Metabolic Flashcards
1
Q
- A previously well child presents with hepatomegaly, vomiting, and signs of liver dysfunction. What is the most likely diagnosis?
A
Tyrosinemia type I: Presents in infancy with liver failure, renal dysfunction, and risk of hepatocellular carcinoma. Diagnosis: elevated succinylacetone in urine.
2
Q
- What are the features of homocystinuria?
A
Homocystinuria: Marfanoid habitus, ectopia lentis (downward), developmental delay, thrombosis. Elevated homocysteine, methionine in plasma; positive urine homocystine.
3
Q
- A previously well neonate presents with poor feeding, lethargy, seizures, and maple syrup odor in urine. What is the diagnosis?
A
MSUD (Maple Syrup Urine Disease): Elevated branched-chain amino acids; autosomal recessive. Needs prompt dietary restriction.
4
Q
- What are the clinical and biochemical features of phenylketonuria (PKU)?
A
PKU: AR disorder due to deficiency of phenylalanine hydroxylase. Features: fair skin, eczema, intellectual disability, musty odor. Diagnosis: elevated phenylalanine.
5
Q
- A child developed vomiting, lethargy, and hypoglycemia shortly after consuming fruit juice. What is the most likely diagnosis?
A
Hereditary Fructose Intolerance (HFI): Due to aldolase B deficiency. Presents after fructose/sucrose intake. Avoid fructose, sucrose, sorbitol.
6
Q
- What are the clinical features and diagnosis of classic galactosemia?
A
Galactosemia: Jaundice, hepatomegaly, vomiting, E. coli sepsis, cataracts. Due to GALT deficiency. Diagnosis: elevated galactose-1-phosphate.
7
Q
- A neonate presents with lethargy, hypoglycemia, and hypotonia during illness. Urine negative for ketones. Diagnosis?
A
Carnitine transporter defect: Hypoketotic hypoglycemia due to impaired fatty acid oxidation. Treatment: carnitine supplementation.
8
Q
- What is the physiological role of carnitine in fatty acid metabolism?
A
Carnitine transports long-chain fatty acids into mitochondria for β-oxidation. Deficiency causes hypoketotic hypoglycemia and muscle weakness.
9
Q
- How is medium-chain acyl-CoA dehydrogenase (MCAD) deficiency diagnosed?
A
Diagnosis: Acylcarnitine profile shows elevated C8, C6, C10. Hypoglycemia, no ketones. Genetic testing confirms.
10
Q
- What are the clinical features of MCAD deficiency?
A
Most common fatty acid oxidation disorder. Presents with lethargy, vomiting, seizures during fasting or illness. Risk of sudden death.
11
Q
- A previously well child presents with lethargy and hypoglycemia during illness. What metabolic defect should be suspected?
A
Fatty Acid Oxidation Disorder (FAOD): Triggered by fasting/illness. Presents with lethargy, hepatomegaly, seizures. Labs: hypoglycemia, no ketosis.
12
Q
- What are the features of CPT II deficiency?
A
Carnitine Palmitoyltransferase II (CPT II) deficiency: Myopathic form presents in adolescence/adulthood with muscle pain, rhabdomyolysis, myoglobinuria, especially after exercise.
13
Q
- What is the role of acylcarnitine profile in metabolic disorder diagnosis?
A
Detects fatty acid oxidation disorders (FAODs), organic acidemias, some aminoacidopathies. Specific acylcarnitine patterns guide diagnosis.
14
Q
- What are the differences between urea cycle disorders and organic acidemias based on acid-base status?
A
UCD: Respiratory alkalosis (hyperammonemia). Organic acidemias: Metabolic acidosis with increased anion gap. Useful clue for differential diagnosis.
15
Q
- What are key initial lab tests in a suspected inborn error of metabolism?
A
ABG, serum lactate, ammonia, glucose, LFTs, electrolytes. Urine ketones and reducing substances. Acylcarnitine profile and plasma amino acids follow.
16
Q
- What is Glutaric aciduria type I and how does it present?
A
GA-I: AR disorder due to glutaryl-CoA dehydrogenase deficiency. Macrocephaly, dystonia, basal ganglia injury. Diagnosed via urine organic acids (elevated glutaric acid).
17
Q
- What are disorders that present with elevated lactate and normal anion gap?
A
Mitochondrial disorders. Elevated lactate without significant acidosis. May present with multi-system involvement: myopathy, cardiomyopathy, seizures.
18
Q
- What is Niemann-Pick disease and how is it classified?
A
Niemann-Pick disease: Types A/B: Sphingomyelinase deficiency (hepatosplenomegaly, neurodegeneration). Type C: Cholesterol trafficking defect (vertical gaze palsy, ataxia).
19
Q
- What are inborn errors of metabolism (IEM)?
A
Genetic enzyme deficiencies causing accumulation or deficiency of metabolites. Often present in neonates with vomiting, lethargy, seizures, or failure to thrive.
20
Q
- A previously well neonate develops metabolic acidosis, hypotonia, and hepatomegaly within days of life. What is the likely diagnosis?
A
Glutaric acidemia type II (GA-II / MADD): Severe neonatal presentation with metabolic acidosis, hypoglycemia, and hypotonia. Defect in multiple acyl-CoA dehydrogenases.
21
Q
- What metabolic disorders present with hypoketotic hypoglycemia?
A
FAODs such as MCAD, CPT1, carnitine transport defects. Presentation: fasting intolerance, lethargy, hepatomegaly, seizures. Labs: low glucose, absent ketones.
22
Q
- A previously well child develops progressive motor regression, spasticity, and peripheral neuropathy. MRI shows periventricular white matter changes. Diagnosis?
A
Metachromatic leukodystrophy (MLD): AR, arylsulfatase A deficiency. Progressive demyelination, gait disturbances, cognitive decline.
23
Q
- How does long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency present?
A
LCHAD: Hypoketotic hypoglycemia, liver dysfunction, cardiomyopathy, retinal abnormalities. Can lead to sudden death. Detected via acylcarnitine profile (elevated C14-OH).
24
Q
- What is the significance of dicarboxylic aciduria in metabolic disorders?
A
Seen in FAODs like MCAD and carnitine cycle defects. Indicates alternative omega-oxidation pathway activation during β-oxidation block.
25
77. A previously well child presents with metabolic acidosis, ketosis, and hypoglycemia. Urine organic acids show elevated 3-methylcrotonylglycine. Diagnosis?
3-Methylcrotonyl-CoA carboxylase (3-MCC) deficiency: A form of organic acidemia. May be asymptomatic or cause metabolic crisis during illness.
26
78. A child with vomiting, lethargy, and metabolic acidosis has low biotinidase activity. Diagnosis?
Multiple carboxylase deficiency: Caused by biotinidase or holocarboxylase synthase deficiency. Treat with biotin supplementation.
27
57. What are aminoacidopathies and how are they diagnosed?
Disorders due to enzyme defects in amino acid metabolism (e.g., PKU, MSUD, homocystinuria). Diagnosed via plasma amino acid chromatography.
28
29. A child with macrocephaly, hypotonia, and developmental delay has elevated NAA in urine and brain MRI shows spongy white matter. Diagnosis?
Canavan disease: AR, ASPA gene mutation. NAA accumulates due to aspartoacylase deficiency. Supportive care only.
29
40. What is the best management during acute metabolic crisis in a child with known IEM?
Stop protein intake, provide IV glucose and lipids, correct acidosis. Treat hyperammonemia if present. Monitor electrolytes and hydration.
30
80. What are clinical clues to a late-onset inborn error of metabolism?
Failure to thrive, developmental regression, episodic vomiting, unexplained acidosis, organomegaly, peculiar odor. Triggered by stress/infection.
31
28. What are the types and features of leukodystrophies?
Inherited white matter disorders (AR or X-linked). Progressive spasticity, seizures, vision loss. MRI: symmetric white matter involvement. Examples: MLD, Canavan, Krabbe.
32
3. What are the common categories of inborn errors of metabolism (IEM)?
Aminoacidopathies, organic acidemias, urea cycle disorders, FAODs, carbohydrate disorders, lysosomal storage diseases, mitochondrial disorders.
33
18. What is biotinidase deficiency and how does it present?
Seizures, hypotonia, dermatitis, alopecia, developmental delay. Can mimic other metabolic disorders. Treated with oral biotin.
34
2. A previously well neonate presents with lethargy, poor feeding, and vomiting. What are red flags suggesting IEM?
Recurrent vomiting, metabolic acidosis, abnormal odor, seizures, hepatomegaly, developmental regression. Triggered by illness or fasting.
35
21. What are the clinical features and diagnosis of Pompe disease?
GSD II. AR, acid alpha-glucosidase deficiency. Cardiomegaly, hypotonia, macroglossia, hepatomegaly. Elevated CK, echo shows cardiomyopathy.
36
22. How does Cori disease (GSD III) present?
Debranching enzyme deficiency. Hepatomegaly, fasting hypoglycemia, growth delay, elevated transaminases, cardiomyopathy.
37
23. A child presents with exercise intolerance, muscle cramps, and myoglobinuria. What is the diagnosis?
McArdle disease (GSD V): Muscle phosphorylase deficiency. Symptoms triggered by exercise. Labs: high CK, myoglobinuria.
38
9. What is the pathophysiology and presentation of Von Gierke disease?
GSD I: Glucose-6-phosphatase deficiency. Presents with fasting hypoglycemia, lactic acidosis, hepatomegaly, doll-like face, hyperlipidemia.
39
62. What are disorders causing hyperammonemia with high anion gap metabolic acidosis?
Organic acidemias (e.g., MMA, propionic acidemia). Features: lethargy, vomiting, hypotonia, hyperammonemia, acidosis. Confirmed via urine organic acids.
40
61. What are disorders associated with hyperammonemia and normal anion gap?
Urea cycle disorders (e.g., OTC deficiency). Presents with vomiting, lethargy, respiratory alkalosis. Normal glucose, no acidosis. Plasma amino acids confirm.
41
34. What are lysosomal storage disorders and how do they present?
Caused by deficiency of lysosomal enzymes leading to accumulation of unmetabolized substrates. Present with organomegaly, coarse facies, skeletal anomalies, CNS symptoms in neuronopathic types.
42
31. What are the features and diagnosis of Krabbe disease?
AR, galactocerebrosidase deficiency. Presents in infancy with irritability, spasticity, developmental delay, optic atrophy. MRI: white matter demyelination.
43
24. What are the key features of Hurler syndrome?
AR, α-L-iduronidase deficiency. Coarse facial features, corneal clouding, hepatosplenomegaly, skeletal deformities, developmental delay.
44
25. What are the features and inheritance of Hunter syndrome?
X-linked recessive, iduronate sulfatase deficiency. Coarse facies, hepatosplenomegaly, joint stiffness, aggressive behavior. No corneal clouding (unlike Hurler).
45
39. What are the key differences between Tay-Sachs and Sandhoff disease?
Tay-Sachs: Hexosaminidase A deficiency. Sandhoff: Hex A and B deficiency. Both show neurodegeneration, cherry-red macula. Sandhoff may have hepatosplenomegaly.
46
38. What are the features and diagnosis of Tay-Sachs disease?
AR, β-hexosaminidase A deficiency. Normal until 6 months, then hypotonia, developmental delay, seizures, cherry-red spot, no hepatosplenomegaly.
47
37. What are the types of Gaucher disease?
Type 1: Non-neuronopathic (hepatosplenomegaly, anemia, bone pain). Type 2: Acute neuronopathic (infantile, CNS involvement). Type 3: Chronic neuronopathic. Deficiency: glucocerebrosidase.
48
36. A child with hepatosplenomegaly, bone pain, anemia, and Erlenmeyer flask deformity on X-ray. Diagnosis?
Gaucher disease: Glucocerebrosidase deficiency. Type 1 most common. Bone crises, cytopenias, hepatosplenomegaly.
49
26. How do mucopolysaccharidoses (MPS) present?
Coarse facial features, joint stiffness, hepatosplenomegaly, corneal clouding (in some types), skeletal abnormalities, developmental delay.
50
44. What are the treatment options for Wilson disease?
Zinc (blocks absorption), chelators like penicillamine or trientine (increase urinary copper excretion), low copper diet. Liver transplant in severe cases.
51
41. What are the key features of Menkes disease?
X-linked defect in ATP7A gene (copper transport). Features: kinky hair, developmental delay, seizures, hypopigmentation, arterial tortuosity. Low serum copper and ceruloplasmin.
52
42. A child presents with hepatitis, neurologic signs, and Kayser-Fleischer rings. What is the diagnosis?
Wilson disease: Copper accumulation in liver, brain. AR defect in ATP7B. Presents with hepatic failure, neuropsychiatric symptoms, K-F rings on slit lamp.
53
43. What lab findings support the diagnosis of Wilson disease?
Low ceruloplasmin, elevated urinary copper excretion, elevated hepatic copper content. Sometimes low serum copper. Confirmed by genetic testing.
54
76. How is mitochondrial disease diagnosed?
Muscle biopsy shows ragged red fibers. Labs: elevated lactate, alanine. Genetic testing confirms mtDNA mutations. MRI may show stroke-like lesions.
55
69. What is MELAS syndrome and how does it present?
MELAS = Mitochondrial Encephalopathy, Lactic Acidosis, and Stroke-like episodes. Features: seizures, short stature, diabetes, hearing loss. mtDNA mutation (e.g., A3243G).
56
68. What are characteristic MRI findings in Leigh syndrome?
Symmetric necrotic lesions in basal ganglia, brainstem, and thalamus. Presents with developmental regression, hypotonia, respiratory failure.
57
67. A child presents with lactic acidosis, vomiting, hypotonia, and poor feeding. What is the most likely category of disorder?
Mitochondrial disorder. Often multisystem involvement. Confirmed with lactate, MRI, muscle biopsy, and genetic tests.
58
55. What is lactic acidosis and how is it interpreted in metabolic disease?
Lactate >5 mmol/L, pH <7.35. Suggests impaired oxidative metabolism. Seen in mitochondrial disorders, pyruvate dehydrogenase deficiency, shock states.
59
20. A child with developmental delay, lactic acidosis, and elevated pyruvate. What is the likely diagnosis?
Pyruvate dehydrogenase (PDH) deficiency: X-linked or AR. Presents with neurodegeneration, lactic acidosis. Diagnosis: low PDH activity in fibroblasts.
60
54. What are the clinical and lab features of pyruvate carboxylase deficiency?
Lactic acidosis, failure to thrive, hypotonia, seizures. Labs: elevated lactate, pyruvate, alanine. Rare AR disorder. Biotin is ineffective.
61
52. How does the lactate-to-pyruvate ratio help differentiate metabolic disorders?
Lactate:pyruvate >25 suggests mitochondrial disorder. Ratio <10 suggests pyruvate dehydrogenase (PDH) deficiency. Important clue in lactic acidosis evaluation.
62
59. What is the utility of urine organic acid analysis in metabolic disorders?
Detects organic acidemias, lactic acidosis, and ketosis. Helpful in diagnosing MMA, propionic acidemia, MSUD, glutaric aciduria, isovaleric acidemia.
63
15. How do you differentiate methylmalonic acidemia (MMA) from propionic acidemia?
MMA: ↑ methylmalonic acid, responds to B12 in some cases. Propionic acidemia: ↑ propionylcarnitine, ↑ glycine, ↑ ammonia. Both present with metabolic acidosis and ketosis.
64
65. A child presents with metabolic acidosis, vomiting, and a “sweaty feet” odor. Diagnosis?
Isovaleric acidemia: AR disorder of leucine metabolism. Labs: metabolic acidosis, ketosis, ↑ isovalerylglycine. Management: glycine, carnitine, dietary protein restriction.
65
66. What is the best management strategy during acute decompensation in organic acidemias?
Stop protein intake, start high-calorie glucose infusion, correct acidosis, give carnitine, monitor ammonia. Dialysis in severe cases.
66
58. What are organic acidemias and how do they present?
AR enzyme defects in amino acid breakdown. Present with vomiting, lethargy, metabolic acidosis, ketosis, hyperammonemia. Diagnosed via urine organic acids.
67
14. What is the biochemical and clinical profile of methylmalonic acidemia?
AR, methylmalonyl-CoA mutase or B12 metabolism defect. Presents with acidosis, ketosis, hyperammonemia, hypotonia. Elevated methylmalonic acid in urine.
68
13. What are the clinical features of propionic acidemia?
AR, propionyl-CoA carboxylase deficiency. Presents in neonates with vomiting, hypotonia, metabolic acidosis, ketosis, hyperammonemia. Diagnosis: urine organic acids.
69
5. What are the biochemical features of organic acidemias?
High anion gap metabolic acidosis, ketosis, elevated lactate and ammonia, specific organic acids in urine. Carnitine may be decreased.
70
27. A neonate presents with seizures, hypotonia, hepatomegaly, and elevated VLCFA. Diagnosis?
Zellweger syndrome: Peroxisomal biogenesis defect. Dysmorphic features, liver dysfunction, elevated very long-chain fatty acids. No cure; supportive care.
71
33. A boy presents with behavioral changes, adrenal insufficiency, and spasticity. VLCFA levels are elevated. Diagnosis?
X-linked adrenoleukodystrophy (X-ALD): ABCD1 mutation → VLCFA accumulation in brain and adrenals. MRI: white matter demyelination. Treat with Lorenzo’s oil, supportive care.
72
75. What are common peroxisomal markers used in diagnosis?
Elevated very long-chain fatty acids (VLCFA), phytanic acid, pristanic acid, low plasmalogens. Used to screen for Zellweger spectrum, X-ALD.
73
30. What are peroxisomal disorders and how do they present?
Include Zellweger spectrum and X-ALD. Present with hypotonia, seizures, dysmorphism, hepatomegaly, vision/hearing loss. Labs: ↑ VLCFA, ↓ plasmalogens.
74
50. What are the benefits and scope of tandem mass spectrometry (MS/MS) in newborn screening?
Detects amino acidopathies, FAODs, organic acidemias. Rapid, sensitive, screens multiple disorders in one test. Requires confirmatory testing.
75
49. What is the role of newborn screening in metabolic disorders?
Identifies treatable IEMs early (e.g., PKU, MSUD, MCAD). Allows timely intervention and improved outcomes. Tandem MS and enzyme assays used.
76
4. A neonate presents with lethargy, vomiting, respiratory alkalosis, and hyperammonemia. Diagnosis?
Urea cycle disorder (likely OTC deficiency). No acidosis, normal glucose, elevated ammonia. Confirm with plasma amino acids and genetic testing.
77
46. A child presents with recurrent vomiting, protein aversion, and elevated urinary orotic acid. Diagnosis?
Ornithine transcarbamylase (OTC) deficiency: X-linked. Hyperammonemia, respiratory alkalosis, ↑ orotic acid. Commonest urea cycle defect.
78
64. What is the best management approach for argininosuccinic aciduria?
Protein restriction, sodium benzoate/phenylbutyrate, arginine supplementation. Monitor ammonia levels. Liver transplant in refractory cases.
79
63. How does citrullinemia type I present and how is it managed?
Neonatal hyperammonemia, vomiting, lethargy, seizures. Labs: ↑ citrulline. Management: protein restriction, arginine, ammonia scavengers.
80
47. How is hyperammonemia managed in urea cycle disorders?
Stop protein intake, give IV glucose/lipids, ammonia scavengers (sodium benzoate, phenylbutyrate), arginine. Dialysis in severe cases.
