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Genetic and Developmental Disorders

Sickle cell disease:


Missense mutation. Adenine replaces thymidine, causing valine to replace glutamic acid in sixth position of beta-globin chain. RBCs spontaneously sickle.

Beta-thalassemia major:
Nonsense mutation. Stop codon causes premature termination of DNA transcription. Decreased synthesis of hemoglobin A (alpha2beta2).

Tay-Sachs:
Frameshift mutation. Defective lysosomal enzyme, hexoaminidase.

Trinucleotide repeat disorders:


Anticipation. Female carriers may be symptomatic. Examples: Fragile X, Huntington's disease, Friedreich's ataxia, myotonic dystrophy.

Autosomal dominant diseases:


Hereditary angioedema:
C1 esterase inhibitor deficiency.

Hereditary spherocytosis:
Ankyrin.

Familial hypercholesterolemia:
LDL receptor.

Neurofibromatosis:
Neurofibromin.

Autosomal recessive diseases:


Sickle cell anemia:
Sickle hemoglobin.

G6PD deficiency (Von Gierke):


G6PD.

Cystic fibrosis:

CF transmembrane regulator.

PKU:
Phenylalanine hydroxylase deficiency.

X-linked recessive diseases:


Only expressed in males. Males transmit mutant gene to all their daughters, who would be asymptomatic. Asymptomatic females transmit the gene to 50% of their sons, who would be symptomatic. Hemophilia A: factor VIII. Eg., Fragile X syndrome, Lesch-Nyhan.

X-linked dominant diseases:


Expressed in males and females. Eg., vitamin D-resistant rickets. Alport's disease: hereditary glomerulonephritis with nerve deafness.

Mutations due to Translocations and Deletions


Down syndrome:
Non-disjunction (most common cause). Unequal separation of chromosomes during the first phase of meiosis. Robertsonian translocation (second most common cause). t(14,21).

Cru du chat syndrome:


Deletion: Loss of short arm of chromosome 5. Mental retardation, cat-like cry, ventricular septal defect.

Edward's syndrome:
Trisomy 18. Mental retardation, VSD, early death.

Patau's syndrome:
Trisomy 13.

Turner's syndrome:
Mosaicism. (second most common cause) Unequal separation of chromosomes during the first phase of meiosis. Non-disjunction: 45, X. (most common cause) Short, obese, webbed neck, amenorrhea, normal intelligence, hypothyroidism. No barr bodies.

Klinefelter's syndrome:
Non-disjunction: XXY. (one cause) Gynecomastia, soft skin, female hair distribution. One barr body. Learning disabilities.

XYY syndrome:

Paternal non-disjunction. Aggressive behavior. Normal gonadal function.

Prader-Willi and Angelman syndromes:


Microdeletion of entire gene site on paternal (with corresponding maternal inactivation) and maternal (with corresponding paternal inactivation) chromosomes 15, respectively.

Sexual development:
No Y chromosome:
Germinal tissue differentiate into ovaries.

Y chromosome present:
Germinal tissue differentiate into testes. MIF, testosterone, 5alpha-reductase, DHT present.

Testicular feminization:
XR. Deficiency of androgen receptors. Vagina ends in a blind pouch. Normal male levels of testosterone and DHT - but no receptors. Genotypically male, but phenotypically female.

Congenital malformations:
Occur between third and ninth weeks of pregnancy. SLE = heart block in new-born. Diabetes mellitus = neural tube defects + heart disease in new-born. Hypothyroidism = cretinism in new-born. HOX gene mutation (getting acne treatment during pregnancy) = abnormal craniofacial development.

Oligohydramnios:
Decreased amniotic fluid.

Tests:
Amniocentesis: genetic defects. Ultrasound: rule out neural tube defects. AFP: increased in neural tube defects. Down syndrome: decreased AFP and urine estriol; increased hCG.