Huntington Disease & Spinocerebellar Ataxias

Trinucleotide repeat expansion diseases — Huntington disease and the spinocerebellar ataxias (SCAs) — are a heterogeneous group of dominantly inherited neurodegenerative disorders united by their genetic mechanism (an expanded triplet repeat in coding or non-coding regions) and their characteristic patterns of selective neuronal vulnerability. The conditions illustrate how a single molecular mechanism (toxic gain of function from polyglutamine-containing proteins, RNA toxicity, or protein loss of function) can produce diverse clinical syndromes depending on which neuronal populations are vulnerable. This page covers Huntington disease and the major SCAs.

Huntington Disease (HD)

Genetics

  • Autosomal dominant.
  • HTT gene on chromosome 4p16.3.
  • CAG repeat expansion in exon 1 of HTT.
  • Normal: ≤ 26 repeats.
  • Intermediate: 27-35 (no clinical disease but may transmit expansion).
  • Reduced penetrance: 36-39 repeats.
  • Full penetrance: ≥ 40 repeats.
  • Repeat size inversely correlates with age of onset.
  • Anticipation: expansion can grow when transmitted, especially through paternal inheritance.

Pathology

  • Caudate atrophy (head): characteristic gross finding.
  • Putaminal atrophy: less than caudate.
  • Cortical atrophy: layer III-VI pyramidal cells; later in disease.
  • “Box-car” or square ventricular shape: from caudate atrophy.
  • Selective loss of medium spiny neurons of striatum.
  • Preferential loss of indirect pathway neurons (enkephalin-positive) early; both pathways later.
  • Sparing of striatal interneurons.
  • Reactive astrogliosis throughout striatum.
  • Vonsattel grading (0-4): based on striatal severity.

Inclusions

  • Intranuclear polyglutamine inclusions: in neurons; positive for huntingtin protein and ubiquitin.
  • Particularly prominent in cortex.
  • Anti-polyglutamine antibody 1C2 detects them.

Clinical Features

  • Motor: chorea (early), eventually dystonia, bradykinesia, rigidity, gait dysfunction. Westphal variant: rigidity predominant; juvenile onset.
  • Cognitive: executive dysfunction, subcortical dementia.
  • Psychiatric: depression, anxiety, irritability, psychosis, suicide risk.
  • Weight loss: despite caloric intake.
  • Mean onset: 40s; death 15-20 years after onset.
  • Juvenile HD (< 20): rigidity and dystonia rather than chorea.

Treatment

  • No disease-modifying therapy.
  • Tetrabenazine, deutetrabenazine, valbenazine: VMAT2 inhibitors for chorea.
  • Antidepressants, antipsychotics, anxiolytics for psychiatric symptoms.
  • Antisense oligonucleotide therapies in trials (mixed results so far).
  • Multidisciplinary care.

Spinocerebellar Ataxias (SCAs)

Heterogeneous group; ~50 genetic subtypes (SCA1, SCA2, SCA3, etc.). Mostly autosomal dominant.

Pathologic Themes

  • Cerebellar Purkinje cell loss.
  • Inferior olivary nucleus loss (often).
  • Pontine nuclei.
  • Spinal cord involvement (spinocerebellar tracts, dorsal columns, corticospinal).
  • Brainstem nuclei.
  • Cortex variable.
  • Selective vulnerability depends on the specific gene.

SCA1, SCA2, SCA3 (Machado-Joseph Disease)

  • Polyglutamine repeat expansions (CAG in coding region).
  • SCA1: ATXN1 gene; cerebellar + brainstem + corticospinal.
  • SCA2: ATXN2; cerebellar + neuropathy + sometimes parkinsonism; slow saccades.
  • SCA3 (MJD): ATXN3; cerebellar + brainstem + dystonia + parkinsonism + neuropathy. Most common SCA worldwide.
  • Intranuclear polyglutamine inclusions.
  • Anticipation common.

SCA6

  • CACNA1A gene (calcium channel); small CAG expansion.
  • Pure cerebellar predominant.
  • Late-onset, slower progression.

SCA7

  • ATXN7; CAG expansion.
  • Cerebellar + retinal degeneration with visual loss.

SCA8, SCA10, SCA12, SCA17

  • SCA8: CTG expansion in noncoding region; RNA toxicity hypothesized.
  • SCA10: ATTCT pentanucleotide expansion; cerebellar + seizures.
  • SCA17: TBP gene; CAG expansion; HD-like with chorea and dementia.

SCA36 (Asidan)

  • NOP56 gene; hexanucleotide repeat expansion.
  • Cerebellar + motor neuron features.

Other SCAs

Dozens of additional subtypes; each with characteristic clinical features and inheritance.

Friedreich Ataxia (FA)

  • Autosomal recessive (not technically an SCA in the dominant sense).
  • FXN gene; GAA repeat expansion in intron 1 → frataxin protein loss of function.
  • Frataxin is a mitochondrial protein involved in iron-sulfur cluster assembly.

Clinical Features

  • Childhood/adolescent onset.
  • Combined cerebellar + sensory ataxia (dorsal column degeneration).
  • Romberg positive.
  • Areflexia (sensory) + extensor plantar (corticospinal) — mixed pattern.
  • Cardiomyopathy (often hypertrophic; cardiac death common).
  • Diabetes mellitus.
  • Kyphoscoliosis, pes cavus.
  • Optic atrophy, hearing loss in some.

Pathology

  • Dorsal root ganglion neuron loss → dorsal column degeneration.
  • Dorsal spinocerebellar tract degeneration.
  • Corticospinal tract degeneration.
  • Dentate nucleus of cerebellum.
  • Optic nerves.
  • Heart: hypertrophic cardiomyopathy.

Treatment

Omaveloxolone (Nrf2 activator) approved 2023 for FA — modest disease-modifying effect; cardiac and other supportive care.

Other Hereditary Ataxias

  • Ataxia-telangiectasia: ATM mutations; cerebellar + telangiectasias + immunodeficiency + malignancy risk.
  • Episodic ataxia (EA1, EA2): KCNA1, CACNA1A; brief episodes of ataxia.
  • FXTAS (fragile X-associated tremor/ataxia syndrome): FMR1 premutation; older men; tremor + ataxia + middle cerebellar peduncle sign on MRI.
  • Autosomal recessive ataxias: ARCA (multiple types).
  • Vitamin E deficiency ataxia (AVED): TTPA gene; treatable.
  • Refsum disease: PHYH; cerebellar + retinitis pigmentosa + neuropathy + cardiac.

Diagnosis

  • Family history, age of onset, clinical features.
  • Genetic panel for SCAs and related ataxias.
  • MRI for atrophy patterns.
  • Exclusion of acquired causes (paraneoplastic, autoimmune, nutritional, toxic).

🔍 Did You Know?

The phenomenon of genetic anticipation in trinucleotide repeat expansion diseases — earlier onset and more severe disease in successive generations — was once thought to be an artifact of ascertainment bias. The discovery that it reflects a real biological phenomenon, namely meiotic instability of the expanded repeat with paternal transmission (especially in CAG-expansion diseases like Huntington), transformed our understanding of these conditions. In Huntington disease, paternal transmission can expand a repeat from 40 to 60 to 80 repeats over successive generations, with disease onset shifting from 50s to 20s to childhood (juvenile HD). The largest expansions, in juvenile HD with paternal inheritance, can produce very early onset with rigid-akinetic features (Westphal variant) rather than the classical chorea of adult-onset HD. The mechanism reflects the instability of long CAG tracts during male spermatogenesis. The clinical implications are substantial: a patient with juvenile HD often has a paternally transmitted larger expansion than the affected parent; family planning counseling must consider not only the risk of transmission but the possibility of expansion. The same principle applies to SCAs (especially SCA1, 2, 3, 7 with anticipation), to myotonic dystrophy (DM1, the CTG expansion in DMPK can grow to thousands of repeats causing congenital severe disease), and to other repeat-expansion disorders. The lesson: the genetic mechanism in repeat-expansion diseases is itself unstable, and the clinical phenotype can vary dramatically within a single family across generations.

Pitfalls and Pearls

  • Huntington disease: HTT CAG expansion; caudate atrophy; medium spiny neuron loss; intranuclear polyglutamine inclusions.
  • Vonsattel grading: 0-4 by striatal severity.
  • Box-car ventricles: caudate atrophy in HD.
  • HD anticipation: especially with paternal transmission.
  • Juvenile HD (Westphal): rigid-akinetic; paternal expansion to very large size.
  • VMAT2 inhibitors (tetrabenazine, deutetrabenazine, valbenazine): chorea treatment.
  • SCA3 (Machado-Joseph): most common SCA worldwide; cerebellar + brainstem + dystonia + parkinsonism.
  • SCA6: pure cerebellar; CACNA1A small expansion.
  • SCA17: HD-like with chorea and dementia.
  • Friedreich ataxia: autosomal recessive; FXN GAA expansion; cerebellar + sensory ataxia + cardiomyopathy.
  • Omaveloxolone: 2023-approved for FA.
  • Ataxia-telangiectasia: cerebellar + telangiectasias + immunodeficiency + malignancy.
  • FXTAS: FMR1 premutation; older men with tremor + ataxia.
  • Genetic panels: SCAs, FA, FXTAS, ataxia-telangiectasia, vitamin E deficiency.
  • Polyglutamine 1C2 antibody: detects polyQ inclusions in HD and several SCAs.

References

  1. Love S, Budka H, Ironside JW, Perry A, eds. Greenfield’s Neuropathology. 9th ed. CRC Press; 2015.
  2. Vonsattel JP, Myers RH, Stevens TJ, Ferrante RJ, Bird ED, Richardson EP Jr. Neuropathological classification of Huntington’s disease. J Neuropathol Exp Neurol. 1985;44(6):559-577.
  3. Bates GP, Dorsey R, Gusella JF, et al. Huntington disease. Nat Rev Dis Primers. 2015;1:15005.
  4. Klockgether T, Mariotti C, Paulson HL. Spinocerebellar ataxia. Nat Rev Dis Primers. 2019;5(1):24.
  5. Pandolfo M. Friedreich ataxia: the clinical picture. J Neurol. 2009;256(Suppl 1):3-8.
  6. 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.