Clinical and electrophysiological investigations and nerve biopsies were carried out on 61 patients shown to have a chromosome 17p11.2 duplication (hereditary motor and sensory neuropathy-HMSN Ia). Of these, 50 showed a Charcot-Marie-Tooth (CMT) phenotype and eight could be classified as having the Roussy-Lévy syndrome. Of the patients with a CMT phenotype, three had associated pyramidal signs and of these one had 'complicated' HMSN and also signs of cerebellar and bulbar involvement. Diaphragmatic weakness was present in three severely affected cases, one of whom also had denervation of the anal sphincter associated with faecal incontinence. One unusual case presented in middle life with incapacitating muscle cramps associated with calf hypertrophy and only mild clinical signs of neuropathy. Prominent distal sensory loss was a consistent feature in one family, resulting in acrodystrophic changes in several members. Concurrent focal peripheral nerve lesions were seen with both the CMT and Roussy-Lévy phenotypes, in seven patients. Upper limb motor nerve conduction velocity was 19.9 m/s +/- 1.3 (SEM), range 5-34 m/s. This corresponds to values previously obtained for autosomal dominant HMSN I. This series consisted mainly of older patients with more advanced disease. In contrast to the findings in younger patients, in their nerve biopsies, myelin thickness tended to be relatively reduced for axon size, indicating remyelination and/or hypomyelination; there was also regression of the onion bulbs. It is concluded that the possession of two copies of the peripheral myelin protein 22 gene within the duplicated region on chromosome 17p gives rise to a range of phenotypes and not solely to a CMT syndrome, and that the pattern of histological change in the peripheral nerves alters with advance of the disease.

Friedreich's ataxia (FRDA) is an autosomal recessive disorder with a frequency of 1 in 50 000 live births. In 97% of patients it is caused by the abnormal expansion of a GAA repeat in intron 1 of the FRDA gene on chromosome 9, which encodes a 210 amino acid protein called frataxin. Frataxin is widely expressed and has been localized to mitochondria although its function is unknown. We have investigated mitochondrial function, mitochondrial DNA levels, aconitase activity and iron content in tissues from FRDA patients. There were significant reductions in the activities of complex I, complex II/III and aconitase in FRDA heart. Respiratory chain and aconitase activities were decreased although not significantly in skeletal muscle, but were normal in FRDA cerebellum and dorsal root ganglia, although there was a mild decrease in aconitase activity in the latter. Mitochondrial DNA levels were reduced in FRDA heart and skeletal muscle, although in skeletal muscle this was paralleled by a decline in citrate synthase activity. Increased iron deposition was seen in FRDA heart, liver and spleen in a pattern consistent with a mitochondrial location. The iron accumulation, mitochondrial respiratory chain and aconitase dysfunction and mitochondrial DNA depletion in FRDA heart samples largely paralleled those in the yeast YFH1 knockout model, suggesting that frataxin may be involved in mitochondrial iron regulation or iron sulphur centre synthesis. However, the severe deficiency in aconitase activity also suggests that oxidant stress may induce a self-amplifying cycle of oxidative damage and mitochondrial dysfunction, which may contribute to cellular toxicity.

Friedreich ataxia (FRDA), the most common of the inherited ataxias, is an autosomal recessive degenerative disorder, characterized clinically by onset before the age of 25 of progressive gait and limb ataxia, absence of deep tendon ref lexes, extensor plantar responses, and loss of position and vibration sense in the lower limbs. FRDA is caused by a GAA triplet expansion in the first intron of the FRDA gene on chromosome 9q13 in 97% of patients. The FRDA gene encodes a widely expressed 210-aa protein, frataxin, which is located in mitochondria and is severely reduced in FRDA patients. Frataxin function is still unknown but the knockout of the yeast frataxin homologue gene (YFH1) showed a severe defect of mitochondrial respiration and loss of mtDNA associated with elevated intramitochondrial iron. Here we report in vivo evidence of impaired mitochondrial respiration in skeletal muscle of FRDA patients. Using phosphorus magnetic resonance spectroscopy we demonstrated a maximum rate of muscle mitochondrial ATP production (V max ) below the normal range in all 12 FRDA patients and a strong negative correlation between mitochondrial V max and the number of GAA repeats in the smaller allele. Our results show that FRDA is a nuclear-encoded mitochondrial disorder affecting oxidative phosphorylation and give a rationale for treatments aimed to improve mitochondrial function in this condition.Friedreich ataxia (FRDA) is the most common form of inherited ataxia with a frequency of 1 in 50,000 live births. FRDA is an autosomal recessive degenerative disorder, characterized clinically by onset before the age of 25 of progressive gait and limb ataxia, absence of deep tendon reflexes, extensor plantar responses, and loss of position and vibration sense in the lower limbs (1). Cardiomyopathy as defined by echocardiography is present in more than 60% of FRDA patients (2). The cause of FRDA is a GAA triplet expansion in the first intron of the FRDA gene on chromosome 9q13 (3). Ninetyseven percent of FRDA patients are homozygous for the GAA expansion, the remainder carrying a repeat expansion in one FRDA allele and a point mutation in the other (2, 3).The FRDA gene encodes a widely expressed 210-aa protein, frataxin, which is located in mitochondria (4-6) and is severely reduced in FRDA patients (4). Although frataxin function is still unknown, yeast strains carrying a disruption in the frataxin homologue gene (YFH1) showed a severe defect of mitochondrial respiration (5-8) and loss of mtDNA (7, 8) associated with elevated intramitochondrial iron (5,8).In view of the mitochondrial localization of frataxin (4-6), the evidence from the YFH1 knockout model for mitochondrial dysfunction (5-8), and the similarities of the cardinal clinical features present in FRDA with primary mitochondrial diseases (9), we used in vivo 31 phosphorus magnetic resonance spectroscopy ( 31 P-MRS) to test for the presence of mitochondrial dysfunction in skeletal muscle of 12 FRDA patients. Skeletal muscle is an ideal tissue in which to assess in vi...

The aim of the study was to examine several physiological responses to a climbing-specific task to identify determinants of endurance in sport rock climbing. Finger strength and endurance of intermediate rock climbers (n = 11) and non-climbers (n = 9) were compared using climbing-specific apparatus. After maximum voluntary contraction (MVC) trials, two isometric endurance tests were performed at 40% (s = 2.5%) MVC until volitional exhaustion (continuous contractions and intermittent contractions of 10 s, with 3 s rest between contractions). Changes in muscle blood oxygenation and muscle blood volume were recorded in the flexor digitorum superficialis using near infra-red spectroscopy. Statistical significance was set at P < 0.05. Climbers had a higher mean MVC (climbers: 485 N, s = 65; non-climbers 375 N, s = 91) (P = 0.009). The group mean endurance test times were similar. The force-time integral, used as a measure of climbing-specific endurance, was greater for climbers in the intermittent test (climbers: 51,769 N x s, s = 12,229; non-climbers: 35,325 N x s, s = 9724) but not in the continuous test (climbers: 21,043 N x s, s = 4474; non-climbers: 15,816 N x s, s = 6263). Recovery of forearm oxygenation during rest phases (intermittent test) explained 41.1% of the variability in the force-time integral. Change in total haemoglobin was significantly greater in non-climbers (continuous test) than climbers (P = 0.023--40% test timepoint, P = 0.014--60% test timepoint). Pressor responses were similar between groups and not related to the force-time integral for either test. We conclude that muscle re-oxygenation during rest phases is a predictor of endurance performance.

Background: Decreased mitochondrial respiratory chain function and increased oxidative stress have been implicated in the pathogenesis of Friedreich ataxia (FRDA), raising the possibility that energy enhancement and antioxidant therapies may be an effective treatment.Objective: To evaluate the long-term efficacy of a combined antioxidant and mitochondrial enhancement therapy on the bioenergetics and clinical course of FRDA.Design: Open-labeled pilot trial over 47 months.Patients: Seventy-seven patients with clinical and genetically defined FRDA.Intervention: A combined coenzyme Q 10 (400 mg/d) and vitamin E (2100 IU/d) therapy of 10 patients with FRDA over 47 months.Main Outcome Measures: Clinical assessment using echocardiography and the International Cooperative Ataxia Rating Scale and cardiac and skeletal muscle bioenergetics as assessed using phosphorus P 31 magnetic resonance spectroscopy.Results: There was a significant improvement in cardiac and skeletal muscle bioenergetics that was maintained throughout the 47 months of therapy. Echocardiographic data revealed significantly increased fractional shortening at the 35-and 47-month time points. Comparison with cross-sectional data from 77 patients with FRDA indicated the changes in total International Cooperative Ataxia Rating Scale and kinetic scores over the trial period were better than predicted for 7 patients, but the posture and gait and hand dexterity scores progressed as predicted. Conclusion:This therapy resulted in sustained improvement in mitochondrial energy synthesis that was associated with a slowing of the progression of certain clinical features and a significant improvement in cardiac function.

Friedreich's ataxia (FA) is the most common form of autosomal recessive spinocerebellar ataxia and is often associated with a cardiomyopathy. The disease is caused by an expanded intronic GAA repeat, which results in deficiency of a mitochondrial protein called frataxin. In the yeast YFH1 knockout model of the disease there is evidence that frataxin deficiency leads to a severe defect of mitochondrial respiration, intramitochondrial iron accumulation, and associated production of oxygen free radicals. Recently, the analysis of FA cardiac and skeletal muscle samples and in vivo phosphorus magnetic resonance spectroscopy (31P-MRS) has confirmed the deficits of respiratory chain complexes in these tissues. The role of oxidative stress in FA is further supported by the accumulation of iron and decreased aconitase activities in cardiac muscle. We used 31P-MRS to evaluate the effect of 6 months of antioxidant treatment (Coenzyme Q10 400 mg/day, vitamin E 2,100 IU/day) on cardiac and calf muscle energy metabolism in 10 FA patients. After only 3 months of treatment, the cardiac phosphocreatine to ATP ratio showed a mean relative increase to 178% (p = 0.03) and the maximum rate of skeletal muscle mitochondrial ATP production increased to 139% (p = 0.01) of their respective baseline values in the FA patients. These improvements, greater in prehypertrophic hearts and in the muscle of patients with longer GAA repeats, were sustained after 6 months of therapy. The neurological and echocardiographic evaluations did not show any consistent benefits of the therapy after 6 months. This study demonstrates partial reversal of a surrogate biochemical marker in FA with antioxidant therapy and supports the evaluation of such therapy as a disease-modifying strategy in this neurodegenerative disorder.

A high proportion of FRDA patients have a decreased serum CoQ(10) level which was the best predictor of a positive clinical response to CoQ(10)/vitamin E therapy. Low and high dose CoQ(10)/vitamin E therapies were equally effective in improving ICARS scores.

Satisfactory relief of intractable vomiting from diabetic gastroparesis was achieved by a novel radical surgical procedure. Histopathological findings suggest that gastromyopathy may contribute to the production of this syndrome.