Inborn Errors of Metabolism Practice Exam with Answers

UTAR MBBS Year 1 | Block 4 | Inborn Errors of Metabolism Practice Examination INBORN ERRORS OF METABOLISM UTAR MBBS Year 1 — Block 4 — Metabolic / Endocrine Block Integrated Practice Examination — SAQ, SBA & EMQ Instructions to candidates • This paper has three sections. Section A: 5 Short-Answer Questions (SAQ), 10 marks each — write your answers in the boxes provided. Section B: 30 Single-Best-Answer (SBA) questions — choose ONE best option (A–D). Section C: 5 Extended-Matching Questions (EMQ) — for each item choose the SINGLE most appropriate option from the list; an option may be used once, more than once, or not at all. • Total: SAQ 50 marks + SBA 30 marks + EMQ 15 marks. • The answer key and SAQ marking points are on the final pages. SECTION A - SHORT-ANSWER QUESTIONS (SAQ) [5 x 10 = 50 marks] SAQ 1 A 6-month-old infant is brought in with a protuberant abdomen, massive hepatomegaly and a 'doll-like' face. Blood glucose after a 4-hour fast is 1.8 mmol/L. Investigations show raised lactate, raised urate and raised triglycerides. (a) Name the deficient enzyme and state the mode of inheritance of this condition. [2 marks] (b) Explain the pathogenesis of (i) the fasting hypoglycaemia and (ii) the lactic acidosis. [4 marks] (c) Explain the biochemical mechanisms responsible for (i) the hyperuricaemia and (ii) the [4 marks] hyperlipidaemia. For self-assessment / revision use Page 1 UTAR MBBS Year 1 | Block 4 | Inborn Errors of Metabolism Practice Examination SAQ 2 Two infants are referred to the metabolic clinic. Infant A vomits, becomes jaundiced and develops E. coli septicaemia shortly after milk feeds are started. Infant B remains well on milk but vomits and becomes hypoglycaemic each time fruit puree is introduced. (a) State the deficient enzyme and the offending sugar for EACH infant. [4 marks] (b) For Infant A (galactosaemia), explain the mechanism of the hypoglycaemia and list TWO long-term complications if left untreated. [3 marks] (c) For Infant B, name the toxic metabolite that accumulates and explain how it produces hypoglycaemia. [3 marks] For self-assessment / revision use Page 2 UTAR MBBS Year 1 | Block 4 | Inborn Errors of Metabolism Practice Examination SAQ 3 A 9-month-old infant, born in a region where newborn screening was unavailable, presents with developmental delay, seizures, eczema, fair hair and a musty body odour. (a) State the primary enzyme deficiency, name its essential cofactor, and give the mode of [3 marks] inheritance. (b) Describe the pathogenesis of (i) the mental retardation and (ii) the hypopigmentation. [4 marks] (c) A second infant with hyperphenylalaninaemia fails to improve on a strict low-phenylalanine diet. Give the likely explanation, and state the principle of treatment of classic PKU. [3 marks] SAQ 4 A previously well 3-day-old male becomes lethargic and tachypnoeic after feeds and progresses to coma. Plasma ammonia is grossly elevated, blood gas shows a respiratory alkalosis and blood glucose is normal. Urinary orotic acid is high and plasma citrulline is low. (a) Briefly outline the flow of nitrogen from amino acid catabolism to urea, naming the two [3 marks] key reactions and their enzymes. For self-assessment / revision use Page 3 UTAR MBBS Year 1 | Block 4 | Inborn Errors of Metabolism Practice Examination (b) Name the deficient enzyme in this infant, justify your answer using the biochemical findings, and state its mode of inheritance. [4 marks] (c) State the general rule relating the site of the enzyme block to the severity of hyperammonaemia, and list TWO principles of management. [3 marks] For self-assessment / revision use Page 4 UTAR MBBS Year 1 | Block 4 | Inborn Errors of Metabolism Practice Examination SAQ 5 A 5-year-old child has short stature, exercise intolerance, hypotonia and an episode resembling a stroke. Plasma lactate, pyruvate, alanine and creatine kinase are all elevated. Several relatives on the mother's side are similarly affected. (a) Name THREE enzyme systems whose defects can cause mitochondrial energy metabolism (MITEM) disorders. [3 marks] (b) Explain why lactate and alanine accumulate when the respiratory chain is defective. [4 marks] (c) State the mode of inheritance suggested by the family history and give TWO named examples of mtDNA disorders. [3 marks] For self-assessment / revision use Page 5 UTAR MBBS Year 1 | Block 4 | Inborn Errors of Metabolism Practice Examination SECTION B - SINGLE BEST ANSWER (SBA) [30 x 1 = 30 marks] For each question select the SINGLE best answer (A, B, C or D). 1. A 5-month-old infant presents with massive hepatomegaly, a 'doll-like' face and a documented blood glucose of 1.8 mmol/L after a short fast. Blood tests show lactic acidosis, hyperuricaemia and hyperlipidaemia. Which enzyme is deficient? A. Glucose-6-phosphate dehydrogenase B. Debranching enzyme C. Hepatic glycogen phosphorylase D. Glucose-6-phosphatase 2. In the infant above (von Gierke disease), what is the principal mechanism of the hyperuricaemia? A. Increased flux through the pentose phosphate pathway producing ribose-5-phosphate, raising purine synthesis, plus reduced renal urate excretion due to competition from lactate B. Reduced glomerular filtration from renal glycogen deposition alone C. Increased de novo pyrimidine synthesis D. Increased breakdown of muscle protein releasing purines 3. A 30-year-old man develops painful muscle cramps and weakness during vigorous exercise and notices burgundy-coloured urine afterwards. An ischaemic forearm exercise test shows no rise in venous lactate. Which enzyme is deficient? A. Lysosomal acid alpha-glucosidase B. Muscle glycogen phosphorylase C. Muscle phosphofructokinase D. Hepatic glycogen phosphorylase 4. A floppy infant with feeding difficulty has marked cardiomegaly and hypotonia and dies of cardiorespiratory failure before 1 year. Liver biopsy shows ballooned lysosomes engorged with glycogen. The deficient enzyme is: A. Lysosomal acid alpha-glucosidase (acid maltase) B. Branching enzyme C. Muscle glycogen phosphorylase D. Glucose-6-phosphatase 5. Which feature best distinguishes a 'hepatic' GSD (e.g. von Gierke) from a 'myopathic' GSD (e.g. McArdle)? A. Exercise-induced cramps are typical of the hepatic form B. Hyperuricaemia occurs only in the myopathic form C. Fasting hypoglycaemia is prominent in the hepatic form but not the myopathic form D. Hepatomegaly is the dominant feature of the myopathic form 6. A newborn begins vomiting with diarrhoea after starting breast milk, develops jaundice and hepatomegaly, and is found to have E. coli septicaemia. Urine is positive for reducing substances but negative on the glucose-oxidase dipstick. Cataracts are noted. The diagnosis is: A. Hereditary fructose intolerance B. Galactokinase deficiency C. Von Gierke disease D. Classic galactosaemia (GALT deficiency) 7. In classic galactosaemia, the hypoglycaemia after milk feeds is best explained by: A. Galactose stimulating excess insulin secretion B. Galactose-1-phosphate inhibiting glycogenolysis C. Deficiency of glucose-6-phosphatase D. Galactose irreversibly inhibiting hexokinase For self-assessment / revision use Page 6 UTAR MBBS Year 1 | Block 4 | Inborn Errors of Metabolism Practice Examination 8. A toddler is well while breastfed but vomits and becomes hypoglycaemic whenever fruit or fruit juice is introduced; he has developed an aversion to sweets. Hepatomegaly and renal tubular dysfunction are present. The deficient enzyme is: A. Glucose-6-phosphatase B. Fructokinase C. Fructose-1-phosphate aldolase (aldolase B) D. Galactose-1-phosphate uridyl transferase 9. The toxic metabolite that accumulates in hereditary fructose intolerance causes hypoglycaemia by: A. Stimulating insulin release B. Inhibiting both glycogenolysis and gluconeogenesis C. Activating glycogen phosphorylase D. Inhibiting only glycogenesis 10. A neonate presents with fasting hypoglycaemia, severe lactic acidosis and hyperalaninaemia, but with NO hepatomegaly and NO hyperuricaemia, suggesting an inborn error of gluconeogenesis. Which of the following is NOT one of the four key gluconeogenic enzymes implicated? A. Pyruvate dehydrogenase B. Pyruvate carboxylase C. Fructose-1,6-bisphosphatase D. Phosphoenolpyruvate carboxykinase 11. Hyperalaninaemia in congenital lactic acidosis arises because: A. Dietary alanine fails to be absorbed B. Alanine cannot be deaminated C. Accumulated pyruvate is transaminated to alanine D. Alanine synthase becomes overactive 12. A 4-year-old boy has short stature, exercise intolerance, hypotonia and an episode of stroke-like neurological deficit. Lactate, pyruvate, alanine and creatine kinase are raised, and muscle biopsy shows abnormal mitochondria. His mother and maternal uncle have milder similar symptoms. The most likely mode of inheritance is: A. Autosomal dominant B. X-linked recessive C. Autosomal recessive D. Maternal (mitochondrial) 13. Which acronym does NOT denote a recognised mitochondrial (mtDNA) disorder? A. LHON B. MODY C. MERRF D. MELAS 14. In a respiratory chain (oxidative phosphorylation) defect, lactate accumulates primarily because: A. Glucose-6-phosphatase is deficient B. Excess NADH inhibits pyruvate dehydrogenase and drives the lactate dehydrogenase equilibrium toward lactate C. Pyruvate carboxylase becomes activated D. Lactate dehydrogenase is congenitally absent 15. A 9-month-old (no newborn screening available) has developmental delay, a musty/mousy body odour, eczema, and unusually fair hair and blue eyes despite dark-skinned parents. The biochemical hallmark is: A. Markedly elevated plasma phenylalanine B. Markedly elevated plasma tyrosine C. Elevated plasma branched-chain amino acids D. Marked hyperammonaemia For self-assessment / revision use Page 7 UTAR MBBS Year 1 | Block 4 | Inborn Errors of Metabolism Practice Examination 16. In untreated PKU, the hypopigmentation (fair hair and skin) is due to: A. Dietary deficiency of tyrosine B. A separate independent mutation in a melanin gene C. High phenylalanine inhibiting tyrosine hydroxylase, reducing melanin synthesis D. Destruction of melanocytes by phenylketones 17. A child with hyperphenylalaninaemia is placed on a strict low-phenylalanine diet but continues to deteriorate neurologically with poor head control. The most likely explanation is: A. Tyrosine toxicity B. Inadequate dietary protein C. Coexisting galactosaemia D. Tetrahydrobiopterin (BH4) deficiency 18. The cofactor required by phenylalanine hydroxylase is: A. Pyridoxal phosphate B. Biotin C. Tetrahydrofolate D. Tetrahydrobiopterin (BH4) 19. A middle-aged man notices that his urine turns black on standing. He has degenerative arthritis and bluish-black discolouration of the ear cartilage and sclera. The deficient enzyme is: A. Branched-chain alpha-ketoacid dehydrogenase B. Phenylalanine hydroxylase C. Tyrosine aminotransferase D. Homogentisic acid oxidase 20. Tyrosine is the precursor for ALL of the following EXCEPT: A. Melanin B. Thyroid hormones C. Histamine D. Dopamine and catecholamines 21. A breastfed neonate is well at birth but by day 4 develops poor feeding, lethargy, seizures and coma. The urine has a sweet, caramel/maple-syrup smell and plasma leucine is markedly raised. The deficient enzyme is: A. Ornithine transcarbamoylase B. Homogentisic acid oxidase C. Branched-chain alpha-ketoacid dehydrogenase D. Phenylalanine hydroxylase 22. Which set of amino acids accumulates in maple syrup urine disease? A. Glycine, serine, alanine B. Leucine, isoleucine, valine C. Arginine, ornithine, citrulline D. Phenylalanine, tyrosine, tryptophan 23. A 3-day-old male becomes lethargic and hyperventilates after breastfeeds, then becomes comatose. Plasma ammonia is grossly elevated, blood glucose is normal and there is a respiratory alkalosis (no metabolic acidosis). Urinary orotic acid is high and plasma citrulline is low. The most likely diagnosis is: A. Ornithine transcarbamoylase deficiency B. Carbamoyl phosphate synthetase I deficiency C. Citrullinaemia (argininosuccinate synthetase deficiency) D. Arginase deficiency For self-assessment / revision use Page 8 UTAR MBBS Year 1 | Block 4 | Inborn Errors of Metabolism Practice Examination 24. Which urea cycle disorder is inherited in an X-linked manner, unlike the others which are autosomal recessive? A. Argininosuccinate synthetase deficiency B. Ornithine transcarbamoylase deficiency C. Arginase deficiency D. Carbamoyl phosphate synthetase I deficiency 25. A neonate with hyperammonaemia has greatly elevated plasma citrulline and raised urinary orotate. The deficient enzyme is: A. Argininosuccinate synthetase B. Arginase C. Ornithine transcarbamoylase D. Argininosuccinate lyase 26. The allosteric activator essential for the activity of carbamoyl phosphate synthetase I is: A. Aspartate B. Citrulline C. Ornithine D. N-acetylglutamate 27. In urea cycle disorders, the general rule regarding severity of hyperammonaemia is that: A. The more proximal the enzyme block, the more severe the hyperammonaemia B. The more distal the block, the more severe the hyperammonaemia C. Only arginase deficiency causes hyperammonaemia D. Severity is unrelated to the position of the block 28. The enzyme that catalyses the reversible reaction 'alanine + alpha-oxoglutarate <-> pyruvate + glutamate' is: A. Arginase B. Alanine aminotransferase (ALT) C. Aspartate aminotransferase (AST) D. Glutamate dehydrogenase 29. Oxidative deamination of glutamate ('glutamate + NAD + H2O <-> 2-oxoglutarate + NADH + NH3') is catalysed by: A. Glutamate dehydrogenase B. Glutamine synthetase C. Alanine aminotransferase D. Carbamoyl phosphate synthetase 30. A patient with established liver cirrhosis develops confusion, asterixis and drowsiness; blood ammonia is elevated. The biochemical basis is: A. Overproduction of urea by the kidney B. Failure of the liver to convert ammonia to urea C. Dietary protein deficiency D. Excessive renal excretion of ammonia For self-assessment / revision use Page 9 UTAR MBBS Year 1 | Block 4 | Inborn Errors of Metabolism Practice Examination SECTION C - EXTENDED MATCHING QUESTIONS (EMQ) [5 x 3 = 15 marks] EMQ 1 - Enzyme defects in disorders of carbohydrate metabolism A. Glucose-6-phosphatase E. Galactokinase B. Muscle glycogen phosphorylase F. Fructose-1-phosphate aldolase (aldolase B) C. Lysosomal acid alpha-glucosidase G. Debranching enzyme D. Galactose-1-phosphate uridyl transferase (GALT) H. Fructokinase For each scenario below, select the single most appropriate option. 1. A 6-month-old with hepatomegaly, fasting hypoglycaemia, lactic acidosis and hyperuricaemia. 2. A floppy infant with cardiomegaly and ballooned, glycogen-filled lysosomes, dying of heart failure before age 1. 3. An infant who vomits and becomes hypoglycaemic only after fruit is introduced, with hepatomegaly and renal tubular dysfunction. EMQ 2 - Enzyme defects in aromatic and branched-chain amino acid disorders A. Phenylalanine hydroxylase E. Branched-chain alpha-ketoacid dehydrogenase B. Tetrahydrobiopterin (BH4) F. Tyrosinase C. Homogentisic acid oxidase G. Glutamate dehydrogenase D. Tyrosine aminotransferase H. Glucose-6-phosphatase For each scenario below, select the single most appropriate option. 1. A child with developmental delay, a musty odour and fair hair; plasma phenylalanine is very high and tyrosine is low; the child responds to dietary phenylalanine restriction. 2. An adult whose urine turns black on standing, with ochronotic arthritis and bluish discolouration of the sclera. 3. A neonate well at birth, then by day 4 in coma with seizures, maple-syrup-smelling urine and markedly raised leucine. EMQ 3 - Urea cycle disorders (match the biochemical profile) A. Carbamoyl phosphate synthetase I E. Arginase B. Ornithine transcarbamoylase (OTC) F. N-acetylglutamate synthase C. Argininosuccinate synthetase (ASS) G. Glutamate dehydrogenase D. Argininosuccinate lyase (ASL) H. Pyruvate carboxylase For each scenario below, select the single most appropriate option. 1. Hyperammonaemia with HIGH urinary orotic acid and LOW plasma citrulline; inheritance is X-linked. 2. Hyperammonaemia with HIGH plasma citrulline and HIGH urinary orotic acid. 3. Hyperammonaemia with normal/low urinary orotic acid and reduced carbamoyl phosphate; the most proximal block of the cycle. For self-assessment / revision use Page 10 UTAR MBBS Year 1 | Block 4 | Inborn Errors of Metabolism Practice Examination EMQ 4 - Match the clinical/biochemical feature to its mechanism A. Gal-1-phosphate inhibits glycogenolysis E. Fructose-1-phosphate inhibits glycogenolysis and gluconeogenesis B. Glucose-6-phosphate diverted to the pentose phosphate pathway raising purine synthesis F. Failure of the liver to convert ammonia to urea C. Excess NADH inhibits pyruvate dehydrogenase and shifts LDH toward lactate G. Pyruvate is transaminated to alanine D. Elevated phenylalanine inhibits tyrosine hydroxylase For each scenario below, select the single most appropriate option. 1. The mechanism of hyperuricaemia in von Gierke disease. 2. The mechanism of hypopigmentation in untreated phenylketonuria. 3. The mechanism of encephalopathy and raised ammonia in a patient with liver cirrhosis. EMQ 5 - Name the disorder A. Von Gierke disease (GSD I) E. Hereditary fructose intolerance B. McArdle disease (GSD V) F. Phenylketonuria C. Pompe disease (GSD II) G. Maple syrup urine disease D. Classic galactosaemia H. Alkaptonuria For each scenario below, select the single most appropriate option. 1. A 30-year-old with exercise-induced cramps, myoglobinuria and a flat venous lactate on ischaemic forearm testing. 2. A neonate with vomiting, jaundice, cataracts and E. coli septicaemia after starting milk. 3. An adult whose urine blackens on standing, with arthritis and bluish-grey sclera. For self-assessment / revision use Page 11 UTAR MBBS Year 1 | Block 4 | Inborn Errors of Metabolism Practice Examination ANSWER KEY Section B - SBA answers 1. D 2. A 3. B 4. A 5. C 6. D 7. B 8. C 9. B 10. A 11. C 12. D 13. B 14. B 15. A 16. C 17. D 18. D 19. D 20. C 21. C 22. B 23. A 24. B 25. A 26. D 27. A 28. B 29. A 30. B Section C - EMQ answers EMQ 1: 1=A; 2=C; 3=F EMQ 2: 1=A; 2=C; 3=E EMQ 3: 1=B; 2=C; 3=A EMQ 4: 1=B; 2=D; 3=F EMQ 5: 1=B; 2=D; 3=H Section A - SAQ marking points (model answers) SAQ 1 - von Gierke disease (GSD I) (a) Enzyme: glucose-6-phosphatase. Inheritance: autosomal recessive. (2) (b)(i) Hypoglycaemia: the liver cannot release free glucose from glucose-6-phosphate (from both glycogenolysis and gluconeogenesis), so blood glucose falls on fasting. (ii) Lactic acidosis: increased lactate production, and accumulated glucose-6-phosphate inhibits gluconeogenesis so the liver cannot efficiently use lactate. (4) (c)(i) Hyperuricaemia: accumulated G6P is diverted into the pentose phosphate pathway producing ribose-5-phosphate, which drives de novo purine synthesis; purines are catabolised to uric acid. Renal urate excretion is also reduced because lactate competes for tubular secretion. (ii) Hyperlipidaemia: hypoglycaemia raises fat-mobilising hormones and there is relative insulin deficiency, increasing free fatty acid release and hepatic uptake, raising triglyceride and VLDL synthesis. (4) SAQ 2 - Galactosaemia and Hereditary fructose intolerance (a) Infant A: galactose-1-phosphate uridyl transferase (GALT); offending sugar galactose (lactose/milk). Infant B: fructose-1-phosphate aldolase (aldolase B); offending sugar fructose (fruit). (4) (b) Hypoglycaemia: galactose-1-phosphate inhibits glycogenolysis. Long-term complications (any 2): cataracts, intellectual disability/neurological damage, liver damage/cirrhosis, renal (Fanconi) dysfunction. (3) (c) Toxic metabolite: fructose-1-phosphate. It inhibits both glycogenolysis and gluconeogenesis, so glucose cannot be released or synthesised, producing hypoglycaemia. (3) SAQ 3 - Phenylketonuria (a) Enzyme: phenylalanine hydroxylase (PAH); cofactor: tetrahydrobiopterin (BH4); inheritance: autosomal recessive. (3) (b)(i) Mental retardation: PAH deficiency causes marked accumulation of phenylalanine (hyperphenylalaninaemia) which is toxic to the developing brain. (ii) Hypopigmentation: high phenylalanine inhibits tyrosine hydroxylase, reducing conversion of tyrosine to DOPA and hence melanin. (4) (c) Likely explanation: BH4 deficiency (a cofactor defect), where dietary phenylalanine restriction alone is insufficient. Treatment of classic PKU: lifelong dietary restriction of phenylalanine. (3) SAQ 4 - Urea cycle disorders (a) The alpha-amino group is removed by transamination (transaminases, e.g. ALT/AST) transferring it to alpha-ketoglutarate to form glutamate; glutamate then undergoes oxidative deamination (glutamate dehydrogenase) releasing ammonia, which is converted to urea via the urea cycle in the liver. (3) (b) Enzyme: ornithine transcarbamoylase (OTC). Justification: hyperammonaemia with HIGH urinary orotic acid and LOW citrulline (carbamoyl phosphate accumulates and overflows into orotate; the downstream product citrulline is reduced). Inheritance: X-linked. (4) For self-assessment / revision use Page 12 UTAR MBBS Year 1 | Block 4 | Inborn Errors of Metabolism Practice Examination (c) Rule: the more proximal the block, the more severe the hyperammonaemia. Management (any 2): dietary protein restriction, measures to lower ammonia, liver transplantation. (3) SAQ 5 - Mitochondrial energy metabolism (MITEM) defects (a) Any 3 of: pyruvate dehydrogenase complex; citric acid cycle enzymes; respiratory chain (oxidative phosphorylation) enzymes; combined defects. (3) (b) A respiratory chain defect prevents reoxidation of NADH, so NADH accumulates. Excess NADH inhibits pyruvate dehydrogenase (causing pyruvate to build up) and shifts the lactate dehydrogenase equilibrium toward lactate; the accumulated pyruvate is also transaminated to alanine - hence raised lactate and alanine. (4) (c) Inheritance: maternal (mitochondrial). Named examples (any 2): MELAS, MERRF, LHON, NARP. (3) For self-assessment / revision use Page 13