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Genetic disorders

Karyotyping Definition: It is the study of number, size & shape of the chromosomes in a single human cell

Human Chromosomal number

◘ 46 chromosomes (diploid number) 44 autosomes & 2 sex chromosomes. ◘ Autosomal Chr. are arranged by size & position of centromere into groups (A-B-C-

D-E-F-G)

What is gene? : Part of DNA that code for synthesis of single polypeptide chain Each human has about 30.000 genes most are in pairs except those on the X chromosome in male

Q: Indications or Karyotyping (when do we suspect chromosomal

abnormalities)

1- Abnormal features

Odd face as mongloid look of down syndrome(discuss)

Eye : mongloid or anti-mongloid look

Ear: malformed ear

Mouth: cleft lip and palate

Hand and feet: syndactyly or clinodactyly 2- Mental retardation 3- Ambiguous genitalia 4- Delayed puberty: Turner & Klinefelter 5- Short stature in (female) 6- Spontaneous abortion (7% chromosomal abnormalities)

Classification of genetic disorders

◘ Single gene disorders ◘ Multifactorial (polygenic) inheritance ◘ Mitochondria inheritance ◘ Chromosomal abnormalities (structural and numerical)

Polydactyly

Ambiguous

genitalia

Cleft palate

Chapter 2 Genetics

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Numerical chromosomal anomalies A. Autosomal

◘ Trisomies: Extrachromosome is present (trisomy 21, 13, 18). ◘ Monosomies: One chromosome is missing (as monosomy 21 and 22)

B. Sex chromosomes ◘ Klinefelter syndrome ◘ Turner syndrome ◘ Super female Mention when do we suspect chromosomal abnormalities?

Structural chromosomal abnormalities 1. Unbalanced Reciprocal Translocation: Exchange of unequal amount of genetic

material between non-homologous chromosomes

2. Deletion: Loss of portion of chromosome. Example1: Cri du chat syndrome:

Loss of the tip of the short arm of chromosome 5 (5p)

C.P.: High-pitched mewing cry (like a cat) +Mental retardation

Example2: Prader-Willi syndrome: deletion of chromosome 15 C.P.: hypotonia – Obesity- hypogonadism

3. Ring chromosome: special deletion in which the broken ends reunite → ring. 4. Inversion: Fragmentation of a chromosome then reconstitution in inverted manner. 5. Duplication: Presence of an extra piece of a chromosome. 6. Isochromosomes: Division of centrosome transversely instead of longitudinally 7. Fragile chromosomes:{fragile X chromosome}: in male it present with mental

retardation – face (prominent forehead , mandible ear and long face) – large testes

N.B.: Balanced reciprocal translocation: Exchange of equal amount of genetic material between homologous chromosomes asymptomatic

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Examples on Numerical chromosomal anomalies

Down syndrome (Trisomy 21 or Mongolism) ◘ 47 chromosomes: There are 3 chromosome No 21 instead of 2 (G trisomy)

Incidence ◘ It is the most common autosomal trisomy.

◘ The incidence = 1/700

◘ The incidence rise with advanced maternal age

Clinical picture A. Abnormal features:

► Head: ◘ Vault: Thin silky hair - small head - Flat occiput (brachycephaly) -delayed closure

of the anterior fontanel

◘ Eye: Upward slanting palpebral fissure medial epicanthal folds- Brush field spots (white spots on the iris) - strabismus.

◘ Mouth: Delayed teething - protruded fissured tongue (scrotal tongue) - small mandible

◘ Ear: Low seated small ears overfolded helix – underdeveloped ear lobule

◘ Nose: Flat nasal bridge

► Neck: short neck

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► Trunk:Hernia - Broad iliac bones - Abdominal distention

► Genitalia: Small penis -Undescended testes

► Hands: Simian crease (single transverse palmer crease) - Clinodactyly -Broad hand &

fingers ► Feet: Big space between the first and second toes ( sandal sign)- Longitudinal planter

creases

B. Growth and development

◘ Most of measures of growth are delayed ◘ Delayed motor development (discuss) ◘ Delayed mental development (discuss)

C. System involvement

◘ CVS: Congenital heart disease (in 40% of cases): Endocardial cushion defect- VSD - ASD - PDA - Fallot's tetralogy

◘ CNS: Hypotonia -laxity of ligaments (acrobatic maneuver) -Epilepsy

◘ GIT: Imperforate anus - duodenal atresia - hirsch sprung disease

◘ Renal: renal anomalies (detected by US) ◘ Endocrinal: High incidence of (diabetes- hypothyroidism )

◘ Higher incidence of hearing & Visual impairment

D. Complications

◘ Higher susceptibility for infection especially recurrent respiratory infections. ◘ Heart failure (the cause of death in infancy). ◘ Higher incidence of leukemia ◘ Accidents

E. Prognosis

◘ In the absence of congenital heart and leukemia normal survival ◘ Usually happy and love music ◘ Down fertility and lipido but a female down may have a child (50%) down

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Genetic types of Down syndrome

1- Non disjunction 2- Translocation

Incidence 94% 5%

Number of chromosomes

47 46 but with large abnormal chromosome (2 X 21)

Mechanism

◘ Non disjunction of the matted pair of chs. No: 21 in maternal meiosis

◘ It results in zygote with 47 chs. in which 3 chs. are 21

Unbalanced Robertsonian translocation ◘ The extra chromosome No: 21 is

translocated to one of the chs. of: D group (13,14,15) or G group (21,22)

Risk factor Advanced age of the mother Familial

Risk of recurrence

◘ with maternal age

◘ 1/1000 at 30 years

◘ 1% at 40 years

◘ 1:10 at 50 years

◘ To the D group (calculated) 1/3 carrier – 1/3 down syndrome – 1/3 normal (run in family).

◘ To G (21) group:100 % Down syndrome

3- Mosaic down syndrome

Incidence: 1%

Number of chromosomes: Some cells: 46 - Other cells : 47

Mechanism: after fertilization and normal zygote formation Non disjunction in early mitotic division →2 cell lines one with 46 and the other with 47 chromosomes

Risk factors: not dependent on Family history or the Age of mother Prognosis: less features and less mental affection

Investigations Prenatal diagnosis

◘ Triple test :(↓↓ α fetoprotein -↓↓ estradiol - ↑↑ HCG) ◘ Ultrasonography (↑↑thickness of the nuchal fold) ◘ Amniocentesis or Chorionic villous sampling (for karyotyping)

Karyotyping (chromosomal study)

◘ For the infant to confirm the diagnosis and determine genetic type. ◘ Parental Karyotyping only in translocation type.

Echocardiography congenital heart disease

U/S intestinal anomalies.

Hearing and vision testing

Check thyroid profile & blood glucose.

Management 1. Proper nutrition 2. Diagnose and manage possible complications. 3. Educational & social rehabilitation in specialized institutes like speech therapy aiming

to make the child as independent as possible.

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Some sex chromosome abnormalities

Klinefelter syndrome

Cytogenetic: 47 (44 +XXY) male.

Incidence : 1/1000 male Features

1. Mild Mental retardation +Behavioral abnormalities 2. Tall stature 3. Gynecomastia 4. Hypogonadism with small testes & absent spermatogenesis 5. Infertility (most common presentation)

Prognosis: Normal life expectancy Investigation

1. karyotyping 2. FSH &LH ↑↑ 3. Gonadal biopsy: dysgenesis

Treatment: Testosterone at time of puberty

N.B. Trisomy 18(Edward's Syndrome) Hypertonia- Prominent occiput - overlapping finger –Rocker bottom feet

N.B. Trisomy 13 (Patau syndrome) Small eyes (microphthalmia) and other eye defects - Cleft lip and palate - Polydactyly

N.B. both numerical chromosomal abnormalities show mental retardation – Microcephaly –

congenital heart – prognosis: death before the age of 1 year

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Turner syndrome

Cytogenetics: 45 (44 +XO) Female. Incidence : 1/5000 (Recurrence risk 1%). Features ► Newborn: Lymph edema of hands and feet.

► Childhood: (see the photo)

Investigation 1. Hormonal profile (high FSH and LH but low estradiol). 2. Gonadal biopsy: dysgenesis (streak ovary).

Treatment ◘ Hormonal replacement: growth hormone till puberty then cyclic estrogen and

progesterone 2ry sexual charchters only, but still infertile.

Super female

Cytogenetic: 47 [44 +XXX] female Features Impaired mentality &reproductive problems

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Single gene disorders

1. Autosomal dominant inheritance

2. Autosomal recessive inheritance

definition ◘ Appears even if a single copy of an abnormal gene located on one of the autosomes.

◘ Appears if only 2 copies of an abnormal gene located on 2 of the autosomes.

Affected individuals

◘ Homozygous (have 2 copies) or heterozygous(have only one copy).

◘ only homozygous (i.e. they have 2 abnormal genes, one from each parent)

Unaffected individuals

Normal (no carrier state) Normal or carriers (heterozygous)

Recurrence risk

◘ Heterozygous 50% ◘ Homozygous 100%

◘ When parents have one affected child, the risk to each subsequent offspring is 25%

Distribution Equal distribution to males & females Equal distribution to males & females

Consanguinity No relation Strong relation

Disease Usually structural defect Usually enzymatic defect

Examples

◘ Hematology: C. spherocytosis - Von Willebrand disease

◘ Skeletal disorders: Achondroplasia- osteogenesis imperfect- Ehlers Danlos $- Marfan $- Otosclerosis

◘ Neuro: Tuberous sclerosis, neurofibromatosis- Huntington's disease – myotonic dystrophy

◘ Renal: AD polycystic kidney

◘ Hematology: Thalassemia -sickle cell anemia.

◘ Endocrinal :Adrenogenital $ - goitrous cretinism

◘ Metabolic: Phenyl ketonuria-cystic fibrosis- galactosemia – Glycogen storage disease

◘ Neuro.: Werding Hoffman-

N.B. Some carriers of AR diseases are biologically fitter than normal (sickle

cell carrier are resistant to infection with malaria)

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3. Sex-linked inheritance Sex-linked disorders are those, which are caused by abnormal genes on the X or Y chromosome.

X-linked recessive inheritance

Female Females may be affected if:

◘ She has inherited 2 copies of the abnormal gene ◘ She has Turner syndrome (45,X) ◘ Lyonization

Recurrence

◘ The carrier female transmits the abnormal gene to 50 % for each son (to be affected) & to 50% of her daughters (carriers).

Carrier female may show mild symptoms or abnormal laboratory finding (Discuss)

Male Male will be affected from carrier or affected mother only (not from father).

No carrier in males

Recurrence: The affected male will transmit the abnormal gene to all of his daughters who will be carriers and to none of his sons

Examples 1. Agammaglobulinemia

2. Blood diseases: G6PD deficiency, hemophilia A & B

3. Color blindness( green –red) 4. Duchenne muscle dystrophy & Becker’s muscle dystrophy

5. Errors of metabolism MPS II (Hunter syndrome)

X-linked dominant inheritance The affected female transmits the disorder to half of her daughters & half of her sons. The affected male transmits the disorder to all of his daughters & to none of his sons

Examples: Pseudohypoparathyroidism - Vitamin D resistant rickets.

Y-linked inheritance Y chromosome carries genes that determine sexual differentiation

and spermatogenesis (if affected infertility) Genes on the Y chromosome show holandric inheritance (passed

exclusively from an affected man to all his sons and to none of his daughters)

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Multifactorial (polygenic) inheritance Definition

◘ Interaction of a genetic predisposition with adverse environmental factors ◘ The genetic susceptibility is determined by the effects of many genes

Characteristic features

1. These disorders are much commoner than single gene disorders. 2. The prevalence is (2-5%) & may be more in some diseases). 3. The risk Declines sharply with more distant relationship with the affected individual 4. The risk increase with more than one affected individual in the family or affected

person of the less risky sex

Examples

1. Congenital malformations of infancy:

◘ Cleft lip/palate. ◘ Pyloric stenosis ◘ Congenital heart disease. ◘ Congenital dislocation of the hip ◘ Neural tube defects

(spina bifida – anencephaly). ◘ talipus equinoverus ◘ Hypospadius

2. Acquired disorders of childhood

◘ Atopy and Bronchial asthma. ◘ Type I DM ◘ Epilepsy.

3. Acquired disorders of adult

◘ Diabetes mellitus (type I and type II) ◘ Alzeheimer's

◘ Hypertension. ◘ Atherosclerosis and coronary heart disease

4. Normal criteria : height – intelligence

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Mitochondrial gene inheretance Mitochondria contain small amount of DNA that code for enzymes involved in energy

production Mitochondria are transmitted to the embryo from his mother only Mitochondrial diseases include mitochondrial myopathy & mitochondrial

encephalopathy

Genetic counseling Definition: Providing information about inherited disorders in the family and how to avoid it (by prenatal diagnosis and carrier detection).

Genetic counseling should provide the Recurrence risk ◘ Very low (1%) in chromosomal abnormalities. ◘ Discuss recurrence in down syndrome ◘ (25-50%) in single gene inheritance

◘ (2-5%) in Multifactorial inheritance.

Indications ◘ Consanguineous marriage ( of AR diseases) indicate screening based on

diseases prominent in the population (SCA in black Africans/ thalassemia in Mediterranean area)

◘ Mention indication of Karyotyping + ◘ Microcephaly/ Macrocephaly ◘ Bleeding tendency ◘ Metabolic disorders

Early diagnosis of single gene disorders by DNA

Prenatal diagnosis: beta thalassemia – cystic fibrosis – Duchenne muscle dystrophy

Presymptomatic diagnosis: in some AD diseases (Huntington's disease)

Carrier detection X linked recessive diseases: (Duchenne muscle destrophy – hemophilia)

This could be done with 2 methods

◘ Biochemical assay not reliable

◘ DNA markers accurate Autosomal recessive disease (cystic fibrosis)