Novel homozygous GLDC variant causing late-onset glycine encephalopathy: A case report and updated review of the literature

Abstract

Glycine encephalopathy (MIM #605899) is an autosomal recessive inborn error of metabolism caused by pathogenic variants in three genes GLDC, AMT, GCSH encoding glycine cleavage enzyme system. We report an 8-year-old boy with late-onset glycine encephalopathy who harbors a novel homozygous GLDC likely pathogenic variant c.707G > A p.(Arg236Gln). Polyhydramnios was noted at fetal ultrasound. He displayed global developmental delay, craniofacial dysmorphism, convulsions. Our report expands the phenotypic and genetic spectrum of late-onset nonketotic hyperglycinemia.

Keywords: Chorioangioma; Dandy-Walker malformation; Novel GLDC likely pathogenic variant; Polyhydramnios; glycine encephalopathy.

Fig. 1

A. Placental examination showing moderate villous hydrops associated with large chorioangioma (left picture) and prenatal ultrasound showing polyhydramnios at 26 weeks of gestation (right picture). B. Brain MRI showing Dandy-Walker malformation with cerebellar hypoplasia (red asterisk). C. Front and lateral views of the patient showing facial dysmorphism including elongated face with high forehead, high arched eyebrows, ptosis and strabismus, low-set ears, long philtrum, thin upper lip, upturned corner of the mouth, and bilateral camptodactyly. D. Sanger sequencing identified a homozygous novel GLDC variant c.707G > A p.(Arg236Gln) in the propositus. The parents were heterozygous.

Fig. 2

A. ClustalW showing the Arg²³⁶ is highly conserved among orthologs. B. Graphic representation of the mutation tolerance score of the affected Arg²³⁶ of the glycine cleavage system P protein obtained by MetaDome web server indicating that missense variants occurring at this position is intolerant. C. Phyre² showing 3D glycine cleavage system P protein structure, the replacement of the charged Arg²³⁶ by polar glutamine amino acid is moderately intolerant and represent with green color (Arg²³⁶ is surrounded by red color, mutational sensitivity score = 4).

Supplementary Fig. S1

Structural modelling of GLDC Arg236Gln. Above: location of Arg236 residue (yellow color). Below: non-covalent interaction disrupted by the Arg to Gln replacement, respectively left to right. GLDC Arg236Gln was modelled by Swiss model (PMID: 27899672) using 6i35 as wild-type template. Structural consequences were visualized with Mol*(PMID: 33956175). Arg236Gln is located near the active site of GLDC. Structural modelling showed a complete reorganization of the non-covalent interactions of the region. The long Arg236 sidechain is implicated in several interactions with the nearby residues, which are disrupted by the amino acid change.