Autosomal dominant cerebellar ataxia
Peer reviewed by Dr Adrian Bonsall, MBBSLast updated by Dr Gurvinder Rull, MBBSLast updated 28 Dec 2016
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Most forms of cerebellar ataxia are acquired disorders but hereditary forms can be autosomal dominant or recessive; a few are X-linked. By and large the dominant forms are less severe than the recessive ones. A search for autosomal dominant cerebellar ataxia (ADCA) on the Online Mendelian Inheritance in Man (OMIM) database yields a very large number of results1.
Mapping of genes has shown a vast array of conditions, the names of many beginning with spinal cerebellar ataxia (SCA), reflecting the genetic classification2.
These disorders not only vary genetically but also clinically. They are characterised generally by a slow progression of ataxia of gait, stance and limbs and by dysarthria with or without oculomotor dysfunction due to cerebellar degeneration3. The degenerative process can be limited to the cerebellum, or may also involve the retina, optic nerve, pontomedullary systems, basal ganglia, cerebral cortex, spinal tracts or peripheral nerves.
One classification of ADCA is as follows4:
ADCA type I - eg, SCA1 to SCA4, SCA8, SCA10, SCA12, SCA23, SCA27 and DRPLA (dentatorubral-pallidoluysian atrophy).
ADCA type II - eg, SCA7; conditions in this group are associated with pigmentary maculopathies.
ADCA type III - eg, SCA5, SCA6, SCA11, SCA29, SCA30 and SCA31; conditions are usually pure cerebellar syndromes.
These disorders may show the phenomenon of anticipation with earlier onset and more severe disease in successive generations.
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Pathogenesis
There have been interesting models for the molecular basis of various ADCAs which may ultimately lead to improved therapeutic measures56.
Epidemiology
Prevalence of ADCAs has been estimated as between 0.3 to 2 per 100,0007. It has been reported from many countries around the world with clusters of certain types in various parts of the world reaching a prevalence of 5-7 per 100,000 in some populations6.
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Presentation
Onset is usually between the ages of 30 and 50 years, although early onset in childhood and later onset after age 60 years have been reported.
As well as cerebellar features there may be dementia, seizures, impaired proprioception, movement disorders and polymyoclonus.
Symptoms
The following features are generally typical, although there is some variation between diseases:
Developmental delay.
Episodes of altered level of consciousness or recurrent neurological symptoms.
Family history of similar symptoms in a close relative.
Neurological or developmental regression.
Multisystem involvement in addition to neurological disease.
Presence of a particular neurological sign.
Signs
Ataxia is the fundamental neurological sign. Ataxia is the inability to maintain normal posture and smoothness of movement. There is a broad-based gait, scanning dysarthria, explosive speech, intention tremor, dysdiadochokinesia, dysmetria and abnormalities of eye movements.
There may be movement disorders.
The picture ranges from pure cerebellar dysfunction to mixed patterns of involvement with extrapyramidal, brain-stem and cerebral cortical involvement.
Differential diagnosis
There are many other forms of cerebellar ataxia, both acquired and inherited3. A relatively important one is sporadic Creutzfeldt-Jakob disease that can present with predominantly cerebellar signs8. In most cases of hereditary disease there will be a family history - but not always. SCA1, SCA2 and SCA3 are mentioned here in further detail as they are the most common:
Spinocerebellar ataxia type 1 (SCA1)
SCA1 is due to a mutation on the number 6 chromosome9. Symptoms are variable depending on the length of the CAG repeat in the genetic code.
Onset is commonly in the 2nd to 5th decade (mean age of 37 years in one cohort).
Gait ataxia, dysarthria, dysmetria, nystagmus, muscle wasting and dystonia are seen in the late stages of the disease.
There is gradual progression of disability, with death occurring 10-30 years after onset10.
Spinocerebellar ataxia type 2 (SCA2)
SCA2 is due to a mutation on the number 12 chromosome and it is also known as Wadia-Swami syndrome11.
Onset is between 2 and 65 years.
Ataxia, facial fasciculation, lid retraction, dementia and peripheral neuropathy. The prognosis varies considerably, even within families.
Spinocerebellar ataxia type 3 (SCA3)
SCA3 is also called Machado-Joseph disease and affects people of Portuguese-Azorean descent. The clinical picture is variable. It has been traced back over 100 years in a single family. It is due to a mutation on the number 14 chromosome1213.
Onset is after the fourth decade.
Ataxia, pyramidal and extrapyramidal signs, amyotrophy, facial and lingual fasciculations, ophthalmoplegia and exophthalmos are found.
A late feature may be autonomic dysfunction14.
The disease is gradually progressive with death usually occurring from cachexia or pulmonary complications after 6-29 years13.
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Investigations
MRI scan may show atrophy of the cerebellum and brain stem and sometimes cerebral atrophy.
Electroencephalography may show features of epilepsy.
Electromyography may demonstrate continuous motor unit activity.
Genetic testing may be possible3. All these diseases represent an abnormality of metabolism due to a defect on a chromosome.
Management
Physiotherapy can help the ataxia
Anticonvulsants may be required. In some forms acetazolamide is useful.
Prognosis
Prognosis is highly variable between the different types but improvement is unlikely. Comparatively little is understood of the molecular processes involved in these diseases and so there is little chance of significant interventions to improve prognosis in the near future6. There may also be multiple pathways involved.
Prevention
Further reading and references
- Autosomal Dominant Cerebellar Ataxia; Search for term Autosomal Dominant Cerebellar Ataxia on OMIM database, Online Mendelian Inheritance in Man (OMIM),
- Albin RL; Dominant ataxias and Friedreich ataxia: an update. Curr Opin Neurol. 2003 Aug;16(4):507-14.
- Management of the ataxias - towards best clinical practice; Ataxia UK (2016)
- Whaley NR, Fujioka S, Wszolek ZK; Autosomal dominant cerebellar ataxia type I: a review of the phenotypic and genotypic characteristics. Orphanet J Rare Dis. 2011 May 28;6:33. doi: 10.1186/1750-1172-6-33.
- Kang S, Hong S; Molecular pathogenesis of spinocerebellar ataxia type 1 disease. Mol Cells. 2009 Jun 30;27(6):621-7. doi: 10.1007/s10059-009-0095-y. Epub 2009 Jun 22.
- Duenas AM, Goold R, Giunti P; Molecular pathogenesis of spinocerebellar ataxias. Brain. 2006 Jun;129(Pt 6):1357-70. Epub 2006 Apr 13.
- van de Warrenburg BP, Sinke RJ, Verschuuren-Bemelmans CC, et al; Spinocerebellar ataxias in the Netherlands: prevalence and age at onset variance analysis. Neurology. 2002 Mar 12;58(5):702-8.
- Cooper SA, Murray KL, Heath CA, et al; Sporadic Creutzfeldt-Jakob disease with cerebellar ataxia at onset in the United Kingdom. J Neurol Neurosurg Psychiatry. 2006 Jul 11.
- Spinocerebellar Ataxia 1, SCA1; Online Mendelian Inheritance in Man (OMIM)
- Lin X, Ashizawa T; Spinocerebellar Ataxia Type 1, Gene Reviews, updated Nov 2007
- Spinocerebellar Ataxia 2, SCA2; Online Mendelian Inheritance in Man (OMIM)
- Spinocerebellar Ataxia, Type 3, SCA3, Machado-Joseph Disease; Online Mendelian Inheritance in Man (OMIM)
- Paulson H; Spinocerebellar Ataxia Type 3, Gene Reviews (updated Aug 2007)
- Yeh TH, Lu CS, Chou YH, et al; Autonomic dysfunction in Machado-Joseph disease. Arch Neurol. 2005 Apr;62(4):630-6.
- Goizet C, Lesca G, Durr A; Presymptomatic testing in Huntington's disease and autosomal dominant cerebellar ataxias. Neurology. 2002 Nov 12;59(9):1330-6.
- Rolim L, Leite A, Ledo S, et al; Psychological aspects of pre-symptomatic testing for Machado-Joseph disease and familial amyloid polyneuropathy type I. Clin Genet. 2006 Apr;69(4):297-305.
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Article history
The information on this page is written and peer reviewed by qualified clinicians.
28 Dec 2016 | Latest version

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