Congenital myasthenic syndrome in a cohort of patients with 'double' seronegative myasthenia gravis / Síndrome miastênica congênita em uma série de pacientes com miastenia gravis duplo soronegativa

ABSTRACT Background: Congenital myasthenic syndromes (CMS) have some phenotypic overlap with seronegative myasthenia gravis (SNMG). Objective: The aim of this single center study was to assess the minimum occurrence of CMS misdiagnosed as double SNMG in a Brazilian cohort. Methods: The genetic analysis of the most common mutations in CHRNE, RAPSN, and DOK7 genes was used as the main screening tool. Results: We performed genetic analysis in 22 patients with a previous diagnosis of 'double' SNMG. In this study, one CMS patient was confirmed due to the presence of compound heterozygous variants in the CHRNE gene (c.130insG/p.Cys210Phe). Conclusions: This study confirmed that CMS due to CHNRE mutations can be mistaken for SNMG. In addition, our study estimated the prevalence of misdiagnosed CMS to be 4.5% in 'double' SNMG patients of our center. Based on our findings, genetic screening could be helpful in the diagnostic workup of patients with 'double' SNMG in whom differential diagnosis is recommended.

RESUMO Antecedentes: As síndromes miastênicas congênitas (SMC) podem ter sobreposição fenotípica com a miastenia gravis soronegativa (MG-SN). Objetivo: Estabelecer a prevalência mínima de SMC diagnosticada inicialmente como MG duplo soronegativa em uma série de casos brasileiros. Métodos: A análise genética das mutações mais comuns nos genes CHRNE, RAPSN e DOK7 foi usada como o principal exame de triagem. Resultados: Vinte e dois pacientes com diagnóstico prévio de MG-SN foram geneticamente analisados, sendo que uma paciente foi confirmada com SMC devido a presença de variante em heterozigose composta no gene CHRNE (c.130insG/p.Cys210Phe). Conclusões: O presente estudo confirma que SMC devido mutação no gene CHNRE pode ser inicialmente diagnosticada como MG-SN. O estudo estimou como 4,5% a prevalência de diagnóstico de SMC entre nossos pacientes préviamente diagnosticados como MG-SN. Com base nesse estudo, a análise genética pode ser recomendada para investigação do diagnóstico diferencial em pacientes com MG-SN.

Congenital myasthenic syndrome: Correlation between clinical features and molecular diagnosis.

OBJECTIVES: To present phenotype features of a large cohort of congenital myasthenic syndromes (CMS) and correlate them with their molecular diagnosis. METHODS: Suspected CMS patients were divided into three groups: group A (limb, bulbar or axial weakness, with or without ocular impairment, and all the following: clinical fatigability, electrophysiology compatible with neuromuscular junction involvement and anticholinesterase agents response), group B (limb, bulbar or axial weakness, with or without ocular impairment, and at least one of additional characteristics noted in group A) and group C (pure ocular syndrome). Individual clinical findings and the clinical groups were compared between the group with a confirmed molecular diagnosis of CMS and the group without molecular diagnosis or with a non-CMS molecular diagnosis. RESULTS: Seventy-nine patients (68 families) were included in the cohort: 48 in group A, 23 in group B and 8 in group C. Fifty-one were considered confirmed CMS (30 CHRNE, 5 RAPSN, 4 COL13A1, 3 DOK7, 3 COLQ, 2 GFPT1, 1 CHAT, 1 SCN4A, 1 GMPPB, 1 CHRNA1), 7 probable CMS, 5 non-CMS and 16 unsolved. The chance of a confirmed molecular diagnosis of CMS was significantly higher for group A and lower for group C. Some individual clinical features, alterations on biopsy and electrophysiology enhanced specificity for CMS. Muscle imaging showed at least mild alterations in the majority of confirmed cases, with preferential involvement of soleus, especially in CHRNE CMS. CONCLUSIONS: Stricter clinical criteria increase the chance of confirming a CMS diagnosis, but may lose sensitivity, especially for some specific genes.

Congenital myasthenic syndrome in a cohort of patients with 'double' seronegative myasthenia gravis.

BACKGROUND: Congenital myasthenic syndromes (CMS) have some phenotypic overlap with seronegative myasthenia gravis (SNMG). OBJECTIVE: The aim of this single center study was to assess the minimum occurrence of CMS misdiagnosed as double SNMG in a Brazilian cohort. METHODS: The genetic analysis of the most common mutations in CHRNE, RAPSN, and DOK7 genes was used as the main screening tool. RESULTS: We performed genetic analysis in 22 patients with a previous diagnosis of 'double' SNMG. In this study, one CMS patient was confirmed due to the presence of compound heterozygous variants in the CHRNE gene (c.130insG/p.Cys210Phe). CONCLUSIONS: This study confirmed that CMS due to CHNRE mutations can be mistaken for SNMG. In addition, our study estimated the prevalence of misdiagnosed CMS to be 4.5% in 'double' SNMG patients of our center. Based on our findings, genetic screening could be helpful in the diagnostic workup of patients with 'double' SNMG in whom differential diagnosis is recommended.

Congenital myasthenic syndrome due to DOK7 mutation in a cohort of patients with 'unexplained' limb-girdle muscular weakness.

Congenital myasthenic syndromes (CMS) associated with pathogenic variants in the DOK7 gene (DOK7-CMS) have phenotypic overlap with other neuromuscular disorders associated with limb-girdle muscular weakness (LGMW). Genetic analysis of the most common mutation (c.1124_1127dupTGCC) in DOK7 was performed in 34 patients with "unexplained" LGMW associated with non-specific changes in muscle biopsy. Of the 34 patients, one patient showed the DOK7 c.1124_1127dupTGCC variant in homozygousity. Our study estimates the minimum prevalence of undiagnosed DOK7-CMS to be 2.9% in southern Brazilian patients from our centre. Our data confirm that clinicians should look for DOK7-CMS patients when the clinical manifestation is an 'unexplained' LGMW, mainly if associated with non-specific changes in muscle biopsy.

Clinical variability of early-onset congenital myasthenic syndrome due to biallelic RAPSN mutations in Brazil.

Mutations in RAPSN are an important cause of congenital myasthenic syndrome (CMS), leading to endplate acetylcholine receptor deficiency. We present three RAPSN early-onset CMS patients (from a Brazilian cohort of 61 CMS patients). Patient 1 and patient 2 harbor the mutation p.N88K in homozygosity, while patient 3 harbors p.N88K in compound heterozygosity with another pathogenic variant (p.V165M; c.493G ≥ A). At onset, patient 3 presented with more severe symptoms compared to the other two, showing generalized weakness and repeated episodes of respiratory failure in the first years of life. During adolescence, she became gradually less symptomatic and does not require medication anymore, presenting better long-term outcomes than patients 1 and 2. This case series illustrates the variability of RAPSN early-onset CMS, with patient 3, despite severe onset, revealing an almost complete reversal of myasthenic symptoms, not limited to apneic episodes. Moreover, it suggests that RAPSN CMS may be underdiagnosed in non-European countries.

How to Spot Congenital Myasthenic Syndromes Resembling the Lambert-Eaton Myasthenic Syndrome? A Brief Review of Clinical, Electrophysiological, and Genetics Features.

Congenital myasthenic syndromes (CMS) are heterogeneous genetic diseases in which neuromuscular transmission is compromised. CMS resembling the Lambert-Eaton myasthenic syndrome (CMS-LEMS) are emerging as a rare group of distinct presynaptic CMS that share the same electrophysiological features. They have low compound muscular action potential amplitude that increment after brief exercise (facilitation) or high-frequency repetitive nerve stimulation. Although clinical signs similar to LEMS can be present, the main hallmark is the electrophysiological findings, which are identical to autoimmune LEMS. CMS-LEMS occurs due to deficits in acetylcholine vesicle release caused by dysfunction of different components in its pathway. To date, the genes that have been associated with CMS-LEMS are AGRN, SYT2, MUNC13-1, VAMP1, and LAMA5. Clinicians should keep in mind these newest subtypes of CMS-LEMS to achieve the correct diagnosis and therapy. We believe that CMS-LEMS must be included as an important diagnostic clue to genetic investigation in the diagnostic algorithms to CMS. We briefly review the main features of CMS-LEMS.

A common CHRNE mutation in Brazilian patients with congenital myasthenic syndrome.

The most common causes of congenital myasthenic syndromes (CMS) are CHRNE mutations, and some pathogenic allelic variants in this gene are especially frequent in certain ethnic groups. In the southern region of Brazil, a study found the c.130dupG CHRNE mutation in up to 33% of families with CMS. Here, we aimed to verify the frequency of this mutation among individuals with CMS in a larger cohort of CMS patients from different areas of Brazil and to characterize clinical features of these patients. Eighty-four patients with CMS, from 72 families, were clinically evaluated and submitted to direct sequencing of the exon 2 of CHRNE. The c.130dupG mutation was found in 32 patients (23 families), with 26 patients (19 families, 26.3%) in homozygosis, confirming its high prevalence in different regions of Brazil. Among the homozygous patients, the following characteristics were frequent: onset of symptoms before 2 years of age (92.3%), little functional restriction (92.3%), fluctuating symptoms (100%), ocular muscle impairment (96.1%), ptosis (100%), limb weakness (88.4%), response to pyridostigmine (100%), facial involvement (77%), and bulbar symptoms (70.8%). The pretest probability of finding at least one allele harbouring the c.130dupG mutation was 38.1%. Selecting only patients with impaired eye movement together with limb weakness and improvement with pyridostigmine, the probability increases to 72.2%. This clinical pre-selection of patients is likely a useful tool for regions where CHRNE mutations have a founder effect. In conclusion, the CHRNE mutation c.130dupG leads to fairly benign natural course of the disease with relative homogeneity.

The burden of Duchenne muscular dystrophy: an international, cross-sectional study.

OBJECTIVE: The objective of this study was to estimate the total cost of illness and economic burden of Duchenne muscular dystrophy (DMD). METHODS: Patients with DMD from Germany, Italy, United Kingdom, and United States were identified through Translational Research in Europe-Assessment & Treatment of Neuromuscular Diseases registries and invited to complete a questionnaire online together with a caregiver. Data on health care use, quality of life, work status, informal care, and household expenses were collected to estimate costs of DMD from the perspective of society and caregiver households. RESULTS: A total of 770 patients (173 German, 122 Italian, 191 from the United Kingdom, and 284 from the United States) completed the questionnaire. Mean per-patient annual direct cost of illness was estimated at between $23,920 and $54,270 (2012 international dollars), 7 to 16 times higher than the mean per-capita health expenditure in these countries. Indirect and informal care costs were substantial, each constituting between 18% and 43% of total costs. The total societal burden was estimated at between $80,120 and $120,910 per patient and annum, and increased markedly with disease progression. The corresponding household burden was estimated at between $58,440 and $71,900. CONCLUSIONS: We show that DMD is associated with a substantial economic burden. Our results underscore the many different costs accompanying a rare condition such as DMD and the considerable economic burden carried by affected families. Our description of the previously unknown economic context of a rare disease serves as important intelligence input to health policy evaluations of intervention programs and novel therapies, financial support schemes for patients and their families, and the design of future cost studies.

Salbutamol therapy in congenital myasthenic syndrome due to DOK7 mutation.

INTRODUCTION: Salbutamol is a selective B2-adrenergic agonist, which has previously been described to be associated with partial improvement of myasthenia gravis and congenital myasthenic syndromes (CMS). In this study, we analyzed the effect of salbutamol in five patients with Dok-7 CMS. METHODS: We studied 5 patients (2 male and 3 female), with a mean age of 27±11.06 years, who harbored c.1124_1127dupTGCC, p.G64R and/or p.S45L mutations in DOK7 gene. Salbutamol was given at a dose of 2mg three times daily (6 mg/day) to all patients. The response was assessed by QMG score at baseline, 3, 6, 9 and 12 months; ADL-MG score and 6 minute walk test at baseline and after 12 months during follow-up clinic visits. Side effect profile of salbutamol was also evaluated. RESULTS: We noted an increasingly positive response as measured by the QMG score after 3 months of salbutamol treatment. Improvement in specific subcomponents of the QMG score such as leg outstretched in 45° supine was most marked. In ADL-MG scores and 6 minute walk test, comparison between baseline and after 12 months revealed a clear beneficial response. Salbutamol was well tolerated in all patients. CONCLUSIONS: Salbutamol is an effective treatment in Dok-7 CMS. This study provides class IV evidence that salbutamol given at a dose 6 mg/day improves function as measured by the QMG score, ADL-MG score and 6 minute walk test.