Given the mechanism involved in putative epigenetic silencing of the gene, histone deacetylase inhibitors are being investigated as potential disease modifying agents. One such agent is nicotinamide, a form of vitamin B3. Early stage trials have shown an increase in frataxin expression following treatment with nicotinamide in Friedreich ataxia patients. Gene therapy as a potential disease modifying agent is also under investigation, with introduction of a fully functional frataxin minigene into cells using an adeno-associated virus.
Soon after the publication of Friedreich’s descriptions of a spinal type of hereditary ataxia, reports began to appear of somewhat different diseases in which the ataxia was related to degenerative changes in the cerebellum and brainstem rather than in the spinal cord. Claims of their independence from the spinal type were based largely on a later age of onset, a more definite hereditary transmission (usually of autosomal dominant type), the persistence or hyperactivity of tendon reflexes, and associations with ophthalmoplegia, retinal degeneration, and optic atrophy. Several of these clinical features, particularly briskness of tendon reflexes, are alien to the classic form of Friedreich ataxia.
By 1893, Pierre Marie thought it desirable to create a new category of hereditary ataxia that would embrace all of the non-Friedreich cases. He collated the familial cases of progressive ataxia that had been described by Fraser, Nonne, Sanger Brown, and Klippel and Durante (see both Greenfield and Harding [1993] for references) and proposed that all of them were examples of an entity to which he applied the name hérédo-ataxie cérébelleuse. Marie’s proposition (see Marie et al) was based almost entirely on clinical observations not his own but those made by the aforementioned authors. Later, as members of these families died, postmortem examinations disclosed that Marie’s hereditary cerebellar ataxia included not one but several disease entities. Indeed, as pointed out by Holmes (1907b) and later by Greenfield, in 3 of 4 families the cerebellum showed no significant lesions at all. Yet there was by then no doubt of the existence of a separate class of predominantly cerebellar atrophies, some purely cortical and others associated with a variety of noncerebellar disorders.
Holmes (1907a) described a family of 8 siblings, of whom 3 brothers and 1 sister were affected by a progressive ataxia, beginning with a reeling gait and followed by clumsiness of the hands, dysarthria, tremor of the head, and a variable nystagmus, but without additional features to implicate disease of the spinal cord or brainstem. It may be taken as the prototype of pure cerebellar cortical degeneration. The main distinction from multiple system atrophy with cerebellar degeneration is that the Holmes type spares the pontine nuclei.
The ataxia begins insidiously, usually in the fourth decade but with very wide variability in age of onset, and progresses slowly over many years. Ataxia of gait, instability of the trunk, tremor of the hands and head, and slightly slowed, hesitant speech is the usual clinical picture. Nystagmus is rare and intelligence is usually preserved. The patellar reflexes may be slightly increased but this may be apparent based on the pendular character of reflexes in cerebellar disease; the plantar reflexes are flexor and the ankle jerks are present but there are exceptions and probably mark the process as one of the other genetic ataxias.
This clinical syndrome probably can result from several genetically determined processes, some of which declare themselves as the illness progresses by displaying characteristic signs other than ataxia. The differential diagnosis in the nonfamilial cases is even broader, including many acquired types of ataxias discussed in Chap. 5 (see Table 5-3).