Congenital myasthenia syndrome (CMS) is a group of heterogeneous diseases affecting the neuromuscular endplate. CMS has a considerably different phenotypic presentations, with the onset time ranging from early infancy to late adulthood. Here, we report a case of a CMS due to a new DOK7 mutation in a 28-year-old man and two of his sisters, who have a pure limb-girdle weakness. DOK7 CMS has a varying presentation. Typically, the onset occurs in childhood with ptosis, bulbar symptoms, difficulty walking, weakness, and gait abnormality. This case sheds light on a novel DOK7 gene mutation with a unique presentation of CMS and provides insight into its unique phenotypic presentation.

Congenital myasthenic syndrome (CMS) caused by mutations in MUSK is very rare and the genotype-phenotype relationship in MUSK related CMS is still unclear. Here we identified two patients carrying a homozygous hotspot mutation, c.308A > G in MUSK from a Chinese family. Both of them presented predominant bulbar weakness and atrophy of bilateral temporalis and masticatory muscles. To address the phenotype-genotype relationship, a total of 27 MUSK related CMS patients were reviewed. Patients with nonsense, frameshift or splicing mutations showed earlier onset (10/13 vs 2/14 neonatal onset, p = 0.0018) and more occurrence of vocal cord paralysis or stridor (8/13 vs 0/14, p = 0.0006), indicating a more severe phenotype. Comparing with patients carrying other missense mutations, the four patients carrying a homozygous c.308A > G mutation showed the female predominance (4/10 vs 4/4) and dramatic exacerbation after emotional or physiological stresses (2/10 vs 4/4) like pregnancy, menstrual periods and infection. All these indicated a genotype-phenotype relationship in MUSK-related CMS.

A subset of a larger and heterogeneous class of disorders, the congenital myasthenic syndromes (CMS) are caused by pathogenic variants in genes encoding proteins that support the integrity and function of the neuromuscular junction (NMJ). A central component of the NMJ is the sodium-dependent high-affinity choline transporter 1 (CHT1), a solute carrier protein (gene symbol SLC5A7), responsible for the reuptake of choline into nerve termini has recently been implicated as one of several autosomal recessive causes of CMS. We report the identification and functional characterization of a novel pathogenic variant in SLC5A7, c.788C>T (p.Ser263Phe) in an El Salvadorian family with a lethal form of a congenital myasthenic syndrome characterized by fetal akinesia. This study expands the clinical phenotype and insight into a form of fetal akinesia related to CHT1 defects and proposes a genotype-phenotype correlation for the lethal form of SLC5A7-related disorder with potential implications for genetic counseling.

BACKGROUND: Congenital myasthenia syndrome (CMS) is a rare, heterogeneous group of genetically determined, disorder of neuromuscular transmission. They have a varied presentation and progression and very few studies have addressed the natural history. Aim of the present study is to describe the clinical profile and natural history of patients with CMS.
METHODS: Study includes patients with CMS who attended comprehensive-neuromuscular-clinic (CNMC) during the period January, 2000-2008 with a minimum follow-up of 2 years, with inclusion criteria: (1) Onset in infancy or childhood with fluctuating ocular, bulbar, respiratory or limb muscle weakness (2) Acetylcholine receptor antibody negative (3) normal computed tomography (CT) thymus (4) Abnormal repetitive nerve stimulation (RNS) testing (5) Exclusion of other autoimmune disorders.
RESULTS: Out of 314 patients with myasthenia who attended the CNMC during study period, 15 (4.8%) were with CMS (8 boys, 7 girls). Patients were divided as infantile and childhood onset. The mean age of onset and diagnosis in infantile and childhood onset groups were 5.5 months/3.1 years and 3.6 years/6.5 years respectively. Eleven patients had ptosis and 4 had generalized presentation. Most common site of decremental response was over facial nerve in 12 (75%) patients. All patients showed good response to treatment with acetyl cholinesterase inhibitor with stable course on follow-up without exacerbations. Mean dose for neostigmine was 28 mg/day and for pyridostigmine was 153 mg/day.
CONCLUSIONS: Ptosis is most common symptom at onset in CMS, emphasing importance of RNS of the facial nerve, in the absence of molecular diagnosis of CMS. Our CMS cohort had relatively stable course without intermittent exacerbations with fair response to acetyl cholinesterase inhibitor.