Baker, Peter R3; Friederich, Marisa W3; Swanson, Michael A3; Shaikh, Tamim3; Bhattacharya, Kaustuv3; Scharer, Gunter H3; Aicher, Joseph3; Creadon-Swindell, Geralyn3; Geiger, Elizabeth3; MacLean, Kenneth N3; Lee, Wang-Tso3; Deshpande, Charu3; Freckmann, Mary-Louise3; Shih, Ling-Yu3; Wasserstein, Melissa3; Rasmussen, Malene Bøgehus4; Lund, Allan M3; Procopis, Peter3; Cameron, Jessie M3; Robinson, Brian H3; Brown, Garry K3; Brown, Ruth M3; Compton, Alison G3; Dieckmann, Carol L3; Collard, Renata3; Coughlin, Curtis R3; Spector, Elaine3; Wempe, Michael F3; Van Hove, Johan L K3
1 Section IV. Building 22.4/24.4, Department of Cellular and Molecular Medicine, Faculty of Health and Medical Sciences, Københavns Universitet2 Medical Genetics Program, Department of Cellular and Molecular Medicine, Faculty of Health and Medical Sciences, Københavns Universitet3 unknown4 Section IV. Building 22.4/24.4, Department of Cellular and Molecular Medicine, Faculty of Health and Medical Sciences, Københavns Universitet
Patients with nonketotic hyperglycinemia and deficient glycine cleavage enzyme activity, but without mutations in AMT, GLDC or GCSH, the genes encoding its constituent proteins, constitute a clinical group which we call 'variant nonketotic hyperglycinemia'. We hypothesize that in some patients the aetiology involves genetic mutations that result in a deficiency of the cofactor lipoate, and sequenced genes involved in lipoate synthesis and iron-sulphur cluster biogenesis. Of 11 individuals identified with variant nonketotic hyperglycinemia, we were able to determine the genetic aetiology in eight patients and delineate the clinical and biochemical phenotypes. Mutations were identified in the genes for lipoate synthase (LIAS), BolA type 3 (BOLA3), and a novel gene glutaredoxin 5 (GLRX5). Patients with GLRX5-associated variant nonketotic hyperglycinemia had normal development with childhood-onset spastic paraplegia, spinal lesion, and optic atrophy. Clinical features of BOLA3-associated variant nonketotic hyperglycinemia include severe neurodegeneration after a period of normal development. Additional features include leukodystrophy, cardiomyopathy and optic atrophy. Patients with lipoate synthase-deficient variant nonketotic hyperglycinemia varied in severity from mild static encephalopathy to Leigh disease and cortical involvement. All patients had high serum and borderline elevated cerebrospinal fluid glycine and cerebrospinal fluid:plasma glycine ratio, and deficient glycine cleavage enzyme activity. They had low pyruvate dehydrogenase enzyme activity but most did not have lactic acidosis. Patients were deficient in lipoylation of mitochondrial proteins. There were minimal and inconsistent changes in cellular iron handling, and respiratory chain activity was unaffected. Identified mutations were phylogenetically conserved, and transfection with native genes corrected the biochemical deficiency proving pathogenicity. Treatments of cells with lipoate and with mitochondrially-targeted lipoate were unsuccessful at correcting the deficiency. The recognition of variant nonketotic hyperglycinemia is important for physicians evaluating patients with abnormalities in glycine as this will affect the genetic causation and genetic counselling, and provide prognostic information on the expected phenotypic course.