The GAA expansion is found on both alleles in intron 1 (non-coding) of the frataxin gene in a majority of patients. A number of mechanisms have been put forward to explain the loss of function caused by this mutation. The length of the GAA expansion has been shown to correlate with disease severity and symptom onset; the length of the shorter of the 2 expansions being the most important predictor. Reduced mRNA production has been suggested to occur through abnormal silencing of the gene via epigenetic mechanisms. This may be a potential target for treatment (see in the following text). Aberrant DNA methylation, histone methylation, antisense transcription and secondary structure formation have been shown to be involved in the pathological silencing of this gene.
Clinical features Ataxia of gait is nearly always the initial symptom. Difficulties in standing steadily and in running are early symptoms. The typical age of onset is in the childhood and adolescent period. The hands usually become clumsy months or years after the gait disorder, and dysarthric speech appears after the arms are involved (this is rarely an early symptom). Exceptionally, the ataxia begins rather abruptly after a febrile illness, and one leg may become clumsy before the other. In some patients, pes cavus and kyphoscoliosis (scoliosis) are evident well before the neurologic symptoms; in others, they follow by several years. The characteristic foot deformity takes the form of a high plantar arch with retraction of the toes at the metatarsophalangeal joints and flexion at the interphalangeal joints (hammertoes).
In the fully developed syndrome, the abnormality of gait is of mixed sensory and cerebellar type, aptly called tabetocerebellar by Charcot. According to Mollaret, the author of an authoritative monograph on the disease, the cerebellar component predominates, but in our relatively small experience we have been as impressed almost as much with the sensory (tabetic) aspect. The patient stands with feet wide apart, constantly shifting position to maintain balance. Friedreich referred to the constant teetering and swaying on standing as static ataxia. In walking, as with all sensory ataxias, the movements of the legs tend to be brusque, the feet resounding unevenly and irregularly as they strike the floor, and closure of the eyes causes the patient to fall (Romberg sign). This is one component of the spinal aspect (posterior columns) of the disease. Attempts to correct the imbalance may result in abrupt, wild movements. Often there is a rhythmic tremor of the head. Eventually, the arms are grossly ataxic, and both action and intention tremors are manifest. Speech is slow, slurred, explosive, and, finally, almost incomprehensible. Breathing, speaking, swallowing, and laughing may be so incoordinated that the patient nearly chokes while speaking. Holmes (1907a) remarked on an ataxia of respiration that causes “curious short inspiratory whoops.” Facial, buccal, and arm muscles may display tremulous and sometimes choreiform movements.
Although mentation is generally preserved, emotional lability has been sufficiently prominent to provoke comment. Torsional and vertical nystagmus is rare but “square wave jerks” are seen in the early stages of disease. Horizontal nystagmus may be present late in the course of the illness, but not early, but it is slight in amplitude. Ocular movements usually remain full, and pupillary reflexes are normal. The facial muscles may seem slightly weak, and deglutition may become impaired. Amyotrophy occurs late in the illness and is usually mild, but it may be extreme in patients with an associated neuropathy (see in the following text).