Ch. 5 Diseases

Question 1

Cystic fibrosis

Answer 1

Primary defect: AR mutation of CFTR gene on chromosome 7q31.2 Abnormal fxn of epithelial chloride channel protein leads to abnormally viscous secretions that obstruct organ passages Most common lethal genetic disease in Caucasian populations Clinical features: chronic lung disease secondary to recurrent infxns (Haemophilus influenzae, mucoid/nonmucoid Pseudomonas aeruginosa), bronchiectasis, atelectasis, meconium ileus, pancreatic insufficiency, steatorrhea, acute salt depletion, male infertility Criteria for dx: increased sweat chloride concentration AND sibling w/CF or positive newborn screening result

Question 2

Phenylketonuria

Answer 2

Primary defect: AR deficiency of phenylalanine hydroxylase (PAH) —> MENDELIAN DO Unable to make tyrosine from phenylalanine; strong musty/mousy odor in urine/sweat (maple syrup urine disease) Most commonly affects those of Scandinavian descent Clinical features: normal at birth, w/in 6mo have severe mental retardation; hypopigmentation of hair/skin, eczema Tx: dietary restrictions; if started early enough can prevent pts from progressing

Question 3

Marfan syndrome

Answer 3

Primary defect: AD mutation of FBN1 on chromosome 15q21.1 OR FBN2 on chromosome 5q23.31 Defect in fibrillin-1 or 2 that leads to loss of structural support in microfibril-rich CT and excessive activation of TGF-beta signaling Clinical features: dolicocephalic (long-headed) with frontal bossing and prominent supraorbital ridges, passive dilation of aortic valve ring, aortic dissection, double-jointed

Question 4

Ehlers-Danlos syndrome

Answer 4

Primary defect: defect in synthesis or structure of fibrillar collagen Skin is hyperextensible, joints hyper mobile; minor injuries produce gaping defects Type I/II = classic; easy bruising; AD; COL5A1, COL5A2 gene defects; assoc. w/ diaphragmatic hernia Type IV = vascular; hyperextensibility of small joints; AD; COL3A1 gene defects; can lead to rupture of colon/large arteries Type VI = kyphoscoliosis; ocular fragility, rupture of cornea and retinal detachment; AR; lysyl hydroxylase gene defects

Question 5

Familial hypercholesterolemia

Answer 5

Primary defect: mutation of receptor for LDL One of the most frequent Medialian DOs Heterozygotes: tendinous xanthomas, 2-3 fold increase in cholesterol and increased risk of MI Homozygotes: skin xanthomas; 5-6 fold increase in cholesterol and MI before 20yo

Question 6

Lysosomal storage diseases

Answer 6

Primary defect: catabolism of substrate incomplete due to missing enzyme –> leads to primary accumulation Impaired autophagy gives rise to secondary accumulation of autophagic substrates 3 txs: enzyme replacement therapy, substrate reduction therapy, stem cell transplants (understanding molec basis of deficiency)

Question 7

Tay-Sachs disease

Answer 7

Aka Gm2 gangliosidosis or Hexosaminidase alpha-subunit deficiency Primary defect: mutations in alpha subunit locus on chromosome 15; severe deficiency of hexosaminidase A and inability to catabolism Gm2 gangliosides Most commonly seen in Ashkenzi Jewish populations Clinical features: normal at birth, w/in 6mo motor/mental deterioration, cherry-red spot in macula w/ swollen ganglion cells of retina; accumulation of Gm2 ganglioside in neurons, retina, heart, liver, spleen; 1-2yo vegetative state; death by 2-3yo Fat stains oil red O and Sudan black B are positive; lipid vacuole in neuron cytoplasm and whorled lysosomes seen on histological exam

Question 8

Niemann-Pick disease (type A)

Answer 8

Primary defect: lysosomal accumulation of sphingomyelin due to AR inherited deficiency of sphingomyelinase chronic 11p15.4 Most commonly seen in Ashkenazi Jewish populations Missense mutation; complete lack of sphingomyelinase = severe infantile form, extensive neurons involvement, mkd visceral accumulations of sphingomyelin, progressive wasting; sxs by 6mo, death before 3yo Morphologic changes: foamy cytoplasm; zebra bodies (lysosomes with concentric lamellations) Clinical features: massive splenomegaly; 1/3 to 1/2 have cherry red spot

Question 9

Niemann-Pick disease (type B)

Answer 9

Mildest form; present with organomegaly, no CNS involvement Pts reach adulthood

Question 10

Niemann-Pick disease (type C)

Answer 10

Most common form; transport of free cholesterol from lysosomes to cytoplasm Progressive neurological damage; ataxia, vertical supranuclear gaze palsy, dystonia, dysarthria, psychomotor regression

Question 11

Gaucher disease

Answer 11

Primary defect: AR glucocerebroside mutation Accumulation of glucocerebroside in phagocytes (sometimes CNS) leads to damage and release of IL-1, IL-6, TNF from macrophages Type I (chronic): seen in European Jews, NO CNS involvement, spleen and bone sxs Type II (acute neuronopathic): infantile cerebral pattern, progressive CNS development, early death, hepatosplenomegaly, NOT Jewish Type III (intermediate): systemic involvement with progressive CNS disease beginning in adolescence/early adulthood Morph: Gaucher cells (distended phagocytes) in liver, spleen, bone marrow; pathologic fractures; fibrillary-type cytoplasm = “crumpled tissue paper”; enlarged spleen Tx: allogeneic hematopoietic stem cell transplant, recombinant enzyme replacement

Question 12

Mucopolysaccharidoses (MPS)

Answer 12

Primary defect: deficiency of enzymes degrading GAGs; MPS abundant in ground substance of CT All AR except Hunter syndrome Clinical features: coarse facial features, clouding of cornea, joint stiffness, mental retardation Morph: balloon cells (swollen lysosomes PAS+); lamellate zebra bodies COD: MI and cardiac decompensation

Question 13

Hurler syndrome

Answer 13

MPS I-H Normal at birth, hepatosplenomegaly by 6-24mo; death 6-10yo due to CV complications Growth retardation, coarse facial features, skeletal abnormalities

Question 14

Hunter syndrome

Answer 14

MPS II X-linked inheritance NO corneal clouding; milder clinical course than Hurler syndrome

Question 15

von Gierke disease

Answer 15

Hepatic form of glycogen storage disease (type I) Deficiency in glucose-6-phosphatase leads to increased storage of glycogen in liver and hypoglycemia

Question 16

McArdle disease

Answer 16

Myopathic form of glycogen storage disease (type V) Deficiency in muscle phosphorylase increases glycogen storage in muscle and muscle weakness; muscle cramps after exercise, no increased blood lactate post-exercise

Question 17

Pompe disease

Answer 17

Glycogen storage disease (type II) Deficiency in acid maltase (glucosidase) associated with glycogen storage in many organs and death in early life Cardiomegaly

Question 18

Trisomy 21

Answer 18

Down syndrome Most common chromosomal DO; maternal age has strong influence Clinical features: flat facial profile, oblique palpebral fissures, epicanthic folds; ~40% have congenital heart disease; 10-20 fold increased risk of acute leukemia; abnormal immune responses that predispose to serious infections; pts older than 40 develop Alzheimer disease-like changes

Question 19

Trisomy 18

Answer 19

Edwards syndrome Clinical features: renal malformations (horseshoe kidney), rocker-bottom feet, micrognathia, short neck, overlapping fingers, congenital heart defects

Question 20

Trisomy 13

Answer 20

Patau syndrome Clinical features: renal defects, rocker-bottom feet, cardiac defects, microcephaly and mental retardation, micrognathia, polydactyly, cleft lip/palate

Question 21

Chr 22q11.2 deletion syndrome

Answer 21

Small deletion of band q11.2 on long arm of chromosome 22 Clinical features: T-cell immunodeficiency and hypocalcemia, abnormalities of palate, facial dysmorphism, developmental delay, congenital heart defects

Question 22

DiGeorge syndrome

Answer 22

Chr 22q11.2 deletion syndrome variant Clinical features: thymic hypoplasia w/resultant T-cell immunodeficiency, parathyroid hypoplasia –> hypocalcemia, cardiac malformations, mild facial anomalies

Question 23

Velocardiofacial syndrome

Answer 23

Chr 22q11.2 deletion syndrome variant Clinical features: fascial dysmorphism (prominent nose, retrognathia, long face), cleft palate, cardiovascular anomalies, learning disabilities

Question 24

Kleinfelter syndrome

Answer 24

47, XXY = most common pattern Clinical features: eunuchoid body habits with abnormally long legs; small atrophic testes, small penis; gynecomastia, lower IQ; increased risk of type II DM and metabolic syndrome; 50% mitral valve prolapse, osteoporosis, male infertility 20x increased risk of breast cancer

Question 25

Turner syndrome

Answer 25

45, X0 (~57% missing an entire chromosome) Complete or partial monosomy of X chromosome characterized primarily by hypogonadism in phenotypic females Most common sex chromosome abnormality in females Mosaic patients have 45,X cell population plus >/=1 karyotypically normal or abnormal cell types Cystic hygroma: infant with edema –> swelling of nape of neck due to lymph stasis; swelling subsides but leaves bilateral neck webbing Clinical: short stature, webbing of neck, cubitus values, CV malformations (MCC of increase mortality in children; left-sided CV abnormalities common –> CHD), amenorrhea, lack of 2ndary sex characteristics, fibrotic ovaries (streak ovaries); hypothyroidism in some pts; glucose intolerance, obesity, insulin resistance in minority of pts

Question 26

True hermaphrodite

Answer 26

Presence of both ovarian and testicular tissue

Question 27

Pseudohermaphrodite

Answer 27

Disagreement between phenotypic and gonadal sex Female psuedohermaphrodite = ovaries but male external genitalia Male pseudohermaphrodite = testicular tissues but female-type genitalia

Question 28

Fragile X syndrome

Answer 28

Trinucleotide mutation in familial mental retardation-1 (FMR-1) gene –> 200-4000 repeat expansion Clinical features: long face, large mandible, large everted ears, large testicles, hyperextensible joints, high arched palate, mitral valve prolapse Carrier males: transmit trait through phenotypically normal daughters to affected grandchildren During oogenesis (not spermatogenesis), permutations can be converted to mutations by triplet-repeat amplification Anticipation prominent in this disease

Question 29

Huntington disease

Answer 29

AD disease characterized by progressive movement disorders and dementia caused by degeneration of striatal neurons Prototype of polyglutamine trinucleotide repeat expansion diseases Gene = HTT on chr 4p16.3 –> encodes huntingtin Anticipation prominent in this disease

Question 30

Leber hereditary optic neuropathy

Answer 30

Prototype of mtDNA disorder Clinical manifestations: progressive bilateral loss of central vision first noted between ages 15 and 35 and resulting in blindness; cardiac conduction defects and minor neurologic manifestations noted

Question 31

Prader-Wili syndrome

Answer 31

Paternal chromosome 15 carries the maternal imprint Clinical features: mental retardation, short stature, hypotonia, profound hyperphagia, obesity, small hands/feet, hypogonadism In 65-70% of all cases, interstitial deletion of band q12 in long arm of chromosome 15 [del(15)(q11.2q13)]

Question 32

Angelman syndrome

Answer 32

Maternal chromosome 15 carries the paternal imprint Clinical features: mental retardation, ataxic gait, seizures, inappropriate laughter