

25. Hereditary Diseases • Dominant: if one parent can transmit the genetic information (in genes) that causes a child’s disease (Fam. hypercholestrolemia; Achondroplasia). • Recessive: if both parent lack the disorder (i.e. homozygous for the mutant gene) and pass the disease’s gene to a child (sickle-cell anemia, PKU, lamellar ichthyosis, β-thalassemia, … etc).

26. Achondroplasia… IQ is normal ACH describes short-limb dwarfism due to mutations of fibroblast growth factor receptor-3 gene (FGFR3- 4p16.3)

27. PKU with mental retardation and neurological problems, lighter hair and skin color, enhanced reflexes, convulsive seizures, Autosomal Recessive diseases Phenylketonuria disease due to a mutation of PAH gene Lamellar Ichthyosis due to a mutation in TGM1 gene LI patients suffer from palmoplantar keratoderma, often with painful fissures, digital contractures, and loss of pulp volume. A nail dystrophy including ridging, subugeal hyperkeratosis, or hypoplasia. Ectropion, eclabion (turning outward of the eye lids and lip, respectively), scalp involvement, and loss of eye brows and lashes seem to be more frequent in NCIE than in lamellar ichthyosis.

28. Hereditary diseases… • X-linked: pass from mother (XX) to affect often males (XY) (DMD, Hemophilia A, G6PD). • Y-linked: (Oligospermia, Azoospermia, …). • Mitochondrial: known as maternal inheritance. Only egg cells contribute mitochondria to the developing embryo, only female can pass on mitochondria conditions to their children (Lebre’s hereditary Optic Neuropathy ‘LHON’).

29. WHAT IS MUSCULAR DYSTROPHIES? - DMD/BMD disease - Limb girdle MD - Spinal muscule atrophy - Myotonic MD (AR) - Facioscapulohumeral MD Duchenne Muscular Dystrophy… • Weakness proximal more than distal. • Weakness in lower limb than in upper limb • Pseudohypertrophy. • Hypotonia & Hyporeflexia. • Sensory system intact. • Mental impairment may occur. An 8-y-old boy with D/BMD with enlarged calves

30. Duchenne Muscular Dystrophy… A dystrophin patient (7 y) and his younger brothers (1.5 y) diagnosed in the preclinical stage as D/BMD by the +ve family history and raised CPK level (2845 IU/L).

31. Biochemical Genetics A) The Role of Proteins B) Metabolic Pathways and Disease 1- Defects in amino acid metabolism 2- Defects in Carbohydrate metabolism 3- Defects in Nucleic acid metabolism 4- Defects in Lipid metabolism C) Defects in Receptor Proteins 1- Hemoglobin Variants 2- Thalassemias

32. A) Role of Proteins • Greek Word “proteios” means ‘being of first importance. • Destroy invading microbes (antibodies) • Act as Enzymes, • Act as hormones (insulin), receptors (VDR), transportmolecules (hemoglobin), • Role in DNA replication (helicase, RNA primase, DNA Ligase, …)

33. Gene 1Gene 2Gene 3 Enzyme 1Enzyme 2Enzyme 3 Compound(A) (B) (C) (D) Enzymes … • Enzymesconvert molecules (substrates) into products through a biochemical reaction. • Metabolism is the sum of all biochemical reactions in the cell.

34. B) Metabolic Pathways and Disease • In 1901, Garrod discovered “inborn errors of metabolism” of Alkaptonuria (AKU). • Direct link between specific enzyme and genetic disease was made in 1952 (G6PD & glycogen storage disease). • The major disorders for which dietary control is available are: - PKU - galactosemia - tyrosinemia - Homocystinuria - MSUD.

35. 1-Defects in Amino acid… • Nine essential a.a.: His, isoleu, leu, lys, meth, phe, thr, try and val. • Phenylketonuria (PKU) first discovered by Følling. - Jervis showed that the classical PKU was linked to PAH deficiency. • Alkaptonuria: excretion of homogentisic acid, dark pigment in cartilage areas (ears, tip of nose, whites of eyes, arthritis in later life). • Oculocutaneous albinism (OCA): lack of melanin (hair, skin, eyes) lack of tyrosinase in pigment cells (albino phenotype).

36. Phenylketonuria Disease

37. 2-Defects in Carbohydrates… • Galactosemia: AR disease (1/57,000) results from the inability to metabolize galactose. - Untreated galactosemia causes gastrointestinal disturbance, dehydration, loss of appetite, and lately cataracts and MR. • Fructosuria: AR in 1/130,000 due to lack of fructokinase in liver, kidney, intestine. • Pentosuria: AR in 1/2500-5000 (Ashkenazi Jewish).

38. 3-Defects in Nucleic acid… • Lesch-Nyhan syndrome: XL-disease (1/10,000) associated with a defect in purine metabolism (cause overproduction of uric acid). - Renal failure, spastic movement, MR, strong tendency for self-mutilation?!! • The disease is caused by a lack of hypoxanthine guanine ribosyl transferase (HGPRT). • Allopurinol only may treat the uric acid level.

39. 4-Defects in Lipid… • Tay-Sachs disease (hz <1/100,000; het 1/300):AR-disease shows degeneration of cell structures and high conc of GM2-ganglioside due to lacking of ‘hexosaminidase A’ deposited in the nervous system. • Normal at birth, listless and weak, difficult to feed. • Loss of motor function, delays in learning to sit and stand. A characteristic cherry-red spot develops on retina. At age of 12 m, rapid decrease in mentality, motor function, onset of blindness, deafness, brain enlarge. • Death occurs around 3 y from pneumonia or lung infection. • Sandhoff disease: def. in hexosaminidase A,B.

40. C) Defects in Receptor Proteins • Proteins also play other roles including signal receptors and transducers. • These functions usually takes place in the plasma membrane of the cell. • Mutations in receptor function can have drastic consequences.

41. Defects in Receptor Proteins… Fam. hypercholesterolemia (1/100,000). • It is AD (2p24.1) associated with a defect in cellular receptors that function in cholesterol metabolism. • Affected individuals are susceptible to heart disease and early death. • Cholesterol is ingested, and packaged into particles (LDL) that project by receptors into the cells, and cholesterol is used by the cell.

42. Fam. Hypercholesterolemia… • If the receptors are defective, the LDL builds up in the blood and deposited in the artery walls causing atherosclerotic plaque → heart disease. • Fam. hypercholesterolemia het. have ½ of the usual number of receptors and twice the normal level of LDL. • Heart attacks starts at early 30’s. • 1/500 individuals is heterozygotes, and homozygotes (no function of receptor) estimates 1/million (6-times of normal LDL, and heart attacks at early 2 y age.

43. Defects in Receptor Protein… Test. Feminization Background: - After 4-6 wk: presence of Y-chr → testis, while absence of Y-chr → ovary. - Once testis development is initiated, two hormones are produced testosterone and MIH. - Testosterone is converted to dihydrotestosterone (DHT) which develop the ex. genitalia. - Absence of testis: → development of ovary.

44. Testicular Feminization… Testicular feminization(XL-recessive). • Genotype male (XY) & phenotype female. • Testis formation is induced normally, and testosterone and MIH production occurs normally → no internal genitalia of a female. • Mutation in X-chr blocks the ability of cells to respond to testosterone or DHT. • Hence, Wolffian duct degenerates and indifferent genitalia develops as female structures. • very attractive female, well-developed breast, very little pubic hair, lack of menstruation.

45. Some heritable Traits associated with Defective Receptors

46. Transport Protein: The globin Model • Hemoglobin: an iron-containing protein molecule found in RBCs is involved in transfer of O2 and CO2. • Adult Hb is a tetramer composed of 2 types of polypeptides. • Quaternary structure of Hb A1 consists of 2a & 2β-chains. Hb A2 (2a- & 2d-chains). • - a-genes on 16p & b-gene on locus 11p • The globin gene is composed of 3 exons and 2 introns (IVS).

47. 1- Hemoglobin Variant… • Hb S:Linus Pauling 1949: is an abnormal Hb that becomes insoluble in deoxygenated state. The insoluble molecules polymerize into tubular structures that distort the membrane of RBCs forming sickle shaped cells. • Hb C: is slightly insoluble in the deoxygenated state forming intracellular crystals that makes the RBCs membrane rigid with reduced life span → mild form of anemia. • Hb F (db-chains):there is a persistence of production of fetal Hb into childhood and adult life. This is due to ∆ or point mutations in d and b.

48. Sickle cell anemia… • A fatal (AR) genetic disorder associated with an abnormal type of Hb, a blood transport protein. • Common in US Black. • Protein transports O2 from lungs to tissues. • Under conditions of low O2 tension, the abnormal Hb in SCA causes the sickle-shaped. • The deformed cells are fragile and easily broken apart. • Patients tire easily, develop heart failure because the increased load on the Circulatory system.

49. Sickle cell anemia… • The deformed cells clogthe blood vessels and capillaries, and hence reduces O2 transport and bringing sickling crisis. • As O2 concn. reduced more and more red blood cells become sickled, bringing on intense pain, causing ulcers and sores on the body surface. • Blood blockage in brain leads to strokes and hence partial paralysis.