Phenotype-genotype correlations in Leigh syndrome: new insights from a multicentre study of 96 patients

Sofou, Kalliopi; Coo, I.F.M. de; Østergaard, Elsebet; Isohanni, Pirjo; Naess, K; Meırleır, Linda De; Tzoulis, Charalampos; Uusimaa, Johanna; Lönnqvist, Tuula; Bindoff, Laurence A.; Tulinius, M.; Darín, Niklas

doi:10.1136/jmedgenet-2017-104891

Cited by 61 publications

(83 citation statements)

References 34 publications

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“…In the present study, the genetic complexity of 17 different nuclear and mitochondrial genes was identified. Genetic defects associated with complex I deficiency were the most frequent, with a total diagnostic yield of 64.5% (40/62 families) . These included six mitochondrial genes in 18 families, including MTATP6 , MTND3 , MTND6 , MTND5 , MTND1 , and MTTK , in descending order of frequency.…”

Section: Discussionsupporting

confidence: 92%

“…To date, few large cohort studies of genotype‐phenotype correlations have been conducted . Unlike the patients in a previous study, those in ours with mutations in MTND and NDUF did not show a higher incidence of cardiac or ocular involvement . In addition, neither the cerebral cortex nor the kidney appeared to be more frequently affected in patients with NDUF mutations compared with the other mutation‐positive cases .…”

Section: Discussioncontrasting

confidence: 86%

“…For between‐group comparisons of age at onset, neurologic outcome, and neuroradiologic findings, no significant correlation was found between phenotype and genotype. To date, few large cohort studies of genotype‐phenotype correlations have been conducted . Unlike the patients in a previous study, those in ours with mutations in MTND and NDUF did not show a higher incidence of cardiac or ocular involvement .…”

Section: Discussioncontrasting

confidence: 81%

“…Consistent with a few recent studies on the wide phenotypic spectrum of IARS2 ‐related mitochondrial disease, from non‐syndromic cataract to severe neurologic disorders, such as LS or West syndrome, our study shows various combinations of clinical features with uncertain genotype‐phenotype correlations . Thus, it remains unclear whether genetic defects may predict phenotype, or vice versa . It is clear that LS disease pathogenesis is more complex than previously expected.…”

Section: Discussionmentioning

confidence: 99%

“…However, following the first report on LS, patients with atypical presentations have been noted, expanding the clinical spectrum of the disorder. Likewise, the genetic spectrum has been broadened by advances in genomic technology, such as next‐generation sequencing (NGS) . Along with clinical diversity and overlapping features, genetic heterogeneity complicates the molecular diagnosis of LS.…”

Section: Introductionmentioning

confidence: 99%

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Genetic heterogeneity in Leigh syndrome: Highlighting treatable and novel genetic causes

et al. 2020

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Leigh syndrome (LS), the most common childhood mitochondrial disorder, has characteristic clinical and neuroradiologic features. Mutations in more than 75 genes have been identified in both the mitochondrial and nuclear genome, implicating a high degree of genetic heterogeneity in LS. To profile these genetic signatures and understand the pathophysiology of LS, we recruited 64 patients from 62 families who were clinically diagnosed with LS at Seoul National University Children's Hospital. Mitochondrial genetic analysis followed by whole‐exome sequencing was performed on 61 patients. Pathogenic variants in mitochondrial DNA were identified in 18 families and nuclear DNA mutations in 22. The following 17 genes analyzed in 40 families were found to have genetic complexity: MTATP6, MTND1, MTND3, MTND5, MTND6, MTTK, NDUFS1, NDUFV1, NDUFAF6, SURF1, SLC19A3, ECHS1, PNPT1, IARS2, NARS2, VPS13D, and NAXE. Two treatable cases had biotin‐thiamine responsive basal ganglia disease, and another three were identified as having defects in the newly recognized genes (VPS13D or NAXE). Variants in the nuclear genes that encoded mitochondrial aminoacyl tRNA synthetases were present in 27.3% of cases. Our findings expand the genetic and clinical spectrum of LS, showing genetic heterogeneity and highlighting treatable cases and those with novel genetic causes.

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Section: Discussionsupporting

confidence: 92%

Section: Discussioncontrasting

confidence: 86%

Section: Discussioncontrasting

confidence: 81%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Genetic heterogeneity in Leigh syndrome: Highlighting treatable and novel genetic causes

et al. 2020

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Leigh syndrome caused by mutations in MTFMT is associated with a better prognosis

Hayhurst

Coo

Piekutowska‐Abramczuk

et al. 2019

Ann Clin Transl Neurol

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Objectives Mitochondrial methionyl‐tRNA formyltransferase (MTFMT) is required for the initiation of translation and elongation of mitochondrial protein synthesis. Pathogenic variants in MTFMT have been associated with Leigh syndrome (LS) and mitochondrial multiple respiratory chain deficiencies. We sought to elucidate the spectrum of clinical, neuroradiological and molecular genetic findings of patients with bi‐allelic pathogenic variants in MTFMT. Methods Retrospective cohort study combining new cases and previously published cases. Results Thirty‐eight patients with pathogenic variants in MTFMT were identified, including eight new cases. The median age of presentation was 14 months (range: birth to 17 years, interquartile range [IQR] 4.5 years), with developmental delay and motor symptoms being the most frequent initial manifestation. Twenty‐nine percent of the patients survived into adulthood. MRI headings in MTFMT pathogenic variants included symmetrical basal ganglia changes (62%), periventricular and subcortical white matter abnormalities (55%), and brainstem lesions (48%). Isolated complex I and combined respiratory chain deficiencies were identified in 31% and 59% of the cases, respectively. Reduction of the mitochondrial complex I and complex IV subunits was identified in the fibroblasts (13/13). Sixteen pathogenic variants were identified, of which c.626C>T was the most common. Seventy‐four percent of the patients were alive at their last clinical review (median 6.8 years, range: 14 months to 31 years, IQR 14.5 years). Interpretation Patients that harbour pathogenic variants in MTFMT have a milder clinical phenotype and disease progression compared to LS caused by other nuclear defects. Fibroblasts may preclude the need for muscle biopsy, to prove causality of any novel variant.

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Biallelic variants in COX4I1 associated with a novel phenotype resembling Leigh syndrome with developmental regression, intellectual disability, and seizures

Pillai

AlDhaheri

Ghosh

et al. 2019

American J of Med Genetics Pt A

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Phenotype-genotype correlations in Leigh syndrome: new insights from a multicentre study of 96 patients

Abstract: 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.

Cited by 61 publications

References 34 publications

Genetic heterogeneity in Leigh syndrome: Highlighting treatable and novel genetic causes

Genetic heterogeneity in Leigh syndrome: Highlighting treatable and novel genetic causes

Leigh syndrome caused by mutations in MTFMT is associated with a better prognosis

Biallelic variants in COX4I1 associated with a novel phenotype resembling Leigh syndrome with developmental regression, intellectual disability, and seizures

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