Metabolic Flashcards
- What are inborn errors of metabolism (IEM) and how are they classified?
IEM: Genetic enzyme defects leading to accumulation or deficiency of metabolites
- Classified as: small molecule disorders (amino acid, organic acid, urea cycle), energy defects (mitochondrial, FAOD), complex molecule defects (lysosomal, peroxisomal)
- What are the red flag signs of metabolic disorders in neonates?
Red flags: Poor feeding, vomiting, lethargy, seizures, hypotonia, unexplained acidosis or hypoglycemia, musty or unusual odor, consanguinity, sibling deaths
- What are the common categories of IEM?
Categories: Amino acidopathies, organic acidemias, urea cycle defects, carbohydrate disorders, fatty acid oxidation defects, mitochondrial, lysosomal, peroxisomal
- What is the typical presentation of urea cycle defects in neonates?
Urea cycle defects: Present with vomiting, lethargy, respiratory alkalosis, hyperammonemia without acidosis
- Often in first few days of life
- What are the biochemical features of organic acidemias?
Organic acidemias: Metabolic acidosis with increased anion gap, ketonuria, hyperammonemia, neutropenia, thrombocytopenia, elevated lactate
- What are the signs and lab findings of maple syrup urine disease (MSUD)?
MSUD: Poor feeding, lethargy, seizures, urine smells like maple syrup
- Labs: Elevated leucine/isoleucine/valine, ketoacidosis, no ketonuria initially
- What is the clinical and biochemical picture of phenylketonuria (PKU)?
PKU: AR defect in phenylalanine hydroxylase
- Features: Intellectual disability, fair skin/hair, eczema, musty odor
- Labs: ↑Phenylalanine, normal tyrosine
- What are the features of galactosemia and how is it diagnosed?
Galactosemia: Jaundice, hepatomegaly, vomiting, E. coli sepsis in neonates
- Labs: ↓GALT activity, reducing substances in urine
- Screened in newborns
- What is the pathophysiology and management of glycogen storage disease type I (Von Gierke)?
Von Gierke (GSD I): Glucose-6-phosphatase deficiency
- Features: Hypoglycemia, lactic acidosis, hepatomegaly, doll-like face
- Management: Frequent feeds, cornstarch, avoid galactose/fructose
- What are the common triggers and presentation of fatty acid oxidation defects (FAOD)?
FAODs: Triggered by fasting, illness
- Features: Hypoketotic hypoglycemia, hepatomegaly, muscle weakness
- Most common: MCAD deficiency
- Treat: Avoid fasting, give glucose/lipids
- What are the features of medium-chain acyl-CoA dehydrogenase (MCAD) deficiency?
MCAD: Most common FAOD
- Presents with lethargy, hypoketotic hypoglycemia, vomiting during fasting or illness
- Risk of sudden death in infancy
- How is MCAD deficiency diagnosed and treated?
Diagnosis: Acylcarnitine profile shows elevated C8, C6, C10
- Urine: Dicarboxylic aciduria
- Treatment: Avoid fasting, high-carb diet
- What are the clinical features of propionic acidemia?
Propionic acidemia: AR; vomiting, hypotonia, seizures, metabolic acidosis with ↑anion gap, hyperammonemia
- Labs: ↑propionic acid, ↑glycine
- What is the biochemical profile of methylmalonic acidemia?
Methylmalonic acidemia: AR; similar to propionic but may have neutropenia, elevated methylmalonic acid in urine
- May respond to B12
- How do you differentiate between propionic and methylmalonic acidemias?
Differentiate by: MMA → ↑methylmalonic acid, possible B12 response
PA → ↑propionic acid, both have metabolic acidosis and hyperammonemia
- What are the features of homocystinuria and how does it differ from Marfan syndrome?
Homocystinuria: Marfanoid habitus, ectopia lentis (downward), thromboembolism, ID
- Labs: ↑homocysteine, ↑methionine
- Treat with B6, betaine, folate, B12
- What is the presentation and treatment of tyrosinemia type I?
Tyrosinemia type I: Presents in infancy with liver failure, renal tubulopathy, cabbage odor
- Labs: ↑succinylacetone
- Treat: Nitisinone + dietary restriction
- What is biotinidase deficiency and how does it present?
Biotinidase deficiency: Seizures, hypotonia, dermatitis, alopecia, metabolic acidosis
- Treat: Lifelong biotin supplementation
- What are the clinical signs and labs in fructose-1-phosphate aldolase deficiency (Hereditary Fructose Intolerance)?
HFI: Presents after fructose introduction (juice, fruits)
- Hypoglycemia, vomiting, seizures, hepatomegaly
- Labs: Reducing sugars in urine, no ketones
- What are the signs, diagnosis, and management of pyruvate dehydrogenase deficiency?
PDH deficiency: Presents with lactic acidosis, neurologic signs, hypotonia
- Labs: ↑lactate, ↑alanine
- Treat: Ketogenic diet, thiamine trial
- What are the clinical features of Pompe disease (GSD II)?
Pompe: GSD II, AR, acid alpha-glucosidase deficiency
- Features: Hypotonia, cardiomegaly, macroglossia, hepatomegaly, early death
- Treat: Enzyme replacement
- How does Cori disease (GSD III) present and how is it differentiated from Von Gierke disease?
Cori (GSD III): Debranching enzyme deficiency
- Features: Hepatomegaly, hypoglycemia, elevated transaminases, normal lactate
- Differs from Von Gierke: no lactic acidosis
- What is the presentation and management of McArdle disease (GSD V)?
McArdle (GSD V): Muscle phosphorylase deficiency
- Exercise intolerance, muscle cramps, myoglobinuria
- Labs: ↑CK, ‘second wind’ phenomenon
- Avoid strenuous activity
- What are the key features of Hurler syndrome (MPS I)?
Hurler: AR, alpha-L-iduronidase deficiency
- Features: Coarse facies, hepatosplenomegaly, corneal clouding, developmental delay, dysostosis multiplex
- What are the features and enzyme defect in Hunter syndrome (MPS II)?
Hunter: X-linked, iduronate sulfatase deficiency
- Similar to Hurler but milder
- No corneal clouding, aggressive behavior, later onset
- How do mucopolysaccharidoses (MPS) present and how are they diagnosed?
MPS: Coarse facies, hepatosplenomegaly, joint stiffness, hearing loss
- Diagnosis: Urinary GAGs, enzyme assay
- MRI: White matter changes
- What is the pathophysiology and clinical presentation of Zellweger syndrome?
Zellweger: Peroxisomal biogenesis disorder
- Features: Hypotonia, seizures, craniofacial dysmorphism, liver dysfunction, calcific stippling
- What are the types and features of leukodystrophies in children?
Leukodystrophies: AR or X-linked
- Progressive neurologic deterioration, hypotonia/hypertonia, seizures
- Types: Krabbe, Metachromatic, Canavan, ALD
- What is the presentation of Canavan disease and its diagnostic hallmark?
Canavan: AR, ASPA gene mutation
- Macrocephaly, hypotonia, spongy degeneration
- Diagnosis: ↑N-acetylaspartate in urine/MRS
- What are peroxisomal disorders and how do they typically present in infancy?
Peroxisomal disorders: Zellweger spectrum, X-ALD
- Present with hypotonia, seizures, dysmorphism, liver disease
- Diagnosis: VLCFA profile
- What are the features and biochemical findings in Krabbe disease?
Krabbe: AR, galactocerebrosidase deficiency
- Features: Irritability, stiffness, seizures, optic atrophy, developmental regression
- MRI: Demyelination
- Dx: Enzyme assay
- What is the clinical presentation of metachromatic leukodystrophy (MLD)?
MLD: AR, arylsulfatase A deficiency
- Progressive motor/cognitive decline, ataxia, seizures
- Dx: Urine sulfatides, enzyme assay, MRI
- What is the presentation and diagnosis of X-linked adrenoleukodystrophy (X-ALD)?
X-ALD: ABCD1 gene defect → VLCFA accumulation
- Features: Behavior changes, adrenal insufficiency, spasticity, vision loss
- Dx: VLCFA levels, MRI
- What are lysosomal storage diseases and how are they generally diagnosed?
Lysosomal storage diseases: Accumulation of undigested substrates
- Dx: Enzyme assay, urine oligosaccharides/GAGs, genetic testing
- What is Niemann-Pick disease and how is it classified?
Niemann-Pick: Types A/B (sphingomyelinase deficiency), C (cholesterol trafficking defect)
- Hepatosplenomegaly, neurologic decline, cherry-red spot in type A
- What is the clinical presentation and enzyme defect in Gaucher disease?
Gaucher: Glucocerebrosidase deficiency
- Type 1: Hepatosplenomegaly, anemia, bone crisis
- Type 2/3: Neurologic involvement
- Dx: Enzyme assay
- What are the types of Gaucher disease and how are they managed?
Types:
- Type 1: Non-neuronopathic
- Type 2: Infantile, acute neuronopathic
- Type 3: Chronic neuronopathic
- Tx: Enzyme replacement (ERT), substrate reduction
- What are the features and diagnosis of Tay-Sachs disease?
Tay-Sachs: AR, β-hexosaminidase A deficiency
- Features: Macrocephaly, cherry-red macula, hyperacusis, neurodegeneration
- No hepatosplenomegaly
- What are the key differences between Tay-Sachs and Sandhoff disease?
Tay-Sachs vs Sandhoff:
- Tay-Sachs: Hex A only, no hepatosplenomegaly
- Sandhoff: Hex A & B, with hepatosplenomegaly
- What are the principles of acute metabolic crisis management in neonates?
Crisis mgmt: Stop protein feeds, IV glucose/lipids, correct acidosis/hyperammonemia, monitor lactate, ammonia, electrolytes, involve metabolic specialist
- What are the key features of Menkes disease and its inheritance pattern?
Menkes: X-linked copper transport defect (ATP7A gene)
- Features: Seizures, hypotonia, kinky hair, FTT, early death
- Labs: Low serum copper and ceruloplasmin
- What are the clinical signs of Wilson disease in pediatric patients?
Wilson: Hepatitis, hepatosplenomegaly, neurologic signs (tremor, dysarthria), psychiatric symptoms, Kayser-Fleischer rings
- What lab findings support a diagnosis of Wilson disease?
Wilson labs: Low ceruloplasmin, elevated urinary copper, elevated hepatic copper on biopsy
- What are the treatment options for Wilson disease in children?
Treatment: Zinc, chelators (penicillamine or trientine), low copper diet, liver transplant for failure
- What is Glutaric aciduria type I and how does it present?
Glutaric aciduria I: AR, macrocephaly, dystonia, seizures after illness
- Dx: Elevated glutaric acid in urine
- Avoid lysine-rich foods
- What is the typical presentation of ornithine transcarbamylase (OTC) deficiency?
OTC deficiency: X-linked, most common UCD
- Symptoms: Lethargy, vomiting, coma, respiratory alkalosis, hyperammonemia
- Often males in first week
- How is hyperammonemia managed acutely in urea cycle disorders?
Hyperammonemia: Stop protein, give IV glucose/lipids, sodium benzoate/phenylbutyrate, arginine, dialysis if severe
- What are the differences between respiratory alkalosis and metabolic acidosis in metabolic disorders?
Resp alkalosis: Seen in UCD (hyperammonemia stimulates respiration)
- Met acidosis: Seen in organic acidemias, lactic acidosis
- What is the role of newborn screening in detecting metabolic disorders?
Newborn screening: Detects treatable IEMs early (e.g., PKU, MSUD, MCAD)
- Uses blood spot tests within 48–72 hours of birth
- What are the benefits and limitations of tandem mass spectrometry in metabolic screening?
Tandem MS: Detects amino acidopathies, FAODs, organic acidemias
- Pros: Broad coverage, rapid
- Cons: May miss late-onset forms, false positives/negatives
- What are key lab tests for initial metabolic workup in acutely ill neonates?
Initial workup: ABG, lactate, ammonia, glucose, electrolytes, anion gap, LFTs, urine ketones, reducing substances, plasma amino acids, acylcarnitine profile
- How does lactate:pyruvate ratio help in metabolic diagnosis?
Lactate:pyruvate >25 suggests mitochondrial disorder or pyruvate carboxylase defect
- Ratio <10: poor tissue perfusion, hypoxia
- What is the presentation of carnitine transporter defect and its treatment?
Carnitine transporter defect: Hypoketotic hypoglycemia, hypotonia, cardiomyopathy
- Labs: Low carnitine levels
- Treat: Oral carnitine, avoid fasting
- What are the clinical and biochemical features of pyruvate carboxylase deficiency?
Pyruvate carboxylase deficiency: Lactic acidosis, neurologic deterioration
- Labs: ↑lactate, ↑alanine, ↑glutamine, ↓oxaloacetate
- No good treatment, often fatal
- What is lactic acidosis and what metabolic conditions cause it?
Lactic acidosis: Lactate >5 mmol/L, pH <7.35
- Causes: Mitochondrial defects, PDH deficiency, hypoxia, shock, organic acidemias
- What is the role of acylcarnitine profile in diagnosing metabolic disorders?
Acylcarnitine profile: Detects FAODs, organic acidemias
- Specific chain-length elevations (e.g., C8 in MCAD, C3 in propionic acidemia)
- What are aminoacidopathies and how are they diagnosed?
Aminoacidopathies: Elevated plasma amino acids (e.g., PKU: ↑Phe, MSUD: ↑branched-chain AAs)
- Dx: Plasma amino acid chromatography
- What are organic acidemias and how are they diagnosed?
Organic acidemias: Elevated urinary organic acids (e.g., MMA, propionic, isovaleric)
- Dx: Urine organic acid GC-MS
- What is the utility of urine organic acids in metabolic diagnosis?
Urine organic acids: Detect ketoacidosis, lactic acid, dicarboxylic acids, glutaric acid
- Essential for organic acidemia diagnosis
- What metabolic disorders cause hypoglycemia without ketones (hypoketotic hypoglycemia)?
Hypoketotic hypoglycemia: FAODs (MCAD, CPT1), hyperinsulinism, carnitine deficiency
- No ketones despite low glucose
- What are disorders associated with hyperammonemia and normal anion gap?
Hyperammonemia + normal anion gap: Urea cycle defects (OTC, CPS1, ASS1), citrullinemia, argininosuccinic aciduria
- What are disorders causing hyperammonemia and high anion gap acidosis?
Hyperammonemia + high anion gap: Organic acidemias (propionic, methylmalonic), isovaleric acidemia, lactic acidosis disorders
- How does citrullinemia type I present and how is it diagnosed?
Citrullinemia I: Vomiting, lethargy, hyperammonemia in neonate
- Labs: ↑citrulline, absent argininosuccinate
- Gene: ASS1 mutation
- What are the features and management of argininosuccinic aciduria?
Argininosuccinic aciduria: Like other UCDs with trichorrhexis nodosa, hepatomegaly
- Labs: ↑ASA, ↑citrulline
- Treat: Protein restriction, ammonia scavengers
- What are the signs and biochemical profile of isovaleric acidemia?
Isovaleric acidemia: ‘Sweaty feet’ odor, vomiting, lethargy, seizures
- Labs: Metabolic acidosis, ketonuria, ↑isovalerylglycine in urine
- What are the triggers and management of propionic acidemia crises?
Triggers: Illness, fasting, high protein intake
- Management: Stop protein, IV glucose/lipids, carnitine, biotin, bicarbonate for acidosis
- What are the early signs of mitochondrial disorders in infants?
Mito disorders: Poor feeding, lactic acidosis, hypotonia, seizures, developmental delay, FTT, ophthalmoplegia
- What are characteristic MRI findings in Leigh syndrome?
Leigh syndrome MRI: Symmetric lesions in basal ganglia, brainstem, periaqueductal gray
- Lactate peaks on MRS
- What is MELAS syndrome and how is it diagnosed?
MELAS: Mitochondrial encephalopathy, lactic acidosis, stroke-like episodes
- Dx: mtDNA mutation (A3243G), ↑lactate, MRI changes
- What are the signs of glutaric aciduria type II and its associated biochemical profile?
GA-II (MADD): Severe neonatal acidosis, hypotonia, hypoglycemia, hyperammonemia
- Acylcarnitine: Multiple elevated species
- Urine: Dicarboxylic acids
- What is the role of carnitine in fatty acid metabolism and what causes secondary carnitine deficiency?
Carnitine transports long-chain fatty acids into mitochondria
- Secondary deficiency: Organic acidemias, FAODs, renal losses, malnutrition
- What are the features of carnitine palmitoyltransferase II (CPT II) deficiency?
CPT II: Myopathic form presents in adolescence/adults with muscle pain, rhabdomyolysis, myoglobinuria post-exercise
- Infantile form: Hypoketotic hypoglycemia, hepatomegaly
- How does LCHAD deficiency present and how is it diagnosed?
LCHAD: Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency
- Features: Hypoketotic hypoglycemia, liver dysfunction, cardiomyopathy, retinal issues
- Dx: Acylcarnitine profile (↑C16-OH, C18:1-OH)
- What is the significance of dicarboxylic aciduria in metabolic workup?
Dicarboxylic aciduria: Seen in FAODs, MCAD, carnitine defects
- Indicates shunting of fatty acids via ω-oxidation
- What are common peroxisomal markers used in diagnosis?
Peroxisomal markers: VLCFA, phytanic acid, plasmalogens, bile acid intermediates
- Elevated in Zellweger, X-ALD
- How is mitochondrial disease confirmed when routine labs are inconclusive?
Mito Dx: Muscle biopsy (ragged red fibers), respiratory chain enzyme assay, mitochondrial DNA sequencing
- What is the typical presentation of 3-methylcrotonyl-CoA carboxylase deficiency?
3-MCC deficiency: Metabolic acidosis, ketosis, vomiting, hypoglycemia
- Dx: ↑3-methylcrotonylglycine in urine, abnormal acylcarnitine (C5-OH)
- What are the signs and lab findings of multiple carboxylase deficiency?
Multiple carboxylase deficiency: Defect in biotin recycling (holocarboxylase or biotinidase)
- Features: Dermatitis, alopecia, seizures, acidosis
- Labs: ↑lactate, ↑3-OH-isovaleric acid
- What are disorders with elevated lactate and normal anion gap?
Elevated lactate + normal anion gap: Mitochondrial disease, PDH deficiency, thiamine deficiency
- What are clues to diagnose inborn errors of metabolism beyond the neonatal period?
Delayed IEM clues: FTT, developmental regression, epilepsy, stroke-like episodes, basal ganglia MRI changes, unexplained acidosis or hypoglycemia
