Eri Imagawa1, Aviva Fattal-Valevski2, Ori Eyal3, Satoko Miyatake1, Ann Saada4, Mitsuko Nakashima1, Yoshinori Tsurusaki1, Hirotomo Saitsu1, Noriko Miyake1, Naomichi Matsumoto1. 1. Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan. 2. Paediatric Neurology Unit, Tel Aviv Sourasky Medical Centre, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel. 3. Paediatric Endocrinology Unit, Tel Aviv Sourasky Medical Centre, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel. 4. Monique and Jacques Roboh Department of Genetic Research and the Department of Genetic and Metabolic Diseases, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
Abstract
BACKGROUND: Leigh syndrome (LS) is an early-onset progressive neurodegenerative disorder associated with mitochondrial dysfunction. LS is characterised by elevated lactate and pyruvate and bilateral symmetric hyperintense lesions in the basal ganglia, thalamus, brainstem, cerebral white matter or spinal cord on T2-weighted MRI. LS is a genetically heterogeneous disease, and to date mutations in approximately 40 genes related to mitochondrial function have been linked to the disorder. METHODS: We investigated a pair of female monozygotic twins diagnosed with LS from consanguineous healthy parents of Indian origin. Their common clinical features included optic atrophy, ophthalmoplegia, spastic paraparesis and mild intellectual disability. High-blood lactate and high-intensity signal in the brainstem on T2-weighted MRI were consistent with a clinical diagnosis of LS. To identify the genetic cause of their condition, we performed whole exome sequencing. RESULTS: We identified a homozygous nonsense mutation in C12orf65 (NM_001143905; c.346delG, p.V116*) in the affected twins. Interestingly, the identical mutation was previously reported in an Indian family with Charcot-Marie Tooth disease type 6, which displayed some overlapping clinical features with the twins. CONCLUSIONS: We demonstrate that the identical nonsense mutation in C12orf65 can result in different clinical features, suggesting the involvement of unknown modifiers. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/
BACKGROUND:Leigh syndrome (LS) is an early-onset progressive neurodegenerative disorder associated with mitochondrial dysfunction. LS is characterised by elevated lactate and pyruvate and bilateral symmetric hyperintense lesions in the basal ganglia, thalamus, brainstem, cerebral white matter or spinal cord on T2-weighted MRI. LS is a genetically heterogeneous disease, and to date mutations in approximately 40 genes related to mitochondrial function have been linked to the disorder. METHODS: We investigated a pair of female monozygotic twins diagnosed with LS from consanguineous healthy parents of Indian origin. Their common clinical features included optic atrophy, ophthalmoplegia, spastic paraparesis and mild intellectual disability. High-blood lactate and high-intensity signal in the brainstem on T2-weighted MRI were consistent with a clinical diagnosis of LS. To identify the genetic cause of their condition, we performed whole exome sequencing. RESULTS: We identified a homozygous nonsense mutation in C12orf65 (NM_001143905; c.346delG, p.V116*) in the affected twins. Interestingly, the identical mutation was previously reported in an Indian family with Charcot-Marie Tooth disease type 6, which displayed some overlapping clinical features with the twins. CONCLUSIONS: We demonstrate that the identical nonsense mutation in C12orf65 can result in different clinical features, suggesting the involvement of unknown modifiers. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/
Authors: Chun Su; Mariana Argenziano; Sumei Lu; James A Pippin; Matthew C Pahl; Michelle E Leonard; Diana L Cousminer; Matthew E Johnson; Chiara Lasconi; Andrew D Wells; Alessandra Chesi; Struan F A Grant Journal: Prog Neurobiol Date: 2021-02-02 Impact factor: 10.885
Authors: Maria Wesolowska; Grainne S Gorman; Charlotte L Alston; Aleksandra Pajak; Angela Pyle; Langping He; Helen Griffin; Patrick F Chinnery; James A L Miller; Andrew M Schaefer; Robert W Taylor; Robert N Lightowlers; Zofia M Chrzanowska-Lightowlers Journal: J Neuromuscul Dis Date: 2015-10-07
Authors: Jonathan Marquez; Nina Mann; Kathya Arana; Engin Deniz; Weizhen Ji; Monica Konstantino; Emily K Mis; Charu Deshpande; Lauren Jeffries; Julie McGlynn; Hannah Hugo; Eugen Widmeier; Martin Konrad; Velibor Tasic; Raffaella Morotti; Julia Baptista; Sian Ellard; Saquib Ali Lakhani; Friedhelm Hildebrandt; Mustafa K Khokha Journal: J Med Genet Date: 2020-07-06 Impact factor: 6.318