1.17 Inborn Errors of Metabolism & Storage Disorders
Key Takeaways
Most classic IEMs are autosomal recessive; OTC deficiency is the major X-linked urea-cycle exception genetic counselors must recognize on pedigree and newborn presentation
Phenylketonuria (PAH) requires lifelong Phe control; maternal PKU teratogenicity makes preconception diet optimization a core counseling goal
Classic galactosemia (GALT) presents with feeding intolerance, E. coli sepsis risk, cataracts, and later ovarian failure—immediate lactose/galactose restriction is lifesaving
Lysosomal storage disorders (Gaucher, Tay-Sachs, Pompe) differ by enzyme, substrate, ethnicity carrier rates, and whether enzyme replacement or supportive care is available
Fatty-acid oxidation defects such as MCADD cause hypoketotic hypoglycemia with fasting stress and are major newborn-screening targets with avoidance-of-fasting counseling
1.17 Inborn Errors of Metabolism & Storage Disorders
Quick Answer: Treat IEMs as pathway failures: substrate buildup ± product deficiency. Most are AR; flag OTC as X-linked. PKU = Phe diet + maternal PKU counseling; galactosemia = stop lactose immediately; urea-cycle = hyperammonemia emergency; LSDs = enzyme/substrate logic (Gaucher/Pompe often ERT-eligible; Tay-Sachs not); MCADD = no prolonged fasting.
Domain 1C metabolic items rarely ask you to recite every enzyme Km. They ask whether the presentation, inheritance, NBS status, and management lever fit. Genetic counselors translate biochemical disease into family risk, reproductive options, and coordinated care with metabolic genetics.
How to Organize Any IEM on the Exam
| Axis | What to extract from a vignette |
|---|---|
| Pathway class | AA (e.g., PKU), CHO (galactosemia), urea cycle, FA oxidation, lysosomal storage |
| Inheritance | Usually AR; OTC is the high-yield X-linked urea-cycle disorder |
| Tempo | Neonatal crisis vs infantile neurodegeneration vs adult visceral disease |
| Lab signature | Hyperammonemia, hypoketotic hypoglycemia, elevated Phe, enzyme assay, gene panel |
| Lever | Diet, dialysis/scavengers, ERT/SRT, gene therapy (disease-specific), supportive care |
Exam trap: “Metabolic = always AR” fails when the stem is a boy with hyperammonemia and a mildly symptomatic mother—think OTC.
Phenylketonuria (PKU)
PKU is caused by biallelic pathogenic variants in PAH (phenylalanine hydroxylase), blocking conversion of Phe → tyrosine. Untreated classic PKU produces irreversible intellectual disability, seizures, microcephaly, and eczema/musty odor phenotypes historically described before NBS. In screened populations, the counseling focus shifts to diet adherence, tyrosine sufficiency, and maternal PKU.
| Feature | Counseling anchor |
|---|---|
| Gene / inheritance | PAH · autosomal recessive |
| Core biochemistry | Elevated phenylalanine; BH4-responsive subset exists (cofactor pathway) |
| Treatment | Phe-restricted diet ± medical foods; sapropterin in responsive patients; pegvaliase in selected adults |
| Maternal PKU | High maternal Phe is teratogenic → cardiac defects, microcephaly, growth restriction, ID in offspring—optimize diet before conception |
| Recurrence | 25% for each pregnancy of carrier couple; offer carrier testing to partner of affected/known carrier |
Maternal PKU is a classic cross-domain item: it is not “the fetus has PKU”—it is teratogenicity from maternal hyperphenylalaninemia, so even a fetus without biallelic PAH disease alleles is at risk if mother is poorly controlled.
Galactosemia
Classic galactosemia is usually GALT deficiency (galactose-1-phosphate uridylyltransferase), AR. After milk feeds begin, infants may show vomiting, failure to thrive, hepatotoxicity, coagulopathy, cataracts, and life-threatening E. coli sepsis. Immediate elimination of lactose/galactose (soy or elemental formulas as directed by metabolic team) is the acute intervention.
| Feature | Counseling anchor |
|---|---|
| Gene | GALT (classic); also consider GALK1, GALE for related disorders |
| NBS | Often detected by enzyme/metabolite screens—confirm with definitive testing; Duarte variant counseling differs from classic |
| Long-term | Even with diet, speech/language issues, tremor, and premature ovarian insufficiency in females are important anticipatory guidance topics |
| Inheritance counseling | AR; cascade carrier testing; dietary education for infant feeding |
Do not confuse Duarte galactosemia (partial activity, often milder management) with classic disease when the stem specifies life-threatening neonatal sepsis and cataracts.
Urea-Cycle Disorders
Urea-cycle defects impair ammonia detoxification → hyperammonemia, often with respiratory alkalosis early, encephalopathy, and risk of death or neurologic injury. Most enzyme defects are AR (CPS1, ASS1, ASL, ARG1), but ornithine transcarbamylase (OTC) deficiency is X-linked and the most common urea-cycle disorder.
| Disorder | Inheritance | High-yield clinical note |
|---|---|---|
| OTC deficiency | X-linked | Males often severe neonatal; heterozygous females variable (skewed X-inactivation); postpartum and catabolic triggers |
| CPS1, citrullinemia (ASS1), ASL, arginase | AR | Hyperammonemia ± citrulline/argininosuccinate signatures guiding biochemical differential |
| Acute management theme | — | Stop protein, give calories, ammonia scavengers, dialysis if needed—then definitive enzymatic/molecular diagnosis |
Counseling pearl: a pedigree with affected males, mild or episodic symptoms in females, and maternal-line transmission supports OTC until proven otherwise—and carrier females need crisis-prevention education (illness, surgery, postpartum).
Lysosomal Storage Disorders: Gaucher, Tay-Sachs, Pompe
Lysosomal storage disorders (LSDs) share impaired degradation of macromolecules inside lysosomes. For CGC purposes, master enzyme, substrate logic, ethnicity carrier enrichment when relevant, CNS involvement, and whether enzyme replacement therapy (ERT) exists.
| Disorder | Gene / enzyme | Inheritance | Hallmarks | Therapy theme |
|---|---|---|---|---|
| Gaucher disease | GBA / glucocerebrosidase | AR | Hepatosplenomegaly, cytopenias, bone crises; type 1 non-neuronopathic vs neuronopathic types 2/3; ↑ Ashkenazi carrier frequency | ERT / substrate reduction for visceral disease; neuronopathic forms limited CNS benefit |
| Tay-Sachs | HEXA / hexosaminidase A | AR | Infantile: regression, cherry-red macula, hyperacusis, macrocephaly; Ashkenazi & other founder populations historically high carrier rates | Supportive; no standard ERT for CNS disease—carrier screening historically paradigm-shifting |
| Pompe disease | GAA / acid α-glucosidase (acid maltase) | AR | Infantile: hypotonia, hypertrophic cardiomyopathy, respiratory failure; late-onset: progressive myopathy ± respiratory involvement | ERT available; early diagnosis changes survival in infantile form |
Ashkenazi Jewish carrier screening historically prioritized Tay-Sachs (and later expanded panels including Gaucher and others). Exam items may still use ethnicity as a pretest-probability hint, but modern practice emphasizes offering appropriate carrier screening based on guidelines and patient ancestry without assuming a single ethnicity box.
Gaucher counseling traps: heterozygous GBA variants also confer increased Parkinson disease risk—mention when relevant without equating carrier status to Gaucher disease. Distinguish type 1 (visceral, ERT-responsive theme) from neuronopathic types when the stem includes horizontal gaze palsy or rapid neurodegeneration.
Pompe counseling traps: infantile Pompe looks like a floppy infant with cardiomegaly—pair muscle + heart. Late-onset Pompe can mimic limb-girdle dystrophy; CK may be elevated; dried-blood-spot enzyme assay and GAA sequencing enter the diagnostic path.
Fatty-Acid Oxidation Defects (Focus: MCADD)
Medium-chain acyl-CoA dehydrogenase deficiency (MCADD) (ACADM, AR) is the highest-yield FAO disorder. Impaired β-oxidation → hypoketotic hypoglycemia during fasting or intercurrent illness, with risk of sudden death if unrecognized. Newborn screening has dramatically reduced mortality when paired with avoidance of prolonged fasting, prompt glucose support during illness, and emergency letters.
| Feature | Counseling anchor |
|---|---|
| Trigger | Prolonged fasting, vomiting illness, perioperative NPO without IV glucose |
| Labs | Hypoketotic hypoglycemia; characteristic acylcarnitine profile (e.g., elevated C8) |
| Management message | “Never long fasts”; sick-day plan; medic alert / emergency protocol |
| Family | AR recurrence 25%; siblings may need urgent evaluation even if well-appearing if NBS pending/missed |
Other FAO defects (VLCAD, LCHAD, carnitine cycle) share the fasting-intolerance theme; LCHAD additionally links to maternal HELLP/AFLP risk in heterozygous mothers carrying an affected fetus—a reproductive counseling cross-link.
Diagnostic Strategy Snapshot for Metabolic Stems
- Stabilize (glucose, ammonia, diet stop/start) before exhaustive testing when the child is crashing.
- Draw critical samples (ammonia, blood gas, glucose, lactate, acylcarnitines, plasma AAs, urine organic acids) as directed by metabolic team.
- Pair biochemistry with gene panel / exome when the pathway is broad.
- Offer cascade testing and reproductive counseling once the familial variant is known.
- Tie NBS positive results to confirmatory testing—do not counsel a definitive diagnosis from an unconfirmed screen alone.
This metabolic toolkit returns in Domain 3 (NBS vs diagnostic testing) and Domain 4 (delivering life-limiting neurodegenerative diagnoses such as infantile Tay-Sachs).
A full-term male neonate develops lethargy and hyperammonemia on day 3 of life. His mother recalls protein aversion and episodic confusion after illnesses. Which inheritance pattern and gene pairing best fits this presentation?
Autosomal recessive PAH deficiency (classic PKU)
X-linked OTC deficiency
Autosomal recessive HEXA deficiency (Tay-Sachs)
Autosomal dominant FBN1-related aortopathy
Which counseling point is most specific to maternal PKU rather than to fetal biallelic PAH disease?
The fetus is at risk for teratogenic effects from elevated maternal phenylalanine even if the fetus is only an obligate heterozygote
The couple’s recurrence risk for an affected child is always 50% because PAH is X-linked
Dietary therapy is irrelevant once pregnancy is recognized because organogenesis is already complete
Newborn screening eliminates any need for preconception metabolic control in women with PKU
An Ashkenazi Jewish couple requests counseling after their infant shows developmental regression and a cherry-red macula. Enzyme assay shows hexosaminidase A deficiency. Which statement best guides management expectations?
Standard ERT typically reverses central nervous system disease in infantile Tay-Sachs
This is glucocerebrosidase deficiency and should be managed primarily with bone crisis protocols only
The diagnosis is Tay-Sachs disease; care is supportive, and cascade carrier testing/reproductive options should be offered to the family
The inheritance is X-linked, so only male relatives need carrier testing
A toddler with a positive newborn screen for MCADD presents during gastroenteritis with lethargy. Which physiologic pattern and counseling action pair is most appropriate?
Hyperketotic hyperglycemia; encourage prolonged overnight fasting to induce ketosis
Isolated hyperammonemia without glucose abnormality; start a galactose-free diet only
Hypertrophic cardiomyopathy as the first finding; defer metabolic evaluation
Hypoketotic hypoglycemia risk with fasting stress; provide emergency glucose support and reinforce avoidance of prolonged fasting
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