Novel compound heterozygous variants in the GFPT1 gene leading to rare limb-girdle congenital myasthenic syndrome with rimmed vacuoles

Ma, Yanyan; Xiong, Ting; Liu, Guohua; Ding, Jiaqi; Yang, Rui; Li, Zunbo; Jun, Guo; Shen, Dingguo

doi:10.1007/s10072-020-05021-0

Cited by 7 publications

(7 citation statements)

References 25 publications

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“…Similar to previous reports, patients 1 and 2 also displayed distal limb muscle weakness in addition to predominantly proximal limb involvement ( 6 – 8 , 16 , 18 – 20 , 22 , 23 , 25 ). Most patients with GFPT1 mutations showed fluctuations in symptoms, including diurnal fluctuations, daytime-dependent fluctuations, day–day fluctuations, fluctuations over longer periods ( 8 ), or fluctuations from a few days to a few months ( 6 ).…”

Section: Discussionsupporting

confidence: 90%

“…A decremental response on RNS at 2–3 Hz has been found in GFPT1-related CMS from different countries ( 6 , 8 , 10 – 12 , 14 , 18 , 20 – 22 , 24 – 26 ). Although RNS at high frequency (10–50 Hz) was not performed routinely for patients with LG-CMS, only two previous studies on GFPT1-related CMS, performing repetitive nerve stimulation of the left ulnar nerve at 10 Hz and in the left trapezius, right trapezius, and right abductor digiti minimi muscle at 30 Hz, revealed no decrement ( 18 , 25 ). However, in our three patients, repetitive nerve stimulations at both low and high frequencies showed a significant decrement in the amplitude of CMAP, especially in the trapezius, which is consistent with a previous report that indicated that to increase the accuracy, RNS should be carried out in proximal muscles if an LG-CMS is suspected ( 3 ).…”

Section: Discussionmentioning

confidence: 99%

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Abnormal decrement on high-frequency repetitive nerve stimulation in congenital myasthenic syndrome with GFPT1 mutations and review of literature

Chen

Song

et al. 2022

Front. Neurol.

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Section: Discussionsupporting

confidence: 90%

Section: Discussionmentioning

confidence: 99%

Abnormal decrement on high-frequency repetitive nerve stimulation in congenital myasthenic syndrome with GFPT1 mutations and review of literature

Chen

Song

et al. 2022

Front. Neurol.

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“…The impairment of neuromuscular junction is a main target due to heavy glycosylation of many important proteins in the neuromuscular junction, while it is possible that GFPT1 defect could have additional direct pathological effects on extra‐synaptic regions (Hugo & Schlegel, 2017 ; Niimi et al., 2001 ). Muscle specimens of patients with hypoglycosylated myasthenia have shown prominent myopathic features including fiber‐type disproportion, degenerating mitochondria, and destruction of the muscle fiber organelles associated with autophagy (Bauché et al., 2017 ; Guergueltcheva et al., 2012 ; Helman et al., 2019 ; Huh et al., 2012 ; Luo et al., 2019 ; Ma et al., 2021 ; Maselli et al., 2014 ; Matsumoto et al., 2019 ; O'grady et al., 2016 ; Selcen et al., 2013 ; Senderek et al., 2011 ; Szelinger et al., 2020 ; Yiş et al., 2017 ; Zhao et al., 2021 ). Zebrafish model with GFPT1 knock down also showed abnormalities of both muscle structure and neuromuscular junction (Hugo & Schlegel, 2017 ).…”

Section: Discussionmentioning

confidence: 99%

Diverse myopathological features in the congenital myasthenia syndrome with GFPT1 mutation

et al. 2022

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Introduction Mutations in the GFPT1 gene are associated with a particular subtype of congenital myasthenia syndrome (CMS) called limb‐girdle myasthenia with tubular aggregates. However, not all patients show tubular aggregates in muscle biopsy, suggesting the diversity of myopathology should be further investigated. Methods In this study, we reported two unrelated patients clinically characterized by easy fatigability, limb‐girdle muscle weakness, positive decrements of repetitive stimulation, and response to pyridostigmine. The routine examinations of myopathology were conducted. The causative gene was explored by whole‐exome screening. In addition, we summarized all GFPT1‐related CMS patients with muscle biopsy in the literature. Results Pathogenic biallelic GFPT1 mutations were identified in the two patients. In patient one, muscle biopsy indicated vacuolar myopathic changes and atypical pathological changes of myofibrillar myopathy characterized by desmin deposits, Z‐disc disorganization, and electronic dense granulofilamentous aggregation. In patient two, muscle biopsy showed typical myopathy with tubular aggregates. Among the 51 reported GFPT1‐related CMS patients with muscle biopsy, most of them showed tubular aggregates myopathy, while rimmed vacuolar myopathy, autophagic vacuolar myopathy, mitochondria‐like myopathy, neurogenic myopathy, and unspecific myopathic changes were also observed in some patients. These extra‐synaptic pathological changes might be associated with GFPT1‐deficiency hypoglycosylation and altered function of muscle‐specific glycoproteins, as well as partly responsible for the permanent muscle weakness and resistance to acetylcholinesterase inhibitor therapy. Conclusions Most patients with GFPT1‐related CMS had tubular aggregates in the muscle biopsy, but some patients could show great diversities of the pathological change. The myopathological findings might be a biomarker to predict the prognosis of the disease.

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“…AGRN‐CMS is one of the most frequent subtypes of CMS from both the southern and northern parts of China 13 but is ultrarare in other countries, in which CHRNE‐CMS is usually the most frequent subtype 2,4,6,51 . CMS caused by mutations in GFPT1 52 and DPAGT1 53 has been associated with tubular aggregates that are of diagnostic support for certain subtypes of CMS. For the therapeutic strategy, acetylcholinesterase inhibitors result in some improvement in the majority of CMS but should be avoided in some mutated CMS genes, such as DOK7 10 and COLQ 54 , and should be carefully prescribed for AGRN‐CMS 13 …”

Section: Discussionmentioning

confidence: 99%

Clinicopathological‐genetic features of congenital myasthenic syndrome from a Chinese neuromuscular centre

Huang

Duan

et al. 2022

J Cellular Molecular Medi

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Congenital myasthenic syndrome (CMS) encompasses a heterogeneous group of inherited disorders affecting nerve transmission across the neuromuscular junction. 1 The incidence of CMS was estimated to be 1.8-22.2 per million; however, due to the complexity of the procedures that are used to obtain an accurate diagnosis, incidence rates are likely underestimated. [2][3][4][5][6] Currently, more than 30 proteins are known to be involved in various types of CMS. Generally, proteins related to CMS are located at the presynaptic, synaptic or postsynaptic region of the neuromuscular junction (NMJ), or they undergo abnormal glycosylation. Among them, mutations in CHRNE, RAPSN and COLQ are the most frequent, accounting for half of CMS cases in a large-scale analysis including 680 patients. 7 Mutations in CMS-related genes can be used to accurately diagnose CMS.Generally, CMS is characterized by fatigability or skeletal muscle weakness with an onset at birth to early childhood.Electromyographic findings of a decrease in repetitive nerve stimulation (RNS) and increased jitter on single-fibre electromyography (EMG) may support the diagnosis. 8 Genetic testing or whole-exome sequencing could establish a diagnosis of CMS and guide pharmacological treatment. For example, β2-receptor agonist therapy could

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Novel compound heterozygous variants in the GFPT1 gene leading to rare limb-girdle congenital myasthenic syndrome with rimmed vacuoles

Cited by 7 publications

References 25 publications

Abnormal decrement on high-frequency repetitive nerve stimulation in congenital myasthenic syndrome with GFPT1 mutations and review of literature

Abnormal decrement on high-frequency repetitive nerve stimulation in congenital myasthenic syndrome with GFPT1 mutations and review of literature

Diverse myopathological features in the congenital myasthenia syndrome with GFPT1 mutation

Clinicopathological‐genetic features of congenital myasthenic syndrome from a Chinese neuromuscular centre

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