Setting aside those of congenital type and those caused by a metabolic disorder, Harding (1993) grouped the ataxias by age of onset, pattern of heredity, and associated features. A modification of the classifications of Greenfield and of Harding, which is included in the introductory listing of this chapter, still has clinical value. It divides the progressive cerebellar syndromes into 3 main groups: (1) the spinocerebellar ataxias, with unmistakable involvement of the spinal cord (Romberg sign, sensory loss, diminished tendon reflexes, Babinski signs); (2) the pure cerebellar ataxias, with no other associated neurologic disorders; and (3) the complicated cerebellar ataxias, with a variety of pyramidal, extrapyramidal, retinal, optic nerve, oculomotor, auditory, peripheral nerve, and cerebrocortical accompaniments including what is now referred to as multiple system atrophy.
Without doubt, the advances in molecular genetics of recent years have greatly altered our understanding of the inherited ataxias and have already disclosed a large number of unexpected relationships between mutations and other neural and nonneural disorders. These data are incorporated at appropriate points in the following discussion and in Table 38-5. Inherited ataxias of early onset (before the age of 20 years) are usually of recessive type; those of later onset are more likely to have a dominant pattern but may be autosomal recessive. Table 38-5 lists several types of ataxias that have a genetic basis. At the time of this writing, many more types have been listed in the literature, most of limited clinical consequence and low incidence. We have included the main varieties that may be of interest to clinicians because they appear regularly or offer an insight into this class of disorders. At the same time, it should be emphasized that many patients with chronic progressive ataxia have no family history of an ataxia and may have had a spontaneous mutation; even then, the genetic aspects of many cases have not been elucidated.
This is the prototype of all forms of progressive spinocerebellar ataxias (ataxias with signs of predominantly spinal tract degeneration) and accounts for about half of all cases of hereditary ataxias in most large case series (86 of 171 patients collected by Sjögren); its incidence among
Europeans and North Americans is 1.5 cases per 100,000 per year. Friedreich, of Heidelberg, began in 1861 to report on a form of familial progressive ataxia that he had observed among nearby villagers. It was already known through the writings of Duchenne that locomotor ataxia was the prominent feature of spinal cord syphilis, that is tabes dorsalis, but it was Friedreich who demonstrated a nonsyphilitic hereditary type. This concept was greeted with skepticism, but soon Duchenne himself affirmed the existence of the new disease and other case reports appeared in England, France, and the United States. In 1882, in a thesis on this subject by Brousse of Montpelier, Friedreich’s name was attached to the entity.
The pattern of inheritance is autosomal recessive. It has been shown that in virtually all cases the mutation is an expansion of a GAA trinucleotide repeat within FXN that that codes for the protein. (It is of interest that this mutation is within an intron). In a small proportion of cases, the mutation is a missense mutation rather than an expansion. In either case, the consequence of the mutation is a reduction in levels of frataxin and loss of its function. Cases in which the mutation allows the presence of some residual protein have a milder course.