Diagnostic strategy in mitochondrial disorders – An update

Mitochondrial disorders are an important differenzial diagnosis in neurodegenerative disorders of childhood. More than 50 disease causing genes are known. The prevalence in children is estimated about 1.5 in 10000 but is probably higher as these disorders are under diagnosed due to the large clinical spectrum and the complex diagnostic procedures. In order to improve the diagnostic quality and efficiency we propose the following stepwise proceeding: if clinical evaluation, analysis of metabolites (blood, urine, CSF), neurophysiologic methods and imaging (MRI, MR-spectroscopy, echocardiography) confirm the suspicion of mitochondrial disease the consecutive molecular genetic analysis is useful in typical mitochondrial syndromes. Otherwise biochemical and morphological analysis of affected tissue – commonly muscle- should be performed. The biochemical analysis of freshly biopsied muscle has proven to be the most valid method as it allows the functional analysis of the intact mitochondria. In contrast to frozen tissue also defects of complex V of the respiratory chain and abnormalities of transmembranous transport can be detected (mitochondrial phosphate carrier defect, ANT-defect).

The spectrum of disease causing genes has been considerably enlarged during the last years, e.g. due to the identification of defects of Coenzyme Q10 metabolism and abnormalities of intergenomic communication (mtDNA-depletion/deletion syndromes). New methods like high-throughput screening by DNA-melting point analysis allow to analyze larger numbers of disease genes (e.g. complex I genes) Our experience shows that this stepwise diagnostic procedure is condition for rational and efficient molecular diagnosis and helps to understand genotype/phenotype correlation.