ABMGG Clinical Biochemical Genetics flashcards

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Hyperammonemia with respiratory alkalosis

A metabolic pattern suggesting a urea cycle disorder; obtain plasma amino acids, urine orotic acid, and acylcarnitine profile urgently to identify the specific defect.

Hypoketotic hypoglycemia

Low ketones and low free fatty acids during hypoglycemia suggest a fatty acid oxidation defect; evaluate with acylcarnitine profile and urine organic acids.

Elevated C8 acylcarnitine

A newborn screening finding suggestive of medium-chain acyl-CoA dehydrogenase deficiency; confirm with molecular testing and urine organic acids.

Second-tier newborn screening

Additional testing on the original dried blood spot to reduce false positives; examples include LC-MS/MS for steroids or molecular testing for specific variants.

Urine organic acid analysis

GC-MS method to detect organic acids; used to diagnose organic acidemias, fatty acid oxidation defects, and some urea cycle disorders; proper storage prevents bacterial overgrowth.

Phenylketonuria pathophysiology

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 branched-chain amino acids; leucine is neurotoxic and can cause cerebral edema.

OTC deficiency

X-linked urea cycle disorder causing hyperammonemia with elevated urine orotic acid; carrier females may be symptomatic due to skewed X-inactivation.

Galactosemia

GALT deficiency causes accumulation of galactose-1-phosphate and galactitol; untreated leads to liver failure, cataracts, and cognitive impairment.

Mitochondrial threshold effect

Variable phenotype in mitochondrial disorders due to heteroplasmy; symptoms appear when the proportion of mutant mtDNA exceeds a tissue-specific threshold.

Acute hyperammonemia treatment

Stop protein intake, provide calories, give intravenous ammonia scavengers and arginine, and consider hemodialysis if ammonia >500 µmol/L or neurologic deterioration.

Sapropterin

BH4 analog used in phenylketonuria; responsive patients may relax dietary phenylalanine restriction; response is determined by a loading test.

Enzyme replacement therapy

Treatment for lysosomal storage disorders such as Gaucher, Fabry, and Pompe diseases; administered intravenously and does not cross the blood-brain barrier.

Biotin supplementation

Treatment for biotinidase deficiency; oral biotin 5–20 mg/day prevents neurologic sequelae if started early.

Autosomal recessive recurrence risk

For carrier parents, each pregnancy has a 25% risk of an affected child; offer carrier testing to at-risk relatives and discuss reproductive options.

Informed consent for genetic testing

Must cover purpose, limitations including variants of uncertain significance, incidental findings, and implications for family members.

Critical result reporting

Hyperammonemia, abnormal newborn screening, and positive prenatal results require immediate notification with documented read-back.

Laboratory stewardship

Ordering the most specific test first (e.g., acylcarnitine profile before urine organic acids) reduces cost and false positives.

Proficiency testing

External quality assessment (e.g., CAP, ERNDIM) that laboratories must participate in to maintain accreditation and ensure accurate results.

Plasma amino acid analysis

Ion-exchange chromatography or LC-MS/MS method; requires standardized timing; hemolysis falsely elevates aspartate and glutamate.

Acylcarnitine profile

Tandem mass spectrometry test used in newborn screening and diagnosis; elevated species indicate fatty acid oxidation defects or organic acidemias.

Urea cycle disorder distal defects

AS, AL, and arginase deficiencies cause hyperammonemia with elevated citrulline or argininosuccinate; proximal defects have low citrulline.

Lysosomal storage disorders

Enzyme deficiencies cause substrate accumulation in lysosomes; examples include Gaucher, Fabry, and Pompe diseases.

Medium-chain acyl-CoA dehydrogenase deficiency

Impaired fatty acid oxidation leads to hypoketotic hypoglycemia and lethargy during fasting; risk of death if untreated.

Phenylketonuria treatment

Dietary phenylalanine restriction with synthetic protein substitute; sapropterin for responsive patients; pegvaliase for adults with uncontrolled phenylalanine.

Maple syrup urine disease emergency treatment

Rapid removal of leucine via dialysis or hemofiltration, thiamine trial, and restricted branched-chain amino acid diet.

Fatty acid oxidation defect management

Avoid fasting, provide frequent carbohydrate-rich meals during illness, and give carnitine supplementation for some defects.

Galactosemia diet

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

X-linked carrier females

In X-linked disorders such as OTC deficiency, carrier females may be symptomatic due to skewed X-inactivation; cascade screening is essential.

Variants of uncertain significance

Genetic test results that are not clearly pathogenic or benign; communication should be clear and include follow-up plans.

Newborn screening false positives

Can occur with prematurity, parenteral nutrition, and sample timing <24 hours; second-tier testing reduces false positives.

Prenatal diagnosis

Chorionic villus sampling or amniocentesis with enzyme assay or molecular testing; biochemical assay requires cultured cells and known reference ranges.