This page covers two overlapping clusters: lysosomal storage diseases (Fabry, Pompe, Gaucher, Niemann-Pick, Tay-Sachs, MPS) — many now treatable with enzyme replacement, substrate reduction, or chaperones — and neurocutaneous syndromes (NF1, NF2, schwannomatosis, tuberous sclerosis, von Hippel-Lindau, Sturge-Weber) which present with hereditary tumor predisposition and cutaneous markers. Treatable storage diseases are the highest-yield “never miss” group in neurology genetics.

Lysosomal Storage Diseases

Fabry Disease (α-Galactosidase A Deficiency)

• Test (males): α-Gal A enzyme activity (DBS or leukocytes).
• Test (females): GLA sequencing — mandatory (enzyme often normal in heterozygous females due to skewed X-inactivation).
• Biomarker: plasma lyso-Gb3 elevated.
• Phenotypes: classic (childhood acroparesthesias, angiokeratomas, hypohidrosis, corneal verticillata, renal failure, LVH, premature stroke) and late-onset cardiac variant.
• Treatment: agalsidase α (Replagal — outside US) / agalsidase β (Fabrazyme — ERT); migalastat (Galafold — oral chaperone for amenable GLA mutations).
• Cross-reference: stroke (vascular page) + peripheral neuropathy (PN page).

Gaucher Disease

• First-line test: glucocerebrosidase (GBA1) enzyme in leukocytes.
• Confirmation: GBA1 sequencing.
• Biomarker: plasma glucosylsphingosine (lyso-GL1), chitotriosidase, ACE — elevated in active disease.
• Pseudogene problem: GBA1 has a highly homologous pseudogene (GBAP1) — sequencing labs must use long-range PCR or specialized strategies to avoid false positives/negatives.
• Types:
  • Type I (non-neuronopathic): visceral (hepatosplenomegaly, bone disease, cytopenia). Treatable.
  • Type II (acute neuronopathic): infantile; rapidly fatal.
  • Type III (chronic neuronopathic): oculomotor apraxia, seizures, ataxia. ERT helps systemic disease only.
• Treatment (type I and III): imiglucerase / velaglucerase / taliglucerase (ERT); eliglustat (oral substrate reduction); miglustat.
• Major link: GBA1 mutations are the strongest single genetic risk factor for Parkinson disease and DLB (~10× risk for heterozygotes). Heterozygote GBA1 carriers warrant PD risk counseling. Ambroxol clinical trials ongoing.

Niemann-Pick Disease Type C (NPC)

• First-line biomarker: plasma oxysterols (7-ketocholesterol, cholestane-3β,5α,6β-triol) — sensitive and specific. Lyso-sphingomyelin-509 (lyso-SM-509) is increasingly available and complementary.
• First-line confirmation: NPC1 sequencing (~95%) + NPC2 sequencing — order alongside (or immediately reflex from) the biomarker rather than waiting for filipin.
• Second-line / problem-solving: filipin staining of cultured skin fibroblasts remains useful when biomarker and sequencing are discordant, when variants are of uncertain significance, or when the genetic result alone is non-diagnostic. It is no longer a routine first-line test.
• Clinical clues: vertical supranuclear gaze palsy (highly specific), splenomegaly, ataxia, dystonia, dysarthria, dementia, gelastic cataplexy. Adult-onset NPC mimics psychiatric disease.
• Treatment: miglustat (substrate reduction) slows progression; arimoclomol (Miplyffa) recently approved.

Niemann-Pick Type A/B (Acid Sphingomyelinase Deficiency, ASMD)

• Test: acid sphingomyelinase enzyme in leukocytes + SMPD1 sequencing.
• Type A: neuronopathic, fatal in infancy; “cherry-red spot” + hepatosplenomegaly.
• Type B: visceral only; survives to adulthood.
• Treatment: olipudase alfa (Xenpozyme) — ERT for ASMD (type B and visceral aspects of type A/B).

Tay-Sachs and Sandhoff Disease (GM2 Gangliosidoses)

• Tay-Sachs test: hexosaminidase A (HexA) enzyme in serum/leukocytes (low). Confirmation: HEXA sequencing.
• Sandhoff test: total hexosaminidase (HexA + HexB) low. Confirmation: HEXB sequencing.
• Carrier screening: Ashkenazi Jewish, French-Canadian, Cajun populations — standard preconception screening.
• Adult-onset GM2 gangliosidosis: lower-motor-neuron syndrome (mimicking ALS/SMA) + cerebellar ataxia + psychiatric symptoms — order Hex A enzyme in any unexplained adult lower-motor-neuron syndrome.

Mucopolysaccharidoses (MPS I–VII)

• Screening: urine glycosaminoglycans (GAGs) — elevated in untreated patients.
• Specific testing:
  • MPS I (Hurler / Hurler-Scheie / Scheie): α-L-iduronidase (IDUA) enzyme + IDUA sequencing. Treatable: laronidase ERT; HSCT for severe Hurler.
  • MPS II (Hunter): iduronate-2-sulfatase (IDS) enzyme + IDS sequencing. Treatable: idursulfase ERT; X-linked.
  • MPS III (Sanfilippo, types A-D): neurodegenerative; no currently approved disease-modifying therapy.
  • MPS IV (Morquio): skeletal predominant; elosulfase alfa ERT for type A.
  • MPS VI (Maroteaux-Lamy): galsulfase ERT.
  • MPS VII (Sly): vestronidase alfa ERT.
• HSCT: standard of care for severe MPS I (Hurler) — must be done before age 2.

Other Lysosomal Storage Disorders

• Krabbe disease: see Leukodystrophies page.
• Metachromatic leukodystrophy: see Leukodystrophies page.
• Pompe disease: see Muscular Dystrophies page.
• Salla disease / Sialic acid storage: SLC17A5.
• Mucolipidoses: ML II/III (GNPTAB, GNPTG).

Urea Cycle Defects

• First-line test: plasma ammonia (elevated, often >200 µmol/L in crisis) + plasma amino acids + urine orotic acid.
• Confirmation: gene-specific sequencing or urea cycle panel.
• Major defects:
  • Ornithine transcarbamylase (OTC, X-linked) — commonest.
  • Carbamoyl phosphate synthetase I (CPS1).
  • Argininosuccinate synthetase (ASS1) — citrullinemia.
  • Argininosuccinate lyase (ASL).
  • Arginase (ARG1).
  • N-acetylglutamate synthase (NAGS).
• Clinical clues: episodic encephalopathy + cerebral edema + hyperammonemia, often triggered by protein load, infection, or postpartum. Adult presentation possible (heterozygous OTC females, late-onset CPS1).
• Treatment: low-protein diet, ammonia scavengers (sodium phenylbutyrate, glycerol phenylbutyrate, sodium benzoate), L-arginine/L-citrulline, hemodialysis for acute hyperammonemia, liver transplant for severe forms.

Neurocutaneous Syndromes

Neurofibromatosis Type 1 (NF1)

• Diagnosis: usually clinical (NIH criteria: ≥2 of café-au-lait spots, neurofibromas, axillary/inguinal freckling, Lisch nodules, optic glioma, distinctive bone lesion, first-degree relative).
• Genetic test: NF1 sequencing + deletion/duplication (MLPA) — large gene (60 exons), many mutation types.
• Yield: ~95% (including ~5% large deletions detected by MLPA).
• When to test: atypical presentation, single criterion, prenatal/preimplantation diagnosis, mosaic suspicion (segmental NF1).
• Treatment:
  • Selumetinib (Koselugo): MEK inhibitor for symptomatic, inoperable plexiform neurofibromas (pediatric).
  • Mirdametinib (Gomekli): newer MEK inhibitor for adult plexiform NF.
  • Surveillance: scoliosis, optic pathway gliomas, learning disabilities, MPNST (malignant peripheral nerve sheath tumor) risk.

Neurofibromatosis Type 2 (NF2) — now NF2-related schwannomatosis

• First-line test: NF2 sequencing + deletion/duplication.
• Clinical clue: bilateral vestibular schwannomas (pathognomonic). Also: meningiomas, ependymomas, schwannomas elsewhere, juvenile posterior subcapsular cataract.
• Mosaicism: ~30% of “sporadic” NF2 — deep sequencing or tumor sequencing required if blood negative + clinical disease.
• Treatment: bevacizumab for vestibular schwannomas; surgery; stereotactic radiosurgery.

Schwannomatosis (non-NF2)

• First-line test: SMARCB1 sequencing → LZTR1 sequencing.
• Clinical clue: multiple schwannomas + spinal/peripheral nerve pain WITHOUT bilateral vestibular schwannomas.

Tuberous Sclerosis Complex (TSC)

See Epilepsy page. TSC1 + TSC2 sequencing + MLPA.

Von Hippel-Lindau (VHL)

• First-line test: VHL sequencing + deletion/duplication (MLPA).
• Yield: ~95–100% with combined approach.
• Clinical clues: hemangioblastomas (cerebellar, spinal, retinal), renal cell carcinoma, pheochromocytoma, pancreatic NETs, endolymphatic sac tumors.
• Treatment: belzutifan (HIF-2α inhibitor) for VHL-associated RCC, CNS hemangioblastomas, pNETs. Aggressive surveillance.

Sturge-Weber Syndrome

• First-line test: somatic GNAQ R183Q mutation in affected tissue (skin, brain) — NOT germline.
• Key point: blood-based testing usually NEGATIVE because the mutation is post-zygotic / mosaic.
• Clinical diagnosis: facial port-wine birthmark (V1 distribution) + leptomeningeal angioma + glaucoma. Diagnosis often radiographic + clinical without genetic confirmation.
• Treatment: ASMs for seizures (often refractory); aspirin (anti-stroke); laser for port-wine; hemispherectomy for refractory cases.

PHACE Syndrome

• Diagnosis: clinical — facial hemangioma + posterior fossa malformation + arterial / cardiac / eye anomalies.
• Genetic basis: still being defined; some cases have somatic mutations.

Incontinentia Pigmenti

• First-line test: IKBKG (formerly NEMO) sequencing — common deletion of exons 4–10 detected by long-range PCR.
• X-linked dominant (lethal in males in utero); females with characteristic skin lesions following Blaschko lines + dental + CNS + ophthalmologic findings.

Disease → Test Quick Reference Table

Pitfalls and Pearls

• Enzyme first, sequencing second for most lysosomal storage diseases — cheaper and faster than NGS panels.
• Females with X-linked storage disease: enzyme can be normal; sequencing required (Fabry, Hunter MPS II).
• Pseudodeficiency: a recurring problem (ASA in MLD, hexosaminidase A in Tay-Sachs); always combine enzyme + sequencing + clinical phenotype.
• GBA1 pseudogene: ensure the lab uses appropriate methodology to distinguish gene from pseudogene.
• Sturge-Weber requires affected-tissue sequencing — somatic post-zygotic GNAQ mutation; blood negative is expected.
• NF2 mosaicism (~30%): if blood negative + clinical disease, sequence tumor tissue.
• OTC deficiency in women: heterozygous females may present with adult-onset episodic encephalopathy + hyperammonemia (postpartum, protein load) — easily missed.
• Adult-onset Niemann-Pick C: looks like atypical psychosis, FTD, or schizophrenia. Vertical supranuclear gaze palsy is the giveaway.
• Adult-onset Tay-Sachs: lower-motor-neuron syndrome — order HexA in unexplained ALS/SMA-mimics, especially Ashkenazi background.
• Carrier screening for Tay-Sachs / Canavan / Gaucher routine for Ashkenazi Jewish, French-Canadian, Cajun populations.
• Newborn screening now includes Pompe, Krabbe, MPS I, X-ALD in many US states — confirm what’s covered in your state.
• Treatment access: most ERTs are extraordinarily expensive ($100k–$1M+/year). Sponsored testing programs widely available.
• Combine biomarker + enzyme + sequencing: belt-and-suspenders approach distinguishes true disease from pseudodeficiency and clarifies VUS.

References

1. Mehta A, Hughes DA. Fabry disease. GeneReviews. 2002 (updated 2017).
2. Beck M. Therapy for lysosomal storage disorders. IUBMB Life. 2010;62(1):33-40.
3. Mistry PK, Belmatoug N, vom Dahl S, Giugliani R. Understanding the natural history of Gaucher disease. Am J Hematol. 2015;90 Suppl 1:S6-S11.
4. 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.
5. Häberle J, Boddaert N, Burlina A, et al. Suggested guidelines for the diagnosis and management of urea cycle disorders. Orphanet J Rare Dis. 2012;7:32.
6. Gross AM, Wolters PL, Dombi E, et al. Selumetinib in children with inoperable plexiform neurofibromas. N Engl J Med. 2020;382(15):1430-1442.
7. Jonasch E, Donskov F, Iliopoulos O, et al. Belzutifan for renal cell carcinoma in von Hippel-Lindau disease. N Engl J Med. 2021;385(22):2036-2046.
8. Shirley MD, Tang H, Gallione CJ, et al. Sturge-Weber syndrome and port-wine stains caused by somatic mutation in GNAQ. N Engl J Med. 2013;368(21):1971-1979.