Genetic and Metabolic Disorders (Chromosomal, Lysosomal, Amino Acid) MCQs

Pediatrics · 70 free questions with answers & explanations.

1. A neonate with dysmorphic features including upward-slanting palpebral fissures, a single palmar crease, sandal-gap deformity, hypotonia, and a murmur of VSD is evaluated. Karyotype is 47, XY, +21. What is the MOST common cardiac defect associated with this condition?
2. A 6-month-old infant presents with progressive psychomotor regression, hyperacusis, an exaggerated startle response, and a cherry-red spot on fundoscopy. Enzyme assay confirms hexosaminidase A deficiency. What is the INHERITANCE pattern?
3. A 2-year-old child presents with progressive neurological deterioration, hepatosplenomegaly, and a cherry-red spot on fundoscopy. Electron microscopy of a liver biopsy shows lysosomal storage of sphingomyelin with 'zebra bodies'. Enzyme assay confirms sphingomyelinase deficiency. The disease pattern in this child (rapid neurological decline, early death) corresponds to which type?
4. A 3-day-old neonate is found to have elevated tyrosine and methionine on newborn screening. Succinylacetone is detected in urine. Liver enzymes are markedly elevated. Which enzyme deficiency is the PRIMARY cause of this disorder, and which metabolite is MOST responsible for the hepatotoxicity?
5. A 6-month-old infant presents with progressive psychomotor regression, exaggerated startle response to noise, a cherry-red spot on fundoscopy, and macrocephaly. Enzyme assay shows absent hexosaminidase A activity. Which of the following is the most accurate statement about the molecular basis of Tay-Sachs disease?
6. A 3-year-old boy with coarse facial features, corneal clouding, hepatosplenomegaly, and skeletal deformities (gibbus deformity) is found to have elevated urinary dermatan sulfate and heparan sulfate. Enzyme assay confirms alpha-L-iduronidase deficiency. Which of the following correctly distinguishes Hurler syndrome (MPS I-H) from Scheie syndrome (MPS I-S)?
7. A newborn screening test reveals elevated phenylalanine at 72 hours of life. Plasma phenylalanine is 22 mg/dL. The child appears normal clinically. If untreated, which of the following best describes the mechanism by which phenylketonuria (PKU) causes intellectual disability?
8. A 10-month-old infant presents with developmental regression, exaggerated startle response, cherry-red spot on fundoscopy, and progressive hypotonia. Enzyme assay shows absent hexosaminidase A activity. Which metabolic pathway is disrupted?
9. A 3-year-old child has recurrent bacterial infections (Streptococcus pneumoniae, Haemophilus influenzae) and diarrhoea. Flow cytometry shows absence of CD19+ B cells. Serum IgG, IgA, and IgM are all very low. The most likely diagnosis is:
10. A newborn screen reveals elevated phenylalanine (1200 µmol/L). Repeat confirmatory testing at 2 weeks confirms classic PKU. The dietary phenylalanine restriction should be maintained until:
11. A 6-month-old infant presents with coarse facial features, corneal clouding, hepatosplenomegaly, and skeletal deformities. Urine spot test for glycosaminoglycans (GAGs) is positive (dermatan and heparan sulphate). Enzyme assay is most likely to show deficiency of:
12. A 3-year-old girl presents with alopecia, perioral dermatitis, acrodermatitis enteropathica-like skin lesions, diarrhoea, and failure to thrive. She is exclusively breastfed with minimal complementary feeding. Serum alkaline phosphatase is markedly low. The most likely diagnosis and its inheritance is:
13. A 5-year-old girl with normal development till 18 months now presents with hand-wringing stereotypies, loss of purposeful hand use, autistic features, and decelerating head growth. EEG shows characteristic multifocal spike-wave pattern. The most likely diagnosis and causative gene mutation is:
14. A 3-year-old child presents with progressive hepatosplenomegaly, developmental regression, and a cherry-red spot on fundoscopy. Enzyme assay shows deficient beta-hexosaminidase A AND B activity. Which diagnosis is MOST consistent?
15. A newborn screening test returns positive for phenylketonuria (PKU). The infant is currently being breastfed and is clinically well. Serum phenylalanine is 24 mg/dL. What is the MOST appropriate initial management?
16. A 2-year-old child presents with progressive coarsening of facial features, corneal clouding, stiff joints, recurrent respiratory infections, and hepatosplenomegaly. X-ray shows 'J-shaped' sella and dysostosis multiplex. Urine shows increased dermatan sulfate and heparan sulfate. Which enzyme is DEFICIENT?
17. A neonate presents on day 3 of life with encephalopathy, seizures, and a peculiar odour of 'maple syrup' in urine and cerumen. Plasma amino acids show markedly elevated leucine, isoleucine, and valine with elevated alloisoleucine. Which enzyme complex is deficient?
18. A 6-month-old girl has failure to thrive, developmental regression, a cherry-red spot on fundoscopy, exaggerated startle response (hyperacusis), and hypotonia. The parents are of Ashkenazi Jewish origin. Enzyme assay reveals deficient hexosaminidase A with NORMAL hexosaminidase B. What is the inheritance pattern of this condition?
19. A 3-year-old child is brought with regression of milestones, hyperacusis, a 'cherry-red spot' on fundoscopy, startle response to noise, progressive neurological deterioration, and hepatosplenomegaly is absent. Hexosaminidase A activity is undetectable in leukocytes. What is the inheritance pattern of this condition, and which enzyme/substrate is deficient?
20. A newborn is screened and found to have elevated phenylalanine (18 mg/dL) on day 3 heel-prick test. Urine pterins are normal and dihydrobiopterin reductase (DHPR) activity is normal. The diagnosis is classic phenylketonuria (PKU). Which dietary amino acid must be SUPPLEMENTED in the phenylalanine-restricted diet to prevent deficiency?
21. A 2-year-old girl is evaluated for short stature, coarse facial features, corneal clouding, joint stiffness, and recurrent upper respiratory infections. Skeletal survey shows J-shaped sella turcica, beaking of vertebral bodies (thoracolumbar gibbus), and widened ribs ('oar-shaped'). Urine MPS analysis shows elevated heparan sulfate and dermatan sulfate. Iduronate-2-sulfatase activity is normal. What is the MOST likely diagnosis?
22. A 6-month-old infant presents with hypotonia, seizures, high-pitched cry, and failure to thrive. On examination there is self-mutilation behavior, choreoathetosis, and hyperuricemia. Serum uric acid is grossly elevated. The enzyme deficiency is in the salvage pathway of purine metabolism. What enzyme is deficient in this condition?
23. A neonate develops recurrent hypoglycemia, hepatomegaly, and elevated plasma ammonia (380 μmol/L) without ketosis. Serum acylcarnitines show elevated C8 (octanoylcarnitine). The liver shows microvesicular steatosis on biopsy. Which diagnosis BEST fits this metabolic picture?
24. A 3-month-old infant has bilious vomiting, failure to thrive, and hepatomegaly since birth. Urine positive for reducing substances but urine glucose dipstick is negative. The reducing substance is NOT glucose. Which inborn error of metabolism is MOST consistent with this presentation?
25. A 2-week-old neonate presents with vomiting, lethargy, and odour of burned caramel/maple syrup from the urine. A urine DNPH (dinitrophenylhydrazine) test is positive. Plasma amino acids show elevated leucine, isoleucine, and valine. Which enzyme is deficient in this disorder?
26. A 6-month-old infant presents with regression of milestones (previously smiled and tracked), abnormal startle response to sound (hyperekplexia), cherry-red spot on fundoscopy, and hypotonia. He is of Ashkenazi Jewish descent. Which lipid accumulates and in which cellular organelle?
27. A newborn girl is found to have ambiguous genitalia (enlarged clitoris, posterior labial fusion, urogenital sinus). Blood glucose is 1.8 mmol/L and electrolytes show Na 125 mEq/L, K 6.8 mEq/L. 17-hydroxyprogesterone is markedly elevated. Which enzyme deficiency and inheritance pattern underlies this condition?
28. An 8-month-old boy presents with hypotonia since birth, golden-brown rings at the periphery of the iris on slit-lamp examination, liver disease, and haemolytic anaemia. Serum ceruloplasmin is low and 24-hour urine copper is markedly elevated. The molecular defect in Wilson's disease involves:
29. A 3-year-old child presents with recurrent bacterial infections (Staphylococcus aureus, Aspergillus), lymphadenitis, and hepatomegaly. NBT (nitroblue tetrazolium) test shows failure of dye reduction by neutrophils. Dihydrorhodamine (DHR) flow cytometry confirms absent oxidative burst. The defect is in which molecular complex?
30. A newborn with Down syndrome (trisomy 21) is examined. Besides the characteristic dysmorphic features, which cardiac defect is MOST COMMONLY associated with Down syndrome?
31. A neonate is found to have ambiguous genitalia. Karyotype is 46,XX. Serum 17-hydroxyprogesterone (17-OHP) is markedly elevated at 35,000 ng/dL. Serum sodium is 120 mEq/L, potassium 6.8 mEq/L. This pattern is caused by deficiency of which enzyme?
32. A 6-month-old infant with progressive hypotonia, hepatosplenomegaly, and a cherry-red spot on fundoscopy has an enzyme assay showing markedly reduced hexosaminidase A activity. Which lysosomal storage disorder is this, and what is the mode of inheritance?
33. A 3-year-old boy presents with recurrent episodes of pancreatitis, xanthomas over the elbows and buttocks, and a family history of early cardiovascular disease. Fasting lipid profile shows triglycerides 1800 mg/dL and cholesterol 450 mg/dL. Lipoprotein electrophoresis shows increase in IDL (Type III pattern). Which genetic disorder is this?
34. A newborn screen in India is positive for elevated phenylalanine (850 µmol/L, reference <120 µmol/L). Urine pterins show markedly reduced biopterin. A dihydropteridine reductase (DHPR) assay is normal. Which form of hyperphenylalaninemia does this most likely represent, and what is the critical addition to treatment beyond a low-phenylalanine diet?
35. A 4-year-old boy has recurrent sinopulmonary infections, absent tonsils and lymph nodes, markedly low immunoglobulins (IgG, IgA, IgM), and absent B cells (CD19+ cells 0%) on flow cytometry. Maternal grandfather had similar disease. What is the inheritance pattern, and what gene is mutated?
36. A 10-year-old girl with Wilson disease on D-penicillamine develops worsening neurological symptoms, new resting tremor, and increased dysarthria 3 months after starting treatment. KF rings are present. Liver function is mildly abnormal. What explains this initial neurological deterioration?
37. A 6-month-old infant presents with developmental regression, cherry red spot on fundoscopy, startling hypersensitivity to sound, and progressive hypotonia. The enzymatic deficiency responsible for this condition is:
38. A 3-year-old boy presents with coarse facies, corneal clouding, hepatosplenomegaly, umbilical hernia, and dysostosis multiplex on X-ray. Urine mucopolysaccharide screen is positive with elevation of heparan sulfate and dermatan sulfate. Which enzyme is deficient in this condition?
39. A 2-week-old neonate on newborn screening is found to have elevated blood phenylalanine (18 mg/dL). Urinary pterins show elevated biopterin with low neopterin. Dihydropteridine reductase (DHPR) activity is normal. BH4 loading test shows >30% reduction in phenylalanine. This biochemical profile is consistent with:
40. A male infant presents at 6 months with hypotonia, cardiomegaly, and macroglossia. Echo shows a markedly hypertrophied non-obstructive cardiomyopathy. Muscle biopsy shows PAS-positive vacuoles. Enzyme assay demonstrates deficiency of acid alpha-glucosidase. The most appropriate disease-modifying treatment is:
41. A 14-year-old girl is being evaluated for primary amenorrhea, short stature (height 141 cm), cubitus valgus, and a webbed neck. Karyotype is 45,X. Echocardiography should be performed to screen for the most common cardiovascular abnormality in this syndrome, which is:
42. A 2-year-old child presents with recurrent hospitalizations for hyperammonemia, irritability, and vomiting since infancy. Plasma amino acids show elevation of citrulline to >1000 μmol/L, with low argininosuccinate and low arginine. Urine orotic acid is elevated. The enzyme deficiency causing this condition is:
43. A 6-month-old infant is brought with progressive loss of motor milestones, exaggerated startle response to sound, cherry-red spot on fundoscopy, and no hepatosplenomegaly. Enzyme assay shows deficiency of hexosaminidase A. Which statement about the storage material in this condition is CORRECT?
44. A newborn screen detects elevated phenylalanine (1200 μmol/L). The infant appears normal. Confirmatory testing shows classic PKU (PAH deficiency). What is the MOST CRITICAL principle in dietary management of PKU?
45. A 2-year-old boy has hepatosplenomegaly, progressive bone pain, pathological fractures, and pancytopenia. Bone marrow biopsy shows 'wrinkled paper' (Gaucher) cells. Enzyme assay confirms glucocerebrosidase deficiency. Which is the MOST EFFECTIVE disease-modifying therapy for Type 1 Gaucher disease?
46. A 3-month-old infant presents with coarse facial features, gingival hypertrophy, macroglossia, hepatosplenomegaly, and corneal clouding. Urine spot test for glycosaminoglycans is positive. Enzyme assay shows deficiency of alpha-L-iduronidase. Which mucopolysaccharide accumulates, and what is the MODE OF INHERITANCE?
47. A neonate is diagnosed with congenital hypothyroidism on newborn screening (elevated TSH, low free T4). Mother has Hashimoto's thyroiditis and was taking methimazole during pregnancy for Graves' disease that relapsed. Which is the MOST LIKELY cause of congenital hypothyroidism in this infant?
48. A 10-month-old male infant presents with recurrent bacterial infections (Staphylococcus aureus and Klebsiella), aphthous ulcers, and a skin abscess since 3 months of age. NBT (nitroblue tetrazolium) test is negative (no reduction). Flow cytometry shows normal B and T lymphocyte counts and normal neutrophil count. Which is the MOST LIKELY diagnosis?
49. A 6-month-old baby boy has progressive liver enlargement, generalised hypotonia, macroglossia, and an echocardiogram showing severe hypertrophic cardiomyopathy. Enzyme assay reveals absent acid alpha-glucosidase (GAA) activity. What is the diagnosis?
50. A newborn's urine has a musty/mousy odour. Guthrie bacterial inhibition assay detects elevated phenylalanine. The child has a normal appearance but without treatment will develop intellectual disability. Which enzyme is deficient?
51. A 3-year-old boy has global developmental delay, recurrent pulmonary infections, splenomegaly, and a bone marrow biopsy showing large macrophages with wrinkled tissue-paper cytoplasm (Gaucher cells). The deficient enzyme is glucocerebrosidase (beta-glucosidase). Enzyme replacement therapy (ERT) is indicated. Which clinical feature distinguishes Type 2 (acute neuronopathic) from Type 1 (non-neuronopathic) Gaucher disease and prevents ERT from being curative in Type 2?
52. A newborn screening picks up elevated phenylalanine (2400 µmol/L) in a formula-fed infant at day 5. Confirmatory testing confirms classical phenylketonuria (PAH deficiency). The MOST critical window for starting dietary phenylalanine restriction to prevent intellectual disability is:
53. A 6-month-old infant presents with progressive loss of previously attained motor milestones, an exaggerated startle response to sound (hyperekplexia), a cherry-red spot on fundoscopy, and progressive macrocephaly. Enzyme assay shows absent hexosaminidase A. The diagnosis is:
54. A newborn screening test flags an infant for elevated phenylalanine. Confirmatory plasma amino acid analysis shows phenylalanine 1200 µmol/L (normal <120). The infant is placed on a phenylalanine-restricted diet. The most critical long-term monitoring parameter aside from phenylalanine levels is:
55. A 3-year-old presents with hepatomegaly, recurrent hypoglycemia worsened by fasting, lactic acidosis and growth retardation. Liver biopsy shows glycogen accumulation in hepatocytes. Glucose-6-phosphatase activity is absent. The diagnosis is:
56. A 6-month-old infant presents with hepatosplenomegaly, hypotonia, failure to thrive, and a cherry-red spot on fundoscopy. Bone marrow biopsy shows lipid-laden macrophages (Gaucher cells). Enzymatic analysis shows deficiency of glucocerebrosidase. Which treatment is currently available for this condition?
57. A newborn's newborn screening (NBS) card shows elevated phenylalanine of 22 mg/dL. Confirmatory plasma amino acid chromatography confirms phenylketonuria (PKU). Which tetrahydrobiopterin (BH4) loading test finding would suggest BH4-responsive PKU, making sapropterin dihydrochloride a treatment option?
58. A 6-month-old girl develops progressive hepatosplenomegaly, failure to thrive, and type III (neuronopathic) Gaucher disease is suspected. Bone marrow biopsy shows 'crinkled paper' macrophages. Which enzyme is deficient and what is the STORED substrate?
59. A 3-year-old boy has recurrent severe bacterial infections (Staphylococcus, Klebsiella, Aspergillus, Serratia). His NBT (nitroblue tetrazolium) test is abnormal — neutrophils fail to reduce NBT to blue formazan. Superoxide generation by PMA stimulation is absent. What is the PRIMARY molecular defect?
60. A newborn is found on universal metabolic screening to have elevated phenylalanine (1800 μmol/L, normal <120). The infant is placed on a phenylalanine-restricted diet. The underlying enzyme deficiency in classic PKU is:
61. A 15-month-old infant presents with progressive psychomotor regression, exaggerated startle response (hyperekplexia), cherry-red spot on fundal examination, and hypotonia progressing to hypertonia. Lysosomal enzyme assay shows absence of hexosaminidase A activity. The diagnosis is:
62. A 2-year-old with recurrent infections, absent tonsils, and very low or absent serum immunoglobulins (IgG, IgA, IgM) — all four classes — is found to have a mutation in the BTK (Bruton tyrosine kinase) gene on the X chromosome. This condition is:
63. A newborn is detected on NBS (newborn screening) to have phenylketonuria (PKU). Plasma phenylalanine is 22 mg/dL. The parents ask about the mechanism of intellectual disability if the condition is untreated. The PRIMARY mechanism is:
64. A 10-year-old child has progressive ataxia, dysarthria, hyporeflexia, and Babinski signs developing since age 7. Echocardiography shows hypertrophic cardiomyopathy. Nerve conduction studies show mixed sensorimotor neuropathy. Frataxin protein is markedly reduced. The genetic mechanism involves:
65. A 3-year-old boy presents with recurrent infections with catalase-positive organisms, absolute lymphocyte count (ALC) is normal, immunoglobulins are normal. DHR flow cytometry shows absent oxidative burst. Genetic testing reveals a mutation in gp91phox (CYBB gene on X chromosome). His sister is asymptomatic with normal DHR test. The carrier mother's DHR test would be expected to show:
66. A child is diagnosed with Prader-Willi syndrome (PWS). Which mechanism accounts for the majority (65–70%) of PWS cases?
67. A 2-year-old presents with coarse facies, corneal clouding, hepatosplenomegaly, joint stiffness, and regression of developmental milestones. Urine glycosaminoglycan (GAG) is markedly elevated. Enzyme assay shows absent alpha-L-iduronidase. Which condition is this, and which clinical feature differentiates it from Hunter syndrome (MPS II)?
68. An 8-year-old girl with Turner syndrome (45,X) is being evaluated for associated comorbidities. Which cardiac anomaly is MOST commonly associated with Turner syndrome and requires echocardiographic surveillance throughout life?
69. A newborn with Down syndrome is screened for cardiac defect. The most common congenital heart defect in Down syndrome is:
70. An infant with phenylketonuria (PKU) detected on newborn screening is started on a phenylalanine-restricted diet. If untreated, the primary mechanism of neurological damage in PKU is: