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Common Inherited Disorders > Common inherited disorderes > Flashcards

Common inherited disorderes Flashcards

1
Q

Autosomal dominant polycystic kidney disease (ADPKD)

A

Bilateral kidney enlargement due to large cysts.
Most: mutation in PKD1 (Chr16–16 letters in polycystic kidney)
Some: mutation in PKD2 (Chr4)
AD

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2
Q

Familial adenomatous polyposis

A

Colon covered in adenomatous polyps after puberty, progresses to colon cancer without resection.
Mutation in APC gene (Chr5–5 letters in polyp)
AD

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3
Q

Familial hypercholesterolemia

A

High LDL due to defective/absent LDL receptor–severe atherosclerotic disease, tendon xanthomas.
AD

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4
Q

Hereditary hemorrhagic telangectasia

A

Inherited blood vessel disorder–telangectasia, recurrent epistaxis, skin discolorations, AVMs, GI bleeding, hematuria. AKA Osler-Weber-Rendu Syndrome.
AD

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5
Q

Hereditary spherocytosis

A

Spheroid erythrocytes due to spectrin or ankyrin defect; hemolytic anemia; increased MCHC. Treat with splenectomy.
AD

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6
Q

Huntington disease

A

Sx: depression, progressive dementia, choreiform movements, caudate atrophy, low GABA/Ach in brain. Trinucleotide repeat disorder (CAG), Chr 4, more repeats–earlier onset
AD

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7
Q

Marfan syndrome

A

Fibrillin 1 gene mutation: connective tissue disorder affecting skeleton, heart, eyes. findings: tall, long extremities, pectus excavatum, hypermobile joints, arachnodactyly. Cystic medial necrosis of aorta–aortic incompetence/dissecting aortic aneurysms. Floppy mitral valve. Subluxation of lenses.
AD

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8
Q

Multiple endocrine neoplasias Type I (MEN 1)

A

Tumors of Pituitary, Parathyroid, Pancreas (3 P’s, draw a diamond)
AD

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9
Q

Multiple endocrine neoplasias Type 2A (MEN 2A)

A

Medullary thyroid carcinoma (calcitonin), Parathyroid, and Pheochromocytoma (2 P’s, draw a square)
Mutation in ret
AD

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10
Q

Multiple endocrine neoplasias type 2B (MEN 2B)

A

Medullary thyroid carcinoma (calcitonin), Pheocromocytoma, oral/intestinal ganglioneuromatosis (mucosal neuromas, marfanoid habitus (1 P, draw a triangle with top at mouth)
Mutation in ret
AD

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11
Q

Neurofibromatosis type 1 (von Recklinghausen disease)

A

cafe-au-lait spots, cutaneous neurofibromas.
Mutation in NF-1 gene on Chr17 (17 letters in von Recklinghausen)
AD, 100% penetrance but variable expression

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12
Q

Neurofibromatosis type 2

A

Bilateral acoustic Schwannomas, juvenile cataracts, meningiomas, ependymomas.
NF2 gene, Chr22 (type 2, 22)
AD

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13
Q

Tuberous sclerosis

A

Neurocutaneous disorder w multiorgan system involvement, numerous benign hamartomas.
AD, incomplete penetrance, variable expression

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14
Q

von Hippel-Lindau disease

A

Development of numerous tumors (benign and malignant)
Deletion of VHL gene (tumor suppressor) on Chr 3 (3p).
AD
Von Hippel Lindau = 3 words for Chr3

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15
Q

Cystic fibrosis

A

Defect in CFTR gene on Chr7 (commonly deletion of Phe508), which encodes ATP-gated Cl- channel that secretes Cl- in lungs/GI tract and reabsorbs Cl- in sweat.
AR

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16
Q

X-linked recessive disorders to remember

A 
Bruton agammaglobulinemia
Wiskott-Aldrich syndrome
Fabry disease
G6PD deficiency
Ocular albinism
Lesch-Nyhan syndrome
Duchenne (and Becker) muscular dystrophy
Hunter syndrome
Hemophilia A and B
Ornithine transcarbamylase deficiency
(Be Wise, Fool's GOLD Heeds Silly HOpe)
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17
Q

Duchenne muscular dystrophy

A 
X-linked recessive frameshift mutation--truncated dystrophin--accelerated muscle breakdown.  
Dystophin gene (DMD) has longest coding region of any human gene
Weakness starting in pelvic girdle, moving up; pseudohypertrophy of calfs; Gower maneuver; death by dilated cardiomyopathy.
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18
Q

Becker muscular dystrophy

A

X-linked recessive point mutation in dystrophin gene (no frameshift). Less severe/later onset than Duchenne.

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19
Q

Myotonic type 1 muscular dystrophy

A

CTG trinucleotide repeat expansion in DMPK gene–abnormal expression of myotonin protein kinase–myotonia, muscle wasting, frontal balding, cataracts, testicular atrophy, arrhythmia.
X-linked recessive.

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20
Q

Fragile X syndrome

A

X-linked recessive
Affects methylation/expression of FMR1 gene. Trinucleotide repeat disorder (CGG).
2nd most common cause of genetic intellectual disability.
Findings: post-pubertal macroorchidism, long face/large jaw, large everted ears, autism, mitral valve prolapse

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21
Q

Trinucleotide repeat expansion diseases to remember

A 
Huntington disease  (CAG)
Myotonic dystrophy (CTG)
Friedreich ataxia (GAA)
Fragile X (CGG)
(Tri Hunting My Fried Eggs (X))
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22
Q

Down Syndrome

A 
Trisomy 21, 1:700
Findings:
intellectual disability
Flat facies, prominent epicanthal folds
Single palmar crease
gap between 1st two toes
duodenal atresia
Hirschsprung disease
congenital heart disease (primum-type ASD)
Brushfield spots
Incr. risk of ALL, AML, early Alzheimers

Most due to meiotic nondisjunction, assoc with advanced maternal age
1st trimester: Increased nuchal translucency, hypoplastic nasal bone, PAPP-A low, HCG high
Quad screen: Low AFP, High beta-HCG, Low estriol, High inhibin A

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23
Q

Edwards syndrome (Trisomy 18)

A

1:8000
Findings: severe intellectual disability, rocker-bottom feet, micrognathia, low-set ears, clenched hands, prominent occiput, congenital heart disease, death before 1 year
1st trimester: PAPP-A and HCG Low
Quad screen: Low AFP, Low beta-HCG, Low estriol, Low/normal inhibin A

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24
Q

Patau syndrome (Trisomy 13)

A

1:15000
Findings: severe intellectual disability, rocker-bottom feet, microphthalmia, microcephaly, cleft lip/palate, holoprosencephaly, polydactyly, congenital heart disease, death before one year.
1st trimester: Low HCG, Low PAPP-A, increased nuchal translucency

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25
Q

Cri-du-chat syndrome

A

Congenital microdeletion of short arm of Chr5 (46XX or XY, 5p-)
Findings: microcephaly, moderate/severe intellectual disability, high-pitched crying/mewing, epicanthal folds, cardiac abnormalities (VSD)

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26
Q

Williams syndrome

A

Congenital microdeletion of long arm of Chr 7 (including the elastin gene)
Findings: “elfin” facies, intellectual disability, hypercalcemia (incr. sensitivity to VitD), well-developed verbal skills, friendly with strangers, cardiovascular problems

27
Q

22q11 deletion syndromes

A 
Aberrant development of 3rd/4th branchial pouches.
Variable presentation, including:
Cleft palate
Abnormal Facies
Thymic aplasia--T cell deficiency
Cardiac defects
Hypocalcemia (due to parathyroid aplasia)
(CATCH-22)
Includes:
DiGeorge syndrome (thymic, parathyroid, cardiac defects)
Velocardiofacial syndrome (palate, facial, cardiac defects)
28
Q

DiGeorge syndrome

A 
Due to 22q11 deletion, causing aberrant development of 3rd/4th branchial pouches.
Thymic aplasia (T cel deficiency), parathyroid aplasia (hypocalcemia), cardiac defects
29
Q

Velocardiofacial syndrome

A

Due to 22q11 deletion, causing aberrant development of 3rd/4th branchial pouches.
Cleft lip/palate, cardiac defects

30
Q

Adenosine deaminase deficiency

A

Autosomal recessive; one of the major causes of AR SCID.
ATP/dATP build up, imbalance of nucleotide pool due to feedback inhibition of ribonucleotide reductase, which prevents DNA synthesis and decreases lymphocyte count

31
Q

Lesch-Nyhan syndrome

A

Absence of HGPRT leads to defect purine salvage, resulting in excess uric acid production and de novo purine synthesis.
Tx: allopurinol (or febuxostat)
Findings: HGPRT (Hyperuricemia, Gout, Pissed off [aggression, self-mutilation], Retardation [intellectual disability], dysTonia)
X-linked recessive

32
Q

Osteogenesis imperfecta

A

Bone disorder cause by variety of gene defects (COL1A1 and COL1A2 genes)
Most commonly autosomal dominant with decreased production of otherwise normal type I collagen (Type 1). Other types can have problems with collagen quantity and quality (problems forming triple helix)

33
Q

Ehlers-Danlos syndrome

A

Faulty collagen synthesis–hyperextensible skin, tendency to bleed, hypermobile joints–problem crosslinking collagen molecules
6+ types, inheritance and severity vary (AR or AD).
Most common type: hypermobility type (joint instability)
Classic type: joint and skin symptoms, mutation in type V collagen
Vascular type: Vascular/organ rupture, deficient type III collagen

34
Q

Menkes disease

A

Connective tissue disorder due to impaired copper absorption/transport.
Copper necessary for lysine-hydroxylysine crosslinking in collagen by lysyl oxidase.
Brittle, kinky hair; growth retardation; hypotonia

35
Q

Prader-Willi syndrome

A

Maternal imprinting of genes on Chr15: gene from mom in normally silent and paternal gene is absent or mutated.
Causes hyperphagia, obesity, intellectual disability, hypogonadism, hypotonia
25% of cases due to maternal uniparental disomy.

36
Q

Angelman syndrome

A

Paternal imprinting of genes on Chr15: gene from dad is normally silent, maternal gene is absent/mutated.
Causes inappropriate laughter (happy puppet), seizures, ataxia, severe intellectual disability.
5% due to paternal uniparental disomy.

37
Q

Maturity-onset diabetes of the young (MODY)

A

Mutation in gene for glucokinase (converts glucose to glucose-6-P for glycolysis in liver and Beta cells of pancreas/glycogen synthesis in the liver

38
Q

Pyruvate dehydrogenase complex deficiency

A

Causes a buildup of pyrvate that gets shunted to lactate and alanine.
Findings: neurological defects, lactic acidosis, high serum alanine starting in infancy
Tx: high intake of ketogenic nutrients (high fat, high lysine/leucine content)

39
Q

Glucose-6-phosphate dehydrogenase (G6PD) deficiency

A

G6PD necessary to produce NADPH in HMP shunt. NADPH necessary to keep glutathione reduced so it can detoxify free radicals/peroxides (especially important in RBCs). Absence leads to increased susceptibility of RBCs to oxidative damage and resulting hemolytic anemia in times of oxidative stress (infection, certain meds, fava beans).
Findings: Heinz bodies (oxidized Hb in RBCs), bite cells
X-linked recessive

40
Q

Essential fructosuria

A

Defect in fructokinase, benign (fructose not trapped in cells).
AR

41
Q

Fructose intolerance

A

Aldolase B deficiency leading to accumulation of Fructose-1-P, causing decrease in available P–inhibition of glycogenolysis and gluconeogenesis.
Sx: hypoglycemia, jaundice, cirrhosis, vomiting.
Tx: decreased intake of fructose and sucrose
AR

42
Q

Galactokinase deficiency

A

Hereditary deficiency of galactokinase (AR). Galactitol accumulates if galactose is present in diet. Mild.
Sx: galactosuria/emia. Infantile cataracts.

43
Q

Classic galactosemia

A

Absence of galactose-1-phosphate uridyltransferase, leads to damage due to accumulation of toxic substances (including galactitol, which accumulates in lens).
Sx: failure to thrive, jaundice, hepatomegaly, infantile cataracts, intellectual disability.
Tx: exclude lactose and galactose from diet
Can lead to E. coli sepsis in neonates

44
Q

N-acetylglutamate deficiency

A

N-acetylglutamate is a required cofactor for carbamoyl phosphate synthetase I (rate limiting step of urea cycle). Absence leads to hyperammonemia.
Same presentation as carbamoyl phosphate synthetase I deficiency.

45
Q

Ornithine transcarbamylase deficiency

A

Most common urea cycle disorder. X-linked recessive.
Often evident in first few days of life but may present later. Defective elimination of ammonia.
Excess carbamoyl phosphate is converted to orotic acid (pyrimidine synthesis pathway).
Findings: High orotic acid in blood, decreased BUN, sx of hyperammonemia. No magaloblastic anemia (vs. orotic aciduria)

46
Q

Phenylketonuria

A

Due to decreased phenylalanine hydroxylase or tetrahydrobiopterin cofactor.
Tyrosine become essential.
Phenylketones in urine.
Findings: intellectual disability, growth retardation, seizures, fair skin, eczema, musty body odor.
Tx: decrease phenylalanine and increase tyrosine in diet.
Maternal PKU: causes microcephaly, intellectual disability, growth retardation, and congenital heart defects in fetus.

47
Q

Alkaptonuria

A

Congenital deficiency of homogentisate in degradative pathway of tyrosine to fumarate. Benign.
Findings: dark connective tissue, brown sclerae, urine turns dark on exposure to air, may have bad arthralgias
AR

48
Q

homocystinuria

A

Types:

  1. Cystathionine synthase deficiency (Tx: decrease methioine, increase cysteine, increase B12 and folate)
  2. Decreased affinity of cystathionine synthase for pyridoxal phosphate (Tx: load with B6 and increase cysteine)
  3. Homocysteine methyltransferase (methionine synthase) deficiency (Tx: increase methionine in diet)

All are AR, all result in excess homocysteine.
Findings: homocysteinuria, intellectual disability, osteoporosis, tall statue, kyphoysis, lens subluxation, thrombosis, atherosclerosis.

49
Q

Cystinuria

A

Hereditary defect of renal PCT and intestinal AA transporter for Cysteine, Ornithine, Lysine, Arginine (COLA)
Excess urine cysteine–haxagonal cystine stones
AR, 1:7000
Dx: urinary cyanide-nitroprusside test
Tx: urinary alkalinization, chelating agents, hydration

50
Q

Maple Syrup Urine Disease

A

Blocked degradation of branched amino acids (Isoleucine, Leucine, Valine) due to decreased alpha-ketoacid dehydrogenase (B1).
Increase ketoacids in blood (esp leucine).
Causes severe CNS defects, intellectual disability, death.
Urine has maple syrup odor
Tx: restriction of leucine, isoleucine, valine. Thiamine supplementation
AR

51
Q

Glycogen storage diseases to remember

A

Von Gierke’s, Pompe, Cori, McArdle (Very Poor Carbohydrate Metabolism)
All AR

52
Q

von Gierke disease (type 1)

A

Glycogen storage disease, lacking glucose-6-phosphatase (can’t complete gluconeogenesis)
Findings: severe fasting hypoglycemia, lots of glycogen in the liver, increased blood lactate, hepatomegaly
Tx: frequent oral glucose/cornstarch, avoid fructose/galactose
AR

53
Q

Pompe disease (type II)

A

Glycogen storage disease, lacking lysosomal a-1,4-glucosidase (acid maltase)
Findings: cariomyopathy, systemic findings, early death
AR

54
Q

Cori disease

A

Glycogen storage disease, lacking a-1,6-glucosidase (debranching enzyme).
Like a mild form of von Gierke’s, normal lactate levels, largely intact gluconeogenesis.
AR

55
Q

McArdle disease

A

Glycogen storage disease, missing skeletal muscle glycogen phosphorylase (myophosphorylase).
Increase glycogen in muscle, but can’t break it down–muscle cramps, myoglobinuria, arrhythmia from electrolyte abnormalities
AR

56
Q

Sphingolipidoses (type of lysosomal storage disease) to remember

A 
Fabry disease
Gaucher disease
Niemann-Pick disease
Tay-Sachs disease
Krabbe disease
Metachromatic leukodystrophy
57
Q

Fabry disease

A

Sphingolipidosis (lysosomal storage disease)
Defect in a-galactosidase A
Ceramide and trihexoside accumulate
Peripheral neuropathy, angiokeratomas, cardiovascular/renal disease
X-linked recessive

58
Q

Gaucher disease

A

Sphingolipidosis (lysosomal storage disease)
Defect in glucocerebrosidase (beta-glucosidase)
Glucocerebroside accumulates
Most common lysosomal storage disease.
HSM, pancytopenia, aseptic necrosis of femur, bone crises, Gaucher cells (lipid-laden machrophages resembling crumpled tissue paper)
Tx: recombinant glucocerebrosidase
AR

59
Q

Niemann-Pick disease

A

Sphingolipidosis (lysosomal storage disease)
Defect in sphingomyelinase
Sphingomyelin accumulates
Progressive neurodegeneration, HSM, cherry red spot of macula, foam cells
AR
“No man picks (Niemann-Pick) his nose with his sphinger)

60
Q

Tay-Sachs disease

A

Sphingolipidosis (lysosomal storage disease)
Defect in hexosaminidase A
GM2 ganglioside accumulates
Progressive neurodegeneration, developmental delay, cherry red spot on macula, lysosomes with onion skin, no HSM (vs Niemann-Pick)
AR

61
Q

Krabbe disease

A

Sphingolipidosis (lysosomal storage disease)
Defect in Galactocerebrosidase
Galactocerebroside, psychosine accumulate
Peripheral neuropathy, developmental delay, optic atrophy, globoid cells
AR

62
Q

Metachromatic leukodystrophy

A

Sphingolipidosis (lysosomal storage disease)
Defect in Arylsulfatase A
Cerebroside sulfate accumulates
Central and peripheral demyelination with ataxia, dementia
AR

63
Q

Hurler syndrome

A

Mucopolysaccharidosis (lysosomal storage disease)
Defect in a-L-iduronidase
Heparan sulfate, dermatan sulfate accumulate
Developmental delay, gargoylism, airway obstruction, corneal clouding, HSM
AR

64
Q

Hunter syndrome

A

Mucopolysaccharidosis (lysosomal storage disease)
Defect in Iduronidate sulfatase
Heparan sulfate, dermatan sulfate accumulate
Like Mild Hurler disease plus aggressive behavior, no corneal clouding
X-linked recessive

Common Inherited Disorders (1 decks)

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