USMLE First Aid

Question 1

Orotic Aciduria

Answer 1

Inability to convert orotic acid to UMP (de novo pyrimadine syntheis)

Defect in UMP synthase

Findings: increased orotic acid in urine, megaloblastic anemia (does not improve with folic acid or Vit B12), failure to thrive. No hyperammonemia

Treatment: Oral uridine

Question 2

Adenosine demainase deficiency

Answer 2

Excess ATP and dATP imbalances nucleotide pool via feedback inhibition of ribonucleotide reductase → prevents DNA synthesis and thus decreases lymphocyte count (Major cause of SCID) Autosomal recessive

Question 3

Lesch-Nyhan Syndrome

Answer 3

Defective purine salvage due to the absance of HGPRT (converts hypoxantine to IMP and Guanine to GMP)

Reuslts in excess uric acid

Findings: retardation, self-mutilation, aggression, hyperuricemia, gout, choreoatheosis

X-linked Recessive

Question 4

I-Cell Disease

Answer 4

inherited lysosomal storage disorder; failure of addition of mannose-6-phosphate to lysosome proteins

Results in coarse facial features, clouded corneas, restricted joint movement, high plasma levels of lysosomal enzymes

Question 5

Chédiak-Higashi Syndrome

Answer 5

mutation on the lysosomal trafficking regulator gene (LYST); whose product is required for the microtubule-dependent sorting of endosomal proteins into late multivescular endosomes.

Results in recurrent infections, partial albinism, and peripheral neuropathy

Question 6

Kartagener’s Syndrome

Answer 6

Primary Ciliary Dyskinesa

Immolite cilia due to dynein arm defect.

Results in Infertility, brochiectasis, and recurrent sinusitis

associated with sinus inversus

Question 7

Osteogenesis Imperfecta

Answer 7

Autosomal Dominant defect in Type 1 Collagen

Causes: Multiple fractures with minimal trauma, blue sclerae, hearing loss, dental imperfections due to lack of dentin

Question 8

Ehlers-Danlos Syndrome

Answer 8

Faulty collagen synthesis causing hyperextensible skin, tendency to bleed, and hypermobile joints.

definciencies of lysyl-hydroxylase or pro-collagen peptidase

Question 9

Alports Syndrome

Answer 9

Abnormal type IV collagen

most common form is X-linked recessive

Characterized by progressive hereditary nephritis and deafness

Question 10

Down Syndrome

Answer 10

Mental retardation, flat facies, prominent epicanthal folds, simian crease, gap between 1st and 2nd toes, duodenal atresia, congenital heart disease (most commonly ostium primum-type ASD)

increased ß-hCG and Inhibin

decreased a-fetoprotein and estriol

Question 11

Edwards’ Syndrome

Answer 11

Trisomy 18

Mental retardation, rocker-bottom feet, micrognathia, low-set ears, clenched hands, prominend occiput

decreased a-fetoprotein B-hCG, estriol; normal inhibin A

Question 12

Patau’s Syndrome

Answer 12

Mental retardation, rocker-bottom feet, microphthalmia, microcephaly, cleft lip/palate, holoprosencephaly, polydactyly

decreased B-hCG, PAPP-A

increased nuchal tranlucency

Question 13

Cri-du-chat syndrome

Answer 13

congenital microdeletion of short-arm of chromosome 5

Findings: microcephaly, moderate to severe retardation, high-pitched crying, epicanthal folds, cardiac abnormalities (VSD)

Question 14

Williams Syndrome

Answer 14

Congenital microdeletion of the long arm of chromosome 7

Findings: distinicive “elfin” facies, intellectua disabilitym hypercalcemia, well-developed verbal skills, extreme friendliness with strangers, cardiovascular problems

Question 15

Vitamin A

Answer 15

Antioxidant; comstituent of visual pigments; essential for normal differentiaion of epithelial cells into specialized tissues; prevents squamous metaplasia. Used to treat measles and AML

Deficiency: Night blindness, dry skin

Excess: arthralgias, fatigue, headaches, skin changes sore throat, alpecia. Teratogenic

Question 16

Vitamin B1

Answer 16

Thiamine

In thiamine pyrophosphate (TPP): cofactor for Pyruvate dehydrogenase (links glycolysis to TCA cycle); A-ketoglutarate dehydrogenase (TCA cycle); Transketolase (HMP shunt); Branched-chain amino acid dehydrogenase

Deficiency: Impaired glucose breakdown → ATP depletion worsened by glucose infusion (highly areobic tissues (brain and heart) affected first

Wernicke-Korsakoff, Dry Beriberi, Wet Beriberi

Question 17

Vitamin B2

Answer 17

Riboflavin

Cofactor in oxidation and reduction (eg FAHD₂)

Deficiency: Cheilosis-inflammation of lips, scaling and fissures at the corners of the mouth; Corneal vascularization

Produced in Succinate → Fumarate reaction of TCA

Question 18

Vitamin B3

Answer 18

Niacin

Constituent of NAD⁺ and NADP⁺ Used in redox reactions

Derived from Tryptophan

Synthesis requires Vit B₆

Deficiency: Glossitis. Severe deficiency leads to pellagra

can be caused by Hartnup disease (decreased tryptophan absorption) malignant carcinoid syndrome (increased tryptophan metabolism), and INH (decreased Vit B₆)

Excess: Facial flushing

Question 19

Vitamin B5

Answer 19

Pantothenate

Essential component of CoA and fatty acid synthase

Deficiency: dermatitis, enteritis, alopecia, adrenal insufficiency

Question 20

Vitamin B6

Answer 20

Pyridoxine

converted to ptridoxal phosphate, a cofactor used in transamination, decarboxylation, glycogen phosphorylase.

Synthesis of cystathionine, heme, niacin, histamine, and neurotransmitters

Deficiency: convulsions, hyperirritability, peripheral neuropathy, sideroblastic anemias

Question 21

Vitamin B7

Answer 21

Biotin

Cofactor for carboxylation enzymes: pyruvate carboxylase (pyruvate (3C)→oxaloacetate (4C)); Acetyl-CoA carboxylase (acetyl-CoA (2C)→malonyl-CoA (3C)); Propionyl-CoA carboxylase (propionyl-CoA (3C)→methylmalonyl-CoA(4C))

Deficiency: dermatitis, alpecia, enteritis. Caused by ingestion of raw eggs

Question 22

Vitamine B9

Answer 22

Folic Acid

Converted to tetrahydrofolate (THF); coenzyme for 1-carbon tranfers/methylation reactions

Important for the synthesis of nitrogenous bases in DNA and RNA

Deficiency: Macrocytic, megaloblastic anemia; no neurologic symptoms. Most common vitamin deficiency in the US. Seen in Alcoholism and Pregnancy

Deficiency can be caused by several drugs (Phenytoin, sulfonamides, MTX)

Question 23

Vitamin B12

Answer 23

Cobalamin

Cofactor for homocysteine methyltransferase and methylmalonyl-CoA mutase

Deficiency: Macrocytic, megaloblastic anemia, hypersegmented PMNs, neurological symptoms

Question 24

S-adenosyl-methionine

Answer 24

ATP+Methionine = SAM

SAM is a methyl donor

Required for conversion of NE to epinephrine

Regeneration of Methionine (and SAM) is dependent of Vit B12 and Folate

Question 25

Vitamin C

Answer 25

Antioxidant Necessary for **hydroxylation of proline and lysine in collagen synthesis, dopamine B-hydroxylase (converts Dopamine to NE)** Deficiency: scurvy - swollen gums, brusing, hemarthrosis, anemia, poor wound-healing Excess: Nausea, vomiting, fatigue, sleep problems

Question 26

Vitamin D

Answer 26

Increases intestinal absorption of calcium and phosphate, increases bone mineralization Deficiency: Rickets in children, osteomalacia in adults, hypocalcemic tentany Excess: hypercalcemia, hypercalciuria, loss of appetite, stupor. **seen in sarcoidosis**

Question 27

Vitamin E

Answer 27

Antioxidant (protects erythrocytes and membranes from free-radical damage) Deficiency: increased fragility of erythrocytes, muscle weakness, posterior column and spinocerebellar tract demyelination

Question 28

Vitamin K

Answer 28

Catalyze **gamma-carboxylation of glutamic acid residues on various proteins concerned with blood clotting.** **_Clotting factors II, VII, IX, X, protein C, protein S_** Deficiency: neonatal hemorrhage with increased PT and aPTT but normal bleeding time

Question 29

Zinc

Answer 29

Essential for the activity of 100+ enzymes Important in the formation of zinc fingers Deficiency: delayed wound healing, hypogonanism, decreased adult hair, dygeusia, anosmia

Question 30

Pryuvate Dehydrogenase complex Deficiency

Answer 30

Causes backup of substrates (pyruvate and alanine) **resulting in lactic acidosis** Most cases are due to x-linked gene for E1-a subunit of PDC Treatment: **increased intake of ketogenic nutrients (high fat content or high in lysine and leucine)**

Question 31

Glucose-6-Phosphate dehydrogenase deficiency

Answer 31

NADPH is necessary to keep glutathione reduced **decreased NADPH in RBCs leads to hemolytic anemia due to oxidizing agents** _X-linked Recessive Disorder_ **Heinz Bodies -** oxidized hemoglobin precipitated within RBCs **Bite Cells -** result from the phagocytic removal of Heinz Bodies by splenic macrophages

Question 32

Essential Fructosuria

Answer 32

Defect in **Fructokinase** _Autosomal Recessive_ **Begign, asymptomatic condition, since fructose is not trapped in cells** Symptoms: fructose in urine and blood

Question 33

Fructose Intolerance

Answer 33

Hereditary deficiency of **Aldolase B** _Autosomal Recessive_ **Fructose-1-phosphate accumulates causing a decrease in available phosphate; _leads to inhibition of glycogenolysis and gluconeogenesis_** Symptoms: hypoglycemia, jaundice, cirrhosis, vomiting Treatment: decrease intake of both frutose and sucrose

Question 34

Galactokinase Deficiency

Answer 34

Hereditary deficiecy of **galactokinase** Galactitol accumulates if galactose is present in diet. Relatively mild condition. _Autosomal recessive_ Symptoms: galactose in blood and urine, infitile cataracts

Question 35

Classic Galactosemia

Answer 35

Absence of **galactose-1-phosphate uridyltransferase** _Autosomal Recessive_ accumulation of galactitol (particularly in the lens of the eyes) Treatment: exclude galactose and lactose from diet

Question 36

Ornithine Transcarbamoylase Deficiency

Answer 36

Most common urea cycle disorder _X-linked recessive_ interferes with the body's ability to eliminate ammonia Excess carbamoyl phosphate is converted to orotic acid Findings: **increased orotic acid in blood and Urine, decreased BUN, symptoms of hyperammonemia (tremor, slurring of speech, somnolence, vomiting, cerebral edema)**

Question 37

Phenylketonuria

Answer 37

Due to **decreased phenylalanine hydroxylase or THB cofactor** _Tyrosine becomes essential_ **Increased phenylalanine leads to phenylketones in urine** Findings: **mental retardation, growth retardation, seizures, fair skin, eczema, musty body** Treatment: **Decrease phenylalanine and increase tyrosine**

Question 38

Alkaptonuria

Answer 38

Congenital defect in **Homogentisic acid oxidase** in the degradative pathway of tyrosine to fumarate _Autosomal Recessive_ - Benign Findings: dark connective tissue, brown pigmented sclera, urine turns black, may have debilitating arthralgias

Question 39

Albinism

Answer 39

Congenital defect of either: **Tyosinase** (inability to synthesize melanin from tyrosine) - autosomal recessive **Defective tyrosine transporters** (decreased amounts of tyrosine and thus melanin) can result from a lack of migration of neural crest cells

Question 40

Homocytinuria

Answer 40

3 forms (all autosomal recessive) **Cytathionine synthase deficiency** - Treatment: Decreased Met; Increased Cys, B12, and Folate **Decreased Affinity of Cytathionine synthase for Pyridoxal phosphate** - Treatment: Increased Vit B6 **Homocysteine methyltransferase deficiency** _All forms result in **excess homocysteine; cysteine becomes essential**_ Findings: **INCREASED homocysteine in urine,** mental retardation, osteoporosis, tall stature, kyphosis, **lens subluxation (downward and inward),** and atherosclerosis

Question 41

Cystinuria

Answer 41

Hereditary defect of renal tubular amino acid transporter for **cysteine, ornithine, lysine, and arginine** in the **PCT** Excess cysteine in the urine can lead to precipitation of **hexagonal crystals and renal staghorn calculi** _Autosomal Recessive_ Treatment: good hydration and urinary alkalinization

Question 42

Maple Syrup Urine Disease

Answer 42

Blocked degradation of **Branched Amino Acids** (**Ile, Leu, Val**) due to **Decreased a-ketoacid dehydrogenase** ## Footnote **Causes severe CNS defect, mental retardation and death**

Question 43

Von Gierke's Disease

Answer 43

Type I Deficiency: **Glucose-6-phosphatase** Findings: **Severe fasting hypoglycemia, Increased glycogen in liver, Increase Blood Lactate, _hepatomegaly_** _Autosomal Recessive_

Question 44

Pompe's Disease

Answer 44

Type II Deficiency: **Lysosomal a-1,4-glucosidase** Findings: **Cardiomegaly, and systemic findings leading to early death** _Autosomal Recessive_ _**P**ompe's trashes the **P**ump_

Question 45

Cori's Disease

Answer 45

Type III Deficiency: **Debranching enzyme (a-1,6-glucosidase)** Findings: Milder form of type I with **normal blood lactate** _Autosomal Recessive_ _Gluconeogenesis is intact_

Question 46

McArdle's Disease

Answer 46

Type V Deficiency: **Skeletal Muscle glycogen phosphorylase** Findings: **Increased glycogen in muscle leading to painful muscle cramps, myoglobinuria with strenuous exercise** _Autosomal Recessive_

Question 47

Fabry's Disease

Answer 47

Deficiency: **a-galactosidase A** accumulated substrate: **Ceramide Trihexoside** _X-linked Recessive_ Findings: **Peripheral Neuropathy of hands/feet, angiokeratomas, cardiovascular/renal disease**

Question 48

Gaucher's Disease

Answer 48

Deficiency: **Glucocerebrosidase** Accumulated substrate: **Glucocerebroside** _Autosomal Recessive_ Findings: **Hepatosplenomegaly, aseptic necrosis of femur, bone crises Gaucher's cells** _(macrophages that look like crumpled tissue paper)_ _\*Most Common\*_

Question 49

Niemann-Pick Disease

Answer 49

Deficiency: **Sphingomyelinase** Accumulated Substrate: **Sphingomyelin** _Autosomal Recessive_ Findings: **Progressive neurodegeneration, hepatosplenomegaly, cherry-red spot on macula, foam cells**

Question 50

Tay-Sachs Disease

Answer 50

Deficiency: **Hexosaminidase A** Accumulated Substrate: **GM2 Ganglioside** _Autosomal Recessive_ Findings: **Progressive neurodegeneration, developmental delay, cherry-red spot on macula, lysosomes with onion skin, _no hepatosplenomegaly_**

Question 51

Krabbe's Disease

Answer 51

Deficiency: **Galactocerebrosidase** Accumulated Substrate: **Galactocerebroside** _Autosomal Recessive_ Findings: **Peripheral neuropathy, developmental delay, optic atrophy, globoid cells**

Question 52

Metachromatic Leukodystrophy

Answer 52

Deficiency: **Arylsulfatase A** Accumulated Substrate: **Cerebroside sulfate** _Autosomal Recessive_ Findings: **Central and peripheral demyelination with atacia, dementia**

Question 53

Hurler's Syndrome

Answer 53

Deficiency: **a-L-iduronidase** Accumulated Substrate: **Heparan Sulfate, Dermatan Sulfate** _Autosomal Recessive_ Findings: **Developmental delay, gargoylism, airway obstruction, corneal clouding and hepatosplenomegaly**

Question 54

Hunter's Syndrome

Answer 54

Deficiency: **Iduronate Sulfatase** Accumulated substrate: **Heparan Sulfate, Dermatan Sulfate** _X-linked Recessive_ Findings: Mild Hurler's + **aggressive behavior, no corneal clouding**