Board Exam Biochemical Practice Questions

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New parents bring their 1-week-old baby boy to the pediatrician's office and report that he is not feeding as well over the last 24 hours and that his diapers have an odor like sweaty feet. Which of the following disorders is the most likely cause of this child's problems?
A. Isovaleric acidemia B. Maple syrup urine disease C. Methylmalonic acidemia D. Phenylketonuria E. Propionic acidemia

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A

Front 2

B2. Which of the following laboratory tests is most likely to provide a definitive diagnosis?
Metabolic Panel B. Plasma amino acids C. Plasma ammonium level D. Urine amino acids E. Urine organic acids

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E.

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B3. A six-month-old boy presents with hepatomegaly, renomegaly, hypoglycemia and lactic acidosis. Which GSD enzyme deficiency is correct?
A. Type la is glucose-6-phosphatase deficiency or von Gierke. B. Type II is (alpha-glucosidase (acid maltase) deficiency or Pompe. C. Type III is debrancher deficiency or Forbes. D. Type V is muscle phosphorylase deficiency or McArdle

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A

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B.4 A six-month-old boy presents with severe hypotonia, massive cardiomegaly, progressive weakness and markedly elevated CPK. Which GSD enzyme deficiency is correct?
A. Type la is glucose-6-phosphatase deficiency or von Gierke. B. Type II is (alpha-glucosidase (acid maltase) deficiency or Pompe. C. Type III is debrancher deficiency or Forbes. D. Type V is muscle

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B

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B.5 A four-day-old infant boy is brought to the emergency room lethargic and no longer taking his formula. A metabolic profile reveals metabolic acidosis and his ammonium level is normal. Which of the following diagnoses is most likely to be found with subsequent metabolic screening studies? A. Citrullinemia B. Maple syrup urine disease C. Methylmalonic acidemia D. Ornithine transcarbamylase deficiency E. Proprionic acidemia

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B. High ammonia would be a feature of all of these disorders except maple syrup urine disease.

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B6.A 6 year old girl is referred to genetics following an episode of pancreatitis. During her hospitalization, she received hyperalimentation and became obtunded. An ammonia level during this episode was 200 meq/L. Following discontinuation of the hyperalimentation and treatment of the pancreatitis, the girl was discharged home on a low fat diet. She has not had any further episodes of pancreatitis or lethargy. You suspect she has a specific metabolic disorder. Which of the following laboratory evaluations is the BEST way to obtain a specific diagnosis? A. Gene sequencing B. Plasma amino acids C. Plasma ammonia level D. Protein challenge E. Urine orotic acid

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A. The clinical vignette is suspicious for heterozygous OTC deficiency. Female carriers can become symptomatic when ill or if they receive a high protein load (such as hyperalimentation). In the past, a protein challenge or allopurinol loading test followed by measurement of urine orotic acid was often used to make a diagnosis. Today gene sequencing is the best method. Urine orotic acid alone or ammonia level will not be abnormal unless the patient is in the midst of an acute crisis.

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B7. You are seeing a couple whose first child is a Duarte/classical Galactosemia genetic compound heterozygote. His parents (who have not been tested) ask about the risk for their next child to have classical galactosemia (Gal/Gal). Knowing that the frequencies of the Duarte (1/27) and Gal (1/278) alleles, which of the following do you think is their risk to have a Gal/Gal child? A. 1/278 B. 1/278 x 2/3 C. 1/278 x1⁄2 D. 1/278 x 2/3 x 1⁄2 E. 1/278 x1⁄2x1⁄2

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E. One parent must be a Gal carrier and the other a Duarte carrier. There is a possibility that the parent who is a Duarte carrier is also a Gal carrier. Such individuals have about 25% of normal gal activity, which would not produce clinical signs of galactosemia. The risk that the other allele in this parent is Gal is 1/278. In this case the risk to a child would be 1⁄4. Therefore the overall risk is 1/278 x 1⁄4.

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B8. You are notified by the state newborn screening laboratory that a seven-day-old neonate, born at 33-weeks gestation and is receiving antibiotics for possible sepsis and total parenteral nutrition (TPN). He was found to have a phenylalanine level (Phe) of 4.8 mg/dL (291 (M). Which of the following interventions is the most appropriate next step in evaluating or managing this child's care? A. Stop (TPN) briefly and remeasure Phe on glucose and IV fluids. B. Modify antibiotic coverage patient is probably receiving C. Monitor the phenylalanine level weekly over next month. D. Restrict the infant's phenylalanine intake E. Obtain urine for assessment of biopterin metabolite levels

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A. There are two reasons why this infant may have an elevated phe on newborn screening – immaturity of the HPPD enzyme and TPN. The best way to exclude an inherited disorder in phe metabolism would be to stop the TPN briefly (~4-6 hr) and provide calories with glucose and recheck the phe off the TPN.

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B9. A 3 year old boy is referred to genetics clinic for evaluation of hypotonia, seizures, and developmental delay. His older brother, age 8, was also hypotonic and has been diagnosed with autism. You suspect a disorder of creatine metabolism. Which of the following studies is the best option to confirm a diagnosis for this child? A. Measure plasma guanidinoacetoacetate B. Measure plasma creatine to creatinine ratio C. Perform a brain MRI D. Perform plasma amino acids to measure an ornithine level E. Sequence the SLC6A8 creatine transporter gene

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E. The history is fairly classic for X-linked creatine transporter deficiency which can account for up to ~1% of X-linked MR. Other features include hypotonia, seizures, and autism. Screening can be performed by urine guanidinoacetoacetate (GAA) which is elevated or by finding a low creatine peak on brain MRI with spectroscopy. It is not specific on plain MRI. While the disorder is technically a defect in ornithine metabolism, ornithine levels are normal. Plasma creatine/creatinine ratio is used to detect the 2 other disorders of creatine metabolism (AGAT and GAMT deficiency).

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B10. A nine- month-old infant contracts a viral illness and is unable to take her usual amount of formula over the previous 24 hours. She is found dead in her bed the following morning. Which of the following disorders accounts for approximately 5% of cases of sudden infant death syndrome (SIDS) and is the most likely cause of this unfortunate infant’s death? A. Glutaric aciduria Type I B. Glycogen storage disease Type III C. MCAD deficiency D. OTC deficiency E. Propionic academia

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C. MCAD presents with hypoketotic hypoglycemia and can resemble Reye syndrome or SIDs.

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B11. A couple comes for genetic counseling because the husband’s sister lost a child to Tay-Sachs (TSD) disease. The wife has a negative family history for TSD, is not Jewish, and is currently 6 weeks pregnant. Which of the following evaluations would be most useful in determining this couple’s risk for having a child with Tay-Sachs disease? A. Perform molecular TSD analysis on the wife. B. Perform molecular TSD analysis on both the husband and the wife. C. Perform no testing since the risk is low for having a child with TSD D. Perform serum HexA and molecular TSD analysis on the husband. E. Perform serum HexA testing on the wife

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D Depending on how rapidly one could obtain results, the BEST answer might be serum HexA on husband (+/- molecular) and WBC hexA on the wife. The major points of this question are (1) serum hexA is not accurate during pregnancy and one needs to do WBC hexA determinations and (2) molecular testing is not helpful in the non-Ashkenazi Jewish population since most mutations will not be detected.

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B12. A 9-year-old boy is referred by a neurologist for evaluation of a 6-month history of decreasing intellectual performance. An MRI shows prominent white matter changes. Serum biochemistries reveal evidence of mild adrenal dysfunction. Which of the following biochemical pathway components is most likely to be encoded by the gene for this disorder? A. Lysosomal enzyme B. Mitochondrial enzyme involved in fatty acid oxidation C. Peroxisomal enzyme involved in fatty acid oxidation D. Peroxisomal membrane protein E. Transcription factor

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D The clinical features here are strongly suggestive of X-linked adrenoleukodystrophy. Although biochemically this disorder is characterized by accumulation of VLCFA, the gene defect is NOT an enzyme involved in fatty acid metabolism. Rather, it is a peroxisomal membrane protein which may be involved in transport of the enzyme.

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B13. You are asked to evaluate a one month old asymptomatic girl who had an elevated tyrosine on newborn screening. Succinylacetone testing was subsequently positive. Which of the following interventions is the best initial course of action for this infant? A. Place the infant on a low phenyalanine diet B. Place the infant on NTBC and a low tyrosine diet C. Reassure the family that the infant had transient tyrosinemia of the newborn D. Refer the infant for evaluation for a liver transplant E. Repeat tyrosine levels at monthly intervals

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B. The elevated tyr + succinylacetone is diagnostic for Type I tyrosinemia. Current standard treatment is NTBC + low tyr diet (tyrex formula). The advent of newborn screening and NTBC has resulted in a markedly reduced need for liver transplantation.

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B14. You are asked to evaluate a newborn baby in the neonatal intensive care unit who is noted to have proximal shortening of the humeri (and to a smaller degree the femurs) along with punctate calcifications in cartilage, coronal clefting of the several vertebrae and congenital cataracts. You suspect a peroxisomal disorder as the likely etiology. Which of the following biochemical abnormalities is most likely to be found when appropriate peroxisomal studies are performed? A. Low plasmalogen levels B. High very long chain fatty acid levels C. High 7-dehydrocholesterol levels D. Low phytanic acid levels E. Low very long chain fatty acid levels

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A. Rhizomelic chondrodysplasia patients have normal VLCFA and normal numbers of peroxisomes. Most patients have elevated phytanic acid levels from impaired phytanic acid oxidase acitivity.

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B15. Hyperammonemia is a cardinal finding in the newborn period of several metabolic disorders, however late onset hyperammonemia can also occur. Which of the following disorders is most likely to present outside the newborn period with progressive neurologic findings and mild hyperammonemia? A. Arginase deficiency B. Citrullinemia C. OTC deficiency D. Propionic academia E. Sepsis

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A Arginase deficiency does not present with crises in the newborn period. It presents typically with spastic paraplegia and MR although later episodes of mild hyperammonemia can occur.

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B16. Pycnodysostosis, a skeletal dysplasia, is caused by mutations in which of the following proteins? A. Cartilage-specific parathyroid related protein B. Cathepsin K, a lysosomal enzyme C. Collagen Type IX D. Dystosin, a fibrillar structural protein E. FGFR4

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B. Pycnodysostosis is actually a lysosomal storage disease caused by Cathepsin K deficiency.

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B17. You are asked to evaluate a 10 month old boy with macrocephaly, seizures, and a leukodystrophy pattern on MRI. You suspect Canavan disease. Which of the following analyses is the best screening test to confirm your assumption? A. Acyl carnitine profile B. Lysosomal enzyme screening on white blood cells C. Plasma amino acids D. Urine organic acids E. Very long chain fatty acids

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D. While gene sequencing would be a definitive test, screening can be performed by urine organic acids which will detect elevated N-acetylaspartic acid (NAA). An elevated NAA peak could also be seen on MRI spectroscopy.

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B18. Acute intermittent prophyria, a defect in heme biosynthesis, is characterized by which of the following inheritance patterns? A. A digenic disorder in 2 sequential enzymes in the heme biosynthesis B. As an autosomal dominant disorder C. As an autosomal recessive disorder D. As an X-linked disorder affecting only males E. Maternally since the enzyme is encoded by the mitochondrial genome

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B Most are asymptomatic

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B19. A 15 month old boy with hypotonia, optic atrophy, and neurologic regression is found to have metachromatic leukodystrophy with 0.3 nmol/hr/mg protein Arylsulfatase A activity in white blood cells. Activity in the mother’s and father’s white blood cells is 8.6 nmol/hr/mg and 1.2 nmol/hr/mg protein, respectively, with a normal control range of 11-25 nmol/hr/mg protein. The low activity in the father is most likely the result of which of the following genetic issues? A. Non-paternity B. Pseudodeficiency C. Unreliability of the assay for carrier testing D. Decline of enzyme activity with age E. His being affected with the disease but asymptomatic

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B. Pseudodeficiency, with 5-15% of normal enzyme activity, is found in ~2% of European Caucasian alleles. It results from 2 single base “polymorphisms” in the Arylsulfatase A gene and can complicate carrier testing and prenatal diagnosis. For families where this is found, molecular testing or use of sulfatide loading as a natural substrate is the preferred assay. The slightly low level of activity in the mother would be typical for an obligate carrier.

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A. Enzyme assay of liver or muscle B. Enzyme assay of skin fibroblasts or liver C. Enzyme assay of liver or molecular analysis of the glucose-6-phosphatase gene D. Molecular analysis of the glucose-6-translocase gene only E. Western blotting of muscle with specific antibody to the protein

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C. The glucose-6-phosphatase enzyme is expressed only in liver. Prior to isolation of the gene, prenatal diagnosis was not possible.

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B21. A new autosomal recessive disorder of N-linked glycosylation and sterol metabolism has recently been described and involves a defect in an enzyme involved in the synthesis of the dolichol, a polyprenol required for the synthesis and transfer of dolichol-linked monosaccharides to proteins. Which of the following screening tests is most likely to detect this new disorder? A. Enzyme assay of the new protein B. Plasma cholesterol C. Plasma sterol analysis D. Serum transferrin isoelectric focusing E. Urine oligosaccharide chromatography

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D. Since this involves a defect in N-linked glycosylation, serum transferrin isoelectric focusing should produce an abnormal pattern. This would be the most efficient screening test. Cholesterol and sterol patterns may be normal

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B22. The metabolic defect in Fabry disease is a deficiency of which of the following enzymes? A. α-galactosidase B. α-glucosidase C. -galactosidase D. -glucosidase E. cerebroside -galactosidase

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A

Front 23

E. very long chain fatty acid excess

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E. Pipecolic acidemia and plasmalogen deficiency can occur in various peroxisomal disorders. Cerebrosidase β-galactosidase deficiency is the defect in Krabbe disease. Dicarboxylic aciduria is characteristic of some of the defects of fatty acid oxidation. The hallmark metabolic abnormality in adrenoleukodystrophy is accumulation of very long chain fatty acids, although this abnormality also occurs in other peroxisomal disorders.

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B24. Malignancy is a major risk in which of the following metabolic disorders? A. Cystinosis B. Hurler syndrome C. Maple syrup urine disease D. Propionic acidemia E. Tyrosinemia

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E Some autosomal recessive disorders with substantial risk of malignancy are glycogen storage disease type I, tyrosinemia, hemochromatosis, and others less prominently. Immunodeficiency disorders and DNA repair disorders also relevant.

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B25. A 35 year woman is referred for evaluation of ptosis, limitation of eye gaze, and a cardiac arrhythmia. You suspect a mitochondrial disorder. Which of the following mutations would be most compatible with her clinical features? A. A de novo dominant mutation in a nuclear encoded gene for an OXPHOS subunit B. A heteroplasmic deletion involving a portion of the mitochondrial genome C. A homoplasmic missense mutation in a mitochondrial gene for an OXPHOS subunit D. A heteroplasmic single base change in a mitochondrial rRNA gene E. A heteroplasmic single base change in a mitochondrial tRNA gene

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B. The features are classic for Kearn-Sayre syndrome which involves heteroplasmic deletions or duplications of portions of the mitochondrial genome.

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B26. The best diagnostic approach for screening for Zellweger syndrome in an infant with organomegaly and dysmorphic features is which of the following tests? A. Chromosome analysis B. CT scan of the brain C. Plasma carnitine levels D. Plasma very long chain fatty acids levels E. Radiographs of entire infant skeleton

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D. Chromosome analysis and

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B27. Which of the follwoing abnormalities is the most likely diagnosis in a 3-day-old infant who develops lethargy, vomiting, respiratory alkalosis and hyperammonemia with undetectable plasma citrulline and massive orotic aciduria? A. argininosuccinate synthetase deficiency B. carbamylphosphate synthase I deficiency C. nonketotic hyperglycinemia D. ornithine transcarbamylase deficiency E. propionic acidemia

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D. The clinical features are classic for a urea cycle disorder. Levels of citrulline on amino acids are key to deciding which disorder is present. Undetectable citrulline is found in males with OTC and CPS deficiencies. In OTC, carbamyl phosphate is shunted to pyrimidine synthesis resulting in high orotic acid. In CPS deficiency, no carbamyl phosphate is made and so there is no elevation in orotic acid. (see pathway)

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B28. An asymptomatic infant who is found to have hyperphenylalaninemia on newborn screening should be tested for which of the following associated problems? A. biopterin synthetic defects B. catechol-o-methyltransferase C. liver disease D. microdeletion deficiency of chromosome 12 E. porphyria cutanea tarda

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A. Tetrahydrobiopterin is a cofactor for phenylalanine hydroxylase (along with oxygen) that converts phe to tyr ~2% of infants with inherited hnyperphenylalaninemia have a defect in the synthesis or recycling of the biopterin cofactor. All infants with confirmed hyperphe should be tested for a biopterin defect by blood and urine pterin screening.

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B29. Which of the following disorders is the most likely diagnosis in an infant with progressive liver failure, elevated serum alpha-fetoprotein and succinylacetone in the urine? A. 1-antitrypsin deficiency B. hepatitis C C. hepatorenal tyrosinemia D. tyrosine aminotransferase deficiency E. acetyl CoA-carboxylase deficiency

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C Hepatorenal tyrosinemia is also called tyrosinemia type I and results from a defect in last step of tyrosine degradation fumarylacetoacetate hydrolase (FAH).

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B30. A 37 year old woman is referred for a history of unexplained stroke. During her evaluation she was found to have proteinuria. Her 42 year old brother has been on renal dialysis for 2 years and is awaiting a renal transplant. Which of the following is the most likley diagnosis in this family? A. Alport syndrome B. Fabry disease C. MELAS syndrome D. Von Hippel Lindau syndrome E. X-linked Adrenoleukodystrophy

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B.In the past several years, it has been recognized that most female Fabry carriers develop symptoms. Proteinuria develops in late childhood although only ~10% develop frank renal failure. Most affected males (disorder is X-linked) develop renal failure if untreated, with onset of symptoms around 30 years of age. Fabry accounts for ~5% cryptogenic strokes and can be seen. Alport is often X-linked and has renal disease (nephritis) and hearing loss, but not strokes. MELAS has strokes but not this pattern of renal disease. In Von Hippel Lindau, vascular malformatons are present in multiple tissues and there can also be renal cysts

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B31. Which of the follwoing abnormalities is shared by the hyperornithinemia-hyperammonemia- homocitrullinuria (HHH) syndrome and gyrate atrophy of the choroid and retina? A. hyperammonemia B. hyperglutaminemia C. hyperornithinemia D. orotic aciduria E. progressive retinal degeneration

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C. Gyrate atrophy of the retina is caused by deficiency of ornithine aminotransferase (OAT). It is diagnosed by finding elevated ornithine on plasma amino acids.

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B32. Intermittent treatment with metronidazole is recommended in patients with propionic academia or methylmalonic acidemia for which of the following therapeutic effects? A. gut flora produce substantial amounts of propionate B. it promotes normal bowel function C. it provides a source of reducing equivalents D. it reduces the incidence of sepsis E. reduction of enteric bacteria synthesis of valine and isoleucine

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A. Metronidazole is an antibiotic used against anaerobic bacteria and protozoa. Some gut flora can generate propionate (which can be converted to MMA). Thus, some doctors advocate using medtronidazole to reduce gut flora and propionate production in PA or MMA.

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B33. Neonatal hypotonia, seizures, apnea and hiccups are features of which of the following inborn errors of metabolism? A. citrullinemia B. galactosemia C. isovaleric acidemia D. maple syrup urine disease E. nonketotic hyperglycinemia

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E. These are classic findings in nonketotic hyperglycinemia, particularly the seizures and hiccups, which may occur prenatally.

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B34. A six month old girl is referred for megaloblastic anemia. She is otherwise healthy and has been exclusively breast fed. Metabolic screening reveals mildly elevated methylmalonic acid in her urine and a plasma total homocysteine level of 27 uM (nl 5-8). The mother states that her older daughter, now age 3, who is the patient’s maternal half-sister, had similar anemia as an infant, but is “now fine.” Which of the following assessments is the best course of action in the evaluation of this patient?A. Cobalamin complementation studies on the patient’s fibroblasts B. Measurement of serum B12 level and total homocysteine in the mother C. Measurement of serum B12 level and total homocysteine in the sister D. Measurement of transcobalamin II levels in the patient E. Sequencing the methylmalonyl CoA mutase gene in the patient

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This is likely a transient B12 deficiency in the patient and her sister secondary to B12 deficiency in the mother. The fact that the sisters have different fathers makes a defect in cobalamin metabolism itself in the patient or her sister much less likely. While transcobalamin II deficiency can produce megaloblastic anemia in infants (often with FTT and other sx), this is very rare and is also an autosomal recessive disorder. The reason for B12 deficiency in the mother is often undiagnosed pernicious anemia, but it can also occur in strict vegans.

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B35. Very long branch-chain fatty acids undergo -oxidation in which of the cellular organelles? A. endoplasmic reticulum B. Golgi apparatus C. mitochondria D. nuclear envelope E. peroxisomes

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E

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B36. Transferrin isoelectric focusing is useful in diagnosing which of the following disorders?: A. Acute Intermittent Porphyria B. Congenital disorders of glycosylation C. Hemophilia B D. Iron-deficiency anemia E. Marfan syndrome

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B

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B37. Which of the following mucopolysaccharidoses includes preserved cognitive function? A. Hunter syndrome (MPS II) B. Hurler syndrome (MPS IH) C. Maroteaux-Lamy syndrome (MPS VI) D. Sanfilipo syndrome (MPS III) E. Sly disease (MPSVII)

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Intellectual function is usually normal in MPSVI. It is also preserved in MPS IVA (Morquio) and the Scheie variant of Hurler (MPS IS). The correct answer is C.

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B38. A seven month old boy is referred for coarse facial features and hepatomegaly. His x-rays demonstrate beaking of the lumbar vertebrae, a J-shaped sella tursica, and ribs that widen anteriorly. Lysosomal enzyme screening from blood reveals elevated levels of arylsulfatase A and β-glucuronidase. Whichof the following diagnoses is most likely to explain this infant’s clinical findings? A. Hurler syndrome B. I-cell disease C. Metachomatic leukodystrophy D. MPS VII, Sly disease E. Pseudo-Hurler polydystrophy

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The features are suggestive of a mucopolysaccharidosis or storage disorder with significant somatic involvement. Elevation of multiple lysosomal enzymes occurs in I-cell disease (ML II) and pseudo- Hurler polydystrophy (MLIII) because the enzymes are not targeted to the lysosome properly and are, instead, secreted. The two disorders are allelic with I-cell being more severe and presenting earlier. The defect is in a sugar phosphotransferase found in the Golgi that properly targets enzymes to the lysosome.

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B39. Metabolic defects that cause Congenital Adrenal Hyperplasia usually involve which of the following enzyme deficiencies? A. Androgen receptor deficiency B. Aromatase deficiency C. Cholesterol desmolase deficiency D. 5-α-Reductase deficiency. E. 21-Hydroxylase deficiency

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21-Hydroxylase deficiency causes ~95% of cases of CAH. Aromatase deficiency causes inability to synthesize estrogen and affected females have ambiguous genetalia and primary amenorrhea. 5-• -Reductase deficiency converts testosterone into the more potent dihydrotestosterone. Affected males can have pseudovaginal perineoscrotal hypospadias Androgen receptor deficiency causes androgen insensitivity and feminization of affected males.

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B40. Thrombosis and strokes are a frequent complication of which one of the following diseases? A. Congenital Adrenal Hyperplasia B. Galactosemia C. Homocystinuria D. Medium Chain AcylCoA Dehydrogenase Deficiency E. Phenylketonuria

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B40. The correct answer is C. Thromboembolic events cause the death of 50% of individuals affected by Homocystinuria by 20 yrs.