The effects of genetic understanding on clinical evaluation and therapy of Friedreich ataxia (FRDA) are reviewed from the University of Pennsylvania School of Medicine, Philadelphia. The major genetic mutation of FRDA involves a novel gene (X25 or FRDA) encoding the protein frataxin. FRDA results from a deficiency of functional frataxin, a protein involved in mitochondrial iron homeostasis. The resultant iron accumulation and mitochondrial abnormalities lead to oxidant damage. Expanded clinical manifestations have resulted from the recognition of broader phenotypic features, including later age of onset and spasticity with hyperreflexia and without ataxia. Diseases that clinically overlap with FRDA include 1) ataxia with vitamin E deficiency; 2) autosomal recessive spastic ataxia of Charlevoix-Saguenay, occurring in Quebec; 3) posterior column ataxia with retinal pigmentary changes; 4) early-onset cerebellar atrophy with retained reflexes; and 5) atypical cases of Charcot-Marie-Tooth disease. In diagnosis, the standard genetic testing measures the GAA repeat length on both alleles, with 95-98% detection rate. Genetic testing also identifies carriers of FRDA. In treatment, observation for progressive cardiomyopathy, arrhythmias, scoliosis, and diabetes mellitus may improve life span, and trials of antioxidants are of potential but unproven value. [1]

COMMENT. Friedreich ataxia is a progressive neurodegenerative disorder affecting 1 in 50,000, the most prevalent early-onset hereditary ataxia. Degeneration involves the dorsal root ganglion neurons, their axons in the dorsal columns, spinocerebellar tracts, and dentate nuclei in the cerebellum. The ataxia is both sensory, due to loss of proprioception, and partially of cerebellar origin. Additional manifestations include cardiomyopathy, scoliosis, and diabetes mellitus. The discovery of the genetic mutation and deficiency of frataxin protein has provided a better understanding of the disease mechanisms and potential therapies.