When a patient presents with ataxia, a diagnostician must synthesize an extraordinary amount of clinical information to guide his or her differential diagnosis. Genetic testing is guided by this process and is based on the findings of a thorough neurological exam, family history, and other testing, according to Joseph J. Higgins, MD, FAAN, Medical Director for Neurology. When a genetic test is indicated, Athena’s Ataxia Algorithm can guide the choice of the most informative test. “We don’t want physicians to order an entire ataxia test panel if they don’t need it,” Dr. Higgins says. “Most of the time, it should be possible to narrow the number of genes tested based on the patient’s clinical presentation and family history.”
“Ataxia is a relatively nonspecific sign with a large differential diagnosis,” he says. “Alcoholism and head trauma are the most common causes. The inherited ataxias are much rarer.”
The first question a neurologist asks is whether the patient has a neurologic disease at all. For example, ataxia may be due to another cause, from something as simple as foot pain or as complex as a psychiatric disorder. A detailed neurologic exam should help localize a lesion that causes ataxia or incoordination. A broad-based gait, speech abnormalities, nystagmus, and dysmetria all point to the spinocerebellar system.
Blood tests should be performed to rule out treatable causes of ataxia, including deficiencies of vitamin B12, vitamin E, or biotinidase. An MRI is useful in determining whether the cerebellum is atrophied—a characteristic sign of the autosomal dominant spinocerebellar ataxias. In contrast, cerebellar atrophy is inconsistent with a diagnosis of Friedreich ataxia. Neuroimaging may also reveal structural lesions, including stroke or tumor, as other etiologies.
All of these findings, and especially the family history, guide the decision to perform a genetic test. The ataxia algorithm provides clear guidance for which test is recommended. A negative family history in the absence of any other suspected cause may indicate a recessive disorder. Friedreich ataxia “is by far the most common recessive ataxia,” Dr. Higgins notes, and is suspected when the MRI is normal and there is evidence for a sensory reason for incoordination. A high level of alpha-fetoprotein suggests ataxia-telangiectasia, a rarer condition that increases the risk for cancer. When the tests for the most common recessive ataxias are negative, it may be useful to test for a larger group of much rarer recessive disorders.
The spinocerebellar ataxias are the most common group of dominantly inherited ataxias. Most are due to repeat expansions, and may show anticipation (earlier onset in successive generations) as an expansion increases in length in successive family generations. This occasionally means that an individual may have an earlier more severe onset than their parent or even may be symptomatic before their parent.
As outlined in the algorithm, clinical findings can be used to narrow the choice of testing. Retinal degeneration is a feature of SCA7. Pyramidal signs, extrapyramidal signs, or peripheral neuropathy suggest SCA1, SCA2, or SCA3. “Pure cerebellar ataxia, with no other signs or symptoms, is most likely SCA6,” Dr. Higgins says. More than half of all dominantly inherited ataxias fall into a group of eight disorders (SCA1, SCA2, SCA3, SCA6, SCA7, SCA8, SCA10 and SCA17). This group is offered as the Ataxia, Common Repeat Expansion Evaluation and is based on prevalence. This test is useful because there is a lot of phenotypic overlap among these disorders. If the most prevalent causes of SCA are negative, “then it may be worthwhile to perform the Supplemental Dominant Evaluation,” comprising 16 rarer dominantly inherited ataxias.
Finally, when there is no family history or clinical findings to narrow down the testing, it may be worthwhile to consider the Ataxia, Comprehensive Evaluation. “This test is reserved for special circumstances where you have considered all possibilities and turn up nothing.”