Review of Congenital Myasthenic Syndrome Caused by Pathogenic Variants in GFPT1

ABSTRACT

Glutamine:fructose‐6‐phosphate transaminase 1 (GFPT1) catalyzes the first and rate‐limiting step of the hexosamine biosynthetic pathway (HBP) to generate UDP‐GlcNAc. GFPT1 exon 9 is specifically spliced in in striated muscles, which makes a long isoform of GFPT1 (GFPT1‐L). In contrast, a short isoform (GFPT1‐S) is generated in the other tissues. GFPT1‐L was likely acquired in evolution to suppress the HBP in striated muscles to flow more glucose into the glycolytic pathway. Loss‐of‐function variants of GFPT1 cause limb‐girdle congenital myasthenic syndrome (CMS). A total of 146 patients in 115 pedigrees with GFPT1 ‐CMS have been reported with 71 pathogenic variants. The mean age of onset was 8.3 ± 10.1 years (range 0 to 69 years). Limb‐girdle muscle weakness, tubular aggregates in muscle biopsy, and elevated serum CK were observed in 100%, 66.7%, and 42.5%, respectively. Involvements of palpebral, extraocular, facial, bulbar, and respiratory muscles were rare and were observed in less than one in seven patients. Pyridostigmine, amifampridine, and salbutamol were effective in 95.8%, 76.3%, and 86.4%, respectively. Mechanistic studies show that hypoglycosylation of the acetylcholine receptor δ subunit is likely to be a key for defective acetylcholine receptor clustering. In mouse models, complete lack of GFPT1 in skeletal muscle developed CMS in 6 weeks of age, whereas lack of GFPT1‐L in skeletal muscle required 12 months to develop CMS, which was likely to be accounted for by the expression of a low level of GFPT1‐S. In accordance with this notion, null variants were enriched in exon 9 in GFPT1 ‐CMS.