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Case Reports
. 2014 Feb;137(Pt 2):366-79.
doi: 10.1093/brain/awt328. Epub 2013 Dec 11.

Variant non ketotic hyperglycinemia is caused by mutations in LIAS, BOLA3 and the novel gene GLRX5

Peter R Baker 2nd  1 , Marisa W Friederich, Michael A Swanson, Tamim Shaikh, Kaustuv Bhattacharya, Gunter H Scharer, Joseph Aicher, Geralyn Creadon-Swindell, Elizabeth Geiger, Kenneth N MacLean, Wang-Tso Lee, Charu Deshpande, Mary-Louise Freckmann, Ling-Yu Shih, Melissa Wasserstein, Malene B Rasmussen, Allan M Lund, Peter Procopis, Jessie M Cameron, Brian H Robinson, Garry K Brown, Ruth M Brown, Alison G Compton, Carol L Dieckmann, Renata Collard, Curtis R Coughlin 2nd, Elaine Spector, Michael F Wempe, Johan L K Van Hove
Affiliations
Case Reports

Variant non ketotic hyperglycinemia is caused by mutations in LIAS, BOLA3 and the novel gene GLRX5

Peter R Baker 2nd et al. Brain. 2014 Feb.

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.

Keywords: iron-sulphur cluster; leukodystrophy; lipoic acid; nonketotic hyperglycinemia.

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Figures

Figure 1
Figure 1
Metabolic pathway of the glycine cleavage enzyme system and the synthesis of its lipoate cofactor. Disorders of components of the glycine cleavage enzyme (GLDC and AMT) cause classic NKH. Disorders of the biosynthesis of lipoyl-H (LIAS, GLRX5, BOLA3) cause variant NKH.
Figure 2
Figure 2
Neuroimaging of patients with variant nonketotic hyperglycinemia. (A) Brain MRI of Patient 1 at 10 years of age shows multifocal lesions of increased signal affecting the cerebrum on T2 sequence of the brain on axial images (left), and lesions of decreased signal intensity in the upper cervical spinal cord as shown on T1 sequence (right). (B) Spinal MRI images of Patient 2 show central lesions of the upper spinal cord of increased intensity on T2 sequence on axial and sagittal series. (C) Brain MRI of Patient 4 at 6 months of age shows lesions of increased signal on T2 sequence in the periventricular white matter (left) and central cervical spinal cord (right). (D) Brain MRI of Patient 5 at age 18 months shows extensive central lesions of increased signal on T2 sequence on axial and coronal images. (E) Brain MRI of Patient 6 at 9 years of age shows mild cerebral and cerebellar atrophy on T2 sequences. (F) Brain MRI of Patient 8 at 20 days of age, shows cerebral atrophy particularly of the white matter and increased signal in thalami and basal ganglia on T2 sequences. In the diffusion weighted images, there is diffusion restriction in the long tracts of the brainstem (yellow arrow) and white matter of the cerebellum, the posterior crux of the internal capsule (yellow arrow) and the basal ganglia (red arrow), and in cortical areas (blue arrow).
Figure 3
Figure 3
Mutations in GLRX5. (A) On phylogenetic alignment, the deleted amino acid K51 is completely conserved from human to Drosophila. (B) The amount of GLRX5 protein on western blot is not reduced. (C) Western blot of lipoylated proteins in fibroblast lysate shows normal signal for the lipoylated E2 components of pyruvate dehydrogenase (PDH) and αKGDH in controls. In fibroblasts from Patients (Pt) 1 and 2 this band is almost completely absent, but it is clearly present after transfection of the fibroblasts of Patient 2 with a full-length construct of GLRX5 (Pt2-T). Images of citrate synthase shown as a loading control. (D) Three-dimensional modelling of the GLRX5 protein (PDB: 2WUL) shows the deleted lysine K51 to be located at the interface of the first α-helix and the first β-sheet. The active site K59 and the iron-sulphur cluster are indicated. (E) K51 (deleted in Patients 1–3) is in close proximity to residues D52 and Y88 (ball and stick). Average distances between residues in all four chains of the tetrameric crystal structure as well as standard deviations are shown in the table (insert). Distances were measured between the NZ of K51, closest O of D52 and OH of Y88. The relative positions of C67, which ligates the iron-sulphur cluster (orange and yellow spheres), and the bound glutathione (stick) are also shown.
Figure 4
Figure 4
Mutations in BOLA3. (A) The location of the missense mutation in Patients 4, 5 and 6 at R46 is indicated in relation to the wild-type sequence and the mutation reported in Cameron et al. (2011). (B) Western blot of lipoylated proteins in fibroblast lysates shows normal signal for the lipoylated E2 components of pyruvate dehydrogenase (PDH) and α-ketoglutarate dehydrogenase (αKGDH) in controls. In Patients 4 and 6 this band is substantially reduced in intensity. Images of citrate synthase shown as a loading control.
Figure 5
Figure 5
Mutations in lipoate synthase. (A) On phylogenetic alignment, the mutated amino acids E159 and D215 are completely conserved from human to Drosophila. (B) Three-dimensional modelling of the lipoate synthase protein shows the mutated amino acids in relation to the iron-sulphur cluster. (C) Western blot of lipoylated proteins in fibroblast lysate shows normal signal for the lipoylated E2 components of pyruvate dehydrogenase (PDH) and αKGDH in controls. In Patient 7 (Pt7), this band is absent (C), whereas in Patient 8 it is reduced (D). A ninth patient with variant non-ketotic hyperglycinaemia but with normal lipoylation is shown (P). Images of citrate synthase shown as a loading control.
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