[Mitochondrial encephalopathy due to complex I deficiency. Brain tissue biopsy findings and clinical course following pharmacological]. / Encefalopatia mitocondrial por deficit del complejo I. Hallazgos en la biopsia cerebral y evolucion clinica tras tratamiento farmacologico.

INTRODUCTION: Mitochondrial encephalomyopathies belong to a heterogeneous group of diseases with a range of neurological symptoms caused by a dysfunction somewhere in the nervous system. They may arise from mutations of the mitochondrial DNA or nuclear DNA in the genes that code for the subunits of the respiratory chain. The results obtained from using different drugs to treat these diseases vary widely. CASE REPORT: A 33-year-old female with a history of migraine with aura, who was admitted to hospital because of epileptic seizures. Neuroimaging tests showed left-side occipital insult and a biopsy study of a sample of brain tissue revealed gliosis and vacuolisation of the white matter. Lactic acid levels in blood were normal. No ragged red fibres were seen in the muscle biopsy, but there was evidence of a complex I deficiency in the respiratory chain. After establishing treatment with coenzyme Q and riboflavin, the patient had no further episodes of neurological disorders. CONCLUSIONS: The absence of elevated levels of lactate, ragged red fibres in the muscle biopsy or the negative results for mutations in the genetic study do not rule out the possible existence of a mitochondrial disease. The gliosis and vacuolisation of the white matter with respect to the neurons that were found in the results of the brain tissue biopsy must lead us to consider a mitochondrial disease.

Additive effects of POLG1 and ANT1 mutations in a complex encephalomyopathy.

MtDNA instability is associated with a wide spectrum of clinical presentations, from dominant or recessive progressive external ophthalmoplegia (PEO) to juvenile-onset spino-cerebellar ataxia and epilepsy (SCAE) or infantile Alpers-Huttenlocher syndrome. We present here the clinical and molecular features of a patient with a clinical presentation characterized initially by PEO with mtDNA multiple deletions lately evolving into a severe neurological syndrome, which included sensory and cerebellar ataxia, peripheral neuropathy, parkinsonism, and depression. This complex phenotype is the result of mutations in two distinct proteins, ANT1 and PolgammaA, which cause additive, deleterious effects on mtDNA maintenance and integrity.

A novel mutation in the mitochondrial tRNA Asn gene associated with a lethal disease.

We describe a lethal mitochondrial disease in a 10-month-old child who presented with encephalomyopathy. Histochemical and electron microscopy examinations of skeletal muscle biopsy revealed abnormal mitochondria associated with a combined deficiency of complexes I and IV. After excluding mitochondrial DNA deletions and depletion, direct sequencing was used to screen for mutation in all transfer RNA (tRNA) genes. A T-to-C substitution at position 5693 in the tRNA(Asn) gene was found in blood and muscle. Microdissection of muscle biopsy and its analysis revealed the highest level of this mutation in cytochrome c oxidase (COX)-negative fibres. We suggest that this novel mutation would affect the anticodon loop structure of the tRNA(Asn) and cause a fatal mitochondrial disease.

Cerebral white matter disease in children may be caused by mitochondrial respiratory chain deficiency.

Several mitochondrial diseases are known to occasionally involve the cerebral white matter, namely Leigh syndrome, Kearns-Sayre syndrome, and MELAS syndrome, but in these cases the major finding is alteration in the basal ganglia and brainstem. Here we report on severe diffuse white matter involvement and respiratory chain enzyme deficiency or mitochondrial DNA rearrangement in 5 unrelated families. It is interesting that white matter lesions were the only abnormal neuroradiologic feature in 3 of the 5 families, and multiple small cyst-like white matter lesions were found in 2 of 5 probands. Respiratory chain deficiency should be considered in the diagnosis of severe white matter involvement in childhood.

Multiple mtDNA deletions features in autosomal dominant and recessive diseases suggest distinct pathogeneses.

Multiple mitochondrial DNA (mtDNA) deletions have been described in patients with autosomal dominant progressive external ophthalmoplegia (AD-PEO) and in autosomal recessive disorders including mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) and autosomal recessive cardiomyopathy ophthalmoplegia (ARCO). The pathogenic bases of these disorders are unknown. We studied three patients with AD-PEO and three patients with autosomal recessive (AR)-PEO (two patients with MNGIE and one patient with ARCO). Histochemistry and Southern blot analyses of DNA were performed in skeletal muscle from the patients. Muscle mtDNA was used to characterize the pattern and amounts of the multiple mtDNA rearrangements; PCR analysis was performed to obtain finer maps of the deleted regions in both conditions. The patients with AD-PEO had myopathic features; the patients with AR-PEO had multisystem disorders. The percentage of ragged-red and cytochrome c oxidase-negative fibers tended to be higher in muscle from the patients with AD-PEO (19% +/- 13.9, 29.7 +/- 26.3) than in muscle from the patients with AR-PEO (1.4% +/- 1.4, 3.3% +/- 3.2; p < 0.10). The sizes of the multiple mtDNA deletions ranged from approximately 4.0 to 10.0 kilobases in muscle from both groups of patients, and in both groups, we identified only deleted and no duplicated mtDNA molecules. Patients with AD-PEO harbored a greater proportion of deleted mtDNA species in muscle (31% +/- 5.3) than did patients with AR-PEO (9.7% +/- 9.1; p < 0.05). In the patients with AD-PEO, we identified a deletion that included the mtDNA heavy strand promoter (HSP) region, which had been previously described as the HSP deletion. The HSP deletion was not present in the patients with AR-PEO. Our findings show the clinical, histologic, and molecular genetic heterogeneity of these complex disorders. In particular, the proportions of multiple mtDNA deletions were higher in muscle samples from patients with AD-PEO than in those from patients with AR-PEO.

Problems with the biochemical diagnosis in mitochondrial (encephalo-)myopathies.

Patients suffering from a mitochondrial (encephalo-)myopathy have a remarkable clinical heterogeneity. A reliable and extensive investigation must be performed in order to obtain a correct diagnosis, but many factors may influence the ultimate results of these investigations leading, under certain circumstances, to an incorrect diagnosis. Patients selection is of crucial importance. Metabolic examination of body fluids, particularly with respect to lactate accumulation, is used as a selection criterion for further examinations. Numerous aspects associated with this metabolic examination have been critically evaluated, including the phenomenon of other causes of lactic acidaemia apart from mitochondrial disorders. Correct performance of in vivo function tests may contribute to a reduction of the number of missed diagnoses. Selection of the controls for biochemical investigations must be accurately be performed to obtain reliable reference values. Knowledge of the age-dependency of the biochemical parameters is necessary for a correct interpretation. It goes without saying that the choice of the tissue for biochemical investigations is of utmost importance. Knowledge of the tissue-specific occurrence of some defects in the mitochondrial respiratory chain is necessary. The biochemical examinations can be performed both in biopsy and autopsy material but only under certain conditions. Diagnostic approach requires application of reliable biochemical methods which are described. One of the most intriguing aspects in the diagnosis of mitochondrial disorders is the significance of a defect in relation to the residual enzyme activity found in the patient. Moreover, attention is paid to relevant items such as the occurrence of multiple and secondary defects.(ABSTRACT TRUNCATED AT 250 WORDS)

Sudden loss of hearing and vestibular function, muscular weakness, and multiple white matter lesions in preschool children.

Sudden cochlear hearing loss, occurring successively or simultaneously in both ears, was observed in four unrelated preschool children. Vestibular testing could be carried out in three patients and showed complete bilateral loss of function. All patients had a mildly retarded motor development due to nonprogressive muscular weakness. On MR imaging all patients showed multiple periventricular and subcortical white matter lesions. These lesions were not clearly progressive in one patient examined repeatedly over 6 years. Virological, bacteriological, immunological, and metabolic examinations were normal in all patients. Muscle biopsy showed morphologically abnormal mitochondria in two and lipid storage in one patient. No indications have been found for a disturbed functioning of the muscle mitochondria. The identical pattern and course of the disease in these patients suggests a new nosological entity, the aetiology of which can only speculatively be attributed to a vascular process associated with a mitochondriopathy.