Long-term follow-up in patients with congenital myasthenic syndrome due to RAPSN mutations
Introduction
Congenital myasthenic syndromes (CMS) are a heterogeneous group of genetic disorders, all of which impair neuromuscular transmission. At present, 25 different genes have been identified in association with CMS. These genes code for proteins involved in neuromuscular junction structure or function [1], [2], [3], [4]. All CMSs share the clinical feature of fatigable weakness, but age of onset, presenting symptoms, distribution of weakness, and response to treatment differ depending on the molecular mechanism that results from the genetic defect.
Rapsyn is a 43-kDa postsynaptic protein that binds to the long cytoplasmic loop of the AChR subunits and is essential for clustering and anchoring the AChR in the postsynaptic membrane. Mutations in rapsyn compromise the safety margin of neuromuscular transmission by causing endplate AChR deficiency [5]. Rapsyn is composed of several functionally distinct regions: a myristoylated N-terminal is required for membrane interaction; seven tetratricopeptide repeats are involved in rapsyn self-aggregation and binding to the cytoplasmic portion of the muscle-specific kinase MuSK; the coiled-coil domain interacts with the cytoplasmic loops of AChR subunits; and the C-terminal domain binds to cytoskeletal protein beta-dystroglycan and thereby links the rapsyn–AChR complex to the cytoskeleton.
Today it is estimated that RAPSN mutations account for approximately 14–27% of all CMS patients [3], [6]. Mutations in RAPSN were first described in recessive forms of CMS by Ohno et al. in 2002 [7].
Two distinct phenotypes are described: an early-onset phenotype that presents at birth or in infancy with arthrogryposis, hypotonia, apnoeic crisis, and feeding difficulties; and a less common late-onset phenotype that presents during childhood, or even in adulthood, with weakness and sometimes wasting of distal upper limb muscles. The response to anticholinesterase medication is good in both phenotypes [8].
We describe the clinical and molecular genetic findings as well as long-term follow-up data of 10 patients with CMS due to RAPSN mutations. We also aimed to establish reliable clinical signs which might suggest this specific diagnosis.
Section snippets
Patients and methods
Patients with genetically confirmed CMS due to mutations in the RAPSN gene followed-up in the departments of Paediatric Neurology and Neurology of six Spanish Centers (Hospital Sant Joan de Déu, Barcelona; Hospital San Jorge, Huesca; Hospital de Cruces, Bilbao; Hospital La Fe, Valencia; Hospital 12 de Octubre, Madrid; Hospital Rey Juan Carlos, Madrid) were included.
Patients were systematically assessed every six months for the duration of follow-up. Each patient was reassessed and underwent a
Results
Ten patients (6 males, 4 females) from 8 unrelated families were followed up serially in our clinics over a mean period of 14.5 years (range from 1 to 28 years).
All patients were Spanish with a Caucasian origin. None of the cases were born from consanguineous marriages. Patients 7, 8 and 9 are siblings. The mean age at the first examination was 6 years (7 of 10 were examined for the first time during neonatal period). The patients were aged between 2–53 years old when they were last reviewed.
Discussion
Here, we present a comprehensive description of the clinical findings of ten patients with CMS due to mutations in RAPSN. Furthermore, all patients were followed over a period of several years allowing longitudinal assessment of disease course and progression. This cohort of patients with a long-term follow-up enabled us to refine the phenotype linked to rapsyn–CMS in Spain. We present two novel missense mutations.
In this subset of rapsyn–CMS patients, the disease manifested at birth in all
Acknowledgements
The first author was partially supported by a SENEP (Spanish Pediatric Neurology Society) fellowship.
H Lochmüller, A Töpf and T Evangelista are supported by the Medical Research Council UK (reference G1002274, grant ID 98482), and by the European Union Seventh Framework Programme (FP7/2007-2013) under grant agreement No. 305444 (RD-Connect) and 305121 (Neuromics).
The authors thank the patients and family members for their participation in this study.
We also wish to acknowledge the contribution
References (22)
Current status of the congenital myasthenic syndromes
Neuromuscul Disord
(2012)- et al.
Rapsyn mutations in humans cause endplate acetylcholine-receptor deficiency and myasthenic syndrome
Am J Hum Genet
(2002) - et al.
Novel truncating RAPSN mutations causing congenital myasthenic syndrome responsive to 3,4-diaminopyridine
Neuromuscul Disord
(2004) - et al.
Distinct phenotypes of congenital acetylcholine receptor deficiency
Neuromuscul Disord
(2004) - et al.
A newly identified chromosomal microdeletion of the rapsyn gene causes a congenital myasthenic syndrome
Neuromuscul Disord
(2004) - et al.
Acetylcholine receptor pathway mutations explain various fetal akinesia deformation sequence disorders
Am J Hum Genet
(2008) Congenital myasthenic syndromes in 2012
Curr Neurol Neurosci
(2012)- et al.
Congenital myasthenic syndromes: achievements and limitations of phenotype-guided gene after- gene sequencing in diagnostic practice: a study of 680 patients
Hum Mutat
(2012) - et al.
Congenital myasthenic syndromes and the neuromuscular junction
Curr Opin Neurol
(2014) - et al.
Structure and superorganization of acetylcholine receptor–rapsyn complexes
Proc Natl Acad Sci U S A
(2013)
How common is childhood myasthenia? The UK incidence and prevalence of autoimmune and congenital myasthenia
Arch Dis Child
Cited by (32)
Successful treatment of congenital myasthenic syndrome caused by a novel compound heterozygous variant in RAPSN
2022, Brain and DevelopmentCitation Excerpt :Moreover, fatigability was not readily apparent due to a low activity level. Most rapsyn deficiency patients respond well to acetylcholinesterase inhibitors, including pyridostigmine and 3,4-diaminopyridine, and have a benign course [14,15]. The administration of edrophonium chloride is useful to confim the impaired neuromuscular junctional transmition, but it may exacerbate the symptoms of some types of CMS.
Congenital myasthenic syndromes in the Thai population: Clinical findings and novel mutations
2020, Neuromuscular DisordersCitation Excerpt :The clinical phenotypes of our CMS patients with COLQ mutations compared with previous reports are summarized in Table 3 (Supplementary material). CMS patients with RAPSN mutations have been reported to have two main phenotypes: late-onset with fatigable limb weakness or early-onset characterized by arthrogryposis, high-arched palate, and facial, cervical, and bulbar weakness [27–30]. Patient 8 had an early onset of symptoms without arthrogryposis.
Pyrostigmine therapy in a patient with VAMP1-related congenital myasthenic syndrome
2020, Neuromuscular DisordersCitation Excerpt :Congenital myasthenic syndrome (CMS) comprises a group of heterogeneous, inherited disorders resulting from impaired neuromuscular junction transmission [1,2]. These disorders have been reported in various populations worldwide [3-12], with an estimated prevalence of 9.2 cases per million children in 2014 in the UK [13]. However, there are no epidemiologic data available for CMS in the Saudi Arabian population.
Prevalence and genetic subtypes of congenital myasthenic syndromes in the pediatric population of Slovenia
2020, European Journal of Paediatric NeurologyCitation Excerpt :Two rarely reported genes were causative of CMS in two of eight patients, namely CHRND and MUSK mutations. Genotype-phenotype correlations in our cohort were similar to those found in previous reports, namely RAPSN and CHRNE mutations carrying a relatively benign and stable clinical course, compared to patients carrying CHAT, CHRND and MUSK mutations who are prone to episodic apnea in early period [3,20,21]. Tracheostomy due to episodic apnea and/or severe respiratory distress was in our cohort performed in the first months of life in patients with CHAT and MUSK mutation and at the age of six years, in the patient with CHRND mutation.
- 1
Both authors have equal contribution.