Variant non ketotic hyperglycinemia is caused by mutations in LIAS, BOLA3 and the novel gene GLRX5
Journal
Brain
Journal Volume
137
Journal Issue
2
Pages
366-379
Date Issued
2014
Author(s)
Baker P.R.
Friederich M.W.
Swanson M.A.
Shaikh T.
Bhattacharya K.
Scharer G.H.
Aicher J.
Creadon-Swindell G.
Geiger E.
Maclean K.N.
Deshpande C.
Freckmann M.-L.
Shih L.-Y.
Wasserstein M.
Rasmussen M.B.
Lund A.M.
Procopis P.
Cameron J.M.
Robinson B.H.
Brown G.K.
Brown R.M.
Compton A.G.
Dieckmann C.L.
Collard R.
Coughlin C.R.
Spector E.
Wempe M.F.
Van Hove J.L.K.
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. ? 2013 The Author (2013).
Subjects
iron-sulphur cluster; leukodystrophy; lipoic acid; nonketotic hyperglycinemia
SDGs
Other Subjects
anticonvulsive agent; BolA type 3 protein; glutaredoxin; glutaredoxin 5; glycine; glycine cleavage system; hypertonic solution; iron; iron sulfur protein; lamotrigine; mitochondrial protein; protein; pyruvate dehydrogenase; thioctic acid; topiramate; unclassified drug; article; blood cerebrospinal fluid barrier; borderline state; brain disease; cardiomyopathy; cerebrospinal fluid level; child; childhood disease; clinical article; clinical feature; controlled study; dysarthria; enzyme activity; female; gene mutation; gene sequence; genetic counseling; genetic transfection; growth, development and aging; human; hyperglycinemia; iron metabolism; Leigh disease; leukodystrophy; lipoylation; male; medical history; nerve degeneration; nuclear magnetic resonance spectroscopy; onset age; optic nerve atrophy; pathogenicity; phenotype; preschool child; priority journal; respiratory chain; school child; spastic paraplegia; spinal cord lesion; iron-sulphur cluster; leukodystrophy; lipoic acid; nonketotic hyperglycinemia; Atrophy; Child; Child, Preschool; Fatal Outcome; Female; Genetic Variation; Glutaredoxins; Humans; Hyperglycinemia, Nonketotic; Infant; Male; Mutation; Proteins; Severity of Illness Index; Sulfurtransferases
Publisher
Oxford University Press
Type
journal article