Basic Science Clinical
Anatomy Physiology Pharmacology Pathology Neuropathology
Basic Science
Pathology
10 notes available
1 Last Minute Review 2 Neuropathology Fundamentals 3 Embryology & Developmental Malformations 4 Neurocutaneous Syndromes (Phakomatoses) 5 CNS Tumors 6 Metabolic & Storage Diseases 7 Leukodystrophies 8 Mitochondrial Disorders 9 Neurotoxicology & Nutritional Deficiencies 10 Neurogenetics
Basic Science › Pathology

Metabolic & Storage Diseases

Metabolic & Storage Diseases

What You'll Learn

  • 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)
HighYield Pearls
  • 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).
🔍 Quick ReferenceClinical / 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
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