Comprehensive mutation analysis of GLDC, AMT, and GCSH in nonketotic hyperglycinemia

Department of Medical Genetics, Tohoku University School of Medicine, Sendai, Japan.
Human Mutation (Impact Factor: 5.05). 04/2006; 27(4):343-52. DOI: 10.1002/humu.20293
Source: PubMed

ABSTRACT Nonketotic hyperglycinemia (NKH) is an inborn error of metabolism characterized by accumulation of glycine in body fluids and various neurological symptoms. NKH is caused by deficiency of the glycine cleavage multi-enzyme system with three specific components encoded by GLDC, AMT, and GCSH. We undertook the first comprehensive screening for GLDC, AMT, and GCSH mutations in 69 families (56, six, and seven families with neonatal, infantile, and late-onset type NKH, respectively). GLDC or AMT mutations were identified in 75% of neonatal and 83% of infantile families, but not in late-onset type NKH. No GCSH mutation was identified in this study. GLDC mutations were identified in 36 families, and AMT mutations were detected in 11 families. In 16 of the 36 families with GLDC mutations, mutations were identified in only one allele despite sequencing of the entire coding regions. The GLDC gene consists of 25 exons. Seven of the 32 GLDC missense mutations were clustered in exon 19, which encodes the cofactor-binding site Lys754. A large deletion involving exon 1 of the GLDC gene was found in Caucasian, Oriental, and black families. Multiple origins of the exon 1 deletion were suggested by haplotype analysis with four GLDC polymorphisms. This study provides a comprehensive picture of the genetic background of NKH as it is known to date.

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    • "Glycine cleavage H protein (GCSH) deficiency So far, no patient with clear mutations in the GCSH gene has been identified (Van Hove et al 1993; Kure et al 2006). A complex GCSH gene rearrangement has been reported (Koyata and Hiraga 1991), and there was biochemical evidence for GCSH deficiency in an early publication (Hiraga et al 1981). "
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    ABSTRACT: Lipoate is a covalently bound cofactor essential for five redox reactions in humans: in four 2-oxoacid dehydrogenases and the glycine cleavage system (GCS). Two enzymes are from the energy metabolism, α-ketoglutarate dehydrogenase and pyruvate dehydrogenase; and three are from the amino acid metabolism, branched-chain ketoacid dehydrogenase, 2-oxoadipate dehydrogenase, and the GCS. All these enzymes consist of multiple subunits and share a similar architecture. Lipoate synthesis in mitochondria involves mitochondrial fatty acid synthesis up to octanoyl-acyl-carrier protein; and three lipoate-specific steps, including octanoic acid transfer to glycine cleavage H protein by lipoyl(octanoyl) transferase 2 (putative) (LIPT2), lipoate synthesis by lipoic acid synthetase (LIAS), and lipoate transfer by lipoyltransferase 1 (LIPT1), which is necessary to lipoylate the E2 subunits of the 2-oxoacid dehydrogenases. The reduced form dihydrolipoate is reactivated by dihydrolipoyl dehydrogenase (DLD). Mutations in LIAS have been identified that result in a variant form of nonketotic hyperglycinemia with early-onset convulsions combined with a defect in mitochondrial energy metabolism with encephalopathy and cardiomyopathy. LIPT1 deficiency spares the GCS, and resulted in a combined 2-oxoacid dehydrogenase deficiency and early death in one patient and in a less severely affected individual with a Leigh-like phenotype. As LIAS is an iron-sulphur-cluster-dependent enzyme, a number of recently identified defects in mitochondrial iron-sulphur cluster synthesis, including NFU1, BOLA3, IBA57, GLRX5 presented with deficiency of LIAS and a LIAS-like phenotype. As in DLD deficiency, a broader clinical spectrum can be anticipated for lipoate synthesis defects depending on which of the affected enzymes is most rate limiting.
    Journal of Inherited Metabolic Disease 04/2014; 37. DOI:10.1007/s10545-014-9705-8 · 4.14 Impact Factor
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    • "Biochemically, the glycine cleavage enzyme system is composed of the P-protein (GLDC gene, MIM# 238300), which removes CO 2 from glycine and transfers the amino-methyl group to lipoate on the H-protein (GCSH gene, MIM# 238330), and the T-protein (AMT gene, MIM# 238310) which releases ammonia and forms methylenetetrahydrofolate, after which the reduced lipoate is reoxidized by the L-protein (Fig. 1) (Kikuchi et al., 2008). In typical NKH, 72% of patients have a causative mutation in GLDC, and 24% in AMT, with no mutations identified in GCSH (Kure et al., 2006; Hamosh et al., 2009). In 4% of patients, no mutations were identified in a gene encoding a constituent of the glycine cleavage enzyme, despite proven deficient glycine cleavage enzyme activity and elevated glycine levels. "
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    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.
    Brain 12/2013; DOI:10.1093/brain/awt328 · 10.23 Impact Factor
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    • "A noninvasive [13] C-glycine breath test and screening system for genomic deletion with GLDC also help confirm diagnosis [12] [13]. Genes known to associate with NKH are GLDC (encoding P-protein component of the GCS complex), AMT (encoding T-protein component), and GCSH (encoding H-protein component) [12]. Molecular genetic testing of all three genes is available on a clinical basis. "
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    ABSTRACT: In encephalopathic infants, cerebrospinal fluid hyperglycinemia and elevated cerebrospinal fluid to plasma glycine ratio are considered pathognomonic of nonketotic hyperglycinemia (NKH). We present a case of NKH complicated by neonatal intractable seizures. Increased ratio of cerebrospinal fluid to plasma glycine concentrations of 0.28 was seen as a strong diagnostic indicator of nonketotic hyperglycinemia. Evaluating sick neonates with hypotonia, encephalopathy, and/or seizures is a diagnostic challenge. NKH should be considered; elevated cerebrospinal fluid/plasma glycine ratio will allow correct identification and treatment more often in the future.
    06/2012; 2(2):80–82. DOI:10.1016/j.biomed.2012.04.002
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