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Leigh syndrome is a severe neurodegenerative disease with heterogeneous genetic etiology. We report a novel m.4296GA variant in the mitochondrial tRNA isoleucine gene in a child with Leigh syndrome, mitochondrial proliferation, lactic acidosis, and abnormal respiratory chain enzymology. The variant is present at75% heteroplasmy in blood and cultured fibroblasts from the proband,5% in asymptomatic maternal relatives, and is absent in 3000 controls. It is located in the highly conserved anticodon region of tRNA(Ile) where three other pathogenic changes have been described. We conclude that there is strong evidence to classify m.4296GA as a pathogenic mutation causing Leigh syndrome.

Mitochondrial medicine is a young subspecialty. Clinicians have limited evidence-based guidelines on which to formulate clinical decisions regarding diagnosis, treatment and management for patients with mitochondrial disorders. Mitochondrial medicine specialists have cobbled together an informal set of rules and paradigms for preventive care and management based in part on anecdotal experience. The Mitochondrial Medicine Society (MMS) assessed the current state of clinical practice including diagnosis, preventive care and treatment, as provided by various mitochondrial disease providers in North America. In this second of two reports, we present data related to clinical practice that highlight the challenges clinicians face in the routine care of patients with established mitochondrial disease. Concerning variability in treatment and preventative care approaches were noted. We hope that sharing this information will be a first step toward formulating a set of consensus criteria and establishing standards of care.

Mitochondrial medicine is a young subspecialty. Clinicians have a limited evidence base on which to formulate clinical decisions regarding diagnosis, treatment and patient management. Mitochondrial medicine specialists have cobbled together an informal set of rules and paradigms for preventive care and management based in part on anecdotal experience. The Mitochondrial Medicine Society (MMS) assessed the current state of clinical practice from diagnosis, to preventive care and treatment, as provided by various mitochondrial disease specialists in North America. We hope that by obtaining this information we can begin moving towards formulating a set of consensus criteria and establishing standards of care.

We have followed 8 patients (4 males) with biochemically and/or molecular genetically proven deficiencies of the E1α subunit of the pyruvate dehydrogenase complex (PDC; 3 patients) or complexes I (1 patient), IV (3 patients) or I+IV (1 patient) for 10.9 to 16.5 years. All subjects originally participated in randomized controlled trials for dichloroacetate (DCA) and were continued on an open-label chronic safety study. Patients (1 adult) ranged in age from 3.5 to 40.2 years at the start of DCA administration and are currently aged 16.9 to 49.9 years (mean±SD: 23.5±10.9 years). Subjects were either normal or below normal body weight for age and gender. They have been evaluated at least twice annually for routine tests of hematopoietic, renal, hepatic, lipid and lipoprotein metabolism, peripheral nerve conduction and plasma trough DCA concentrations. The 3 PDC deficient patients consumed a modestly increased fat diet (~2 fat:1 carbohydrate+protein). Oral DCA was administered at a dose of 12.5 mg/kg every 12 h. Potentially relevant concomitant medications included carbamazepine and clonazepam (1 patient) and progesterone (1 patient). DCA was well-tolerated and maintained normal blood lactate concentrations, even in PDC deficient children on essentially unrestricted diets. Hematological, renal and electrolyte status remained stable. Mean serum alanine transaminase (ALT) levels were modestly higher on DCA (1.609-fold above baseline; p=0.008), but serum aspartate transaminase and lipid and lipoprotein levels were not significantly altered while on the drug. Nerve conduction either did not change or decreased modestly and led to reduction or temporary discontinuation of DCA in 2 patients. We conclude that chronic DCA administration is effective in maintaining normal blood lactate levels and is generally well-tolerated, particularly in pediatric patients with PDC deficiency and other congenital causes of lactic acidosis.