Autosomal Dominant Cerebellar Ataxia

Most forms of cerebellar ataxia are acquired disorders but hereditary forms can be autosomal dominant or recessive, and 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 results.¹

Mapping of genes has shown a vast array of conditions.² Only a few will be considered here.
The classification includes the following diseases:

• ADCA types I, II and III
• Cerebellar ataxia, dominant pure
• Cerebello-olivary atrophy
• Olivo-ponto-cerebellar atrophy
• Pierre Marie cerebellar ataxia
• Spinocerebellar ataxia (SCA), types 1-8,10-19, 21-22

Autosomal dominant spinocerebellar ataxias (ADSCAs) are clinically and genetically varied disorders characterised by a slow progression of ataxia of gait, stance and limbs, and dysarthria with or without oculomotor dysfunction due to cerebellar degeneration. The degenerative process can be limited to the cerebellum (ADCA type III) or may also involve the retina (ADCA type II), optic nerve, ponto-medullary systems, basal ganglia, cerebral cortex, spinal tracts or peripheral nerves (ADCA type I). In the genetic classification, ADSCAs are called spinocerebellar ataxias (SCAs) and are numbered in the order SCA-1 to SCA-22. They may show the phenomenon of anticipation with earlier onset and more severe disease in successive generations.

There have been interesting models for the molecular basis of the SCAs. These may ultimately lead to improved therapeutic measures.³

Prevalence of ADSCAs has been estimated as between 0.8 and 2 per 100,000.⁴ 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 populations.³

Onset is usually between ages 30 and 50, although early onset in childhood and later onset after age 60 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
• Multi-system 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, brainstem and cerebral cortical involvement.

There are many other forms of cerebellar ataxia, both acquired and inherited. A relatively important one is sporadic Creutzfeldt-Jakob disease that can present with predominantly cerebellar signs.⁵ In most cases of hereditary disease there will be a family history, but not always. Of the autosomal dominant types, only the features of SCA1, 2 and 3 are mentioned here as they are the most common:

Spinocerebellar ataxia (SCA-1)

It is due to a mutation on the number 6 chromosome.⁶ 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 37 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 onset.⁷

Spinocerebellar ataxia (SCA-2)

It is due to a mutation on the number 12 chromosome and it is also known as Wadia-Swami syndrome.⁸

• 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 (SCA-3)

It is also called Machado-Joseph disease and affects people of Portuguese-Azorean descent. 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 chromosome.^9,10

• 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 dysfunction too.¹¹
• Disease is gradually progressive with death usually occurring from cachexia or pulmonary complications after 6-29 years¹⁰

• MRI scan may show atrophy of the cerebellum and brainstem and sometimes cerebral atrophy.¹²
• Electroencephalography may show features of epilepsy.
• Electromyography may demonstrate continuous motor unit activity.
• Genetic testing may be possible. All these diseases represent an abnormality of metabolism due to a defect on a chromosome.

• Physiotherapy can help the ataxia
• Anticonvulsants may be required. In some forms acetazolamide is useful.

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 future.³ There may also be multiple pathways involved.

Genetic testing enables identification of the causative gene in 50 to 80% of cases of ADCA.¹³ Pre-symptomatic testing is available but not always wanted. It is usually requested for family planning purposes. SCA-3 is similar to Huntington's chorea in that the onset is fairly late in life, there is no effective treatment and screening may produce much anxiety. Most has been done in Portugal where the incidence of SCA-3 is high. The psychological impact of testing does not seem high.¹⁴

1. Autosomal Dominant Cerebellar Ataxia, Online Mendelian Inheritance in Man (OMIM); Search for term Autosomal Dominant Cerebellar Ataxia on OMIM database.
2. Albin RL; Dominant ataxias and Friedreich ataxia: an update. Curr Opin Neurol. 2003 Aug;16(4):507-14. [abstract]
3. Duenas AM, Goold R, Giunti P; Molecular pathogenesis of spinocerebellar ataxias. Brain. 2006 Jun;129(Pt 6):1357-70. Epub 2006 Apr 13. [abstract]
4. van de Warrenburg BP, Sinke RJ, Verschuuren-Bemelmans CC, et al; Spinocerebellar ataxias in the Netherlands: prevalence and age at onset variance Neurology. 2002 Mar 12;58(5):702-8. [abstract]
5. 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. [abstract]
6. OMIM; SCA1
7. Lin X, Ashizawa T, Spinocerebellar Ataxia Type 1, Gene Reviews, updated Nov 2007
8. OMIM; SCA2
9. Spino-cerebellar ataxia type 3 (SCA3) Machado-Joseph disease; Online Mendelian Inheritance in Man (OMIM)
10. Paulson H, Spinocerebellar Ataxia Type 3, Gene Reviews (updated Aug 2007)
11. Yeh TH, Lu CS, Chou YH, et al; Autonomic dysfunction in Machado-Joseph disease. Arch Neurol. 2005 Apr;62(4):630-6. [abstract]
12. Ormerod IE, Harding AE, Miller DH, et al; Magnetic resonance imaging in degenerative ataxic disorders. J Neurol Neurosurg Psychiatry. 1994 Jan;57(1):51-7. [abstract]
13. 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. [abstract]
14. 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. [abstract]

• Prasad A, Prasad C; Ataxia with identified genetic and biochemical defects. eMedicine, Sept 2005.
• Ataxia.org.uk; Cerebellar ataxia. A guide for the medical profession.