A multicenter study on Leigh syndrome: disease course and predictors of survival

Abstract

BackgroundLeigh syndrome is a progressive neurodegenerative disorder, associated with primary or secondary dysfunction of the mitochondrial oxidative phosphorylation. Despite the fact that Leigh syndrome is the most common phenotype of mitochondrial disorders in children, longitudinal natural history data is missing. This study was undertaken to assess the phenotypic and genotypic spectrum of patients with Leigh syndrome, characterise the clinical course and identify predictors of survival in a large cohort of patients.MethodsThis is a retrospective study of patients with Leigh syndrome that have been followed at eight centers specialising in mitochondrial diseases in Europe; Gothenburg, Rotterdam, Helsinki, Copenhagen, Stockholm, Brussels, Bergen and Oulu.ResultsA total of 130 patients were included (78 males; 52 females), of whom 77 patients had identified pathogenic mutations. The median age of disease onset was 7 months, with 80.8% of patients presenting by the age of 2 years. The most common clinical features were abnormal motor findings, followed by abnormal ocular findings. Epileptic seizures were reported in 40% of patients. Approximately 44% of patients experienced acute exacerbations requiring hospitalisation during the previous year, mainly due to infections. The presence of pathological signs at birth and a history of epileptic seizures were associated with higher occurrence of acute exacerbations and/or relapses. Increased lactate in the cerebrospinal fluid was significantly correlated to a more severe disease course, characterised by early onset before 6 months of age, acute exacerbations and/or relapses, as well as brainstem involvement. 39% of patients had died by the age of 21 years, at a median age of 2.4 years. Disease onset before 6 months of age, failure to thrive, brainstem lesions on neuroimaging and intensive care treatment were significantly associated with poorer survival.ConclusionsThis is a multicenter study performed in a large cohort of patients with Leigh syndrome. Our data help define the natural history of Leigh syndrome and identify novel predictors of disease severity and long-term prognosis.

Leigh-Like Syndrome Due to Homoplasmic m.8993T>G Variant with Hypocitrullinemia and Unusual Biochemical Features Suggestive of Multiple Carboxylase Deficiency (MCD)

“…Typically, onset occurs between age three and 12 months, often triggered by an acute infection. Prenatal expression of mitochondrial disease has been described with oligohydramnios, intrauterine growth restriction and abnormal brain neuroimaging (Kumakura et al 2009;Sofou et al 2014). Late-onset Leigh syndrome has been associated with predominant extrapyramidal features, slow progression, acute deterioration, usually after decompensation with illness, and atypical presentations including features of Guillain-Barré syndrome, hypertrophic cardiomyopathy, anaemia and leukopenia (Huntsman et al 2005).…”

“…Causative variants have been identified in up to 75 genes involved in energy metabolism, encoded by either the nuclear or mitochondrial genomes, including each of the five OXPHOS complexes, electron carrier coenzyme Q10 (CoQ10) and components of the pyruvate dehydrogenase complex (Lake et al 2015). Mitochondrial DNA (mtDNA) mutations underlie approximately 10-20% of LS cases (Rahman et al 1996;Sofou et al 2014). Approximately 10% of individuals have either the MT-ATP6 (mitochondrially encoded ATP synthase 6) m.8993T>G or m.8993T>C variants which represent the only established genetic cause of a Complex V-mediated LS (Santorelli et al 1993;Rahman et al 1996;Thorburn and Rahman 2014).…”

Clinical, biochemical, and genetic features of four patients with short‐chain enoyl‐CoA hydratase (ECHS1) deficiency

“…No general curative treatment is available for this devastating disorder, although several recent studies imply that early treatment might be beneficial for some patients depending on the gene or process affected, for example, the ketogenic diet has been noted to be helpful in patients with PDHc deficiency and some patients with PDHc deficiency and LS may show small benefits from vitamin or co‐factor supplementation with coenzyme Q10, thiamine or riboflavin (Baertling et al, 2014; Gerards, Sallevelt, & Smeets, 2016; Sofou et al, 2014). Mahajan, Constantinou, and Sidiropoulos (2017) describe a case of ECHS1 deficiency‐associated paroxysmal exercise‐induced dyskinesias with initial symptomatic improvement after 3 months treatment with a mitochondrial cocktail.…”

Leigh map: A novel computational diagnostic resource for mitochondrial disease

“…Leigh syndrome is a progressive neurodegenerative disorder defined neuropathologically by spongiform basal ganglia and brainstem lesions 4, 5. Clinical manifestations include psychomotor retardation, with regression, and progressive neurological abnormalities related to basal ganglia and/or brainstem dysfunction, often resulting in death within 2 years of initial presentation 4, 6. However, many patients may also present with multisystemic (eg, cardiac, hepatic, renal, or hematological) phenotypes.…”