Motor Neuron Disease — Genetic Workup

Genetic testing in motor neuron disease has shifted from optional to standard of care for any ALS patient — because SOD1-positive ALS is now eligible for the disease-modifying antisense oligonucleotide tofersen (FDA-approved 2023). Spinal muscular atrophy (SMA) genetics drives selection between three different disease-modifying therapies (nusinersen, risdiplam, onasemnogene). Kennedy disease has an unambiguous single-gene answer (AR CAG expansion). This page covers the highest-yield first-line test for each.

Amyotrophic Lateral Sclerosis (ALS) — Familial and Sporadic

First-Line Test

• ALS NGS panel covering all major ALS genes — SOD1, FUS, TARDBP, TBK1, VCP, PFN1, UBQLN2, OPTN, SQSTM1, CHCHD10, MATR3, ANXA11, NEK1, others.
• PLUS specialized C9orf72 hexanucleotide repeat expansion testing (RP-PCR / Southern blot / long-read).
• Order in every ALS patient — not just those with family history. ~10–15% of “sporadic” ALS has a pathogenic variant.

Why Test Every ALS Patient?

• SOD1-positive ALS is now treatable: tofersen (anti-SOD1 antisense oligonucleotide) is FDA-approved (April 2023) for SOD1-positive ALS. Without genetic testing, eligible patients are missed.
• C9orf72 expansion: most common genetic cause in many populations; identifies patients at risk for FTD overlap (cognitive surveillance).
• Cascade family testing: identifies at-risk relatives who may benefit from predictive testing or research participation.
• Research / trial eligibility: many active ALS trials enroll based on genetic status.

SOD1-Specific Considerations

• Tofersen (Qalsody): intrathecal administration; FDA-approved on accelerated pathway based on neurofilament light biomarker reduction; VALOR trial showed treatment-effect signal in faster-progressing SOD1 patients.
• Genotype-phenotype: SOD1 A4V variant (US/European populations) causes very rapid progression; many other variants cause more typical phenotypes.
• Pre-symptomatic testing: emerging — formal counseling protocol required.

C9orf72 — How to Test

• Standard NGS does NOT detect the GGGGCC hexanucleotide expansion.
• Methodology: specialized repeat-primed PCR (RP-PCR), Southern blot, or long-read sequencing.
• Repeat sizes: ~2–25 normal; ~25–60 “intermediate” (uncertain pathogenicity); ≥30–60+ disease range (often hundreds to thousands).
• Phenotypic overlap: ALS, FTD, ALS-FTD, parkinsonism with cognitive change.

When ALS Panel Is Negative

• Trio WES if the patient is young, has multi-system features, or atypical phenotype.
• Most “sporadic” ALS remains genetically unsolved — polygenic risk + environmental factors.

Spinal Muscular Atrophy (SMA)

First-Line Test

• SMN1 exon 7 deletion analysis (MLPA or qPCR).
• Yield: ~95% of SMA is caused by homozygous deletion of SMN1 exon 7.

Reflex Testing

• If SMN1 deletion not found but SMA strongly suspected: SMN1 full-gene sequencing for a point variant on the second allele (~5% of cases).

SMN2 Copy Number — Critical for Treatment

• SMN2 copy number drives both prognosis AND treatment selection:
  • 1–2 copies of SMN2: typically severe SMA type 0/1 (infantile onset, rapid progression).
  • 3 copies: typically SMA type 2 (intermediate).
  • 4+ copies: typically SMA type 3 (later onset, milder).
• Treatment options (all FDA-approved):
  • Nusinersen (Spinraza, intrathecal antisense oligonucleotide).
  • Risdiplam (Evrysdi, oral small molecule).
  • Onasemnogene abeparvovec (Zolgensma, gene therapy — single IV infusion; restricted to patients ≤2 years and ≤21 kg).
• Newborn screening for SMA is now universal in the US (added 2018) — early identification + treatment dramatically alters outcome.

Carrier Testing

• ~1 in 40–60 carriers (SMN1 deletion).
• Standard reproductive carrier screening before pregnancy is appropriate.
• “Silent carriers” (2 SMN1 copies on one chromosome, 0 on the other) are missed by deletion-only testing — limitation to disclose.

Kennedy Disease (Spinal-Bulbar Muscular Atrophy, SBMA)

• First-line test: AR (androgen receptor) CAG repeat sizing.
• Inheritance: X-linked recessive — affects males; females are usually asymptomatic carriers.
• Clinical clues:
  • Adult-onset (30s–50s) proximal weakness + bulbar involvement.
  • Tongue atrophy + dysarthria + dysphagia.
  • Gynecomastia + reduced fertility (mild androgen insensitivity).
  • Often mistaken for ALS but progresses more slowly.
• Repeat size:
  • ≤34 CAG: normal.
  • ≥38 CAG: disease.

Other Hereditary Motor Neuron / Motor Disease

• Distal hereditary motor neuropathy (dHMN): dHMN NGS panel.
• Hereditary spastic paraplegia (HSP): HSP NGS panel — covered on the Peripheral Neuropathy page.
• Pure motor lower-MND with bulbar onset: consider Kennedy disease (AR CAG).
• Childhood-onset SMA-like: SMA-LED1 (DYNC1H1), SMA-LED2 (BICD2), UBA1-X-linked SMA, others — included in pediatric SMA / motor panels.
• ALS plus cognitive features: think C9orf72; FTD-MND overlap.

Disease → Test Quick Reference Table

Pitfalls and Pearls

• Order genetic testing in EVERY ALS patient — SOD1 positivity unlocks tofersen; family history is not required.
• C9orf72 expansion: standard NGS misses it; verify specialized expansion testing is included.
• SMA: MLPA for SMN1 exon 7 deletion first; sequence SMN1 if negative (~5% point variants).
• SMN2 copy number: critical for treatment choice (nusinersen / risdiplam / onasemnogene).
• SMA newborn screening is universal in the US — affected newborns identified before symptoms.
• “Silent SMA carriers” (2+0 SMN1 configuration) are missed by standard deletion testing — counsel about this limitation.
• Kennedy disease: AR CAG repeat (X-linked); often mistaken for ALS but bulbar + gynecomastia + slow progression.
• FTD-MND overlap: think C9orf72 in any ALS patient with cognitive features or FTD patient with motor signs.
• Pre-symptomatic testing: formal counseling protocol required, especially for SOD1, C9orf72.
• Sponsored testing programs for ALS panels (Biogen, others) — usually free for symptomatic patients.

References

1. Miller TM, Cudkowicz ME, Genge A, et al. Trial of antisense oligonucleotide tofersen for SOD1 ALS. N Engl J Med. 2022;387(12):1099-1110.
2. Renton AE, Chiò A, Traynor BJ. State of play in amyotrophic lateral sclerosis genetics. Nat Neurosci. 2014;17(1):17-23.
3. Roggenbuck J, Quick A, Kolb SJ. Genetic testing and genetic counseling for amyotrophic lateral sclerosis: an update for clinicians. Genet Med. 2017;19(3):267-274.
4. Lefebvre S, Bürglen L, Reboullet S, et al. Identification and characterization of a spinal muscular atrophy-determining gene. Cell. 1995;80(1):155-165.
5. Mendell JR, Al-Zaidy S, Shell R, et al. Single-dose gene-replacement therapy for spinal muscular atrophy. N Engl J Med. 2017;377(18):1713-1722.
6. Finkel RS, Mercuri E, Darras BT, et al. Nusinersen versus sham control in infantile-onset spinal muscular atrophy. N Engl J Med. 2017;377(18):1723-1732.
7. La Spada AR, Wilson EM, Lubahn DB, et al. Androgen receptor gene mutations in X-linked spinal and bulbar muscular atrophy. Nature. 1991;352(6330):77-79.