Genetic peripheral neuropathy testing is dominated by Charcot-Marie-Tooth (CMT) — the commonest hereditary neuromuscular disease — followed by hereditary spastic paraplegia (HSP), hereditary sensory and autonomic neuropathies (HSAN), hereditary ATTR amyloid polyneuropathy (treatable!), and Fabry-related neuropathy. This page covers the highest-yield first-line test for each.

Charcot-Marie-Tooth (CMT)

Step 1: PMP22 Duplication Testing

• Test: PMP22 duplication analysis by MLPA (or genome-wide arrayCGH).
• Yield: CMT1A (caused by PMP22 1.4 Mb duplication on chromosome 17p) is ~40–50% of all CMT.
• Why first: most common CMT subtype + standard NGS may miss the duplication.

Step 2: CMT NGS Panel

• If PMP22 duplication negative: CMT NGS panel covering >80 known CMT genes.
• Major subgroups:
  • CMT1 (demyelinating, AD): PMP22, MPZ, EGR2, NEFL.
  • CMT2 (axonal, AD): MFN2 (commonest), MPZ, HSPB1, NEFL, GDAP1, RAB7A, many others.
  • CMTX (X-linked): GJB1 (connexin-32) — second most common form after CMT1A.
  • CMT4 (recessive, demyelinating): GDAP1, MTMR2, SH3TC2, SBF2, others.
  • HMSN-Russe / CMT-DI: dominant intermediate forms.

Yield & Algorithm

• Step 1 (PMP22 dup): ~40–50% of CMT.
• Step 2 (NGS panel): additional ~30–40%.
• Combined yield: ~70–85% in clinical CMT.
• If both negative + atypical features: trio WES.

NCS Pattern Drives Pre-Test Probability

• Demyelinating (NCV <38 m/s upper limb): most likely CMT1A → start with PMP22 dup.
• Axonal (normal NCV, low CMAP amplitude): CMT2 → NGS panel directly.
• X-linked pattern (males more severe than females): CMTX (GJB1) — many panels include this.

Hereditary ATTR Amyloid Polyneuropathy

• First-line test: TTR sequencing.
• Clinical clues:
  • Adult-onset progressive sensorimotor neuropathy + autonomic dysfunction.
  • Family history of similar (often from specific geographic regions — Portugal, Sweden, Japan, parts of Brazil).
  • Cardiac involvement (HCM-like cardiomyopathy).
  • Carpal tunnel syndrome years before neuropathy.
  • Small fiber neuropathy in middle-aged adults.
• Variant TTR (hereditary): V30M (most common); V122I (commoner in African ancestry); T60A; many others.
• Wild-type ATTR: older adults; cardiac predominant; less neuropathy. TTR sequencing is normal — diagnosis is clinical / pyrophosphate scan / fat-pad biopsy / endomyocardial biopsy.
• Treatment relevance — major:
  • For hATTR polyneuropathy (US FDA approvals):
    • Patisiran (Onpattro): siRNA, IV every 3 weeks.
    • Vutrisiran (Amvuttra): siRNA, subcutaneous every 3 months.
    • Inotersen (Tegsedi): antisense oligonucleotide, subcutaneous weekly.
  • Tafamidis (Vyndaqel 61 mg / Vyndamax) — for hATTR cardiomyopathy, NOT polyneuropathy: in the US, tafamidis is FDA-approved for ATTR cardiomyopathy (ATTR-CM) only. (In Europe, low-dose Vyndaqel 20 mg is EMA-approved for early-stage hATTR polyneuropathy — but not in the US.) Counsel about tafamidis when the hATTR patient also has cardiomyopathy.
• Cascade family testing: first-degree relatives should be tested for the known familial variant.

Fabry Disease (Neuropathy)

• First-line test in males: α-galactosidase A enzyme activity.
• First-line test in females: GLA sequencing — enzyme can be normal in heterozygous females.
• Biomarker: plasma lyso-Gb3 (elevated in disease).
• Clinical clues:
  • Childhood / young adult onset of acral painful neuropathy (burning hands/feet).
  • Angiokeratomas (bathing-trunk distribution).
  • Hypohidrosis.
  • Corneal verticillata (slit lamp).
  • Renal failure, left ventricular hypertrophy, stroke in young (overlap with vascular page).
• Treatment relevance: enzyme replacement (agalsidase α/β) or chaperone (migalastat for amenable GLA mutations).

Hereditary Spastic Paraplegia (HSP)

• First-line test: HSP NGS panel covering >80 SPG genes.
• Major genes:
  • SPG4 (SPAST): most common autosomal dominant form (~40% of AD HSP).
  • SPG3A (ATL1): childhood-onset AD HSP.
  • SPG6 (NIPA1), SPG10 (KIF5A), SPG11 (SPG11, recessive with thin corpus callosum).
  • SPG7 (SPG7): recessive; often atypical with cerebellar features.
  • Many others, including X-linked forms.
• Yield: ~50–70% in clinically suspected HSP with family history.
• If panel negative: trio WES.

Hereditary Sensory and Autonomic Neuropathy (HSAN)

• First-line test: HSAN NGS panel.
• Major types:
  • HSAN1 (SPTLC1, SPTLC2, ATL1, DNMT1): adult-onset sensory loss + autonomic dysfunction.
  • HSAN2 (WNK1/HSN2, FAM134B, KIF1A): congenital sensory neuropathy.
  • HSAN3 (familial dysautonomia, IKBKAP): Riley-Day syndrome, common in Ashkenazi Jewish.
  • HSAN4 (NTRK1): congenital insensitivity to pain with anhidrosis.
  • HSAN5 (NGF): congenital insensitivity to pain.
• When to test: childhood-onset sensory loss + recurrent injuries; autonomic dysfunction + sensory neuropathy; family history.

Refsum Disease

• First-line test: plasma phytanic acid (elevated in disease).
• Confirmation: PHYH sequencing (classical form); PEX7 sequencing (atypical Refsum).
• Clinical clues: progressive sensorimotor neuropathy + retinitis pigmentosa + cerebellar ataxia + cardiac arrhythmia + ichthyosis + anosmia + hearing loss.
• Treatment: strict phytanic-acid-restricted diet. Plasmapheresis for acute exacerbations. Treatable!

Hereditary Neuropathy with Liability to Pressure Palsy (HNPP)

• First-line test: PMP22 deletion by MLPA — the mirror image of CMT1A duplication.
• Clinical clues: recurrent episodes of focal nerve palsy after trivial pressure; EMG shows conduction blocks at common entrapment sites.
• Inheritance: autosomal dominant.

Other Hereditary Peripheral Neuropathies

• Distal hereditary motor neuropathy (dHMN): dHMN NGS panel (some overlap with CMT2 panel).
• Giant axonal neuropathy: GAN sequencing — childhood-onset; characteristic frizzly hair.
• Tangier disease: ABCA1 sequencing; HDL deficiency + neuropathy + orange tonsils.
• Mitochondrial neuropathy: see Mitochondrial page.

Disease → Test Quick Reference Table

Pitfalls and Pearls

• CMT step 1 = PMP22 dup (commonest), step 2 = NGS panel. Combined yield ~70–85%.
• NCS pattern: demyelinating → likely CMT1A; axonal → CMT2; X-linked → GJB1 (CMTX).
• HNPP: PMP22 deletion (opposite of CMT1A); recurrent pressure palsies.
• hATTR polyneuropathy: treatable with patisiran / vutrisiran / inotersen (tafamidis is FDA-approved for ATTR-cardiomyopathy only in the US, not for the polyneuropathy indication) — order TTR sequencing routinely in unexplained adult sensorimotor neuropathy.
• Fabry neuropathy: treatable; α-Gal A in males, GLA sequencing in females (enzyme often normal).
• HSP: SPG4 (SPAST) is the most common AD form; SPG7 with cerebellar features is recessive; SPG11 has thin corpus callosum.
• HSAN: think with congenital sensory loss + recurrent injuries; autonomic dysfunction; family history.
• Refsum: treatable with strict diet — phytanic acid + PHYH in any sensorimotor neuropathy + retinitis pigmentosa.
• Sponsored testing programs for CMT (CMTA / Athena), HSP, hATTR (Alnylam / industry) widely available.
• Trio WES if panel negative + atypical features.

References

1. Pareyson D, Marchesi C. Diagnosis, natural history, and management of Charcot-Marie-Tooth disease. Lancet Neurol. 2009;8(7):654-667.
2. Saporta AS, Sottile SL, Miller LJ, et al. Charcot-Marie-Tooth disease subtypes and genetic testing strategies. Ann Neurol. 2011;69(1):22-33.
3. Adams D, Gonzalez-Duarte A, O’Riordan WD, et al. Patisiran, an RNAi therapeutic, for hereditary transthyretin amyloidosis. N Engl J Med. 2018;379(1):11-21.
4. Maurer MS, Schwartz JH, Gundapaneni B, et al. Tafamidis treatment for patients with transthyretin amyloid cardiomyopathy. N Engl J Med. 2018;379(11):1007-1016.
5. Politei J, Schenone AB, Burlina A, et al. Recommendations for evaluation of the nervous system in Fabry disease. Mol Genet Metab. 2014;112(2):95-101.
6. Fink JK. Hereditary spastic paraplegia: clinico-pathologic features and emerging molecular mechanisms. Acta Neuropathol. 2013;126(3):307-328.
7. Wanders RJ, Komen J, Ferdinandusse S. Phytanic acid metabolism in health and disease. Biochim Biophys Acta. 2011;1811(9):498-507.