Pediatrics

Spinocerebellar ataxia

OVERVIEW: What every practitioner needs to know

Are you sure your patient has spinocerebellar ataxia? What are the typical findings for this disease?

The spinocerebellar ataxias (SCAs) are a group of diseases with gradually progressive neurological impairment that localizes to the cerebellum and sometimes to other areas of the nervous system, including cortical spinal tract, basal ganglia, and retina. The classically described SCAs are autosomal dominant (AD). Linkage and subsequently specific genetic mutations were identified in large kindreds showing AD inheritance patterns. However, there are SCAs with other Mendelian inheritance patterns. Most SCAs present in adulthood, but some have been described to have a range of onset that includes childhood, and some manifest genetic anticipation.

Key findings are impaired ability to coordinate muscle activity to generate normal or expected movements (ataxia) and spasticity and hyper-reflexia, prominently in the legs. This can be manifest by broad-based, unsteady, spastic gait, tremor in the limbs, and eye movement abnormalities.

Dementia, dystonia, parkinsonism, chorea, nystagmus, slow saccades, and visual loss can all occur depending on the type and severity of the SCA. In general, a careful clinical examination may narrow the differential diagnosis but not confirm a single entity due to phenotypic overlap.

Key Point: Spinocerebellar ataxias are rare, especially in children, but should be suspected in chronic, gradually progressive ataxia, particularly in the presence of an autosomal dominant family history. Key point: The SCAs which have been most often described to have childhood onset are SCA 1, 2, 5, 7, and 13. However, in general, adult onset is more common for this group of conditions.

What other disease/condition shares some of these symptoms?

There are an enormous number of genetic diseases that present with gradually progressive ataxia. Ataxia is non-specific. However, cases with acute and subacute ataxia are unlikely to be SCAs. Ataxia is non-specific and tends to indicate disease involvement in the cerebellum.

What caused this disease to develop at this time?

The pathophysiology of SCA depends on the function of the responsible gene. In some cases, the function of the gene and the pathway whereby cerebellum is damaged has not been discovered.

What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?

The evaluation is highly specialized, and genetic testing is very expensive. An alpha-fetoprotein level is important in cases of sporadic or autosomal recessive ataxia in childhood. For autosomal dominant transmission, when an SCA is suspected, genetic testing will be confirmatory, but a shot-gun approach is not advisable.

Currently, genetic testing is available for 18 of the SCAs. See http://www.ncbi.nlm.nih.gov/sites/GeneTests/

Would imaging studies be helpful? If so, which ones?

In chronic progressive ataxias, brain MRI is helpful to characterize involvement of cerebellum versus another brain region and to establish whether there is predominantly gray matter or white matter involvement. In cases where the history is unclear, a congenital malformation, mass lesion, or other process may be identified as well.

Confirming the diagnosis

A useful clinical algorithm requires a high level of neurological knowledge.

A general approach is:

1. Based on examination and imaging, regional involvement of the cerebellum should be determined (e.g., vermis, anterior/posterior lobes cerebellum).

2. Based on examination and imaging, involvement of other parts of the neuraxis should also be determined.

3. Based on thorough, detailed physical examination, involvement of other organ systems should be considered.

4. Based on symptoms and examination, ophthalmological examination (retina) may be advised.

5. Obtain a three-generation family history and examine other family members, at least the parents if possible.

6. Based on these, narrow the diagnostic possibilities. The use of Online Mendelian Inheritance in Man (OMIM) is very helpful (http://www.omim.org).

7. Referral to neurologist or movement disorder specialist familiar with ataxias is advised.

8. Note - if a parent has an SCA and wants a pre-symptomatic child to be tested, examine the child carefully or refer to neurology. If the child is asymptomatic, genetic counseling is advised rather than pre-symptomatic testing from the primary physician's office. It is also important in the proper clinical setting to consider the autosomal recessive ataxias, e.g., ataxia with vitamin E deficiency, ataxia telangiectasia, and Friedreich's ataxia.

If you are able to confirm that the patient has spinocerebellar ataxia, what treatment should be initiated?

  • Referral to a specialty clinic is advised.

  • Physical and occupational therapy, wheelchair clinic, and other supportive modes.

  • There is no specific treatment for the SCAs. Care is supportive.

What are the adverse effects associated with each treatment option?

What are the possible outcomes of spinocerebellar ataxia?

Outcomes depend on genetic diagnosis, but even with this there may be a broad landscape of possibilities. Involvement with a specific support group may be very helpful.

What causes this disease and how frequent is it?

  • Classically described SCAs are genetic and inheritance is autosomal dominant.

  • Prevalence of the AD SCAs is approximately 1 to 4 per 100,000

How do these pathogens/genes/exposures cause the disease?

There are a variety of mechanisms that appear to cause dysfunction or cell death within the cerebellum and/or its afferent or efferent pathways. Some diseases appear to target cell populations, e.g., Purkinje cells. Many pathways are incompletely characterized.

Other clinical manifestations that might help with diagnosis and management

Abnormal eye movements, e.g., slow saccades, various forms of nystagmus, can be helpful. Discussion of findings with an ophthalmologist or neuro-ophthalmologist may be useful.

What complications might you expect from the disease or treatment of the disease?

The autosomal dominant SCAs are gradually progressive. There are no disease modifying treatments.

Are additional laboratory studies available; even some that are not widely available?

Reconsideration and re-review at the GeneTestsTM website (http://www.ncbi.nlm.nih.gov/sites/GeneTests or http://www.genetests.org) is useful periodically in undiagnosed cases.

How can spinocerebellar ataxia be prevented?

There are no disease-modifying therapies, including none that prevent or postpone symptom onset in individuals carrying the mutated genes. For diseases in which genetic testing is available, some laboratories do offer prenatal genetic testing.

What is the evidence?

Perlman, SL. "Spinocerebellar degenerations". Handb Clin Neurol. vol. 100. 2011. pp. 113-40.

This is a helpful general reference for clinicians interested in this level of detail.

Klockgether, T. "Update on degenerative ataxias". Curr Opin Neurol. vol. 24. 2011. pp. 339-45.

An excellent review by an expert in the field.

Trujillo-Martin, MM, Serrano-Aguilar, P, Monton-Alvarez, F, Carrillo-Fumero, R. "Effectiveness and safety of treatments for degenerative ataxias: a systematic review". Mov Disord. vol. 24. 2009. pp. 1111-24.

A helpful overview of treatments.

Lynch, DR, Perlman, SL, Meier, T. "A phase 3, double-blind, placebo-controlled trial of idebenone in Friedreich ataxia". Arch Neurol. vol. 67. 2010. pp. 941-7.

A recent study of idebenone in 70 ambulatory pediatric patients (age, 8-18 years) with Friedreich ataxia.
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