Respiratory chain complex I deficiency - An underdiagnosed energy generation disorder

Objective: To define the spectrum of clinical and biochemical features in 5 1 children with isolated complex I deficiency. Background: Mitochondrial re spiratory chain defects are one of the most commonly diagnosed inborn error s of metabolism. Until recently there have been technical problems with the diagnosis of respiratory chain complex I defects, and there is a lack of i nformation about this underreported cause of respiratory chain dysfunction. Methods: A retrospective review of clinical features and laboratory findin gs was undertaken in all diagnosed patients who had samples referred over a 22-year period. Results: Presentations were heterogeneous, ranging from se vere multisystem disease with neonatal death to isolated myopathy. Classic indicators of respiratory chain disease were not present in 16 of 42 patien ts in whom blood lactate levels were normal on at least one occasion, and i n 23 of 37 patients in whom muscle morphology was normal or nonspecific. Ra gged red fibers were present in only five patients. Tissue specificity was observed in 19 of 41 patients in whom multiple tissues were examined, thus the diagnosis may be missed if the affected tissue is not analyzed. Nine pa tients had only skin fibroblasts available, the diagnosis being based on en zyme assay and functional tests. Modes of inheritance include autosomal rec essive (suggested in five consanguineous families), maternal (mitochondrial DNA point mutations in eight patients), and possibly X-linked (slight male predominance of 30:21). Recurrence risk was estimated as 20 to 25%. Conclu sion: Heterogeneous clinical features, tissue specificity, and absence of l actic acidosis or abnormal mitochondrial morphology in many patients have r esulted in underdiagnosis of respiratory chain complex I deficiency.