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Friedreich's ataxia is the most common hereditary ataxia. This neurological disorder was initially defined by the association of ataxia, cerebellar syndrome, and pyramidal signs. Atypical forms are increasingly recognised. The gene was mapped to 9q13-q21.1 in 1988 and identified in 1996. We report on a patient with a spastic paraparesis, of which molecular analysis confirmed the diagnosis of Friedreich's ataxia.
A 39 year old woman without any past condition presented with difficulty in walking since the age of 20. Neurological examination showed a spastic paraparesis, with tetrapyramidal signs, including generalised brisk reflexes, bilateral Babinski's signs, and clonus at the knees and ankles. Spasticity only concerned the lower limbs and spared the arms. Spastic paraparesis resulted in impaired walking at the time of the examination. No other neurological abnormalities were found; notably, proprioception and vibration sense, and cerebellar function were normal. No sensory symptoms were noted. No skeletal deformities were found. All hematological investigations (including lactate and pyruvate concentrations, cholesterol, apolipoproteinemia, Vitamin E, very long chain fat acid concentrations, arylsulfatase, and hexosaminidase activities) were normal. Electromyography, sensory and motor nerve conduction studies in the upper and lower limbs, including sural nerve action potentials (right sural nerve action potential 7 μV, normal>6 μV; left sural nerve action potential 8 μV, normal>6 μV) were normal. Cardiological tests (electrocardiography, transthoracic echocardiography) were normal. Cerebral and spinal resonance MRI were normal. No familial condition was found, except the sister who presented the same symptoms. No mutations involved in mitochondriopathies were found (3243tRNAleu, 8344tRNALys, nt 8993). The molecular analysis of the gene coding for Friedreich's ataxia was performed by Southern blotting from DNA extracted from peripheral blood and showed two abnormal expansions of 2.5 kb and 3.1 kb on the chromosome 9q13-q21.1 (Dr M Schmitt, CHRU de Strasbourg, France). These expansions correspond to 830 and 1030 repeats. Diagnosis of Friedreich' s ataxia identified by an isolated paraparesis was definitevely retained.
Friedreich's ataxia, an autosomal recessive disorder, is one of the most common hereditary ataxias. The frequency of the gene is close to 1/90 in the general population and the prevalence of the disease is estimated to be 1/50 000. Diagnosis is classically based on the association of recessive inheritance, onset before the age of 25, progressive ataxia of the four limbs, loss of deep tendon reflexes, pyramidal signs, cerebellar dysarthria, distal loss of position and vibration sense, and electrophysiological evidence of axonal neuropathy.1 Association of pes cavus, scoliosis, cardiomyopathy, hearing loss, diabetes, and retinal disease are inconstantly seen. By contrast, atypical clinical symptoms are increasingly encountered—for example, late onset, brisk reflexes, spasticity, and slow progression of the disease,2 and idiopathic ataxia.3 Friedreich's ataxia is a genetically homogeneous condition. The frataxin gene was mapped to 9q13-q21.1 in 1988,4 and identified in 1996.5 The mutations are most often GAA expansions located in the first intron.5-7 Normal alleles range from 6 to 36 GAA repeats, whereas pathological alleles range from 90 to 1300 repeats. Ninety six per cent of patients are homozygous for GAA trinucleotide repeat expansions in the first intron of the frataxin gene. The remaining patients are compound heterozygotes for a GAA expansion and point mutations (missense, nonsense, and splice site mutations).5 7 Frataxin, the protein encoded by the gene, is a protein associated with the inner mitochondrial membrane.8 It is thought to regulate the flux of iron in or out the mitochondria. Identification of the mutated gene allowed the correlation of certain phenotypes with genotypes. Larger expansions of the GAA repeats are correlated with an earlier age of onset, a faster progression of the disease, and additional clinical manifestations such as cardiomyopathy, pes cavus, scoliosis, and extensor plantar responses.6 The length of the expansion explains 50% of the variability of age at onset only. Other factors are certainly involved in the phenotype variability. We note that the correlations were established from expansions measured in lymphocytic DNA. We cannot exclude the possibility of somatic mutations. Thus, the length of expansion in affected tissues would be different from the length found in lymphocytes. Some punctual mutations (D122Y, G130V) are correlated with a mild phenotype.7 Previous reports have noted that patients with Friedreich's ataxia could present with spasticity, usually associated with other neurological signs.9 Our report of isolated paraparesis confirmed again that the phenotypic range of Friedreich's ataxia is much broader than previously considered.3 6 In addition, the spastic paraparesis presented by our patient could be related to the cases of mitochondriopathies presenting with spastic paraplegia. Similar clinical symptoms in these two diseases can be an additional argument for the implication of frataxin in mitochondrial function.