Congenital myasthenic syndrome with tubular aggregates caused by GFPT1 mutations

Abstract

Congenital myasthenic syndrome (CMS) is a clinically and genetically heterogeneous group of inherited disorders of the neuromuscular junction. A difficult to diagnose subgroup of CMS is characterised by proximal muscle weakness and fatigue while ocular and facial involvement is only minimal. DOK7 mutations have been identified as causing the disorder in about half of the cases. More recently, using classical positional cloning, we have identified mutations in a previously unrecognised CMS gene, GFPT1, in a series of DOK7-negative cases. However, detailed description of clinical features of GFPT1 patients has not been reported yet. Here we describe the clinical picture of 24 limb-girdle CMS (LG-CMS) patients and pathological findings of 18 of them, all carrying GFPT1 mutations. Additional patients with CMS, but without tubular aggregates, and patients with non-fatigable weakness with tubular aggregates were also screened. In most patients with GFPT1 mutations, onset of the disease occurs in the first decade of life with characteristic limb-girdle weakness and fatigue. A common feature was beneficial and sustained response to acetylcholinesterase inhibitor treatment. Most of the patients who had a muscle biopsy showed tubular aggregates in myofibers. Analysis of endplate morphology in one of the patients revealed unspecific abnormalities. Our study delineates the phenotype of CMS associated with GFPT1 mutations and expands the understanding of neuromuscular junction disorders. As tubular aggregates in context of a neuromuscular transmission defect appear to be highly indicative, we suggest calling this condition congenital myasthenic syndrome with tubular aggregates (CMS-TA).

Mutations in GFPT1-related congenital myasthenic syndromes are associated with synaptic morphological defects and underlie a tubular aggregate myopathy with synaptopathy

“…Fifty-two individuals with LG-CMS due to 41 distinct GFPT1 mutations have been reported in the literature since 2011 [15,21,22,25]. In this study, we reinforce the high number of loss-of-function GFPT1 mutations as causing LG-CMS with identification of 9 new mutations in 11 individuals from the French cohort of CMS.…”

“…These structures are organized with a large accumulation of tubules originating from the whole sarcoplasmic reticulum [27,30]. TAs are rarely observed in CMS except in individuals suffering from LG-CMS with mutations in GFPT1 [15,21], DPAGT1 [16,17] and ALG2 [18] and most rarely in individuals suffering from slow channel CMS [31]. The role of such structures in skeletal muscles as well as their pathological consequences are still subjects of debate [32,33].…”

“…Yet, none of these studies was dedicated to a long-term clinical follow-up, and investigation of the endplate was only reported for 7 patients [15,21,22,25]. In this study, we report the retrospective clinical description and the molecular investigations of 11 individuals from 9 unrelated families with LG-CMS linked to recessivelyinherited mutations in GFPT1.…”

“…(alpha-1,3-mannosyltransferase), ALG14 (UDP-N-acetylglucosaminyltransferase subunit) and most recently GMPPB (GDP-mannose pyrophosphorylase B) [15][16][17][18][19][20][21]. Hallmarks of GFPT1-related LG-CMS are the presence of tubular aggregates (TAs) in patients' skeletal muscle biopsies and functional improvement with the use of acetylcholinesterase inhibitors (AChEI) to improve neuromuscular transmission [22,23].…”

“…Since 2011, a total of 52 patients with GFPT1 mutations have been clinically reported [15,21,22,25]. …”