期刊
MOVEMENT DISORDERS CLINICAL PRACTICE
卷 9, 期 2, 页码 218-228出版社
WILEY
DOI: 10.1002/mdc3.13398
关键词
NDUFA12; dystonia; optic atrophy; Leigh syndrome; phenotypic heterogeneity
资金
- Wellcome Trust
- National Institute for Health Research University College London Hospitals Biomedical Research Centre
- project RAC [2121053]
- Edmond J. Safra Foundation
- research grant Fondo Gianesini
- UniCredit Foundation
- University of Verona, Italy
- Wellcome Centre for Mitochondrial Research [203, 105/Z/16/Z]
- MRC International Centre for Genomic Medicine in Neuromuscular Disease [MR/S005021/1]
- Mitochondrial Disease Patient Cohort (UK) [G0800674]
- UK NIHR Biomedical Research Centre for Aging and Age-related disease award
- The Lily Foundation
- Pathology Society
- UK NHS Highly Specialized Service for Rare Mitochondrial Disorders of Adults and Children
- Wellcome/MRC
- NIHR
- Parkinson's UK
- EU Horizon 2020
- Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) [418081722, 433158657]
- UK NHS
- Medical Research Council (UK) [MR/N025431/1, MR/V009346/1]
- European Research Council [309548]
- Newton Fund (UK/Turkey) [MR/N027302/1]
- Addenbrookes Charitable Trust [G100142]
- Evelyn Trust
- Stoneygate Trust
- Lily Foundation
- MRC strategic award [MR/S005021/1]
- NIHR Cambridge Biomedical Research Centre [BRC-1215-20,014]
- MRC [MR/S005021/1, MR/S01165X/1, G0601943]
- Rosetree Trust
- Ataxia UK
- MSA Trust
- Brain Research UK
- Sparks GOSH Charity
- Muscular Dystrophy UK (MDUK)
- Muscular Dystrophy Association (MDA USA)
- [WT093205 MA]
- [WT104033AIA]
- Medical Research Council [MR/S01165X/1, MR/S005021/1, G0601943] Funding Source: researchfish
- MRC [MR/S005021/1] Funding Source: UKRI
This study presents newly identified cases of NDUFA12-related mitochondrial disease, demonstrating phenotypic and genotypic heterogeneity. The cases exhibited various clinical presentations, including movement disorders and optic atrophy, with distinct MRI findings. The study highlights the clinical diversity associated with the same genetic variant within and between families.
Background Biallelic loss-of-function NDUFA12 variants have hitherto been linked to mitochondrial complex I deficiency presenting with heterogeneous clinical and radiological features in nine cases only. Objectives To fully characterize, both phenotypically and genotypically, NDUFA12-related mitochondrial disease. Methods We collected data from cases identified by screening genetic databases of several laboratories worldwide and systematically reviewed the literature. Results Nine unreported NDUFA12 cases from six pedigrees were identified, with presentation ranging from movement disorder phenotypes (dystonia and/or spasticity) to isolated optic atrophy. MRI showed basal ganglia abnormalities (n = 6), optic atrophy (n = 2), or was unremarkable (n = 1). All carried homozygous truncating NDUFA12 variants, three of which are novel. Conclusions Our case series expands phenotype-genotype correlations in NDUFA12-associated mitochondrial disease, providing evidence of intra- and inter-familial clinical heterogeneity for the same variant. It confirms NDUFA12 variants should be included in the diagnostic workup of Leigh/Leigh-like syndromes - particularly with dystonia - as well as isolated optic atrophy.
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