Hongyan Li, MD, PhD
DESCRIPTION
- Cerebellar ataxia is the leading manifestation of many progressive neurodegenerative diseases. In general, these diseases can be grouped into hereditary and non-hereditary ataxias. Hereditary cerebellar ataxias include autosomal dominant, autosomal recessive, X chromosome-linked, and mitochondrial types. Non-hereditary (or sporadic) cerebellar ataxias include acquired and idiopathic types (1,2,3).
- Spinocerebellar ataxias (SCAs) compose of the majority of the autosomal dominant cerebellar ataxias (ADCAs). Besides SCAs, dentatorubropallidoluysian atrophy (DRPLA) and episodic ataxias (EAs) are also included in the ADCA category. Researchers have also showed that a few SCA subtypes inherit in an X-linked recessive pattern (SCAX). EAs and other types of cerebellar ataxias are the topics of other chapters and therefore are not discussed here.
- At present, more than 30 different SCA subtypes have been reported.
EPIDEMIOLOGY
Incidence
1–5/100,000
Prevalence
- 0.9–3/100,000 (2)
- SCA1, 2, 3, 6 and 7 account for ~75% of SCAs (2). SCA3 (Machado-Joseph disease) is the most common subtype worldwide (20–50% of all SCAs).
- Geographical distribution of SCA subtypes varies significantly. For example, SCA3 accounts for 80% of SCAs in Brazil and Portugal. SCA3, 6, 16, 31 are common in Japan. SCA2 is seen in Cuba, SCA8 in Finland, SCA32 in China, and SCA10 in Mexico (4).
RISK FACTORS
Family history of typical symptoms. However, a familial history may be absent.
Genetics
- Genetic mutations (4):
- Include translated or untranslated repeat expansions and point mutations
- Trinucleotide CAG repeats: SCA1, 2, 3, 6, 7, 12, 17, and DRPLA
- Other repeats: SCA8 (CTG), 10 (ATTCT), and SCA31 (TGGAA)
- Other mutations: SCA5, 11, 12, 13, 14, 15, 16, 23, and 27
- Hereditary patterns: Autosomal dominant for all subtypes except SCAX1-5
- Characteristics of inheritance
- Some SCAs demonstrate anticipation (most prominent in SCA1, 7, DRPLA).
- Preference to paternal transmission
- Affected genes, gene products, and chromosomal loci (partial listing) (3,4,5):
- SCA1: ATXN1, ataxin-1, 6p23
- SCA2: ATXN2, ataxin-2, 12q24
- SCA3: ATXN3, ataxin-3, 14q24.3-q31
- SCA4: Q9H7K4, puratrophin-1, 16q22.1
- SCA5: SPTBN2, spectrin β chain, 11q13
- SCA6: CACNA1A, voltage-gated calcium channel α-1A subunit, 19p13
- SCA7: ATXN7, ataxin-7, 3p21.1-p12
- SCA8: KLHL1AS, 13q21
- SCA10: ATXN10, ataxin-10/E46L, 22q13
- SCA11: 15q14-q21.3
- SCA12: PPP2R2B, protein phosphatase 2A brain specific regulatory subunit, 5q31-q33
- SCA13: 19q13.3-q13.4
- SCA14: PRKCG, protein kinase C γ subunit, 19q13.4
- SCA27: FGF14, fibroblast growth factor 14, 13q34
- SCA28: AFG3L2, ATPase family gene 3-like 2, 18p11.22
- SCA30: ODZ3 (candidate gene), 4q34.3-q35.1
- SCA31: TGGAA repeat insertion, 16q22.1
- SCA32: 7q32-q33
- SCA35: TGM6, transglutaminase 6, 20p13
- SCA Unlinked: No chromosomal linkage
- DRPLA: DRPLA, atrophin-1, 12p13.31
- SCAX1: Xp11.21-q21.3
- SCAX5: Xq25-q27.1
PATHOPHYSIOLOGY
- Genes with mutations may become unstable, miscode, or lose their functions. These genetic errors may eventually result in gene products in reduced or excessive amounts, as well as defected products. Consequently, the specifically coded phenotypes by these genes may be expressed incorrectly or even missing. Genetically defected cells therefore may be functionally or structural abnormal. Patients with SCA6, 13, and 27 have defective ion channels. Those with SCA5 and DRPLA have defective neurotransmitter receptors. SCA1, 2, and 3 are associated with defected cytoplasmic or nuclear proteins.
- Many mutations interrupt degradation of the gene products. Intracytoplasmic or intranuclear accumulations of these products in excessive amounts lead to progressive degeneration and eventual cell death. SCAs with repeat mutations (such as CAG with SCA1, 2, 3, 6, 7, 12, 17, and DRPLA) share this phenomenon.
ETIOLOGY
All SCAs are hereditary diseases. However, family history may not always be identified (SCA6 is an example of this).
COMMONLY ASSOCIATED CONDITIONS
Cerebellar ataxia, pyramidal and extrapyramidal signs, peripheral neuropathy, cortical symptoms (mental retardation, dementia, epileptic seizures, and psychosis), and ocular signs (ophthalmoplegia, pigmentary retinopathy, nystagmus, impaired gaze control, etc.).
HISTORY
- Common symptoms (4):
- Progressive cerebellar ataxia (gait ataxia and dysarthria) is the hallmark symptom for all SCAs.
- Pyramidal signs (upper motor neuron signs, hyperreflexia, and spasticity): SCA1, 3, 7, 8, 11, 12, 23, 35
- Extrapyramidal symptoms (tremor, dystonia, choreoathetosis, dyskinesia, etc.): SCA2, 3, 9, 12, 16, 17, 21, 27, SCAX2, DRPLA
- Axonal peripheral neuropathy: SCA1, 2, 3, 4, 8, 12, 14, 18, 25, 27
- Oculomotor abnormalities: Hypermetric saccades (SCA1), hypometric saccades (SCA2, 7, 17), slow saccades (SCA2, 7, 35), nystagmus (SCA3, 6, unlinked), and ophthalmoplegia (SCA1, 2, 3, 9, 28).
- Impaired cognition: SCA1, 2, 3, 12, 13, 14, 17, 19, 21, 17, 32, SCAXs, DRPLA
- Other symptoms: Pigmentary retinal degeneration (SCA7), seizures (SCA7, 10, 17, DRPLA), myoclonus (SCA2, 14, 19, DRPLA), hearing loss (SCA7, SCAX3), muscular atrophy (SCA18), hyporeflexia (SCA22), palatal tremor (SCA20), psychiatric disorders (SCA27, DRPLA), spasmodic torticollis (SCA35), azospermia (SCA32), etc.
- Symptomatic classification:
- ADCA I: Cerebellar ataxia plus other central neurological symptoms (SCA1, 2, 3, 4, 8, 9, 12, 17, 27, 28, and 35)
- ADCA II: Cerebellar ataxia plus pigmentary retinopathy (SCA7)
- ADCA III: Pure cerebellar ataxia (SCA5, 6, 10, 11, 15, 22, 26, 30, 31, and SCA unlinked)
- Other: SCA13
- The onset ages are usually during adulthood with the majority in their 30–50s. SCA2, 5, 7, 13, SCAXs, and DRPLA start during childhood. SCA6 may become symptomatic after age 60.
- Progression: The disease durations vary significantly from less than a decade (SCA10, SCAXs) to normal lifespan (SCA6, 8, 11, 30). Slow progression occurs in SCA5, 15, 22, and 23.
PHYSICAL EXAM
Neurological examination shows significant cerebellar ataxia with or without the other physical abnormalities as aforementioned.
DIAGNOSTIC TESTS AND INTERPRETATION
Lab
Initial Lab Tests
- Tests to rule out other causes of cerebellar ataxias, especially acquired conditions.
- Samples of blood and cerebrospinal fluid are usually tested.
Follow-Up & Special Considerations
- Results from the initial laboratory testing may lead to considerations of further investigations.
- Genetic tests, which use DNA samples from blood cells, are available for many hereditary ataxias. Selection is based on clinical and initial laboratory evaluations.
Imaging
Initial Approach
- Brain MRI with contrast is the initial imaging of choice. Significant findings include cerebellar and brainstem atrophies. Brain MRI also helps to rule out other causes of cerebellar ataxia.
- Functional studies, such as functional MRI, MRS, diffusion tensor MRI, and positron emission tomography, may also be used as indicated.
Follow-Up & Special Considerations
- Brain MRI may be repeated once every 6–12 months.
Diagnostic Procedures/Other
- Family history and pattern of inheritance
- Genetic tests: Commercially available for many SCA subtypes (SCA1, 2, 3, 6, 7, 8, 10, 12, 13, 14, 17, and 18) (Athena Diagnostics, Inc., Website: www.athenadiagnostics.com).
- Pathology from autopsy when possible.
Pathological Findings
- Cerebellar atrophy is the hallmark pathological feature for all SCAs although its severity varies significantly among different subtypes.
- Diffuse degeneration is essential. Meanwhile, some subtypes may preferentially affect certain regions. For example, SCA15 mainly affects dorsal vermis and SCA19 prefers hemispheres (4).
- Degeneration and loss of Purkinje cells are the consistent findings. However, Purkinje cells are spared in SCA3. Granular cells may also been affected.
- SCA1, 2, 3, 7, 23 affect dentate nucleus.
DIFFERENTIAL DIAGNOSIS
- Other hereditary cerebellar ataxias
- Other ADCAs (EAs)
- Autosomal recessive cerebellar ataxias (Friedreich's ataxia, ataxia with primary vitamin E deficiency, ataxia telangiectasia, abetalipoprotinemia, autosomal cerebellar ataxias, etc.)
- X chromosome-linked ataxias: Fragile X-associated tremor/ataxia syndrome, adrenoleukodystrophy
- Mitochondrial cerebellar ataxias
- Non-hereditary cerebellar ataxias: Thiamin deficiency-related cerebellar degeneration, paraneoplastic cerebellar lesions (presence of anti-Hu, Yo, Ri, Tr, mGlu-R antibodies), autoimmune-mediated cerebellar injuries (presence of anti-glutamic acid decarboxylase and antigliadin antibodies).
- Infections: Post-infection cerebellitis (varicella and Epstein-Barr viruses) and prion diseases
- Cerebellar lesions resulting from alcoholism or exposures to neurotoxic agents (lithium, toluene, phenytoin, amiodarone, 5-fluorouracil, and cytosine arabinoside) or heavy metals (mercury and thallium).
- Sporadic degenerative ataxias such as multiple system atrophy
MEDICATION
First Line
Specific treatment is unavailable.
Second Line
- Symptomatic treatments of complications.
- Treatments for some symptoms: Nystagmus (benzodiazepams, gabapentin), tremor and myoclonus (benzodiazepams, topiramate, valproic acid), seizures (antiepileptic drugs), spasticity (baclofen), cognitive deficits (antidepressants, memantine, amphetamines), etc.
ADDITIONAL TREATMENT
General Measures
- Family and social supports
- Environmental modifications to ensure safety
Issues for Referral
- Genetic counseling
- Physical therapy and physiatric evaluation
Additional Therapies
Equipments: Special supporting devices, canes, walkers, wheelchair, automatic scooters
COMPLEMENTARY AND ALTERNATIVE THERAPIES
Investigational therapies include 3,4-diaminopyridine, memantine, amantadine, antioxidant cocktail (Co-Q10, vitamin E, and vitamin C), L-carnitine, acetazolamide, idebenone, 5-hydroxytryptophan, physostigmine, N-acetylcysteine, phosphatidylcholine, vigabatrin, and trimethoprim–sulfamethoxazole.
SURGERY/OTHER PROCEDURES
- Injections (baclofen and botulinum toxin) and implanted delivery pumps (balofen) for spasticity.
- Alleviative surgeries for contracture release, tracheostomy, and feeding tube placements.
FOLLOW-UP RECOMMENDATIONS
Regular office follow-ups once every 3–12 months to monitor disease progression and complications. Frequency and intervals may be individually adjusted.
PATIENT EDUCATION
National Ataxia Foundation, 2600 Fernbrook Lane Suite 119, Minneapolis, MN 55447-4752 Tel: 763 553-0020 Fax: 763 553-0167 E-mail: naf@ataxia.org Website: www.ataxia.org
PROGNOSIS
All SCA subtypes are progressive and eventually debilitating. However, the disease progression and severity of debilitation vary significantly. These with SCA6, 8, 11, and 30 may expect normal lifespan.
COMPLICATIONS
- Injuries from falls, seizures, and aspiration
- See other complications as listed in HISTORY and PHYSICAL EXAM.
