Dataset Information

SLC35A2-CDG: Novel variant and review.

ABSTRACT: SLC35A2 encodes the X-linked transporter that carries uridine diphosphate (UDP)-galactose from the cytosol to the lumen of the Golgi apparatus and the endoplasmic reticulum. Pathogenic variants have been associated to a congenital disorder of glycosylation (CDG) with epileptic encephalopathy as a predominant feature. Among the sixty five patients described so far, a strong gender bias is observed as only seven patients are males. This work is a review and reports a SLC35A2-CDG in a male without epilepsy and with growth deficiency associated with decreased serum IGF1, minor neurological involvement, minor facial dysmorphism, and camptodactyly of fingers and toes. Sequence analysis revealed a hemizygosity for a novel de novo variant: c.233A > G (p.Lys78Arg) in SLC35A2. Further analysis of SLC35A2 sequence by comparing both orthologous and paralogous positions, revealed that not only the variant found in this study, but also most of the reported mutated positions are conserved in SLC35A2 orthologous, and many even in the paralogous SLC35A1 and SLC35A3. This is strong evidence that replacements at these positions will have a critical pathological effect and may also explain the gender bias observed among SLC35A2-CDG patients.

SUBMITTER: Quelhas D

PROVIDER: S-EPMC7851840 | biostudies-literature | 2021 Mar

REPOSITORIES: biostudies-literature

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Publications

SLC35A2-CDG: Novel variant and review.

Quelhas Dulce D Correia Joana J Jaeken Jaak J Azevedo Luísa L Lopes-Marques Mónica M Bandeira Anabela A Keldermans Liesbeth L Matthijs Gert G Sturiale Luisa L Martins Esmeralda E

Molecular genetics and metabolism reports 20210130

<i>SLC35A2</i> encodes the X-linked transporter that carries uridine diphosphate (UDP)-galactose from the cytosol to the lumen of the Golgi apparatus and the endoplasmic reticulum. Pathogenic variants have been associated to a congenital disorder of glycosylation (CDG) with epileptic encephalopathy as a predominant feature. Among the sixty five patients described so far, a strong gender bias is observed as only seven patients are males. This work is a review and reports a SLC35A2-CDG in a male w ...[more]

PMID: 33552911

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Project description:We recently redefined phosphoglucomutase-1 deficiency not only as an enzyme defect, involved in normal glycogen metabolism, but also an inborn error of protein glycosylation. Phosphoglucomutase-1 is a key enzyme in glycolysis and glycogenesis by catalyzing in the bidirectional transfer of phosphate from position 1 to 6 on glucose. Glucose-1-P and UDP-glucose are closely linked to galactose metabolism. Normal PGM1 activity is important for effective glycolysis during fasting. Activated glucose and galactose are essential for normal protein glycosylation. The complex defect involving abnormal concentrations of activated sugars leads to hypoglycemia and two major phenotypic presentations, one with primary muscle involvement and the other with severe multisystem disease. The multisystem phenotype includes growth delay and malformations, like cleft palate or uvula, and liver, endocrine and heart function with possible cardiomyopathy. The patients have normal intelligence. Decreased transferrin galactosylation is a characteristic finding on mass spectrometry. Previous in vitro studies in patient fibroblasts showed an improvement of glycosylation on galactose supplements. Four patients with PGM1 deficiency have been trialed on d-galactose (compassionate use), and showed improvement of serum transferrin hypoglycosylation. There was a parallel improvement of liver function, endocrine abnormalities and a decrease in the frequency of hypoglycemic episodes. No side effects have been observed. Galactose supplementation didn't seem to resolve all clinical symptoms. Adding complex carbohydrates showed an additional clinical amelioration. Based on the available clinical data we suggest to consider the use of 0.5-1g/kg/day d-galactose and maximum 50 g/day oral galactose therapy in PGM1-CDG. The existing data on galactose therapy have to be viewed as preliminary observations. A prospective multicenter trial is ongoing to evaluate the efficacy and optimal d-galactose dose of galactose supplementation.

Dataset Information

SLC35A2-CDG: Novel variant and review.

Publications

SLC35A2-CDG: Novel variant and review.

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