TY - JOUR

T1 - Phenotype-genotype correlations in Leigh syndrome

T2 - new insights from a multicentre study of 96 patients

AU - Sofou, Kalliopi

AU - de Coo, Irenaeus F M

AU - Østergaard, Elsebet

AU - Isohanni, Pirjo

AU - Naess, Karin

AU - De Meirleir, Linda

AU - Tzoulis, Charalampos

AU - Uusimaa, Johanna

AU - Lönnqvist, Tuula

AU - Bindoff, Laurence Albert

AU - Tulinius, Már

AU - Darin, Niklas

PY - 2018

Y1 - 2018

N2 - BACKGROUND: Leigh syndrome is a phenotypically and genetically heterogeneous mitochondrial disorder. While some genetic defects are associated with well-described phenotypes, phenotype-genotype correlations in Leigh syndrome are not fully explored.OBJECTIVE: We aimed to identify phenotype-genotype correlations in Leigh syndrome in a large cohort of systematically evaluated patients.METHODS: We studied 96 patients with genetically confirmed Leigh syndrome diagnosed and followed in eight European centres specialising in mitochondrial diseases.RESULTS: We found that ataxia, ophthalmoplegia and cardiomyopathy were more prevalent among patients with mitochondrial DNA defects. Patients with mutations in MT-ND and NDUF genes with complex I deficiency shared common phenotypic features, such as early development of central nervous system disease, followed by high occurrence of cardiac and ocular manifestations. The cerebral cortex was affected in patients with NDUF mutations significantly more often than the rest of the cohort. Patients with the m.8993T>G mutation in MT-ATP6 gene had more severe clinical and radiological manifestations and poorer disease outcome compared with patients with the m.8993T>C mutation.CONCLUSION: Our study provides new insights into phenotype-genotype correlations in Leigh syndrome and particularly in patients with complex I deficiency and with defects in the mitochondrial ATP synthase.

AB - BACKGROUND: Leigh syndrome is a phenotypically and genetically heterogeneous mitochondrial disorder. While some genetic defects are associated with well-described phenotypes, phenotype-genotype correlations in Leigh syndrome are not fully explored.OBJECTIVE: We aimed to identify phenotype-genotype correlations in Leigh syndrome in a large cohort of systematically evaluated patients.METHODS: We studied 96 patients with genetically confirmed Leigh syndrome diagnosed and followed in eight European centres specialising in mitochondrial diseases.RESULTS: We found that ataxia, ophthalmoplegia and cardiomyopathy were more prevalent among patients with mitochondrial DNA defects. Patients with mutations in MT-ND and NDUF genes with complex I deficiency shared common phenotypic features, such as early development of central nervous system disease, followed by high occurrence of cardiac and ocular manifestations. The cerebral cortex was affected in patients with NDUF mutations significantly more often than the rest of the cohort. Patients with the m.8993T>G mutation in MT-ATP6 gene had more severe clinical and radiological manifestations and poorer disease outcome compared with patients with the m.8993T>C mutation.CONCLUSION: Our study provides new insights into phenotype-genotype correlations in Leigh syndrome and particularly in patients with complex I deficiency and with defects in the mitochondrial ATP synthase.

KW - Cell Nucleus/metabolism

KW - DNA/genetics

KW - DNA, Mitochondrial/genetics

KW - Female

KW - Follow-Up Studies

KW - Genetic Association Studies

KW - Humans

KW - Infant

KW - Leigh Disease/genetics

KW - Male

KW - Mutation/genetics

KW - Phenotype

U2 - 10.1136/jmedgenet-2017-104891

DO - 10.1136/jmedgenet-2017-104891

M3 - Journal article

C2 - 29101127

VL - 55

SP - 21

EP - 27

JO - Journal of Medical Genetics

JF - Journal of Medical Genetics

SN - 0022-2593

IS - 1

ER -