Myopathic involvement and mitochondrial pathology in Kennedy disease and in other motor neuron diseases.

Kennedy disease (spinal and bulbar muscular atrophy, or SBMA) is a motor neuron disease caused by a CAG expansion in the androgen-receptor (AR) gene. Increasing evidence shows that SBMA may have a primary myopathic component and that mitochondrial dysfunction may have some role in the pathogenesis of this disease. In this article, we review the role of mitochondrial dysfunction and of the mitochondrial genome (mtDNA) in SBMA, and we present the illustrative case of a patient who presented with increased CK levels and exercise intolerance. Molecular analysis led to definitive diagnosis of SBMA, whereas muscle biopsy showed a mixed myopathic and neurogenic process with "mitochondrial features" and multiple mtDNA deletions, supporting some role of mitochondria in the pathogenesis of the myopathic component of Kennedy disease. Furthermore, we briefly review the role of mitochondrial dysfunction in two other motor neuron diseases (namely spinal muscular atrophy and amyotrophic lateral sclerosis). Most likely, in most cases mtDNA does not play a primary role and it is involved subsequently. MtDNA deletions may contribute to the neurodegenerative process, but the exact mechanisms are still unclear. It will be important to develop a better understanding of the role of mitochondrial dysfunction in motoneuron diseases, since it may lead to the development of more effective strategies for the treatment of this devastating disorder.

Targeting mitochondrial dysfunction and neurodegeneration by means of coenzyme Q10 and its analogues.

Coenzyme Q10 is a small electron carrier of the respiratory chain with antioxidant properties, widely used for the treatment of mitochondrial disorders. Mitochondrial diseases are neuromuscular disorders caused by impairment of the respiratory chain and increased generation of reactive oxygen species. Coenzyme Q10 supplementation is fundamental in patients with primary coenzyme Q10 deficiency. Furthermore, coenzyme Q10 and its analogues, idebenone and mitoquinone (or MitoQ), have been also used in the treatment of other neurogenetic/neurodegenerative disorders. In Friedreich ataxia idebenone may reduce cardiac hypertrophy and, at higher doses, also improve neurological function. These compounds may also play a potential role in other conditions which have been linked to mitochondrial dysfunction, such as Parkinson disease, Huntington disease, amyotrophic lateral sclerosis and Alzheimer disease. This review introduces mitochondrial disorders and Friedreich ataxia as two paradigms of the tight links existing between oxidative stress, respiratory chain dysfunction and neurodegeneration, and focuses on current and emerging therapeutic uses of coenzyme Q10 and idebenone in neurology.

Tetracycline treatment in patients with progressive external ophthalmoplegia.

BACKGROUND: Tetracyclines could have neuroprotective effects in neuromuscular and neurodegenerative disorders. AIMS OF THE STUDY AND METHODS: Objective of this double-blind randomized pilot study (followed by an adjunctive open-label phase) was to evaluate whether tetracycline (500 mg/day × 14 days/month × 3 months) could be useful in patients (n = 16) with progressive external ophthalmoplegia (PEO). RESULTS: Our results do not formally support any effect of tetracycline on eye motility in PEO. However, some possible protective effects could not be completely ruled out, i.e. a further analysis suggests a possible difference between the tetracycline group and the placebo group, significant at least for oblique motility, when comparing the ratio between the end of the double-blind phase and baseline. Tetracycline could modify some oxidative stress biomarkers in patients with PEO. CONCLUSIONS: Further studies are needed to confirm such effects of tetracycline in patients with PEO, if any, and to clarify the mechanisms of action for antioxidant effects of tetracyclines in mitochondrial disorders and other diseases.