Friedreich's Ataxia: A Clinical and Genetic Study of 90 Families With an Analysis of Early Diagnostic Criteria and Intrafamilial Clustering of Clinical Features

Abstract

The clinical features of 115 patients from 90 families with Friedreich's ataxia are described. Onset of symptoms was before the age of 25 (mean 10.52) years in all the index cases. An analysis of early cases suggested that limb and truncal ataxia and absent tendon reflexes in the legs were the only consistent diagnostic criteria within five years of presentation. Dysarthria, signs of pyramidal tract dysfunction in the legs and loss of joint position and vibration sense are not necessarily present during the first five years of symptoms, but appear to develop eventually in all cases. Scoliosis and ECG evidence of cardiomyopathy were found in over two-thirds of the patients studied; pes cavus, distal amyotrophy, optic atrophy, nystagmus and deafness were all less frequent. The disorder was gradually progressive in all cases. The mean age of losing the ability to walk was 25 years; 95 per cent were chair-bound by the age of 44 years. About 10 per cent of the patients had diabetes mellitus which was controlled by oral hypoglycaemic drugs in one quarter. Diabetes appeared to be associated with a higher incidence of optic atrophy and deafness. Diabetes also clustered within sibships; the risk of an individual with Friedreich's ataxia developing diabetes if an affected sib has it is over 40 per cent. Similarly, cardiomyopathy ran true within affected members of the same sibship, but there were instances of discordance which suggest that the development of the non-neurological features of Friedreich's ataxia may be controlled by modifying genes rather than heterogeneity of the main gene. Segregation analysis and an increased consanguinity rate amongst parents of patients (5.55 per cent) confirmed that this disorder is of autosomal recessive inheritance. A study of 101 first degree relatives of the patients with Friedreich's ataxia failed to demonstrate any neurological or electrocardiographic abnormalities which could be ascribed to the heterozygous state.

Homozygosity mapping of spinocerebellar ataxia with cerebellar atrophy and peripheral neuropathy to 9q33–34, and with hearing impairment and optic atrophy to 6p21–23

“…Friedreich ataxia (FRDA) usually associate limb and gait ataxia, cerebellar dysarthria, extensor plantar reflexes, and reduced or absent tendon reflexes, loss of vibration/position sense and muscle weakness in lower limbs with hypertrophic cardiomyopathy, scoliosis, pes cavus and an increased frequency of impaired glucose tolerance and diabetes. 1,2 Ataxia-telangiectasia 3 is associated with conjunctival telangiectasias, immunodeficiency and an increased incidence of lymphoma and leukaemia. Serum gammaglobulins are reduced, and alpha-foetoprotein and carcinoembryonic antigen are elevated.…”

Bone marrow transplantation stimulates neural repair in Friedreich's ataxia mice

“…This triplet expansion results in transcriptional repression of frataxin,2 a small mitochondrial protein involved in iron–sulfur cluster biosynthesis. Typically, patients with the condition experience insidious accumulation of neurological disability characterized pathologically by lesions in the dorsal root ganglia (DRG), sensory peripheral nerves, spinal cord, and cerebellar dentate nucleus 3, 4…”

Cytokine therapy‐mediated neuroprotection in a Friedreich's ataxia mouse model

“…Friedreich's ataxia patients inevitably acquire neurological disability, with progressive ataxia, dysarthria, neuropathy, and pyramidal weakness, as well as cardiac and endocrine disease 2. In most cases, Friedreich's ataxia is caused by homozygous GAA.TTC trinucleotide repeat expansion within intron 1 of the FXN gene,3 causing transcriptional repression of frataxin 4.…”