Lysosomal Storage & Peroxisomal Disorders

Sphingolipidoses (Gaucher, Niemann-Pick, Tay-Sachs, Fabry, Krabbe, MLD) · Mucopolysaccharidoses (Hurler, Hunter, Sanfilippo) · Mucolipidoses · Oligosaccharidoses · Peroxisomal biogenesis (Zellweger) · Single enzyme defects (ALD, Refsum)
🧬 Key concepts: Enzyme deficiencies → substrate accumulation. Cherry-red spot (Tay-Sachs, Niemann-Pick). Hepatosplenomegaly (Gaucher, Niemann-Pick, MPS). Coarse facies, dysostosis multiplex (MPS). Enzyme replacement therapy for Gaucher, Fabry, MPS I, II, VI. Hematopoietic stem cell transplant for MPS I, Krabbe, MLD.

📖 Lysosomal & peroxisomal disorders: clinical and biochemical features

🧬 Sphingolipidoses
Gaucher (glucocerebrosidase): hepatosplenomegaly, bone pain, cytopenias. Niemann-Pick (ASM): cherry-red spot, neurodegeneration. Tay-Sachs (Hex A): cherry-red spot, neurodegeneration. Fabry (α-galactosidase A): angiokeratomas, acroparesthesia, renal failure. Krabbe (galactocerebrosidase): irritability, spasticity, optic atrophy. MLD (arylsulfatase A): leukodystrophy, peripheral neuropathy.
🦴 Mucopolysaccharidoses (MPS)
MPS I (Hurler): coarse facies, hepatosplenomegaly, dysostosis multiplex, corneal clouding, ID. MPS II (Hunter): X-linked, no corneal clouding. MPS III (Sanfilippo): severe ID, mild somatic. MPS IV (Morquio): skeletal dysplasia, ligamentous laxity, normal intellect. MPS VI (Maroteaux-Lamy): similar to Hurler, normal intellect.
🧫 Peroxisomal disorders
Zellweger syndrome (peroxisome biogenesis): hypotonia, seizures, dysmorphism, hepatomegaly, VLCFA elevated. Adrenoleukodystrophy (X-ALD): adrenal insufficiency, leukodystrophy, VLCFA elevated. Refsum disease (phytanoyl-CoA hydroxylase): retinitis pigmentosa, peripheral neuropathy, elevated phytanic acid.
💊 Therapy
Enzyme replacement (Gaucher, Fabry, MPS I, II, VI). Hematopoietic stem cell transplant (MPS I, Krabbe, MLD). Substrate reduction (miglustat, eliglustat). Symptomatic care.
⚠️ Red flags for lysosomal disease: Coarse facies, organomegaly, skeletal abnormalities, developmental regression, cherry-red spot, angiokeratomas, recurrent bone pain, unexplained splenomegaly.

🩺 Diagnostic approach to lysosomal & peroxisomal disorders

1
History & physical – Age of onset, regression, organomegaly, coarse facies, skeletal deformities (dysostosis multiplex), cherry-red spot, angiokeratomas, corneal clouding, hearing loss, neurological decline.
2
Screening tests – Urine GAGs (MPS), oligosaccharides (oligosaccharidoses). Sphingolipidoses: leukocyte enzyme assays (β-glucosidase, sphingomyelinase, hexosaminidase, α-galactosidase, etc.).
3
Peroxisomal screening – VLCFA (C26:0, C24/C22, C26/C22 ratios), phytanic acid, pristanic acid, pipecolic acid. Plasma. Confirmatory enzyme assays (e.g., phytanoyl-CoA hydroxylase).
4
Genetic testing – Confirmatory molecular analysis for family counseling and prenatal diagnosis.
📌 Clinical pearl: Cherry-red spot with hepatosplenomegaly suggests Niemann-Pick type A (infantile) or Tay-Sachs (no organomegaly). Cherry-red spot without organomegaly suggests Tay-Sachs.

📋 Stepwise management of lysosomal & peroxisomal disorders

1
Enzyme replacement therapy (ERT) – Available for Gaucher (imiglucerase, velaglucerase), Fabry (agalsidase), MPS I (laronidase), MPS II (idursulfase), MPS VI (galsulfase), Pompe (alglucosidase).
2
Hematopoietic stem cell transplant (HSCT) – Curative for MPS I (Hurler) if done early, Krabbe (infantile), MLD. Slows neurological progression.
3
Substrate reduction therapy – Miglustat (Gaucher type 1, Niemann-Pick type C), eliglustat (Gaucher type 1).
4
Symptomatic & supportive care – Orthopedic surgery for MPS skeletal deformities, hip dislocation. Corneal transplantation. Seizure management. Physical therapy, hearing aids.
5
Adrenoleukodystrophy (ALD) – Hematopoietic stem cell transplant for early cerebral ALD. Lorenzo's oil (erucic acid) for asymptomatic boys. Adrenal hormone replacement.
6
Refsum disease – Dietary restriction of phytanic acid (avoid dairy, beef, lamb, certain fish). Plasmapheresis for acute decompensation.
🚨 Emergency in ALD: Adrenal crisis (hypoglycemia, hypotension, vomiting). Immediate IV hydrocortisone, fluids.

🧠 Reflex prompts: lysosomal & peroxisomal disorders

🧬 3-year-old with hepatosplenomegaly, bone pain, cytopenias. Bone marrow shows Gaucher cells. Diagnosis?
Gaucher disease type 1 (non-neuronopathic). ERT with imiglucerase.
🩸 12-year-old with acroparesthesia, angiokeratomas, and proteinuria. Diagnosis?
Fabry disease (α-galactosidase A deficiency). ERT, monitor renal function.
👶 6-month-old with cherry-red spot, developmental regression, hypotonia. No organomegaly. Diagnosis?
Tay-Sachs disease (hexosaminidase A deficiency). No cure.
🦴 2-year-old with coarse facies, hepatosplenomegaly, corneal clouding, gibbus deformity. Urine GAGs elevated. Diagnosis?
Hurler syndrome (MPS I). HSCT if early, ERT available.
🧬 Boy with progressive spastic paraparesis, adrenal insufficiency, and elevated VLCFA. Diagnosis?
X-linked adrenoleukodystrophy. HSCT for cerebral disease.
🧠 Neonate with hypotonia, seizures, dysmorphic facies, hepatomegaly. VLCFA elevated. Diagnosis?
Zellweger syndrome (peroxisome biogenesis). Supportive care.
👁️ Adolescent with retinitis pigmentosa, peripheral neuropathy, and elevated phytanic acid. Diagnosis?
Refsum disease. Dietary phytanic acid restriction.
🧬 X-linked condition with no corneal clouding (unlike MPS I), coarse facies, hepatosplenomegaly, ID. Diagnosis?
Hunter syndrome (MPS II). ERT idursulfase.
🧪 Most common lysosomal storage disorder?
Gaucher disease (type 1 most common).
💊 Which LSDs have FDA-approved enzyme replacement therapy?
Gaucher, Fabry, MPS I, II, IVA? (actually MPS I, II, VI, IVA investigational), Pompe.