Review of Congenital Myasthenic Syndrome Caused by Pathogenic Variants in <i>GFPT1</i>

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.