Autosomal Dominant Cerebellar Ataxia

Most forms of cerebellar ataxia are acquired disorders but hereditary forms can be autosomal dominant, recessive or a few are X-linked. By and large the dominant forms are less severe than recessive ones. A search for autosomal dominant cerebellar ataxia 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:

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

Autosomal dominant spinocerebellar ataxias (ADCA) are clinically and genetically varied disorders³ characterised by a slow progression of ataxia of gait, stance and limbs, 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, ADCAs are called spinocerebellar ataxias (SCAs) and numbered in the order SCA1 to SCA22. 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 spinocerebellar ataxias. These may ultimately lead to improved therapeutic measures.⁴

Prevalence of ADCAs has been estimated as between 0.8 and 3.5 per 100,000. It has been reported from many countries around the world with clusters of certain types in various parts of the world.

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 commonest:

Spinocerebellar ataxia (SCA-1)

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

• Onset is in the 4th decade.
• Gait ataxia, dysarthria, dysmetria, nystagmus, muscle wasting, and dystonia are seen in the late stages of the disease.
• The outlook is bleak with gradual progression to disability and death within 10 to 20 years.

Spinocerebellar ataxia (SCA-2)

It is due to a mutation on the number 12 chromosome and it is also known as Wadia-Swami syndrome.⁷

• Onset is between 2 and 65 years.
• Ataxia, facial fasciculation, lid retraction, dementia, 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.⁸ It is due to a mutation on the number 14 chromosome.⁹

• 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.¹⁰
• Only 40% die as a result of the disease.¹¹

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

Non-drug

Physiotherapy can help the ataxia.

Drugs

• Anticonvulsants may be required. In some forms acetazolamide is useful.
• In Machado-Joseph disease fluoxetine 20 mg daily has not been shown to improve motor function.¹³
• Tandospirone, a 5HT1A agonist appears to be beneficial.¹⁴
• Physostigmine is not helpful.¹⁵

It has been postulated that there may be shared mechanisms underlying episodic ataxia and other far more prevalent paroxysmal conditions such as epilepsy and migraine.¹⁶ Of interest also is the recent finding of three loci showing vulnerability to restless legs syndrome (RLS or Ekbom syndrome) in French-Canadian and Italian families in chromosomes 12q, 14q and 9q with an autosomal dominant mode of inheritance.¹⁷ Links with Parkinson's disease have also been looked at but none found.¹⁸

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.⁴ There may also be multiple pathways involved.

Genetic testing enables identification of the causative gene in 50 to 80% of cases of ADCA.¹⁹ Pre-symptomatic testing is available but not always wanted. It is usually requested for family planning purposes. SCA3 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 SCA3 is high. The psychological impact of testing does not seem high.²⁰