Suspected Adult-Onset Congenital Myasthenic Syndrome Associated With a Heterozygous CHRND Variant in a Patient With Seropositive Rheumatoid Arthritis: A Case Report

Introduction

Congenital myasthenic syndrome (CMS) is a clinically and genetically heterogeneous disease characterized by neuromuscular transmission defects caused by mutations affecting either synaptic structure or function. Over the last few decades, the molecular basis of CMS has expanded. To date, more than 35 genes have been associated with this disease. CMS usually presents at birth or during early childhood. However, the first symptoms may appear in adulthood. The prevalence of CMS, ranging from 2.8 to 14.8 per million, is probably underestimated due to the complexity of the diagnostic procedure. Mild forms of CMS, late-onset CMS, and CMS presenting with atypical or complex phenotypes may add to the underestimated prevalence [1,2].

CMS can be classified by the pattern of inheritance, altered proteins involved in the motor plate, or by considering the site at the neuromuscular junction (presynaptic, synaptic, or postsynaptic) involved in dysfunction [3,4]. A generic diagnosis of CMS is supported by onset at birth or in early childhood, fatigable weakness typically affecting the ocular muscles, and a positive family history, together with either a decremental response on nerve conduction study/repetitive nerve stimulation (NCS/RNS) or an abnormal single-fiber electromyography (SFEMG). Tests for anti-acetylcholine receptor and anti-muscle-specific kinase antibodies may be indicated in sporadic cases after 1 year of age and in arthrogrypotic infants, even if the mother has no myasthenic symptoms [2,5]. It should be emphasized that several of these supporting features were absent in the present case: electrophysiological studies, including NCS/RNS and conventional electromyography, were normal, and SFEMG—the most sensitive electrophysiological test for a neuromuscular junction disorder—was not performed. This divergence between the established diagnostic criteria and the findings in our patient is an important limitation that we address explicitly below, and it is the reason the diagnosis is framed as suspected rather than confirmed.

Pharmacological therapy may be useful for some CMS presentations. However, drugs that are beneficial to patients with one type of CMS can be harmful to others. To ensure appropriate management, a specific diagnosis is essential. Monitoring the effects of therapy using objective measures is equally important. These include arm elevation time, the number of times a patient can rise from squatting or from a low stool, the degree of eyelid ptosis, the number of steps they can climb or the distance they can walk before resting, the grade of weakness of selected muscles, maximal inspiratory and expiratory pressures, maximal expiratory flow, and the extent of electromyogram decrement in 1 or more selected muscles [6–9]. Additionally, assessment using the myasthenia gravis activities of daily living (MG-ADL) scale or other validated myasthenia gravis functional scales should be considered. In this case report, we describe a 42-year-old man with seropositive rheumatoid arthritis (RA), who developed adult-onset CMS.

Case Report

A 42-year-old male patient with seropositive RA presented to the neurology clinic with progressive fatigue, fluctuating muscle weakness, and right eye ptosis. His RA was well-controlled with disease-modifying anti-rheumatic drugs and biological therapy. To manage his seropositive RA, the patient was initially treated with methotrexate (25 mg/week, subcutaneous injection) and golimumab (50 mg/month). Due to limited availability, his treatment was switched to adalimumab 40 mg every other week. One year before presentation, he was switched to oral tofacitinib 5 mg twice daily at the patient’s request, with good rheumatological disease control.

Over the preceding year, the patient had developed increasing fatigability and intermittent proximal muscle weakness in both upper and lower limbs. Weakness varied throughout the day and was worst in the afternoon. The patient also complained of bilateral ptosis and intermittent diplopia. Neurological examination revealed the presence of a possible neuromuscular junction disorder. He was commenced on pyridostigmine 60 mg orally 3 times daily, and experienced partial but clinically meaningful symptomatic improvement within the first 2 weeks: his right-sided ptosis became less pronounced, episodes of diplopia resolved, afternoon fatigability decreased, and he was able to complete a full working day with reduced rest requirements. At the 6-week follow-up, improvement in proximal limb endurance was sustained, although mild exertional fatigability persisted.

The patient’s family history revealed consanguinity. His father, aged 78 years, was diagnosed with lung cancer. One brother had died at 47 years of age from liver cancer, and another brother, aged 32 years, had mental and physical disability. Moreover, his sister had symptoms resembling RA. The patient was married to his first cousin and had 3 asymptomatic sons, aged 16, 11, and 4 years.

Examination revealed mild right-sided ptosis, diminished proximal limb strength graded Medical Research Council (MRC) 4/5 in both the deltoids and hip flexors, with further decrement to 4-/5 after sustained abduction and repeated squatting maneuvers, generalized muscle fatigability, and mild facial sensory disturbance. Distal limb strength was preserved at MRC 5/5 throughout. Otherwise, the cranial nerves were preserved, reflexes were maintained, and gait was stable. Of note, the mild facial sensory disturbance is an atypical finding for a disorder of the neuromuscular junction, in which sensation is characteristically spared. It was subjective, non-dermatomal, and not accompanied by any objective sensory deficit on repeated examination; no structural or central cause was identified on brain magnetic resonance imaging (MRI). Its significance therefore remained uncertain, and rather than supporting a neuromuscular junction disorder, it represented an additional atypical feature that, together with the normal electrophysiology, argued for diagnostic caution.

Initial laboratory test results were normal. However, the anti-cyclic citrullinated peptide antibody test was positive (Table 1). Electrophysiological studies, including nerve conduction and repetitive nerve stimulation, were normal, with no evidence of neuromuscular junction disorder or myopathy (Table 2). Computed tomography (CT) scans of the neck, chest, abdomen, and pelvis revealed no remarkable findings (Table 3). Multi-sequence MRI of the brain without contrast showed cerebral parenchyma with no acute infarction, hemorrhage, mass lesions, or abnormal enhancement (Table 3). Importantly, the patient’s normal NCS, RNS, and conventional electromyography do not exclude a neuromuscular junction disorder, as a decremental response may be intermittent or detectable only after prolonged subtetanic stimulation, and milder or postsynaptic defects may be apparent only on SFEMG. However, because SFEMG was not available at the time of evaluation, the electrophysiological diagnosis of a neuromuscular junction disorder in this patient remains unconfirmed, and the clinical diagnosis rests on the phenotype, the exclusion of autoimmune causes, and the genetic findings rather than on objective electrophysiological evidence.

Whole-exome sequencing (WES) revealed a heterozygous loss-of-function variant in CHRND; CHRND-related CMS is classically inherited in an autosomal recessive manner, and the implications of the heterozygous state in this patient are considered further in the Discussion. Subsequent whole-genome sequencing performed in September 2025 reclassified the CHRND finding as a heterozygous pathogenic variant and additionally identified a heterozygous likely pathogenic variant in FH, associated with hereditary leiomyomatosis and renal cell cancer syndrome. A hemizygous FHL1 variant of uncertain significance, previously reported in X-linked myopathies and muscular dystrophies, was also identified. The patient was also a carrier of other autosomal recessive mutations in the G6PC1 (glycogen storage disease type Ia) and IRAK4 (immunodeficiency 67) genes (Table 4). Carrier testing of his wife to assess the genetic risk for their children has been scheduled.

The patient was started on pyridostigmine 60 mg orally, 3 times daily, and advised to avoid strenuous physical activity and prolonged exertion to reduce muscle fatigue. Education on energy conservation and activity pacing was also provided. The patient’s RA remained well-controlled with tofacitinib. Follow-up at the neurology clinic of a tertiary center is ongoing, and further neuromuscular evaluation, including SFEMG, is planned. Genetic counseling was also performed because FH gene mutations predispose patients to renal cell carcinoma.

Discussion

LIMITATIONS AND DIAGNOSTIC CONSIDERATIONS:

Several limitations temper the certainty of the diagnosis and should be made explicit. First, the genetic finding is a single heterozygous variant in CHRND, a gene in which CMS is classically autosomal recessive; no second pathogenic allele was identified on whole-genome sequencing, and a single heterozygous variant cannot by itself confirm the diagnosis. Second, the supporting electrophysiological evidence is incomplete: NCS, RNS, and conventional electromyography were all normal, and SFEMG—the most sensitive test for a neuromuscular junction defect—was not performed, so an objective electrophysiological correlate of impaired neuromuscular transmission was never demonstrated. Third, the mild facial sensory disturbance is atypical for a neuromuscular junction disorder and remains unexplained. Fourth, the symptomatic response to pyridostigmine, while clinically meaningful, is supportive but not specific, as a placebo effect or improvement in a coexisting condition cannot be fully excluded. Fifth, the proposed contributions of the autoimmune milieu and of the FH and FHL1 variants are hypotheses without supporting functional or segregation data. Finally, our description of this combination as previously unreported reflects a search of the available literature and is offered cautiously. For these reasons we regard the diagnosis as a suspected, genetically suggestive adult-onset CMS rather than a definitively confirmed one, and we have framed the report accordingly. Planned SFEMG, parental and offspring segregation testing, and continued follow-up are intended to address these uncertainties.

Conclusions

CMS should be considered in the differential diagnosis of patients presenting with weakness, fatigue, and atypical neuromuscular characteristics, especially when autoimmune and metabolic differentials have been excluded. In our patient, the combination of a compatible adult-onset phenotype, exclusion of autoimmune causes, a heterozygous pathogenic CHRND variant, and a response to pyridostigmine supports a suspected, genetically suggestive diagnosis rather than a definitively confirmed one, given the normal electrophysiology, the absence of SFEMG, and the single heterozygous variant. To our knowledge, the co-occurrence of seropositive RA and suspected CHRND-associated adult-onset CMS has not previously been reported. The principal clinical takeaway is that, in adults with fatigable weakness, normal serology, and normal routine electrophysiology, clinicians should pursue both definitive electrophysiological testing (including SFEMG) and broad genetic analysis, while interpreting an isolated heterozygous variant cautiously and correlating it with phenotype before reaching a firm diagnosis. Heightened awareness of adult-onset CMS and its heterogeneous genetic basis may enable earlier recognition and individualized management.