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بسم الله الرحمن الرحيم. Single Gene Disorders. Dr. Nasser Elhawary. Prof. of Medical Genetics. 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 .

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slide2

Single Gene Disorders

Dr. Nasser Elhawary

Prof. of Medical Genetics

definitions
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.
slide4

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).
how to search for a genetic condition
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
slide6

Genetic disorders…

1- Dominant 2- Recessive

a chromosomal abnormalities
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)

down syndrome ds
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.
down syndrome
Down Syndrome…

Frontal (a) and lateral (b) appearance of a patient with DS

Typical Down’s syndrome foot

Typical Down’s syndrome hand

cytogenetics of ds
Cytogenetics of DS…

Trisomy 21 FISH karyotype

GTG-banding of a trisomy 21 patient

slide13

Hope … associated with Early Intervention

  • Development of communication.
  • Social development.
  • Motor Development
turner syndrome
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.

klinefelter syndrome
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

slide18

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.

slide19

Genetic disorders…

1- Recessive 2- Dominant

b trinucleotide repeats
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).
fragile x syndrome
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
huntington s disease h chorea

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.
huntington s disease
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

slide24

Genetic disorders…

1- Recessive 2- Dominant

slide25

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).
slide26

Achondroplasia…

IQ is normal

ACH describes short-limb dwarfism due to mutations of fibroblast growth factor receptor-3 gene (FGFR3- 4p16.3)

slide27

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.

hereditary diseases
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’).
duchenne muscular dystrophy

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

duchenne muscular dystrophy1
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).

biochemical genetics
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

a role of proteins
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, …)
enzymes

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.
b metabolic pathways and disease
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.

1 defects in amino acid
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).
2 defects in carbohydrates
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).
3 defects in nucleic acid
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.
slide39

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.
slide40

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.
slide41

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.
slide42

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.
slide43

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.

slide44

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.
transport protein the globin model
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).
slide47

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.
slide48

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.
slide49

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.
slide51

2- Thalassemias…

  • Thalassemiasare heritable group characterized by reduction or absence of ‘alpha’ and ‘beta’ globins.
  • Common in Mediterranean basin and Southeast Asia. “Thalassa” Greek word means “for sea”.
  • α-Thalassemia: α-globin is reduced or absent (α1, α2).

* α1→ mild to heterozygotes, α1→ fatal to homozygous (complete ∆ of α-genes).

* α2 →intact to het, α2 →mild anemia to homozygous.

  • β-Thalassemia: β-globin chain is affected éout ∆ (types, βº, β+).

* βº gives very low β-globin protein due to splicing mutations during formation of mRNA (in splicing site).

ii polygenic multifactorial inheritance
II. Polygenic & Multifactorial Inheritance
  • Many disorders doesn’t conform to any recognized pattern of Mendelian Inheritance
slide53
Polygenic disorder: A phenotype that is dependent upon the interaction of a number of genes.
  • Traits showing ‘continuous variation’ that resemble ‘normal distribution’ are controlled by two or more genes are examples of ‘polygenic inheritance’.
  • Discontinuous variation: Phenotypes that fall into 2 or more distinct, non-overlapping classes.

e.g. height, weight, skin color, intelligence, blood pressure, many forms of behaviors.

multifactorial disorders
Multifactorial Disorders
  • Multifactorial traits are those that involve 2 or more genes and strong interaction with the environment.
  • Heritability: It measures the degree of environmental or genetic effects or both on a trait.
  • Linkage Analysis: It is valuable in mapping single-gene disorders by studying the co-segregation of genetic markers with the disease.
  • In multifactorial disorders such MR, Epilepsy, Psychotic illness (manic depression, Schizophrenia).
  • Candidate genes: with Coronary heart disease (CHD), Alzheimer, Bronchial asthma, etc.
slide55

Multifactorial Disorders…

Estimates of Heritability of various disorders

  • Disease Models for multifactorial inheritance:
  • Autism (4-10/10,000)
  • Type 1 Diabetes Mellitus (IDDM) (0.4%)
  • Type 2 Diabetes Mellitus (non-IDDM) (10%)
  • Crohn disease
slide56

Multifacotrial inheritance …

  • Linkage: Co-inheritance of 2 or more nonallelic genes bcuz their loci are in close proximity on the same chromosome, such that after meiosis they remain associated more often than the 50% expected for unlinked genes.
  • Linkage Disequilibrium: The preferential association of a particular allele, i.e. a mutant allele for a disease with a specific allele at a nearby locus more frequently than expected by chance.
  • LOD score: A statistical method that tests whether a set of linkage data indicates two loci are linked or unlinked {+3 (1000:1 odds) is taken of linkage; -2 (100:1 odds against) indicates no linkage}.
association studies
Association Studies
  • Odd ratio (OR): It gives an indication of how much more frequently the disease occurs in individuals with a specific marker than in those without that marker.
  • Transmission disequilibrium test (TDT): requires a collection of an affected proband and both parents (regardless of affected status)
slide58

Genetic Factors in

Common Diseases

  • Population/migration
  • Family studies:
  • Twin studies:
  • Adoption studies:
  • Polymorphism association studies:
  • Biochemical studies