TY - JOUR
T1 - Variant non ketotic hyperglycinemia is caused by mutations in LIAS, BOLA3 and the novel gene GLRX5
AU - Baker, Peter R.
AU - Friederich, Marisa W.
AU - Swanson, Michael A.
AU - Shaikh, Tamim
AU - Bhattacharya, Kaustuv
AU - Scharer, Gunter H.
AU - Aicher, Joseph
AU - Creadon-Swindell, Geralyn
AU - Geiger, Elizabeth
AU - Maclean, Kenneth N.
AU - Lee, Wang Tso
AU - Deshpande, Charu
AU - Freckmann, Mary Louise
AU - Shih, Ling Yu
AU - Wasserstein, Melissa
AU - Rasmussen, Malene B.
AU - Lund, Allan M.
AU - Procopis, Peter
AU - Cameron, Jessie M.
AU - Robinson, Brian H.
AU - Brown, Garry K.
AU - Brown, Ruth M.
AU - Compton, Alison G.
AU - Dieckmann, Carol L.
AU - Collard, Renata
AU - Coughlin, Curtis R.
AU - Spector, Elaine
AU - Wempe, Michael F.
AU - Van Hove, Johan L.K.
N1 - Funding Information:
This work was supported by the Hope for NKH Fund, the NKH Crusaders Fund, and by a pilot grant of the Colorado Clinical and Translational Science Institute, via the National Institute of Health [UL1RR025780 to P.R.B.] and the National Centre of Research Resources. Its contents are the author’s sole responsibility and do not necessarily represent official National Institute of Health views.
PY - 2014/2
Y1 - 2014/2
N2 - 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.
AB - 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.
KW - iron-sulphur cluster
KW - leukodystrophy
KW - lipoic acid
KW - nonketotic hyperglycinemia
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U2 - 10.1093/brain/awt328
DO - 10.1093/brain/awt328
M3 - Article
C2 - 24334290
AN - SCOPUS:84893819382
SN - 0006-8950
VL - 137
SP - 366
EP - 379
JO - Brain
JF - Brain
IS - 2
ER -