Athena:

What symptoms or clinical presentation should prompt a neurologist to suspect that a patient has hereditary ataxia?

Dr. Pulst:    

Ataxias are characterized by variable degrees of dysfunction and degeneration of systems involving motor coordination. The clinical presentation of hereditary ataxias can vary significantly, ranging from pure cerebellar ataxias to symptoms resembling multiple system atrophy or multi-organ disorders. The age of onset can also be highly variable. For example, diseases that usually present in adulthood can present in childhood, and diseases that typically present in childhood, such as Friedreich ataxia, can present in adulthood (see case study). Therefore, other than a positive family history, a chronic progressive course of the ataxic syndrome is often the best indicator of an underlying hereditary cause.

Athena:

When evaluating these patients, what other syndromes or diseases should be considered as part of the differential diagnosis?

Dr. Pulst:

Patients should be screened for thyroid dysfunction and vitamins B₁₂ and E deficiencies. Imaging studies can usually rule out mass lesions or demyelinating diseases that can have a chronic progressive course. In patients with unusual presentations or associated findings, infections (such as syphilis, Lyme disease, Epstein-Barr virus and HTLV-1) need to be ruled out, and an examination for ceruloplasmin, urine copper, and heavy metals is indicated. Physicians also need to think of mitochondrial disorders and some of the inherited and acquired neuropathies in a differential evaluation. Recent studies have also suggested that titers of anti-gliadin antibodies may be increased in patients with chronic ataxias; however, their causal relationship with disease pathogenesis warrants further study.

Athena:

When do you recommend that a neurologist order genetic testing for suspected hereditary ataxia patients?

Dr. Pulst:

Clearly, all patients with a positive family history should be tested. In order to obtain a family history, a formal pedigree should be drawn, including all first- and second-degree relatives (parents of the proband, grandparents, uncles, aunts, and children). Patients with a negative family history may have a recessive disorder or a new mutation; or some may have a negative family history owing to premature death of a parent. Published studies suggest that the percentage of positive gene tests in patients without a positive family history can be as high as 10%.^1,2

Athena:

When is it most appropriate for a neurologist to order single gene testing (e.g., testing the gene associated with spinocerebellar type 1, the SCA1 gene) as opposed to a panel of tests that evaluates multiple genes?

Dr. Pulst:

Once molecular testing has identified a specific ataxia in an individual, it is appropriate for family members to be tested for that specific gene. At times, when a phenotype is very distinctive in an individual or occurs in someone from a region with a high prevalence of a given ataxia, a single gene test can also be used. Examples are patients of Portuguese ancestry (SCA3/ Machado-Joseph disease) or patients of Cuban ancestry with slow saccadic eye movements (SCA2).

Athena:

Since the identification of the gene for Friedreich ataxia (FRDA), it has been shown that adult onset of this disease (see case study), and the disease itself, is much more common than originally believed. When should a neurologist include testing for Friedreich ataxia in his/her workup?

Dr. Pulst:

Although FRDA has a distinctive phenotype, patients with late onset or with small GAA expansions in the FRDA gene can have pure cerebellar or spastic phenotypes. Unless there is a clear history of dominant transmission, I recommend including FRDA testing in most work-ups.

Athena:

There are limited treatment options currently available for patients with spinocerebellar ataxia. How does a positive genetic test result influence your management of an affected patient?

Dr. Pulst:

A positive gene test immediately stops the search for other underlying causes of the chronic degenerative syndrome (it is, of course, possible to have multiple sclerosis in addition to an inherited ataxia). Many patients and physicians feel a sense of relief when they can attach a name to the disorder.

The presence of a specific mutation also has immediate consequences for genetic counseling. In a patient with no known family history and a positive test for a mutation in the FRDA gene, half of the offspring will be carriers of the disease; however, depending on ethnicity, the risk of the offspring developing the disease is small (<0.0025). However, a positive gene test for a dominant ataxia results in very different risk estimates for the offspring, because half of the offspring are at risk to develop the disease.

In the foreseeable future, disease-specific treatments for the inherited ataxias will be a reality. For example, the first treatment trials have been completed for Huntington disease, and treatment trials with idebenone for FRDA are currently underway.

Athena:

With the identification of so many genes responsible for hereditary ataxia, the nomenclature/classification has become complex. How to you see this evolving in the future?

Dr. Pulst:

The Human Genome Organization (HUGO) has a nomenclature committee that is responsible for bringing order to the potential chaos of named genes. The dominant ataxias are designated "SCAs," but recently a new category of spastic ataxia (SPAX1) has emerged. The recessive ataxias tend to have phenotypic names, such as ataxia with ocular apraxia (AOA1), infantile spinocerebellar ataxia (IOSCA) or ataxia telangiectasia (AT). In certain circumstances, the gene names remain confusing; for example, although genes for SCA8 and SCA10 have been identified, SCA9 is undefined.

At the moment, the ataxias are classified according to genotype. It is possible that a new classification will emerge that is based on effects at the protein level. For example, all ataxias caused by expansion of a CAG repeat in the coding region of the gene may be subsumed under the category polyglutamine (polyQ) ataxias.

Athena:

What is the future of research in therapy for hereditary ataxia?

Dr. Pulst:

As I mentioned earlier, the drug idebenone is currently undergoing trials in patients with Friedreich ataxia. Also, we are now at the point of generating animal models of these disorders. This will allow us to test therapeutic interventions. Surprisingly, relatively little research has been done on the natural history of the hereditary ataxias. For example, rating scales, which are essential for therapeutic trials, still need to be validated.

Athena:

Thank you, Dr. Pulst.

A 58-year-old man presented with a five-year history of a progressively worsening gait. In the past year, he has also begun to notice slurring of his speech.

His family history is negative for similar disease presentation; his mother died at age 95 of a stroke and his father died at age 87 of diabetes complications. He has two brothers, neither of whom have similar disease presentation, nor do any of his second-degree relatives.

On exam, his mental status was normal; the cranial nerve examination was remarkable for the presence of fixation instability. The motor examination showed no weakness, but did reveal increased tone in the lower extremities. Reflexes were brisk, but could barely be obtained at the ankle, and toes were up going. His sensory examination was intact and Romberg negative, except for mildly decreased pinprick sensation in his foot. There was minimal dysmetria and his gait was ataxic, but with a distinct spastic quality.

Visual evoked potential testing revealed bilateral prolongation of the P100. His Nerve Conduction Velocity (NCV) examination was normal except for changes consistent with radiculopathy. The MRI examination showed moderately severe cerebellar atrophy involving the hemispheres and the vermis.

Molecular genetic testing for the GAA expansion in the FRDA gene showed a homozygous repeat expansion of 136 GAA repeats.