ABMGG Clinical Biochemical Genetics cheat sheet

Hyperammonemia with respiratory alkalosis and normal anion gap suggests a urea cycle disorder; obtain plasma amino acids, urine orotic acid, and plasma acylcarnitine profile urgently.

Hypoglycemia with suppressed ketones (non-ketotic) and low free fatty acids points to a fatty acid oxidation defect; check acylcarnitine profile and urine organic acids.

Metabolic acidosis with an elevated anion gap and ketosis in a neonate suggests an organic acidemia; urine organic acids and plasma acylcarnitines are first-line tests.

Elevated lactate with normal pyruvate and no hypoperfusion may indicate a mitochondrial disorder; CSF-to-plasma lactate ratio >2 supports CNS involvement.

Urine organic acids showing elevation of 3-hydroxybutyrate and acetoacetate without dicarboxylic acids suggests ketolysis defect; confirm with enzyme or molecular testing.

Plasma amino acid pattern of low citrulline and elevated glutamine/alanine in a neonate with hyperammonemia suggests proximal urea cycle defect (CPS1 or OTC); urine orotic acid distinguishes OTC (high) from CPS1 (low).

Newborn screening tandem mass spectrometry acylcarnitine profiles: elevated C8 and C8/C10 ratio suggests medium-chain acyl-CoA dehydrogenase deficiency; confirm with molecular testing and urine organic acids.

Sweat chloride >60 mmol/L on two occasions supports cystic fibrosis; not a classic metabolic disorder but included in differential of failure to thrive with metabolic alkalosis.

Tandem mass spectrometry in newborn screening quantifies amino acids and acylcarnitines from dried blood spots; false positives occur with prematurity, parenteral nutrition, and sample timing <24 hours.

Urine organic acid analysis by GC-MS identifies volatile and nonvolatile organic acids; sample storage at -20°C prevents bacterial overgrowth that alters results.

Plasma amino acid analysis by ion-exchange chromatography or LC-MS/MS requires fasting or standardized postprandial timing; hemolysis falsely elevates aspartate and glutamate.

Enzyme activity assays in leukocytes or fibroblasts confirm diagnoses (e.g., biotinidase, galactocerebrosidase); pre-analytical variables include transit time and anticoagulant.

Molecular testing strategy: targeted variant analysis for founder variants (e.g., HFE C282Y, PAH R408W), then gene panel or exome; deletion/duplication analysis by MLPA or chromosomal microarray.

Newborn screening second-tier testing (e.g., molecular or biochemical) reduces false positives; example: second-tier 17-hydroxyprogesterone by LC-MS/MS for congenital adrenal hyperplasia.

Quality indicators: false-positive rate, positive predictive value, and time-to-diagnosis; each NBS condition should have a defined confirmatory algorithm.

Prenatal diagnosis via chorionic villus sampling or amniocentesis uses enzyme assay or molecular testing; biochemical assay requires cultured cells and known reference ranges.

Phenylketonuria: PAH deficiency causes phenylalanine accumulation and tyrosine deficiency; untreated leads to intellectual disability, microcephaly, and musty odor.

Maple syrup urine disease: BCKD complex deficiency causes accumulation of leucine, isoleucine, valine, and alpha-ketoisocaproate; leucine is neurotoxic and causes cerebral edema.

Urea cycle disorders: proximal defects (CPS1, OTC) cause hyperammonemia with low citrulline; distal defects (AS, AL, arginase) cause hyperammonemia with elevated citrulline or argininosuccinate.

Medium-chain acyl-CoA dehydrogenase deficiency: impaired fatty acid oxidation leads to hypoketotic hypoglycemia, lethargy, and seizures during fasting or illness; risk of death if untreated.

Mitochondrial disorders: impaired oxidative phosphorylation causes lactic acidosis, myopathy, encephalopathy, and multi-organ involvement; heteroplasmy and threshold effect explain variable phenotype.

Lysosomal storage disorders: enzyme deficiency causes substrate accumulation in lysosomes; examples include Gaucher disease (glucocerebrosidase), Fabry disease (alpha-galactosidase A), and Pompe disease (acid alpha-glucosidase).

Galactosemia: GALT deficiency causes accumulation of galactose-1-phosphate and galactitol; untreated leads to liver failure, cataracts, and cognitive impairment; dietary galactose restriction is lifesaving.

Biotinidase deficiency: inability to recycle biotin causes carboxylase deficiencies; presents with seizures, hypotonia, skin rash, and alopecia; treatable with biotin supplementation.

Acute hyperammonemia management: stop protein intake, provide calories as glucose and lipids, give intravenous ammonia scavengers (sodium phenylacetate/benzoate, arginine), and consider hemodialysis if ammonia >500 µmol/L or neurologic deterioration.

Phenylketonuria: dietary phenylalanine restriction with synthetic protein substitute; sapropterin (BH4) responsive patients may relax diet; pegvaliase for adults with uncontrolled Phe.

Maple syrup urine disease: emergency treatment includes rapid removal of leucine via dialysis or hemofiltration, thiamine trial, and restricted branched-chain amino acid diet.

Fatty acid oxidation defects: avoid fasting, provide frequent carbohydrate-rich meals during illness, and give carnitine supplementation for some defects (e.g., primary carnitine deficiency).

Lysosomal storage disorders: enzyme replacement therapy (ERT) for Gaucher, Fabry, Pompe, and MPS I/II/VI; substrate reduction therapy (miglustat) and chaperone therapy (migalastat) for selected patients.

Galactosemia: lifelong galactose-restricted diet; monitor for speech delay, ovarian failure, and bone density; avoid galactose-containing medications and foods.

Biotinidase deficiency: oral biotin 5–20 mg/day; early treatment prevents neurologic sequelae; newborn screening allows presymptomatic treatment.

Urea cycle disorders: long-term management includes protein restriction, citrulline or arginine supplementation, ammonia scavengers, and liver transplantation for severe cases.

Informed consent for genetic testing must cover purpose, limitations (e.g., variants of uncertain significance), incidental findings, and implications for family members.

Autosomal recessive inheritance: both parents are carriers (25% recurrence risk); offer carrier testing to at-risk relatives and discuss reproductive options including prenatal diagnosis and preimplantation genetic testing.

X-linked inheritance (e.g., OTC deficiency): carrier females may be symptomatic due to skewed X-inactivation; cascade screening and counseling about lyonization are essential.

Communicating uncertain results: use clear language, avoid jargon, and provide written summaries; document discussions and follow-up plans in the medical record.

Laboratory stewardship: order the most specific test first (e.g., acylcarnitine profile before urine organic acids for suspected fatty acid oxidation defect) to reduce cost and false positives.

Quality control: participate in proficiency testing (e.g., CAP, ERNDIM), maintain standard operating procedures, and monitor turnaround times for critical results.

Critical result reporting: hyperammonemia, abnormal newborn screening, and positive prenatal results require immediate notification with documented read-back.

Cultural competence: use interpreters, respect health literacy levels, and tailor communication to family preferences; avoid assumptions about consanguinity or ethnicity.