Dados do Trabalho

Título

Previously unpublished homozygous CHRNA1 c.997C>T variant associated with relatively mild congenital myasthenic syndrome (CMS): a case-report

RESUMO

CASE PRESENTATION
We present a 51-year-old male patient, referred to the neuromuscular unit with history of mild transient neonatal bulbar weakness, presenting with worsening limb and bulbar weakness after 30 years of age. Family and past medical history were unremarkable except for consanguineous parents.
Previous NCS and needle EMG revealed some evidence of post-synaptic neuromuscular junction dysfunction with diffuse myopathic motor unit potentials. Anti-AChR and anti-MuSK results were negative.
The patient was initially diagnosed with seronegative auto-immune myasthenia gravis and received various immunosuppressant therapies and pyridostigmine with partial response. Nevertheless, from 30-50 years of age, the patient underwent multiple hospitalizations due to respiratory infections, with successful recovery.
Genetic testing revealed homozygous c.997C>T variant resulting in a change p.Arg333Trp. In silico prediction tools showed potentially deleterious value, and was reported as probably pathogenic based on previous fast-channel CMS description associated with compound heterozygous for that variant.
After CMS diagnosis, the patient was kept in rehabilitation and waned immunotherapy. By the time of this report, the patient partially recovered motor functions, walks unaided and sustains improvement with pyridostigmine and ephedrine.

DISCUSSION
CMS englobes a variety of genetically inherited neuromuscular junction disorders. The most common form of CMS is post-synaptic and can be primarily due to decrease in its subunit’s expression or by altering the channel’s kinetic. CHRNA1 mutations causing CMS are rare, and generally severe at early onset.
The present report describes a patient with relatively mild clinical features harboring a c.997C>T homozygous variant in CHRNA1 which was only previously reported in a patient with compound heterozygosity. This variant prevalence is approximately 5 in 105 and is probably associated with autosomal recessive CMS.
In summary, this case expands our knowledge of the complex genotype-phenotype correlation of CMS with demonstration of a homozygous mutation expected to cause a very severe phenotype but instead originating a mild adult-onset phenotype.

FINAL REMARKS
Since the only previous report of the same variant was compound heterozygous, and definition of kinetic disturbances and receptor deficiency requires functional proof, we acknowledge the benefit of further histological and advanced neurophysiological testing.

Palavras Chave

Congenital myasthenic syndrome, fast-channel, CHRNA1, c.997C>T, p.Arg333Trp