Metabolic & Storage Diseases
Metabolic & Storage Diseases
What Do You Need to Know?
- Sphingolipidoses: enzyme defects, inheritance, and distinguishing features (Tay-Sachs, Gaucher, Fabry, Niemann-Pick)
- Cherry-red spot diseases: Tay-Sachs, Sandhoff, Niemann-Pick A, GM1 gangliosidosis, sialidosis
- Gaucher disease = most common lysosomal storage disease; GBA mutations are a risk factor for Parkinson disease
- Fabry disease = only X-linked sphingolipidosis; painful acroparesthesias, renal failure, stroke
- Wilson disease: ATP7B, copper accumulation, Kayser-Fleischer rings, low ceruloplasmin, “face of the giant panda” on MRI
- Mucopolysaccharidoses: all AR except Hunter (X-linked); all have corneal clouding except Hunter
- Amino acid disorders: PKU (newborn screening), maple syrup urine disease, homocystinuria (downward lens subluxation)
- Key MRI signs: “eye of the tiger” (PKAN), “face of the giant panda” (Wilson)
🚩 Don’t Miss — Test-Day Priorities
- Cherry-red macula + exaggerated startle + Ashkenazi infant, NO hepatosplenomegaly: Tay-Sachs (HEXA, β-hexosaminidase A deficiency, GM2 ganglioside accumulation, AR); Sandhoff (HEXB) is identical PLUS hepatosplenomegaly and skeletal involvement.
- Vertical supranuclear gaze palsy (especially downgaze) + ataxia + gelastic cataplexy + hepatosplenomegaly in a child/young adult: Niemann-Pick type C (NPC1/NPC2, intracellular cholesterol trafficking defect); MIGLUSTAT slows progression. Distinct from Niemann-Pick A/B (acid sphingomyelinase, SMPD1, “foamy macrophages”).
- Hepatosplenomegaly + bone crises + cytopenias + “crumpled tissue-paper” macrophages: Gaucher type I (GBA, glucocerebrosidase) — most common LSD, treat with ERT; GBA heterozygotes have increased Parkinson disease risk; type III adds oculomotor apraxia.
- X-linked young man with angiokeratomas (umbilicus/groin) + cornea verticillata + acroparesthesias + early stroke + renal/cardiac disease: Fabry (α-galactosidase A, Gb3 accumulation); treat with agalsidase alfa/beta ERT or oral chaperone migalastat.
- Coarse facies + corneal clouding + dysostosis multiplex + intellectual disability: Hurler (MPS I, IDUA, AR) — early HSCT is the CNS disease-modifying treatment when eligible (laronidase ERT does NOT adequately cross the BBB and is not sufficient for CNS disease alone; it helps somatic disease and is used adjunctively/peri-transplant). Hunter (MPS II, IDS, X-linked) is similar but NO corneal clouding; Sanfilippo (MPS III) is CNS-predominant with severe behavioral/sleep disturbance and minimal somatic findings.
- Infantile irritability + opisthotonos + spasticity + globoid multinucleated macrophages: Krabbe (GALC, galactocerebrosidase, AR); HSCT only works PRESYMPTOMATICALLY. “Tigroid” white matter + central + peripheral demyelination + metachromatic granules (toluidine blue) = MLD (ARSA, sulfatide); atidarsagene autotemcel (Lenmeldy in the US, Libmeldy in Europe) ex-vivo gene therapy — FDA indication: pre-symptomatic late infantile MLD, pre-symptomatic early juvenile MLD, or early symptomatic early juvenile MLD.
- Boys with adrenal insufficiency ± parieto-occipital demyelination on MRI (high Loes score): X-ALD/AMN (ABCD1, Xq28, VLCFA accumulation) — SCREEN VLCFA in ALL males with adrenal insufficiency; HSCT for early childhood cerebral form; elivaldogene autotemcel gene therapy approved. Adult AMN = spastic paraparesis.
- Neonatal hyperammonemia + encephalopathy/coma, normal anion gap, low BUN: urea cycle defect (most commonly OTC, X-linked — suspect in postpartum women with altered mental status). Treat with PROTEIN RESTRICTION + sodium benzoate / phenylacetate / glycerol phenylbutyrate scavengers; AVOID VALPROATE.
- Ectopia lentis (downward) + marfanoid habitus + thromboembolism + intellectual disability: homocystinuria (CBS, cystathionine β-synthase); treat with B6 / folate / methionine restriction; many are B6-responsive. Contrast with Marfan (upward lens dislocation, no thrombosis).
- Abdominal pain + autonomic/peripheral neuropathy + psychiatric symptoms + port-wine urine: acute intermittent porphyria (HMBS/PBGD); AVOID barbiturates, valproate, sulfa, estrogens; treat with IV HEME + high-dose glucose / carbohydrate loading.
- Severe neonatal hypotonia + dysmorphic features + hepatomegaly with cysts + neuronal migration defects: Zellweger spectrum (PEX genes, peroxisomal biogenesis disorder); elevated VLCFA, phytanic acid, pipecolic acid. Refsum disease = phytanic acid α-oxidation defect → retinitis pigmentosa + neuropathy + ataxia + ichthyosis; treat with LOW PHYTANIC ACID diet.
- Kinky/sparse hair + cerebellar degeneration + seizures + skeletal abnormalities in a male infant: Menkes (ATP7A, X-linked copper deficiency); treat with copper-histidine. Contrast with Wilson disease (ATP7B, copper OVERLOAD — see dedicated topic).
🔍 Buzzwords & Pathognomonic FindingsClinical / classic findings · Enzyme / gene defect · Treatment / diagnostic
Clinical / classic findings
- Cherry-red macula + exaggerated startle, NO hepatosplenomegaly → Tay-Sachs (GM2)
- Cherry-red macula + hepatosplenomegaly + skeletal involvement → Sandhoff
- Vertical supranuclear gaze palsy (downgaze) + gelastic cataplexy + hepatosplenomegaly → Niemann-Pick type C
- Foamy macrophages + cherry-red spot + hepatosplenomegaly + fatal by age 3 → Niemann-Pick type A
- Crumpled tissue-paper / wrinkled-paper macrophages + bone crises + pancytopenia → Gaucher disease (Gaucher cells)
- Angiokeratomas in bathing-trunk distribution + cornea verticillata + acroparesthesias + early stroke → Fabry disease
- Coarse facies + corneal clouding + dysostosis multiplex → Hurler (MPS I)
- Coarse facies, dysostosis, NO corneal clouding, boys only → Hunter (MPS II)
- CNS-predominant regression + severe behavior/sleep disturbance + mild somatic findings → Sanfilippo (MPS III)
- Globoid multinucleated macrophages + opisthotonos + optic atrophy + peripheral neuropathy → Krabbe disease
- Tigroid white matter + metachromatic granules (toluidine blue) + central + peripheral demyelination → Metachromatic leukodystrophy (MLD)
- Boy with adrenal insufficiency + parieto-occipital demyelination + high Loes score → Childhood cerebral X-ALD
- Retinitis pigmentosa + neuropathy + ataxia + ichthyosis + cardiac conduction defects → Refsum disease (phytanic acid)
- Maple syrup–smelling urine + neonatal cerebral edema + coma → MSUD (branched-chain ketoacid dehydrogenase)
- Musty/mousy body odor + ID + seizures + eczema + fair pigmentation → PKU
- Downward ectopia lentis + marfanoid habitus + thromboembolism → Homocystinuria
- Port-wine / dark urine + abdominal pain + autonomic neuropathy + psychiatric symptoms → Acute intermittent porphyria (AIP)
- Kinky/sparse hair + hypothermia + seizures + cerebellar degeneration in male infant → Menkes disease
Enzyme / gene defect
- HEXA, β-hexosaminidase A deficiency, GM2 accumulation → Tay-Sachs
- HEXB, β-hexosaminidase A + B deficiency → Sandhoff
- SMPD1, acid sphingomyelinase deficiency → Niemann-Pick A/B
- NPC1 / NPC2, intracellular cholesterol trafficking defect → Niemann-Pick C
- GBA, β-glucocerebrosidase deficiency; heterozygotes have ↑ Parkinson risk → Gaucher disease
- α-galactosidase A (GLA), X-linked, Gb3 accumulation → Fabry disease
- IDUA α-L-iduronidase, AR, heparan + dermatan sulfate → Hurler (MPS I)
- IDS iduronate-2-sulfatase, X-linked → Hunter (MPS II)
- Heparan-N-sulfatase (and other subtypes), heparan sulfate → Sanfilippo (MPS III)
- GALNS or GLB1, keratan sulfate, odontoid hypoplasia → Morquio (MPS IV)
- GALC galactocerebrosidase, AR → Krabbe disease (globoid cell leukodystrophy)
- ARSA arylsulfatase A, sulfatide accumulation, AR → Metachromatic leukodystrophy
- PEX gene mutations, peroxisomal biogenesis defect → Zellweger spectrum
- ABCD1 (Xq28), VLCFA accumulation → X-ALD / AMN
- OTC deficiency (X-linked); manifesting carrier females → Most common urea cycle disorder
- CBS cystathionine β-synthase deficiency → Homocystinuria
- ATP7B, copper transporter, hepatic + neuro + Kayser-Fleischer → Wilson disease
- ATP7A, X-linked copper transporter, copper DEFICIENCY → Menkes disease
- HMBS / porphobilinogen deaminase deficiency → Acute intermittent porphyria
- Phenylalanine hydroxylase (PAH) deficiency → PKU
- Branched-chain α-ketoacid dehydrogenase deficiency → MSUD
- Phytanic acid α-oxidation defect (PHYH/PEX7) → Refsum disease
Treatment / diagnostic
- Miglustat (substrate reduction therapy) → Niemann-Pick type C
- Imiglucerase / velaglucerase ERT ± eliglustat / miglustat oral SRT → Gaucher disease type I
- Agalsidase alfa / beta ERT or oral migalastat chaperone → Fabry disease
- Early HSCT for CNS disease (Laronidase ERT is adjunctive/peri-transplant — does NOT adequately cross BBB) → Hurler (severe MPS I)
- HSCT only if PRESYMPTOMATIC (newborn screen positive) → Krabbe disease
- Atidarsagene autotemcel (Lenmeldy in the US; Libmeldy in Europe) ex-vivo gene therapy → Pre-symptomatic late infantile MLD, pre-symptomatic early juvenile MLD, or early symptomatic early juvenile MLD
- Elivaldogene autotemcel gene therapy + HSCT for early cerebral disease → Childhood cerebral X-ALD
- VLCFA screening in ANY male with primary adrenal insufficiency → X-ALD / AMN
- Protein restriction + sodium benzoate / phenylacetate / glycerol phenylbutyrate (avoid valproate) → Urea cycle disorders
- IV heme (hemin) + high-dose glucose / carbohydrate loading; avoid barbiturates, valproate, sulfa, estrogens → Acute intermittent porphyria
- Dietary phenylalanine restriction ± sapropterin (BH4) cofactor → PKU
- Pyridoxine (B6) + folate + B12 + methionine-restricted diet → Homocystinuria
- Low phytanic acid diet (avoid dairy/ruminant fat) ± plasmapheresis → Refsum disease
- Thiamine trial in suspected branched-chain ketoaciduria → Thiamine-responsive MSUD
- Copper-histidine subcutaneous → Menkes disease
- Newborn screen tandem mass spectrometry (acylcarnitines + amino acids) → PKU, MSUD, organic acidurias, urea cycle, fatty acid oxidation defects
- Urine organic acids + plasma ammonia + amino acids in any sick neonate with encephalopathy → Inborn errors of metabolism workup
- Toluidine blue stain on sural nerve / urine sediment showing metachromatic granules → Metachromatic leukodystrophy
Sphingolipidoses
The sphingolipidoses are the most board-tested category of lysosomal storage diseases. All are autosomal recessive except Fabry disease (X-linked recessive).
Sphingolipidoses Overview Table
| Disease | Enzyme Deficiency | Accumulated Substrate | Key Features |
|---|---|---|---|
| Tay-Sachs | Hexosaminidase A | GM2 ganglioside | Cherry-red spot, progressive neurodegeneration, NO hepatosplenomegaly; Ashkenazi Jewish |
| Sandhoff | Hexosaminidase A + B | GM2 ganglioside + globoside | HEXB gene; deficiency of both Hex A (αβ) and Hex B (ββ) isoenzymes (beta-subunit defect); GM2 + globoside + GA2 accumulation; visceral involvement distinguishes from Tay-Sachs |
| Niemann-Pick A | Sphingomyelinase (acid) | Sphingomyelin | Cherry-red spot, foam cells, hepatosplenomegaly, fatal by age 3 |
| Niemann-Pick B | Sphingomyelinase (acid) | Sphingomyelin | Hepatosplenomegaly, pulmonary disease, NO neurologic involvement |
| Niemann-Pick C | NPC1/NPC2 (cholesterol transporter) | Unesterified cholesterol | Vertical supranuclear gaze palsy, ataxia, dystonia, dementia, cataplexy (often triggered by laughter — gelastic-triggered) |
| Gaucher (type 1) | Glucocerebrosidase (GBA) | Glucocerebroside | Most common LSD; hepatosplenomegaly, bone disease; NO neuro involvement |
| Gaucher (type 2/3) | Glucocerebrosidase (GBA) | Glucocerebroside | Neuronopathic forms; type 2 = acute infantile (fatal); type 3 = chronic |
| Fabry | Alpha-galactosidase A | Globotriaosylceramide (Gb3) | X-linked recessive; acroparesthesias, angiokeratomas, corneal verticillata, renal failure, stroke |
| GM1 gangliosidosis | Beta-galactosidase | GM1 ganglioside | Cherry-red spot, skeletal dysplasia, hepatosplenomegaly |
| Krabbe | Galactocerebrosidase | Galactocerebroside | Globoid cell leukodystrophy, irritability, spasticity, peripheral neuropathy |
| Metachromatic leukodystrophy | Arylsulfatase A | Sulfatide | Demyelination (central + peripheral), metachromatic granules on biopsy |
Board Pearl
Tay-Sachs vs. Sandhoff: both have cherry-red spot + GM2 accumulation. Tay-Sachs = hex A only, NO hepatosplenomegaly. Sandhoff = hex A + B, WITH hepatosplenomegaly. Tay-Sachs is the most commonly tested sphingolipidosis on boards.
Cherry-Red Spot Diseases
- The cherry-red spot represents the normal fovea surrounded by lipid-laden, pale-appearing ganglion cells
- Mnemonic — “TaSNiGS”:
- Tay-Sachs
- Sandhoff
- Niemann-Pick A
- GM1 gangliosidosis
- Sialidosis (neuraminidase deficiency)
- Also seen in central retinal artery occlusion (CRAO) — different mechanism (ischemic, not storage)
Tay-Sachs Disease
- Enzyme: hexosaminidase A deficiency
- Inheritance: AR; carrier frequency 1/30 in Ashkenazi Jewish population
- Onset: 3–6 months with exaggerated startle (hyperacusis), developmental arrest; regression begins ~6 months; macrocephaly later from gliosis/storage
- Exam: cherry-red spot on fundoscopy, progressive hypotonia → spasticity, seizures, blindness, macrocephaly
- Key distinction: NO hepatosplenomegaly (GM2 accumulates in neurons only, not viscera)
- Pathology: neuronal swelling with membranous cytoplasmic bodies on EM
- Prognosis: death by age 3–5 years; no specific treatment
Gaucher Disease
- Enzyme: glucocerebrosidase (GBA) deficiency
- Most common lysosomal storage disease
- Pathology: Gaucher cells — macrophages with “crumpled tissue paper” or “wrinkled paper” cytoplasm
Gaucher Disease Types
| Type | Onset | Neurologic? | Features |
|---|---|---|---|
| Type 1 (90%) | Variable | No | Hepatosplenomegaly, pancytopenia, bone crises, Erlenmeyer flask deformity; Ashkenazi Jewish; ERT available |
| Type 2 | Infancy | Yes (acute) | Rapidly progressive; bulbar signs, seizures, spasticity; fatal by age 2 |
| Type 3 | Childhood | Yes (chronic) | Slower neurodegeneration; horizontal supranuclear gaze palsy, myoclonus, ataxia |
Board Pearl
GBA mutations are the most common genetic risk factor for Parkinson disease. Heterozygous GBA carriers have a 5–10x increased risk of developing PD. Gaucher cells with “crumpled tissue paper” cytoplasm are pathognomonic.
Fabry Disease
- Enzyme: alpha-galactosidase A deficiency
- Inheritance: X-linked recessive — the only X-linked sphingolipidosis
- Accumulated substrate: globotriaosylceramide (Gb3)
- Neurologic: painful acroparesthesias (burning pain in hands/feet, triggered by heat/exercise), small fiber neuropathy, stroke (young adults)
- Dermatologic: angiokeratomas (dark red papules, classically in “bathing trunk” distribution)
- Ophthalmologic: corneal verticillata (whorl-like corneal deposits)
- Renal: progressive nephropathy → renal failure (leading cause of death)
- Cardiac: left ventricular hypertrophy, arrhythmias, cardiomyopathy
- Treatment: enzyme replacement therapy (agalsidase alfa or agalsidase beta); oral chaperone therapy (migalastat) for amenable mutations
- Female carriers can be symptomatic due to random X-inactivation (lyonization)
Niemann-Pick Type C
- Gene: NPC1 (95%) or NPC2 — intracellular cholesterol transport defect (NOT a sphingomyelinase deficiency)
- Presentation: childhood-onset progressive ataxia, dystonia, cognitive decline
- Hallmark: vertical supranuclear gaze palsy (initially downgaze, then upgaze)
- Other features: cataplexy (often triggered by laughter — gelastic-triggered), vertical supranuclear gaze palsy, neonatal cholestasis, hepatosplenomegaly
- Diagnosis: filipin staining of skin fibroblasts, oxysterol biomarkers
- Treatment: miglustat (substrate reduction; EU-approved); arimoclomol (FDA-approved 2024 for NPC) — heat-shock-protein 70 amplifier
Board Pearl
Niemann-Pick C is a “cholesterol trafficking” disorder, NOT a sphingomyelinase deficiency (unlike NP-A/B). The combination of vertical supranuclear gaze palsy + ataxia + cognitive decline in a child or young adult should prompt evaluation for NPC.
Mucopolysaccharidoses (MPS)
Group of lysosomal storage diseases caused by defective degradation of glycosaminoglycans (GAGs). All are autosomal recessive except MPS II (Hunter) — X-linked recessive.
MPS Overview Table
| Type | Eponym | Enzyme Deficiency | Inheritance | Key Features |
|---|---|---|---|---|
| MPS I | Hurler / Hurler-Scheie / Scheie (severe → mild spectrum of MPS I) | Alpha-L-iduronidase | AR | Corneal clouding, dysostosis multiplex, coarse facies, intellectual disability (Hurler); Scheie = milder |
| MPS II | Hunter | Iduronate sulfatase | X-linked | Similar to Hurler but NO corneal clouding; pebbly skin lesions (ivory-colored papules) |
| MPS III | Sanfilippo (A–D) | Heparan sulfate degradation enzymes | AR | Severe behavioral and cognitive decline; mild somatic features |
| MPS IV | Morquio | IVA = GALNS (N-acetylgalactosamine-6-sulfatase, keratan sulfate); IVB = beta-galactosidase (same enzyme as GM1 gangliosidosis) | AR | Severe skeletal dysplasia, odontoid hypoplasia (C1–C2 instability), corneal clouding, normal intelligence |
| MPS VI | Maroteaux-Lamy | Arylsulfatase B | AR | Severe somatic disease (dysostosis multiplex, corneal clouding, valvular heart disease), normal intelligence; ERT (galsulfase) available |
| MPS VII | Sly | Beta-glucuronidase | AR | Hydrops fetalis; rare; variable severity; ERT (vestronidase alfa) available |
- All MPS have corneal clouding EXCEPT Hunter (MPS II)
- Hunter is the only X-linked MPS — “Hunters need to see (clear corneas) and are X-linked”
- Diagnosis: elevated urinary GAGs + specific enzyme assay
- Treatment: enzyme replacement therapy and/or hematopoietic stem cell transplantation (MPS I)
Board Pearl
Board-favorite MPS facts: (1) Hunter = only X-linked MPS, NO corneal clouding. (2) Sanfilippo = predominantly neurologic/behavioral with mild somatic features. (3) Morquio = severe skeletal disease but normal intelligence. (4) Hurler = the most severe MPS I phenotype.
Neuronal Ceroid Lipofuscinoses (NCL / Batten Disease)
Group of neurodegenerative disorders characterized by accumulation of autofluorescent lipopigment (ceroid-lipofuscin) in neurons and other cells. All are autosomal recessive.
NCL Types
| Type | Gene / Protein | Onset | Key Features | EM Finding |
|---|---|---|---|---|
| CLN1 (infantile) | PPT1 (palmitoyl protein thioesterase 1) | 6–24 months | Rapid regression, seizures, myoclonus, visual loss | Granular osmiophilic deposits (GRODs) |
| CLN2 (late infantile) | TPP1 (tripeptidyl peptidase 1) | 2–4 years | Seizures first, then motor and cognitive decline, visual loss | Curvilinear profiles |
| CLN3 (juvenile / Batten) | CLN3 protein (battenin) | 4–7 years | Visual loss first (retinal degeneration), then seizures and cognitive decline | Fingerprint bodies |
- Common features: progressive seizures, visual loss, cognitive decline, motor deterioration → early death
- Diagnosis: enzyme assay (CLN1, CLN2), genetic testing, skin/conjunctival biopsy showing autofluorescent lipopigment
- Treatment: cerliponase alfa (intracerebroventricular ERT for CLN2)
Glycogen Storage Diseases with Neurologic Features
Key GSDs Table
| Disease | Enzyme Deficiency | Inheritance | Key Neurologic Features |
|---|---|---|---|
| Pompe (GSD II) | Acid maltase (acid alpha-glucosidase / GAA) | AR | Infantile: severe hypotonia (“floppy baby”), cardiomegaly, macroglossia; Late-onset: limb-girdle weakness + respiratory failure |
| McArdle (GSD V) | Myophosphorylase | AR | Exercise intolerance, myalgia, myoglobinuria, “second-wind” phenomenon; no rise in lactate on forearm exercise test |
| Danon | LAMP2 | X-linked | Cardiomyopathy + myopathy + intellectual disability; vacuolar myopathy with autophagic material |
Pompe Disease — Key Details
- Infantile-onset: massive cardiomegaly, generalized hypotonia, feeding difficulty, tongue enlargement; death by age 1–2 without treatment
- Late-onset: progressive proximal myopathy + early respiratory failure (diaphragmatic weakness — often out of proportion to limb weakness)
- Diagnosis: CK mildly elevated; AST/ALT/LDH elevated; muscle biopsy with PAS-positive vacuoles (lysosomal glycogen); GAA enzyme assay on DBS; GAA gene sequencing
- Treatment: enzyme replacement therapy (alglucosidase alfa) — improves survival in infantile form
McArdle Disease — Key Details
- Exercise intolerance with myalgia and cramping during intense anaerobic exercise
- Second-wind phenomenon: symptoms improve after brief rest and resumption of exercise (switch to fatty acid oxidation)
- Forearm exercise test: no rise in venous lactate (pathognomonic), with exaggerated ammonia rise
- Risk of rhabdomyolysis and myoglobinuria with strenuous exercise
Clinical Pearl
Late-onset Pompe should be in the differential for any patient with limb-girdle pattern weakness + respiratory failure. Unlike most myopathies, respiratory involvement is early and prominent. CK is mildly elevated. Dried blood spot enzyme assay is a simple screening test.
Amino Acid Disorders
Amino Acid Disorders Overview Table
| Disease | Enzyme Deficiency | Inheritance | Key Features |
|---|---|---|---|
| Phenylketonuria (PKU) | Phenylalanine hydroxylase (PAH) | AR | Intellectual disability if untreated, musty/mousy odor, fair skin/hair/eyes, eczema; detected by newborn screening |
| Maple syrup urine disease | Branched-chain alpha-keto acid dehydrogenase | AR | Sweet/maple syrup urine odor, neonatal encephalopathy, feeding difficulty, opisthotonus |
| Homocystinuria | Cystathionine beta-synthase | AR | Marfanoid habitus, lens subluxation (downward), stroke, intellectual disability, osteoporosis |
| Nonketotic hyperglycinemia | Glycine cleavage system | AR | Neonatal seizures, apnea, hiccups; burst-suppression pattern on EEG; elevated CSF:plasma glycine ratio |
Phenylketonuria (PKU)
- Most common amino acid disorder (~1/10,000)
- Deficient conversion of phenylalanine → tyrosine
- Untreated: severe intellectual disability, seizures, microcephaly, hyperactivity
- Fair phenotype: reduced melanin synthesis (tyrosine is a melanin precursor)
- Treatment: phenylalanine-restricted diet (lifelong); sapropterin (BH4 cofactor) for responsive patients
- Maternal PKU: uncontrolled maternal Phe levels → microcephaly, cardiac defects, intellectual disability in offspring (even if fetus does not have PKU)
Homocystinuria
- Lens subluxation: downward and inward (vs. Marfan → upward and temporal)
- Vascular: arterial and venous thromboembolism, stroke at a young age
- Skeletal: tall, thin habitus, arachnodactyly, pectus excavatum, scoliosis, osteoporosis
- Neurologic: intellectual disability, seizures, psychiatric disturbance
- Treatment: B6 (pyridoxine) — ~50% of patients are B6-responsive; also folate, B12, betaine, methionine-restricted diet
Board Pearl
Lens subluxation direction is a board favorite: Homocystinuria = DOWN (and in), Marfan = UP (and out). Both produce Marfanoid habitus, but homocystinuria has thrombosis risk + intellectual disability (Marfan does not). PKU screening is the prototype for newborn metabolic screening.
Urea Cycle Disorders
- Ornithine transcarbamylase (OTC) deficiency is the most common urea cycle disorder
- Inheritance: X-linked recessive (only X-linked UCD; all others are AR)
- Pathophysiology: impaired conversion of ammonia to urea → hyperammonemia
Clinical Presentation
- Neonatal: poor feeding, vomiting, lethargy → seizures → coma (within first few days of life)
- Late-onset: episodic encephalopathy triggered by protein load, illness, or catabolic stress
- Lab findings: elevated ammonia, elevated glutamine, low BUN, respiratory alkalosis (early) → metabolic crisis
- Specific to OTC: elevated urinary orotic acid (distinguishes from carbamoyl phosphate synthetase I deficiency)
Diagnosis and Treatment
- MRS (MR spectroscopy): elevated glutamine peak — hallmark of hyperammonemia
- MRI: diffuse cerebral edema in acute crisis; chronic → cortical atrophy
- Treatment:
- Acute: IV sodium benzoate + sodium phenylacetate (nitrogen scavengers), arginine, hemodialysis if severe
- Chronic: protein restriction, sodium phenylbutyrate (oral nitrogen scavenger), arginine/citrulline supplementation
- Definitive: liver transplantation
Wilson Disease (Hepatolenticular Degeneration)
- Gene: ATP7B (chromosome 13q14.3)
- Inheritance: autosomal recessive
- Pathophysiology: defective biliary copper excretion → copper accumulation in liver, brain (basal ganglia), cornea, kidneys
- Onset: typically age 5–40 years
Clinical Features
Neurologic
- Dystonia (most common neurologic finding)
- Wing-beating tremor (coarse, postural)
- Dysarthria, drooling
- Parkinsonism (rigidity, bradykinesia)
- Cerebellar signs (ataxia)
- Psychiatric: personality changes, depression, psychosis — may precede neurologic symptoms by years
Hepatic
- Acute hepatitis, chronic hepatitis, cirrhosis
- Fulminant hepatic failure (with Coombs-negative hemolytic anemia)
Ophthalmologic
- Kayser-Fleischer rings: copper deposition in Descemet membrane of cornea (greenish-brown ring at limbus)
- Present in >95% of patients with neurologic Wilson; ~50% of hepatic-only Wilson
- Best detected by slit-lamp examination
- Sunflower cataracts (less common)
Diagnostic Workup
| Test | Finding |
|---|---|
| Serum ceruloplasmin | Low (<20 mg/dL) in ~90% of patients |
| 24-hour urine copper | Elevated (>100 mcg/day) |
| Serum free copper | Elevated |
| Hepatic copper | Elevated (>250 mcg/g dry weight) — gold standard |
| Slit-lamp exam | Kayser-Fleischer rings |
| Genetic testing | ATP7B mutations (confirmatory) |
Neuroimaging
- MRI brain: T2/FLAIR hyperintensity in the putamen, caudate, thalamus, midbrain, pons
- “Face of the giant panda” sign: characteristic T2 signal pattern in the midbrain (tegmentum hyperintense, surrounding structures dark)
- T1 hyperintensity in basal ganglia (primarily manganese deposition secondary to hepatic dysfunction, not copper itself)
Treatment
- Chelation: D-penicillamine (historically first-line, but many side effects) or trientine (better tolerated)
- First-line in neurologic Wilson: Many centers now prefer trientine (or zinc) first-line in neurologic Wilson due to lower risk of paradoxical neurologic worsening that occurs with penicillamine in 10–50%
- Zinc: blocks intestinal copper absorption; used for maintenance and presymptomatic patients
- Liver transplantation: curative; indicated for fulminant hepatic failure or decompensated cirrhosis
- Treatment is lifelong — neurologic symptoms may initially worsen with penicillamine
Board Pearl
Wilson disease must be excluded in any patient <40 years with unexplained movement disorder, psychiatric symptoms, or liver disease. Kayser-Fleischer rings are present in >95% of neurologic Wilson. Low ceruloplasmin + high urine copper + KF rings = classic triad. The “face of the giant panda” sign on midbrain MRI is a classic/characteristic association but is NOT pathognomonic and NOT sensitive — not required for diagnosis.
Other Metabolic Disorders
Copper, Iron, and Purine Metabolism Disorders
| Disease | Gene / Enzyme | Inheritance | Key Features |
|---|---|---|---|
| Menkes disease | ATP7A (copper ATPase) | X-linked recessive | Copper deficiency (opposite of Wilson); kinky/steely hair, seizures, connective tissue abnormalities, hypothermia; fatal in infancy |
| PKAN | PANK2 (pantothenate kinase 2) | AR | “Eye of the tiger” sign on MRI (globus pallidus); dystonia, spasticity, pigmentary retinopathy; onset childhood |
| Lesch-Nyhan | HPRT (hypoxanthine-guanine phosphoribosyltransferase) | X-linked recessive | Hyperuricemia, self-injurious behavior (lip/finger biting), dystonia, choreoathetosis, intellectual disability, gout, renal stones |
Menkes vs. Wilson
| Feature | Menkes | Wilson |
|---|---|---|
| Gene | ATP7A | ATP7B |
| Inheritance | X-linked recessive | Autosomal recessive |
| Copper status | Deficiency (low serum copper) | Excess (copper accumulation) |
| Ceruloplasmin | Low | Low |
| Pathophysiology | Impaired intestinal absorption | Impaired biliary excretion |
| Hair | Kinky, depigmented (“steely hair”) | Normal |
| Prognosis | Fatal in infancy | Treatable if diagnosed early |
PKAN (Pantothenate Kinase-Associated Neurodegeneration)
- Most common form of neurodegeneration with brain iron accumulation (NBIA)
- “Eye of the tiger” sign: T2 hypointensity in globus pallidus with central hyperintense spot — highly characteristic
- Progressive dystonia, spasticity, rigidity, dysarthria
- Pigmentary retinopathy, acanthocytosis on blood smear
Clinical Pearl
Both Menkes and Wilson have low ceruloplasmin, but the copper problem is opposite: Menkes = cannot absorb copper (deficiency), Wilson = cannot excrete copper (excess). Menkes presents in infancy with seizures and kinky hair; Wilson presents later with liver disease and movement disorders.
Peroxisomal Disorders
Peroxisomes are organelles responsible for very-long-chain fatty acid (VLCFA) beta-oxidation, plasmalogen synthesis, and phytanic acid alpha-oxidation. Defects produce a spectrum of disorders ranging from severe neonatal multisystem disease to milder adult-onset forms.
Peroxisomal Disorders Overview
| Disease | Gene / Defect | Inheritance | Key Features |
|---|---|---|---|
| Zellweger spectrum | PEX gene group (peroxisomal biogenesis defect) | AR | Neonatal hypotonia, seizures, hepatomegaly, characteristic facies (high forehead, large fontanelles), glaucoma; VLCFA + phytanic acid elevated; perisylvian polymicrogyria on MRI |
| Neonatal ALD | PEX gene group (milder biogenesis defect) | AR | Milder Zellweger spectrum disorder; later onset, longer survival |
| Infantile Refsum disease | PEX gene group | AR | Mildest of Zellweger spectrum; sensorineural hearing loss, retinitis pigmentosa, developmental delay |
| Rhizomelic chondrodysplasia punctata | PEX7 (most common); plasmalogen synthesis defect | AR | Epiphyseal stippling, rhizomelic limb shortening, severe intellectual disability, cataracts |
| X-linked ALD (X-ALD) | ABCD1 (peroxisomal membrane transporter) | X-linked recessive | Peroxisomal single-enzyme defect; childhood cerebral form, adrenomyeloneuropathy; VLCFA elevated; cross-reference Leukodystrophies |
Board Pearl
Zellweger syndrome = severe end of the peroxisomal biogenesis spectrum: neonatal hypotonia + characteristic facies (high forehead, large fontanelles) + hepatomegaly + seizures + perisylvian polymicrogyria. Elevated VLCFA + phytanic acid distinguishes peroxisomal from other neonatal encephalopathies. X-ALD is the most common peroxisomal disorder and is a single-enzyme defect (not a biogenesis defect).
Additional Metabolic Disorders
Other High-Yield Inborn Errors of Metabolism
| Disease | Defect | Key Features | Treatment |
|---|---|---|---|
| Tyrosinemia type I | FAH (fumarylacetoacetate hydrolase) | Hepatorenal disease; succinylacetone elevated (pathognomonic); cabbage-like odor; hepatocellular carcinoma risk | NTBC (nitisinone) + tyrosine/phenylalanine-restricted diet |
| Methylmalonic acidemia (MMA) | Methylmalonyl-CoA mutase | Organic acidemia: metabolic acidosis + hyperammonemia + ketosis; basal ganglia infarcts; failure to thrive | Low-protein diet + carnitine + B12 (hydroxocobalamin) for responsive forms |
| Propionic acidemia (PA) | Propionyl-CoA carboxylase | Organic acidemia: metabolic acidosis + hyperammonemia + ketosis; cardiomyopathy; basal ganglia involvement | Low-protein diet + carnitine; biotin trial |
| Galactosemia | GALT (galactose-1-phosphate uridyltransferase) | Cataracts, hepatic disease, E. coli sepsis (neonatal), intellectual disability; reducing substances in urine | Lactose-free / galactose-free diet |
| ADA-SCID | Adenosine deaminase deficiency | Severe combined immunodeficiency; neurologic features (sensorineural deafness, cognitive impairment); recurrent infections | HSCT, ERT (pegademase), gene therapy |
| Schindler disease | α-N-acetylgalactosaminidase deficiency | Infantile neuroaxonal dystrophy variant; cherry-red spot, developmental regression, seizures | Supportive |
Board Pearl
Triad of metabolic acidosis + hyperammonemia + ketosis in a neonate = organic acidemia (MMA or PA). Distinguish from urea cycle disorders, which have hyperammonemia WITHOUT acidosis (respiratory alkalosis early). Galactosemia presents with E. coli sepsis in a neonate — classic boards association.
Newborn Screening Overview
- PKU was the first newborn-screened metabolic disorder (Guthrie bacterial inhibition assay, 1962)
- Current US Recommended Uniform Screening Panel (RUSP) includes ~35+ metabolic disorders, including:
- Amino acid disorders: PKU, MSUD, homocystinuria, tyrosinemia
- Organic acidemias: MMA, PA, isovaleric acidemia
- Fatty acid oxidation: MCAD, VLCAD, LCHAD
- Lysosomal storage diseases: Pompe, MPS I, Krabbe (in some states)
- Peroxisomal: X-ALD (added 2016)
- Other: biotinidase deficiency, galactosemia, SMA, SCID, congenital hypothyroidism, congenital adrenal hyperplasia, cystic fibrosis, hemoglobinopathies
- Tandem mass spectrometry (MS/MS) on dried blood spot enables simultaneous screening for >30 disorders
Treatment Framework for Metabolic Disorders
| Strategy | Mechanism | Examples |
|---|---|---|
| Enzyme replacement therapy (ERT) | IV recombinant enzyme replaces deficient lysosomal enzyme | Fabry (agalsidase), Gaucher (imiglucerase), Pompe (alglucosidase), MPS I/II/IV/VI/VII |
| Substrate reduction therapy (SRT) | Inhibit upstream synthesis of accumulating substrate | Miglustat (NPC, Gaucher), eliglustat (Gaucher) |
| Pharmacological chaperones | Stabilize mutant enzyme to allow proper trafficking/folding | Migalastat (Fabry, amenable mutations); arimoclomol (NPC, HSP70 amplifier) |
| Gene therapy | Ex vivo lentiviral or in vivo AAV gene addition | X-ALD (elivaldogene autotemcel / Skysona), MLD (atidarsagene autotemcel / Lenmeldy [US] / Libmeldy [EU]), SMA (onasemnogene abeparvovec / Zolgensma); AAV-based therapies emerging for other LSDs |
| Dietary management | Restrict precursor substrate or supplement deficient product | PKU (Phe restriction), galactosemia (lactose-free), UCD (low protein), tyrosinemia (Tyr/Phe restriction) |
| Cofactor supplementation | Provide vitamin/cofactor for residual enzyme activity | B6 (homocystinuria), B12 (MMA), biotin (PA / biotinidase), BH4/sapropterin (PKU) |
| HSCT | Cross-correction by donor-derived enzyme-producing cells | MPS I (Hurler), MLD, Krabbe (presymptomatic), X-ALD (presymptomatic cerebral) |
Quick Reference — High-Yield Associations Table
| Finding / Clue | Think of… |
|---|---|
| Cherry-red spot | Tay-Sachs, Sandhoff, Niemann-Pick A, GM1, sialidosis |
| “Crumpled tissue paper” macrophages | Gaucher disease |
| Foam cells | Niemann-Pick disease |
| Angiokeratomas + acroparesthesias | Fabry disease |
| Vertical supranuclear gaze palsy + ataxia | Niemann-Pick C |
| Corneal verticillata | Fabry disease (also amiodarone) |
| Kayser-Fleischer rings | Wilson disease |
| “Face of the giant panda” on MRI | Wilson disease |
| “Eye of the tiger” on MRI | PKAN |
| Kinky/steely hair + seizures | Menkes disease |
| Self-injurious behavior + hyperuricemia | Lesch-Nyhan syndrome |
| Second-wind phenomenon | McArdle disease (GSD V) |
| Floppy baby + cardiomegaly | Pompe disease (infantile) |
| Limb-girdle weakness + early respiratory failure | Late-onset Pompe disease |
| Musty/mousy odor + fair skin | PKU |
| Downward lens subluxation + Marfanoid | Homocystinuria |
| Burst-suppression EEG + neonatal seizures | Nonketotic hyperglycinemia |
| Elevated glutamine on MRS | Hyperammonemia / urea cycle disorder |
| Elevated urinary orotic acid + hyperammonemia | OTC deficiency |
| Dysostosis multiplex + corneal clouding | MPS I (Hurler) |
| X-linked MPS, no corneal clouding | MPS II (Hunter) |
Clinical Pearl
When evaluating a child with progressive neurodegeneration, hepatosplenomegaly, and cherry-red spot — consider Niemann-Pick A (sphingomyelinase deficiency) or Sandhoff. If cherry-red spot without hepatosplenomegaly — think Tay-Sachs. If hepatosplenomegaly without cherry-red spot — think Gaucher type 1 (no neuro) or type 3 (with neuro).
References
- Ropper AH, Samuels MA, Klein JP, Prasad S. Adams and Victor’s Principles of Neurology. 12th ed. McGraw Hill; 2023.
- Saudubray JM, Baumgartner MR, Walter JH. Inborn Metabolic Diseases: Diagnosis and Treatment. 7th ed. Springer; 2022.
- Pastores GM, Hughes DA. Gaucher Disease. In: Adam MP, et al., eds. GeneReviews. University of Washington; 2000 [updated 2018].
- Roberts EA, Schilsky ML. Diagnosis and treatment of Wilson disease: an update. Hepatology. 2008;47(6):2089–2111.
- Desnick RJ, Ioannou YA, Eng CM. Alpha-galactosidase A deficiency: Fabry disease. In: Scriver CR, et al., eds. The Metabolic and Molecular Bases of Inherited Disease. McGraw-Hill; 2001.
- Patterson MC, Hendriksz CJ, Walterfang M, et al. Recommendations for the diagnosis and management of Niemann-Pick disease type C. Mol Genet Metab. 2012;106(3):330–344.
- Sidransky E, Nalls MA, Aasly JO, et al. Multicenter analysis of glucocerebrosidase mutations in Parkinson’s disease. N Engl J Med. 2009;361(17):1651–1661.
- Blau N, van Spronsen FJ, Levy HL. Phenylketonuria. Lancet. 2010;376(9750):1417–1427.
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