ABMGG Medical Biochemical Genetics cheat sheet

One gene–one enzyme (Beadle & Tatum): a single enzyme defect blocks one metabolic step, causing substrate accumulation and product deficiency.

Cofactor-dependent enzymes (biotin, thiamine, pyridoxine, cobalamin, molybdenum) can produce phenocopies of primary enzyme defects; response to cofactor loading is both diagnostic and therapeutic.

Enzyme activity is reported per unit protein or per cell; residual activity thresholds define severity (e.g., <1% classic, 1–5% variant for many lysosomal disorders).

Substrate accumulation injures tissue by osmotic/lysosomal storage, toxic metabolite formation, or competitive inhibition of transporters.

Mitochondrial disorders follow threshold effect: phenotype appears when mutant mtDNA heteroplasmy exceeds a tissue-specific threshold (often 60–80%).

Inborn errors cluster by compartment: cytosolic (glycolysis, purine), mitochondrial (OXPHOS, fatty acid oxidation, urea cycle), peroxisomal, lysosomal.

Enzyme replacement requires mannose-6-phosphate targeting to lysosomes; small molecule therapies (substrate reduction, chaperones) cross the blood–brain barrier better than enzymes.

Two-hit logic: biochemical phenotype can be modified by modifier genes, cofactor status, and diet, so genotype–biochemistry correlation is imperfect.

Classic organic acidemias (propionic, methylmalonic) present in the first days of life with anion-gap acidosis, ketosis, hyperammonemia, and pancytopenia.

Urea cycle disorders: hyperammonemia without significant acidosis; respiratory alkalosis early, then acidosis; orotic acid distinguishes OTC deficiency (elevated) from CPS1/NAGS (low).

Fatty acid oxidation defects (MCAD) cause hypoketotic hypoglycemia, hepatomegaly, and elevated acylcarnitines (C8, C8:1) after fasting or illness.

Maple syrup urine disease: branched-chain amino acids elevated (leucine, isoleucine, valine), ketoacidosis, encephalopathy; leucine drives cerebral edema.

Phenylketonuria: phenylalanine hydroxylase or BH4 defect; untreated causes intellectual disability, microcephaly, musty odor, hypopigmentation.

Galactosemia: GALT deficiency, jaundice, hepatomegaly, cataracts, E. coli sepsis; galactose-1-phosphate and galactitol accumulate.

Lysosomal storage (e.g., Pompe, Gaucher, MPS) presents as organomegaly, coarse features, regression, or cardiomyopathy depending on enzyme and storage site.

Peroxisomal disorders (Zellweger spectrum) show hypotonia, dysmorphism, elevated very-long-chain fatty acids, and peroxisome biogenesis or single-enzyme defects.

First-tier newborn screening is tandem mass spectrometry (MS/MS) for amino acids and acylcarnitines, plus immunoassay or enzymatic assays for endocrine and other analytes.

Acylcarnitine profiling identifies fatty acid oxidation and organic acidemias; amino acid profiling identifies PKU, MSUD, homocystinuria, tyrosinemia.

Urine organic acids by GC-MS detect methylmalonic, propionic, isovaleric, and glutaric acidurias; urine is preferred over plasma for volatile organic acids.

Plasma amino acid quantitation requires fasting or standardized timing; ammonia samples must be placed on ice and run promptly to avoid false elevation.

Second-tier testing (molecular panels, enzyme assays, repeat dried blood spot) reduces false positives; positive predictive value rises substantially after confirmation.

Acylcarnitine and amino acid results are affected by sample age, hemolysis, and prematurity; borderline results require repeat testing.

Enzyme assays (e.g., GALT, biotinidase, lysosomal enzymes) confirm diagnosis when molecular results are inconclusive; leukocyte or fibroblast sources are preferred over dried blood.

Newborn screening sensitivity/specificity depend on analyte cutoffs; disorders with late-onset forms (e.g., MCAD, PKU) may have missed cases or false positives.

Acute hyperammonemia: stop protein intake, provide calories (glucose ± lipid), give nitrogen scavengers (sodium benzoate, sodium phenylbutyrate), and consider hemodialysis for severe or refractory cases.

Acute decompensation of organic acidemia: treat catabolism with IV glucose, correct acidosis, give carnitine, and avoid fasting; monitor ammonia and electrolytes.

PKU management targets plasma phenylalanine (typically 120–360 µmol/L in children; higher in adults), using low-phenylalanine diet and sapropterin for BH4-responsive patients.

Fatty acid oxidation defects: avoid fasting, use medium-chain triglycerides in long-chain defects, and provide emergency sick-day plans with glucose.

Lysosomal storage diseases: enzyme replacement for non-neurologic disease (Gaucher, Fabry, Pompe, MPS), substrate reduction, chaperones, or hematopoietic stem cell transplant for selected disorders.

Urea cycle disorders: long-term low-protein diet with essential amino acid supplementation, arginine or citrulline, and nitrogen scavengers; liver transplant is curative for enzyme defects.

Maternal PKU: elevated maternal phenylalanine is teratogenic (microcephaly, cardiac defects); strict control before conception is required.

Sick-day protocols must be written, shared with schools and emergency departments, and include emergency doses and contact numbers.

Autosomal recessive inheritance requires biallelic pathogenic variants; carrier frequency and consanguinity affect recurrence risk (25% for carrier couples).

X-linked disorders (e.g., OTC deficiency, Fabry, MPS II) show male predominance; females can be affected due to skewed X-inactivation.

Mitochondrial DNA is maternally inherited; heteroplasmy and threshold effects explain variable severity and tissue specificity.

De novo variants explain simplex cases of dominant disorders (e.g., many skeletal dysplasias); recurrence risk is low but gonadal mosaicism must be considered.

Variant classification follows ACMG/AMP criteria (pathogenic, likely pathogenic, VUS, likely benign, benign); functional and biochemical evidence supports classification.

Genotype–phenotype correlation is strongest when the variant abolishes enzyme function; missense variants often produce milder or variable phenotypes.

Copy number variants and deep intronic variants can be missed by exome sequencing; genome sequencing or deletion/duplication analysis may be needed.

Pharmacogenomic and metabolic modifier variants (e.g., BH4 pathway, cobalamin metabolism) can alter treatment response.

Informed consent for genetic testing must cover purpose, limitations (VUS, incidental findings), privacy, and implications for relatives.

Newborn screening is a public health program with opt-out provisions varying by jurisdiction; confirmatory testing and follow-up are mandatory after positive screens.

Carrier testing and cascade screening require pretest counseling about reproductive risk (25% for autosomal recessive carrier couples).

Predictive testing for adult-onset conditions generally requires informed consent and maturity assessment; minors are usually tested only when benefit exists in childhood.

Genetic information privacy laws (e.g., GINA in the US) restrict health insurer and employer use but do not cover life, disability, or long-term care insurance.

Cultural competency and health literacy affect adherence to dietary therapy; interpreters and written materials should match patient language and literacy.

Ethical conflicts include duty to warn at-risk relatives versus confidentiality; disclosure generally requires patient consent unless harm is imminent and preventable.

Professionalism includes transparent communication of uncertainty, avoiding therapeutic misconception, and documenting shared decision-making.