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Autosomal recessive diseases (10)

1. Albinism
2. ARPKD - autosomal recessive polycystic kidney disease (formerly known as infantile polycystic kidney disease)
3. Cystic fibrosis
4. Glycogen storage diseases
5. Hemochromatosis
6. Mucopolysaccharidoses (except Hunter's)
7. Phenylketonuria
8. Sickle cell anemias
9. Sphingolipidoses (except Fabry's)
10. Thalassemias

Cystic fibrosis:

Which gene is defective? On which chromosome? Which deletion?

Autosomal-recessive defect in CFTR gene on chromosome 7, commonly deletion of Phe 508.

What does the CFTR channel normally do, and what happens with the defective channel? What diseases/conditions result (5)? What happens to the mutated channel?

Normal CFTR channel actively secretes Cl⁻ in lungs and GI tract and actively reabsorbs Cl⁻ from sweat.

Defective Cl⁻ channel → secretion of abnormally thick mucus that plugs lungs, pancreas, and liver →

1. Recurrent pulmonary infections (Pseudomonas spp and S. aureus)
2. Chronic bronchitis
3. Bronchiectasis
4. Pancreatic insufficiency (malabsorption and steatorrhea)
5. Meconium ileus in newborns.

Mutation causes abnormal protein folding, resulting in degradation of channel before reaching cell surface.

What else is CF associated with (4)?

Infertility in males due to bilateral abscence of vas deferens.

Fat-soluble vitamin deficiencies (A, D, E, K).

Can present as failure to thrive in infancy.

Most common lethal genetic disease of Caucasians

CF: diagnosis and treatment

↑ concentration of Cl⁻ ions in sweat test is diagnostic.

Treatment: N-acetylcysteine to loosen mucous plugs (cleaves disulfide bonds within mucous glycoproteins).

X-linked recessive disorders (8)

"Be Wise, Fool's GOLD Heeds Silly Hope"

1. Bruton's agammaglobulinemia
2. Wiskott-Aldrich syndrome
3. Fabry's disease
4. G6PD deficiency
5. Ocular albinism
6. Lesch-Nyhan syndrome
6. Duchenne's (and Becker's) muscular dystrophy
7. Hunter's Syndrome
8. Hemophilia A and B.

Female carriers are rarely affected due to random inactivation of an X chromosome in each cell.

"Be Wise, Fool's GOLD Heeds Silly Hope"

Muscular dystrophies

Duchenne's: which gene is affected? What is the normal function of this gene?

Duchenne's = Deleted Dystrophin

Dystrophin gene (DMD) is the longest known human gene → ↑ rate of spontaneous mutation.

Dystrophin helps anchor muscle fibers, primarily in skeletal and cardiac muscle

Muscular dystrophies

Duchenne's: pathogenesis

X-linked frame-shift mutation → deletion of dystrophin gene → accelerated muscle breakdown.

Weakness begins in pelvic girdle muscles and progresses superiorly.

Muscular dystrophies

Duchenne's: clinical presentation (4)

1. Pseudohypertrophy of calf muscles due to fibrofatty replacement of muscle.

2. Cardiac myopathy.

3. Use of Gower's maneuver, requiring assistance of the upper extremities to stand up, is characteristic.

4. Onset before 5 years of age.

Muscular dystrophies

Becker's: genetic defect, prognosis, age of onset

X-linked mutated dystrophin gene.

Less severe than Duchenne's.

Onset in adolescence or early adulthood

How are muscular dystrophies diagnosed?

↑ CPK and muscle biopsy

Fragile X syndrome: genetic defect

Trinucleotide repeat disorder (CGG)n.

X-linked defect affecting the methylation and expression of the FMRI gene (required for normal neural development).

2nd most common cause of genetic mental retardation (after Down syndrome)

Fragile X syndrome: findings (5)

1. Macro-orchidism (enlarged testes)
2. Long face with a large jaw
3. Large everted ears
4. Autism
5. Mitral valve prolapse

"Fragile X = eXtra-large testes, jaw, ears"

Trinucleotide repeat expansion diseases (4)

HUNTINGton's disease, MYotonic dystrophy, FRIEDreich's ataxia, fragile X syndrome.

"Try (trinucleotide) HUNTING for MY FRIED eggs (X)"

Huntington's disease = (CAG)n
MyoTonic dystrophy = (CTG)n
FraGile X syndrome = (CGG)n
Friedreich's ataxia = (GAA)n

May show genetic anticipation (disease severity ↑ and age of onset ↓ in successive generations; germline expansion in females)

Autosomal trisomies

Down syndrome: chromosome, prevalence, causes

Trisomy 21, 1:700

"Drinking age (21)"

95% due to meiotic nondisjunction of homologous chromosomes (associated with advanced maternal age; from 1:1500 in women < 20 to 1:25 in women > 45).

4% of cases due to Robertsonian translocation.

1% of cases due to Down mosaicism (no maternal association)

Autosomal trisomies

Down syndrome: Findings (8)

1. Mental retardation
3. EPICANTHAL FOLDS (skin fold of upper eye covering inner corner of eye)
4. SIMIAN CREASE (single crease across palm)
5. Gap between 1st 2 toes
6. Duodenal atresia
7. Congenital heart disease (most commonly septum primum-type ASD)
8. Associated with ↑ risk of ALL and Alzheimer's disease (> 35 years of age)

Autosomal trisomies

Down syndrome:

Most common ____ disorder and most common cause of congenital ____ _____.

Most common chromosomal disorder and most common cause of congenital mental retardation.

Autosomal trisomies

Down syndrome: diagnosis

Results of pregnancy quad screen:

↓ α-fetoprotein, ↑ β-hCG, ↓ estriol, ↑ inhibin A.

Ultrasound shows ↑ nuchal translucency

Autosomal trisomies

Edwards' syndrome: which chromosome? Prevalence?

Trisomy 18, 1:8000

"Election age (18)"

Most common trisomy resulting in live birth after Down syndrome

Autosomal trisomies

Edwards' syndrome: findings (8)

1. Severe mental retardation
2. Rocker-bottom feet (prominent calcaneous, convex rounded bottom to foot)
3. MICROGNATHIA (small jaw)
4. Low-set ears
6. Prominent occiput (posterior portion of head)
7. Congenital heart disease
8. Death usually occurs within 1 year of birth

Autosomal trisomies

Patau's syndrome: chromosome location, findings (9)

Trisomy 13, 1:15,000

"Puberty (13)"

1. Severe mental retardation
2. Rocker-bottom feet
3. Microphthalmia (small eye)
4. Microcephaly
8. Congenital heart disease
9. Death usually occurs within 1 year of birth

Robertsonian translocation: what is it?

NONRECIPROCAL chromosomal translocation that commonly involves chromosome pairs 13, 14, 15, 21, 22. One of the most common types of translocation.

Occurs when the long arms of 2 acrocentric chromosomes (chromosomes with centromere near their ends) fuse at the centromere and the 2 short arms are lost.

Balanced translocation normally do not cause any abnormal phenotype.

Unbalanced translocations can result in miscarriage, still birth, and chromosomal imbalance (e.g. Down syndrome, Patau's syndrome)

Cri-du-chat syndrome: genetic defect, findings (5)

Congenital microdeletion of short arm of chromosome 5 (46,XX or XY, 5p-)

1. Microcephaly
2. Moderate to severe mental retardation
3. High-pitched crying/mewing
4. Epicanthal folds
5. Cardiac abnormalities

"Cri du chat = cry of the cat"

Williams syndrome: genetic defect, findings (6)

Congenital microdeletion of long arm of chromosome 7 (deleted region includes elastin gene)

1. Distinctive "elfin" facies
2. Mental retardation
3. Hypercalcemia (↑ sensitivity to vitamin D)
4. Well-developed verbal skills
5. Extreme friendliness with strangers
6. Cardiovascular problems

22q11 deletion syndromes: variable presentation (5), 2 syndromes

Variable presentation, including:
1. Cleft palate
2. Abnormal facies
3. Thymic aplasia → T cell deficiency
4. Cardiac defects
5. Hypocalcemia 2° to parathyroid aplasia

Due to microdeletion at chromosome 22q11.

DiGeorge syndrome - thymic, parathyroid, and cardiac defects

Velocardiofacial syndrome - palate, facial, and cardiac defects

Due to aberrant development of 3rd and 4th branchial pouches.

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