title: Variant non ketotic hyperglycinemia is caused by mutations in LIAS, BOLA3 and the novel gene GLRX5.
abstract: 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.
authors: 1 Department of Pediatrics, University of Colorado, Aurora, Colorado, 80045, USA.
authors: Peter R
authors: PR
authors: Baker
authors: Marisa W
authors: MW
authors: Friederich
authors: Michael A
authors: MA
authors: Swanson
authors: Tamim
authors: T
authors: Shaikh
authors: Kaustuv
authors: K
authors: Bhattacharya
authors: Gunter H
authors: GH
authors: Scharer
authors: Joseph
authors: J
authors: Aicher
authors: Geralyn
authors: G
authors: Creadon-Swindell
authors: Elizabeth
authors: E
authors: Geiger
authors: Kenneth N
authors: KN
authors: MacLean
authors: Wang-Tso
authors: WT
authors: Lee
authors: Charu
authors: C
authors: Deshpande
authors: Mary-Louise
authors: ML
authors: Freckmann
authors: Ling-Yu
authors: LY
authors: Shih
authors: Melissa
authors: M
authors: Wasserstein
authors: Malene B
authors: MB
authors: Rasmussen
authors: Allan M
authors: AM
authors: Lund
authors: Peter
authors: P
authors: Procopis
authors: Jessie M
authors: JM
authors: Cameron
authors: Brian H
authors: BH
authors: Robinson
authors: Garry K
authors: GK
authors: Brown
authors: Ruth M
authors: RM
authors: Brown
authors: Alison G
authors: AG
authors: Compton
authors: Carol L
authors: CL
authors: Dieckmann
authors: Renata
authors: R
authors: Collard
authors: Curtis R
authors: CR
authors: Coughlin
authors: Elaine
authors: E
authors: Spector
authors: Michael F
authors: MF
authors: Wempe
authors: Johan L K
authors: JL
authors: Van Hove
mesh_terms: D001284:Atrophy; D002648:Child; D002675:Child, Preschool; D017809:Fatal Outcome; D005260:Female; D014644:Genetic Variation / Q000235:genetics*; D054477:Glutaredoxins / Q000737:chemistry / Q000235:genetics*; D006801:Humans; D020158:Hyperglycinemia, Nonketotic / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology; D007223:Infant; D008297:Male; D024101:Mitochondrial Proteins; D009154:Mutation / Q000235:genetics*; D011506:Proteins / Q000737:chemistry / Q000235:genetics*; D012720:Severity of Illness Index; D013466:Sulfurtransferases / Q000737:chemistry / Q000235:genetics*
chemical_list: C533597:BolA3 protein, human; C516011:GLRX5 protein, human; D054477:Glutaredoxins; D024101:Mitochondrial Proteins; D011506:Proteins; D013466:Sulfurtransferases; C116435:lipoic acid synthase
keywords: iron-sulphur cluster; leukodystrophy; lipoic acid; nonketotic hyperglycinemia