Adult-onset vocal cord paralysis in slow-channel congenital myasthenic syndrome

PRACTICAL IMPLICATIONS

Consider slow-channel congenital myasthenic syndrome in the differential diagnosis of vocal cord paralysis.

One type of congenital myasthenic syndrome (CMS) is slow-channel CMS (SCCMS), which is an autosomal dominant disorder caused by gain-of-function mutations in acetylcholine receptor (AChR) subunits. These mutations lead to prolongation of the receptor gate opening, which induces cationic overload of the postsynaptic region and results in an endplate myopathy.¹ Here, we report the first case of SCCMS with a CHRNA1 mutation in which adult-onset vocal cord paralysis developed along with dyspnea and apnea.

Clinical presentation

A 49-year-old man was admitted to our hospital because of progressive generalized muscle weakness as well as dyspnea and apnea. His maternal grandmother died of undiagnosed generalized muscle weakness at age 59. His mother developed undiagnosed hypoxia during her fifties and died at age 66, and his daughter first exhibited muscle weakness in the neck and hands at age 11 (figure 1). The patient was normally delivered at full term and showed low athletic ability in childhood. At age 43, he noticed exertional dyspnea. At age 49, he was referred to our hospital because of respiratory failure. As shown in figure 2A, he had a thin, myopathic face with a high-arched palate, thin body, distal muscle atrophy, and weakness in the right more than the left (grade 4/5 on the Medical Research Council [MRC] scale; grip strength, right 21 kg, left 23 kg), and dyspnea with sleep apnea (Apnea-Hypopnea Index, 31.9). Spirometry testing indicated restrictive ventilatory impairment (% predicted vital capacity [%VC], 64.0%). Ultrasonography revealed a thin, hypokinetic diaphragm and mild, diffuse hypokinesia of the heart (ejection fraction, 56%). Laryngoscopic study showed moderate vocal cord paralysis, and whole-exome sequencing revealed a heterozygous mutation in exon 5 of CHRNA1 (NM_000079: c.517G>A (p.Gly173Ser)), which was previously reported as p.Gly153Ser and is known to cause SCCMS.² Repetitive nerve stimulation showed a decremental response, corroborating the existence of myasthenia (figure 2B). At age 52, facial and distal limb muscle atrophy and weakness worsened (grade 3–4/5 on the MRC scale; grip strength, right 16 kg, left 20 kg), and dyspnea and apnea also advanced (%VC, 56.1%) because of severe vocal cord paralysis (figure 2C). The patient finally required tracheotomy. Because the selective serotonin reuptake inhibitor fluoxetine suppresses the opening of the AChR ion-channel gate, it was recently proposed as a treatment for SCCMS.³ Indeed, fluoxetine treatment (40 mg/d) for 9 months improved our patient's muscle weakness (grade 4/5 on the MRC scale; grip strength, right 20 kg, left 22 kg) and dyspnea and apnea (%VC, 60.7%), but the motility of his vocal cords was not affected.

Figure 1. Patient pedigree.

Black filled and white symbols represent affected and unaffected members with SCCMS (arrow, our patient). In addition to our patient, at least 3 family members were suspected of having CMS. CMS = congenital myasthenic syndrome; SCCMS = slow-channel CMS.

Figure 2. Patient's clinical features.

(A) Full-length photograph of the patient. (B) Repetitive nerve stimulation (3 Hz) of the ulnar nerve with recording in the abductor digiti minimi shows a decremental response. (C) A laryngoscopic image demonstrates vocal cord paralysis at respiration.

Discussion

A mutation of CHRNA1 (Gly173Ser, encoding the α-subunit of AChR and previously reported as the Gly153Ser mutation) has been reported to result in SCCMS onset at various ages (1–43 years old), with clinical symptoms including limb weakness, occasional dyspnea, ocular and neck weakness, chewing difficulties, involuntary mouth opening, and general fatigue, but not vocal cord paralysis as identified in this patient.^2,4 CHRNA1-related SCCMS has been reported to demonstrate a correlation between genotype and phenotype, consistent with the similar phenotypes observed among family members of our patient. Of note, our patient exhibited vocal cord paralysis and a thin face with a high-arched palate, suggesting faciopharyngeal anomalies. Vocal cord paralysis is an uncommon presentation of CMS and has been reported only as a cause of neonatal stridor in the context of DOK7, COLQ, and CHRNE mutations,^5,6 but not in the context of mutations of genes, including CHRNA1, that cause SCCMS. Regarding therapeutic approaches, pyridostigmine was found to improve neonatal vocal cord paralysis in a patient with fast-channel syndrome caused by a CHRNE mutation.⁶ Treatment with fluoxetine showed clinical benefit in all patients with CHRNA1-related SCCMS by suppressing AChR ion-channel gate opening,^3,7 but it was not yet clear whether fluoxetine would improve vocal cord paralysis. In our case, fluoxetine improved muscle strength but not vocal cord paralysis. In patients with DOK7 mutations, reduced vocal cord mobility was partially attributed to interarytenoid scarring and laryngomalacia.⁶ Taken together, vocal cord paralysis in CMS might be influenced not only by muscular fatigue but also by laryngeal anomalies, which might explain the drug responses observed in our patient. In summary, the Gly173Ser mutation in CHRNA1 might give rise to facio-pharyngo-laryngeal anomalies, including thin face with high-arched palate, and adult-onset of fatal vocal cord paralysis. This is the first report of vocal cord paralysis in a patient with SCCMS, and further investigations are needed to clarify whether it is a characteristic phenotype of CHRNA1 mutation.

Author contributions

H. Nakamura, H. Komiya, E. Uematsu, Y. Nakae, K. Tanaka, M. Kunii, M. Tada, H. Joki, S. Koyano, H. Doi, H. Takeuchi, and F. Tanaka examined and treated the patient. M. Kunii, H. Doi, and N. Matsumoto performed gene analysis. H. Nakamura, H. Takeuchi, and F. Tanaka wrote the manuscript.

Study funding

No targeted funding reported.

Disclosure

The authors report no disclosures relevant to the manuscript. Full disclosure form information provided by the authors is available with the full text of this article at Neurology.org/cp.