Hereditary Spino Cerebellar Ataxias: A Model for Triplet Repeat Neurogenetic Disease
by Beth A. Pletcher, MD, May 1999

Over the past decade tremendous advances have been made in the elucidation of the genetic causes of many of the hereditary ataxias. For most of these disorders, the DNA defect is actually a series of overly repetitive triplet sequences (CAG to be exact) within a given gene, unlike other triplet repeat disorders such as Fragile X syndrome (CGG) or myotonic dystrophy (CTG) where the triplet repeats lie outside of the actual genetic coding region. For the well characterized subtypes it appears that increasing numbers of excess repeats are directly proportional to an earlier age of onset of symptoms. While these disorders share an autosomal dominant (AD) inheritance pattern, ataxia and dysarthria, there are variable extra-cerebellar signs that help to differentiate these clinical entities. Such findings include: ophthalmoplegia, retinopathy, dystonia, rigidity, chorea, seizures, peripheral neuropathy and dementia. Most of these genes have been localized and a few well characterized and all are under intense investigation at this time.

• SCA1 is associated with a gene on the short arm of chromosome 6 and demonstrates a typical age of onset around age 30 years. In addition to ataxia, lower bulbar palsies, hyperreflexia and scanning speech may be seen. SCA1 is most often associated with hypermetria with exaggerated extra-ocular eye movements and represents about 9% of all cases of AD cerebellar ataxia.

• SCA2 is associated with a gene on the long arm of chromosome 12. Slow eye movements, hyporeflexia, myoclonus and intention tremor are common clinical features of this AD ataxia which represents about 10% of all cases.

• SCA3 or Machado-Joseph disease is the most common of all AD ataxias. This gene has been localized to the long arm of chromosome 14 and is extremely common in descendants of William Machado, originally from an island in the Portuguese Azores. However, it is also seen in non-Portuguese populations and is clinically characterized by gaze-evoked nystagmus, diplopia, severe spasticity, peripheral neuropathy and impaired thermal discrimination. As many as 42% of AD ataxia fits this subtype of SCA.

• SCA4 is associated with a gene on the long arm of chromosome 16 and has been seen in relatively few families. It is clinically distinct from the other ataxias because of the presence of an axonal sensory neuropathy in addition to ataxia with onset of symptoms typically in the 30s and 40s. Hypo or areflexia are also prominent features.

• SCA5 maps to the short arm of chromosome 11 and is interesting from a historical standpoint since the largest family studied descended directly from the paternal grandparents of Abraham Lincoln. This form is associated with simple cerebellar ataxia and demonstrates significant anticipation as one might see in a triplet repeat disorder. The phenomenon of anticipation is defined by earlier and earlier ages of onset of symptoms in subsequent generations associated with increasing numbers of triplet repeats with each meiotic event.

• The SCA6 gene resides on the short arm of chromosome 19 and clinical features are associated with a CAG expansion in one of the alpha-1A calcium channel subunit genes. Of all the SCAs, this subtype is more often described in apparently sporadic cases in the context of a negative family history. This form is also frequently associated with frontal lobe signs and/or dementia.

• SCA7, localized to the short arm of chromosome 3, is associated with retinal degeneration, external ophthalmoplegia and only rarely extrapyramidal features of mild choreic movements of the distal extremities. The CAG repeat number in this subtype is highly variable as is age of onset with reports of some infantile cases and early death.

• SCA8 is caused by excess CAG repeats in a gene on the long arm of chromsome 13 and is characterized by dysarthria, nystagmus, ataxia, spasticity and decreased vibratory sensation. Unlike the other subtypes where expansion occurs relatively equally in male versus female gametes, there appears to be a maternal expansion bias with SCA8.

• SCA10 has been mapped to the long arm of chromosome 22 and is associated with ataxia as well as seizures in some affected individuals. Anticipation in this form suggests a possible repeat expansion mechanism, but the repeat region has yet to be identified.

• Finally, Dentatorubral-Pallidoluysian Atrophy (DRPLA) is an AD ataxia syndrome that is far and away most common in the Japanese population. The gene resides on the short arm of chromosome 12 and a variable CAG expansion has been demonstrated in affected individuals. Clinically this condition is associated with myoclonic epilepsy, dementia, ataxia and choreoathetosis with age of onset typically in the 20s and death in the 40s. There appears to be a proclivity in this condition for paternal transmission due to increased expansion in the paternal allele although maternal transmission clearly occurs.

Based upon these recent molecular advances, adults with progressive AD ataxia can now take advantage of the wide array of genetic tests designed to clearly define the subtype and possibly provide prognostic information. Testing should be considered based upon clinical symptomatology as well as family history. This could potentially provide asymptomatic individuals with information regarding their own future health, but it is most important to consider the risks versus benefits before proceeding with presymptomatic testing for a disorder with relatively few proven therapies and no preventative health care strategies currently under consideration.