Further evidence that d-glycerate kinase (GK) deficiency is a benign disorder

doi:10.1016/j.braindev.2017.01.005

Brain and Development

Volume 39, Issue 6, June 2017, Pages 536-538

https://doi.org/10.1016/j.braindev.2017.01.005 Get rights and content

Abstract

d-Glyceric aciduria is caused by deficiency in d-glycerate kinase (GK) due to recessive mutations in the GLYCTK gene. GK catalyzes the conversion of d-glycerate to 2-phosphoglycerate which is an intermediary reaction in the catabolism of serine and fructose. Deficiency of GK leads to accumulation of d-glycerate, which may be detected in urine organic acid analysis. Debate exists as to whether this is a benign or disease-causing disorder as the reported phenotypes vary significantly. We report two siblings from a consanguineous Pakistani family. The index case is a 5 year old boy with severe autism and global developmental delay. His urine organic acid analysis showed markedly increased excretion of glycerate, determined as d-form by enantioselective gas chromatography. There was no oxalic aciduria. His younger sister (3 years old) is asymptomatic and developmentally normal (already bilingual). Her urine showed similar amounts of d-glycerate. Both children are homozygous for the novel mutation c.767C > G in exon 5 of the GLYCTK gene, predicted to affect the enzyme by replacing the evolutionarily conserved Proline with Arginine (P256R). Both parents are heterozygous carriers.

These cases support the view that d-glycerate kinase deficiency is a benign disorder. Long term follow-up studies with a greater number of individuals may be required for further confirmation.

Introduction

d-Glyceric aciduria is an inborn error of metabolism caused by recessive mutations in GLYCTK gene which encodes for the enzyme d-glycerate kinase (GK). Glycerate kinase catalyzes the conversion of d-glycerate to 2 phosphoglycerate. This conversion is an intermediary reaction found in several metabolic pathways, including the catabolism of serine [1] and fructose [2].

A deficiency in glycerate kinase activity leads to accumulation of d-glycerate in body fluids and tissues and can be measured in urine organic acid analysis. This is a very rare disorder, just 14 patients have been reported including three with genetic confirmation [3], [4].

Glycerate is a three carbon sugar acid which may be difficult to detect during routine organic acid analysis in the urine of healthy individuals [5]. This compound is found in humans in two different configurations, d- and l-glycerate [6]. Increased excretion of glycerate can be observed in two distinct and rare inherited metabolic disorders, d-glyceric and l-glyceric acidurias (the latter is also known as primary hyperoxaluria type II) [3], which are due to genetic deficiencies of d-glycerate kinase and d-glyceric acid dehydrogenase, respectively. The clinical phenotype of l-glyceric aciduria predominantly involves renal alterations, including recurrent nephrolithiasis, while the phenotype of d-glyceric aciduria is less well defined, with some reports of central nervous system involvement, but other reports of clinically well cases, so the question has already arisen as to whether this disorder represents a biochemical variant or a disease [7], [3].

Section snippets

Case report

The index case is a five year old boy who was referred to the metabolic clinic with a background of autism and global developmental delay. He was born at 41 weeks of gestation with a birth weight of 3.4 kg. He has speech delay and was diagnosed with autism at age 3 years. Formal assessment revealed a moderate intellectual disability and severe delay in both his receptive and expressive language skills.

His general health is good and he is an active child, although overweight with head size and

Discussion

d-Glyceric aciduria is an autosomal recessive disorder of the catabolism pathway of the amino acid serine and of fructose metabolism [Fig. 1]. Fructose is phosphorylated to fructose-1-phosphate, which is converted to d-glyceraldehyde. d-glyceraldehyde converts to d-glycerate, which is subsequently phosphorylated by GK to 2-phospho-d-glycerate. Deficiency of GK will result in accumulation of d-glycerate leading to its excretion in urine. This pathway is likely the major source of d-glycerate. d

Conclusion

In view of the heterogeneous clinical presentation of children with d-glyceric aciduria, further work is needed to clarify whether d-glycerate kinase deficiency is a disease or merely a biochemical variant. The differing phenotype in our two patients adds weight to the view that this is a benign disorder. Long term follow up studies with a greater number of individuals may be required for further confirmation.

Acknowledgements

The author thanks Mr Sidney Behringer for expert technical assistance. Financial support to JOS by Jürgen Manchot Stiftung (Düsseldorf, Germany) and Hans Hermann Voss-Stiftung (Wipperfürth, Germany) is gratefully acknowledged.

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d-Glyceric aciduria is caused by genetic deficiency of d-glycerate kinase (GLYCTK)
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There are more references available in the full text version of this article.

Cited by (3)

D-Glycerate kinase deficiency in a neuropediatric patient
2020, Brain and Development
Citation Excerpt :
In another case of genetically proven GLYCTK deficiency, pituitary deficiency due to mutations in the HESX gene explains the clinical phenptype [2]. Notably, not only four siblings diagnosed with DGKD, which has not been confirmed by DNA analysis, were asymptomatic or presented with mild features (essentially speech delay) only, but one of the genetically confirmed siblings with DGKD was also completely asymptomatic [3]. In a recent review of patients with DGA, Zehavi et al. have claimed ‘a clear association between DGA and severe neurological impairment’ [4].
d-Glyceric aciduria (DGA) due to d-glycerate kinase deficiency (DGKD) is a rare autosomal-recessive inborn error of metabolism that is usually linked to the metabolism of fructose and serine. We describe a Moroccan patient with DGKD whose metabolic defect has been characterized by metabolite studies, sequencing of genomic DNA and by studies on the RNA level. Since birth the index patient presented with severe muscular hypotonia, joint hypermobility and tremor. Enantioselective analysis showed elevated d-glyceric acid in the urine of the patient, but not in that of his parents. DNA analysis revealed homozygosity in the GLYCTK gene for c.517G>T [p.(Val173Leu)], the first mutation reported for exon 3 of this gene, as well as for the c.530-4A>G polymorphism. RNA studies suggest that none of these sequence variants affects splicing. The mother was heterozygous for both sequence variants, the father heterozygous for the first one and homozygous for the polymorphism, which further supports that c.517G>T is the functionally relevant nucleotide change. The conservation of GLYCTK throughout evolution suggests an important biological role of this enzyme, although it is not known yet how mutations are linked to clinical features. Future studies should investigate the molecular defect in a more general way and search for additional roles of GLYCTK beyond its established role in catabolism of serine and fructose.
D-Glyceric aciduria does not cause nonketotic hyperglycinemia: A historic co-occurrence
2017, Molecular Genetics and Metabolism
Citation Excerpt :
A large phenotypic spectrum has been reported in published patients with d-glyceric aciduria with a variety of neurological symptoms ranging from severe spasticity, microcephaly and seizures, to mild speech delay [2,3,6,8,14,17,20,22]. However, asymptomatic affected siblings have also been described [2,8]. A pathogenic mechanism linking d-glycerate kinase deficiency to neurologic symptoms observed in d-glyceric aciduria has not been elucidated.
Historically, d-glyceric aciduria was thought to cause an uncharacterized blockage to the glycine cleavage enzyme system (GCS) causing nonketotic hyperglycinemia (NKH) as a secondary phenomenon. This inference was reached based on the clinical and biochemical results from the first d-glyceric aciduria patient reported in 1974. Along with elevated glyceric acid excretion, this patient exhibited severe neurological symptoms of myoclonic epilepsy and absent development, and had elevated glycine levels and decreased glycine cleavage system enzyme activity. Mutations in the GLYCTK gene (encoding d-glycerate kinase) causing glyceric aciduria were previously noted. Since glycine changes were not observed in almost all of the subsequently reported cases of d-glyceric aciduria, this theory of NKH as a secondary syndrome of d-glyceric aciduria was revisited in this work. We showed that this historic patient harbored a homozygous missense mutation in AMT c.350C > T, p.Ser117Leu, and enzymatic assay of the expressed mutation confirmed the pathogeneity of the p.Ser117Leu mutation. We conclude that the original d-glyceric aciduria patient also had classic NKH and that this co-occurrence of two inborn errors of metabolism explains the original presentation. We conclude that no evidence remains that d-glyceric aciduria would cause NKH.
Severe infantile epileptic encephalopathy associated with D-glyceric aciduria: report of a novel case and review
2019, Metabolic Brain Disease

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Case ReportFurther evidence that d-glycerate kinase (GK) deficiency is a benign disorder

Abstract

Introduction

Section snippets

Case report

Discussion

Conclusion

Acknowledgements

Am J Clin Nutr

l-Serine in disease and development

Biochem J

d-Glyceric aciduria is caused by genetic deficiency of d-glycerate kinase (GLYCTK)

Hum Mutat

Aciduria d-glicérica. A propósito de un caso y revisión de la bibliografia (In Spanish)

Acta Pediatr Esp

Case Report
Further evidence that d-glycerate kinase (GK) deficiency is a benign disorder