Movement Disorders & Ataxias — Genetic Workup

Genetic workup for movement disorders splits cleanly into two categories — repeat-expansion disorders (Huntington disease, spinocerebellar ataxias, Friedreich ataxia, DRPLA, Kennedy disease) which require disease-specific repeat assays NGS will miss, and point-mutation / del-dup disorders (Wilson disease, familial Parkinson disease, hereditary dystonia, NBIA) which are addressed by sequencing and dosage analysis. This page walks through the high-yield first-line test for each disease and the appropriate reflex if the first-line is negative. Clinical syndrome descriptions are in the Movement Disorders clinical chapters; here, the focus is on the lab.

Huntington Disease

• First-line test: HTT CAG repeat sizing.
• Methodology: PCR + RP-PCR for sizing; Southern blot for very large expansions.
• Critical point: standard NGS does NOT detect the CAG expansion. Order the disease-specific repeat assay.
• Interpretation:
  • ≤26 repeats: normal.
  • 27–35 (intermediate / “mutable normal”): NOT HD-causing in the proband, but unstable on transmission — the allele can expand into the disease range in offspring (paternal transmission carries the highest expansion risk). Counsel for reproductive risk.
  • 36–39 (reduced-penetrance HD allele): may or may not develop clinical HD; later/milder onset typical when penetrant.
  • ≥40 (full-penetrance HD allele): HD will develop given normal lifespan; age of onset trends younger as repeat count rises.
• Predictive testing protocol: formal pre-test genetic counseling × 2 sessions, mental health screening, cooling-off period, in-person disclosure.
• If negative + HD-like phenotype: HD phenocopy panel — PRNP (HDL1), JPH3 (HDL2), C9orf72, SCA1, SCA2, SCA3, SCA17, TBP.

Spinocerebellar Ataxias (SCAs) — Autosomal Dominant

• First-line test: SCA repeat-expansion panel covering SCA 1, 2, 3, 6, 7, 8, 10, 12, 17, DRPLA.
• Yield: ~20–40% in clinically suspected dominant ataxia, depending on population.
• If negative: hereditary ataxia NGS panel for non-expansion SCAs (SCA5, 11, 13, 14, 15, 19/22, 23, 27, 28, others) and recessive ataxias (ATM, SETX, POLG, SYNE1, ANO10, others).
• If negative + ataxia + neuropathy: long-read sequencing for RFC1 AAGGG biallelic expansion (CANVAS — cerebellar ataxia, neuropathy, vestibular areflexia syndrome).
• If negative + multi-system features: trio WES.

Friedreich Ataxia

• First-line test: FXN GAA repeat sizing.
• Standard clinical methodology: triplet-primed PCR + long-range PCR (or Southern blot for very large expansions) remains the routine clinical assay at most labs.
• Emerging methodology: long-read sequencing (PacBio HiFi, Oxford Nanopore) is increasingly offered for accurate sizing and detection of GAA interruptions that modify phenotype — promising but not yet universal first-line.
• Interpretation:
  • ~5–33 GAA repeats: normal.
  • ~34–65: borderline / premutation.
  • ~66–1,700: disease range (homozygous expansion = classical FA).
• If only one expansion + compatible phenotype: send FXN sequencing for a point variant on the other allele (compound heterozygote).
• Treatment relevance: confirmed FA is now eligible for omaveloxolone (FDA-approved 2023). Order testing in any suspected case.

DRPLA (Dentatorubral-Pallidoluysian Atrophy)

• First-line test: ATN1 CAG repeat sizing.
• Usually included in standard SCA repeat-expansion panels.
• More common in Japanese populations than European.

Wilson Disease

• Clinical workup drives the diagnosis: serum ceruloplasmin (low), 24-hour urine copper (high), liver biopsy copper (high), Kayser-Fleischer rings.
• Genetic confirmation: ATP7B full-gene sequencing + del/dup analysis.
• Note: more than 600 disease-causing ATP7B variants known — sequencing is more sensitive than targeted common-variant testing.
• Family screening with the familial variant is straightforward once identified.

Familial / Early-Onset Parkinson Disease

• First-line test: PD NGS panel covering LRRK2, GBA1, SNCA, PRKN, PINK1, DJ-1 (PARK7), ATP13A2, VPS35, FBXO7, DNAJC6, others.
• When to test:
  • Onset <50 years.
  • Autosomal dominant family history.
  • Multiple affected siblings (recessive).
  • Ashkenazi or North African Jewish background → consider targeted LRRK2 G2019S testing.
• LRRK2 G2019S: most common autosomal dominant PD mutation; especially prevalent in Ashkenazi and North African populations.
• GBA1: most common genetic risk modifier for PD; heterozygous variants increase risk ~5-fold. Counsel about reproductive implications (Gaucher disease in compound heterozygotes / homozygotes).
• Reflex if panel negative: trio WES for atypical / multi-system features.

Hereditary Dystonia

• First-line test: dystonia NGS panel — TOR1A (DYT1, classical early-onset dystonia), THAP1 (DYT6, mixed dystonia), GNAL (DYT25, craniocervical dystonia), ANO3 (DYT24), KMT2B (DYT28 — childhood-onset generalized), SGCE (myoclonus-dystonia), PRKRA (DYT16), TUBB4A (whispering dysphonia + dystonia).
• When to test: early-onset dystonia, generalized dystonia, mixed phenotypes, family history.
• Dopa-responsive dystonia: GCH1 sequencing (most common form) — order separately if classical phenotype (childhood-onset dystonia with diurnal variation, dramatic response to low-dose levodopa).
• Reflex if panel negative: trio WES for atypical / multi-system features.

Kennedy Disease (Spinal-Bulbar Muscular Atrophy)

• First-line test: AR (androgen receptor) CAG repeat sizing — X-linked.
• Clinical features driving testing: adult-onset proximal weakness + bulbar involvement (tongue atrophy, dysarthria) + gynecomastia + reduced fertility in males.
• Repeat sizes:
  • ≤34 CAG: normal.
  • ≥38 CAG: disease.
• Female carriers: usually asymptomatic; may have subclinical motor neuron findings.

Neurodegeneration with Brain Iron Accumulation (NBIA)

• First-line test: NBIA NGS panel.
• Major genes: PANK2 (pantothenate kinase-associated neurodegeneration, classic NBIA), PLA2G6 (PLAN, infantile neuroaxonal dystrophy), C19orf12 (mitochondrial membrane protein-associated neurodegeneration), WDR45 (beta-propeller protein-associated neurodegeneration), FA2H, CP (aceruloplasminemia), FTL (neuroferritinopathy), others.
• Imaging clue: low T2 signal in globus pallidus / substantia nigra (“eye of the tiger” classic for PKAN).
• Reflex if panel negative: trio WES.

Other Repeat-Expansion Movement Disorders

• Fragile X tremor-ataxia syndrome (FXTAS): FMR1 CGG repeat sizing — premutation range (55–200) in adult-onset tremor / ataxia. Distinct from full mutation FXS (>200).
• Myoclonus-dystonia: SGCE sequencing (paternal imprinting — variant inherited from father is symptomatic).
• SCA8, SCA10, SCA12, SCA17, SCA31, SCA36: included in many SCA repeat-expansion panels.

Disease → Test Quick Reference Table

Pitfalls and Pearls

• HD, SCAs, FA, DRPLA, Kennedy disease, FXTAS: all repeat-expansion disorders. NGS misses them. Order the specific repeat assay.
• HD predictive testing: formal multi-session counseling protocol is the standard of care.
• SCA panel first, then hereditary ataxia NGS panel: don’t skip the expansion testing.
• Friedreich ataxia: triplet-primed PCR + long-range PCR remains the standard clinical assay; long-read is emerging — confirm what your lab offers.
• If only one FXN expansion is found: send sequencing for point variant on the other allele.
• Wilson disease: clinical/biochemical drives the diagnosis; ATP7B sequencing confirms (>600 variants known).
• LRRK2 G2019S: prevalent in Ashkenazi and North African populations — consider targeted testing.
• GBA1 variants: most common PD risk modifier; reproductive counseling for Gaucher disease implications.
• Dopa-responsive dystonia (GCH1): treatable with low-dose levodopa — don’t miss it. Trial of levodopa is reasonable while testing.
• Myoclonus-dystonia (SGCE): paternal imprinting — variant inherited from father is symptomatic.
• NBIA “eye of the tiger” sign: classic imaging clue for PKAN (PANK2).
• FXTAS: don’t miss in older adults with progressive tremor + ataxia + cognitive change + MRI MCP sign — FMR1 premutation testing.

References

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2. Cortese A, Tozza S, Yau WY, et al. Cerebellar ataxia, neuropathy, vestibular areflexia syndrome due to RFC1 repeat expansion. Brain. 2020;143(2):480-490.
3. Lill CM. Genetics of Parkinson’s disease. Mol Cell Probes. 2016;30(6):386-396.
4. Sidransky E, Lopez G. The link between the GBA gene and parkinsonism. Lancet Neurol. 2012;11(11):986-998.
5. Klein C, Lohmann-Hedrich K, Rogaeva E, et al. Deciphering the role of heterozygous mutations in genes associated with parkinsonism. Lancet Neurol. 2007;6(7):652-662.
6. Ozelius LJ, Lubarr N. DYT1 early-onset isolated dystonia. GeneReviews. 2024 update.
7. HD Predictive Testing Protocol. J Med Genet. 1994;31(7):555-559.
8. Lynch DR, Chin MP, Delatycki MB, et al. Safety and efficacy of omaveloxolone in Friedreich ataxia (MOXIe Study). Ann Neurol. 2021;89(2):212-225.