A novel mutation in the mitochondrial tRNA for tryptophan causing a late-onset mitochondrial encephalomyopathy.

BACKGROUND: Mitochondrial DNA (mtDNA) mutations are increasingly being recognized as causes of late-onset disease. We report a patient with a late-onset mitochondrial encephalomyopathy caused by a novel G > C transition in mtDNA at position 5556 in the gene encoding the tRNA for tryptophan (MTTW). AIMS: To investigate the cause of disease and assess the pathogenicity of this new mutation. METHODS: Clinical, histopathological and gene sequencing studies. Quantification of the mutation was performed in different tissues from the patient and two relatives and in single muscle fibres. RESULTS: The mutation was heteroplasmic, segregated in biochemically affected muscle fibres and was absent in blood. The level of mutation in skeletal muscle was higher than in brain, although the brain was clinically the most affected tissue. DISCUSSION: The 5556G > C mutation appears sporadic. It was not found in any of the family members tested, although some of them manifested disorders that can be associated with mtDNA disease. In addition to reporting the eighth mutation in MTTW, our case illustrates the challenges posed when assigning pathogenicity to mtDNA mutations.

Clinical evolution of Kearns-Sayre syndrome with polyendocrinopathy and respiratory failure.

BACKGROUND: The triad of progressive external ophthalmoplegia, atypical retinal pigmentation and cardiac conduction defects characterizes Kearns-Sayre syndrome (KSS), which is most often caused by a single, large deletion of mitochondrial DNA. Endocrine disease appears to be more common in KSS than in other mitochondrial diseases. MATERIALS, METHODS AND RESULTS: A patient presenting with KSS developed Addison's disease, hypothyroidism and glucose intolerance. Thyroid peroxidase antibodies and adrenal 21-hydroxylase antibodies were identified. She developed acute respiratory failure requiring invasive ventilatory support, but improved and currently requires only non-invasive, nocturnal BiPAP treatment. DISCUSSION AND CONCLUSION: This case confirms the association of KSS and endocrine dysfunction. Our finding of autoantibodies to thyroid and adrenal glands distinguishes this patient from most other published cases and suggests a potential synergy between the two disease mechanisms. In addition, we demonstrate that respiratory failure can be a treatable event in this disease.

The yield of expanding the therapeutic time window for tPA.

OBJECTIVES: Intravenous thrombolysis with recombinant tissue plasminogen activator (tPA) for acute ischemic stroke has been proved to be effective when given within 3 h of onset of stroke symptoms. Partly due to this time limit, less than 10% of stroke patients are treated with tPA. This study assessed the potential for increased tPA utilization with a theoretical time limit of 6 h. MATERIALS AND METHODS: A total of 117 patients admitted with a diagnosis of acute cerebrovascular disease were prospectively registered over a 3-month period, with emphasis on timing and criteria for tPA treatment. RESULTS: Eighty-eight of 117 patients (75%) had an acute ischemic stroke. Of these, 23% arrived within 3 h, 8% within 3-6 h, and 69% later than 6 h after symptom onset. Of the seven patients in the 3-6 h group, only one had time delay as the only contraindication to tPA. CONCLUSIONS: This study suggests that reducing patient delay, rather than increasing the time limit for thrombolytic treatment, may increase the frequency of tPA utilization. Changing time limits for thrombolysis may reduce time delay from stroke onset to arrival in hospital due to more rapid handling of patients by the emergency medical services.