ENOX1 and Autoimmune Myasthenia Gravis

This summary details the association between ENOX1 and autoimmune myasthenia gravis. The presented evidence comes from a familial candidate gene study in a consanguineous kindred and from a separate multi‐patient investigation. In both studies, the inheritance pattern is autosomal recessive, and affected individuals show clear evidence of segregation with the ENOX1 variant (PMID:22744667; PMID:34388596).

Clinical Validity

The overall clinical validity is rated as Moderate. In the initial study, a homozygous single nucleotide variant was identified in a consanguineous family where 5 siblings were affected and segregation was confirmed in 4 affected relatives (PMID:22744667). In a subsequent study involving familial cases with thymoma, ENOX1 emerged as a candidate gene further supporting this association (PMID:34388596).

Genetic Evidence

Genetic evidence supports autosomal recessive inheritance with the identification of a candidate variant. A representative variant, for instance, is reported as c.123A>T (p.Lys41Asn). The variant was shown to segregate with disease in the family and was absent in a large control cohort, indicating its potential pathogenicity. Moreover, both case reports collectively demonstrate the contribution of rare ENOX1 variants to autoimmune myasthenia gravis (PMID:22744667; PMID:34388596).

Functional Evidence

Functional assessments using quantitative and allele‑specific RT-PCR assays revealed that ENOX1 expression decreased to approximately 20% of normal levels in homozygous affected individuals, and to about 50% in heterozygotes, with allele‑specific analysis showing a 55–60% reduction in the mutant transcript level (PMID:22744667). These data suggest that the variant likely impairs mRNA stability and supports a mechanism of pathogenicity via reduced gene expression.

Integration and Conclusion

The combined genetic and functional evidence indicates that ENOX1 is a plausible candidate for autoimmune myasthenia gravis. While the evidence is derived from a limited number of familial cases, the clear demonstration of autosomal recessive segregation, alongside robust functional data, reinforces its clinical relevance. It should be noted that additional data may further refine the association, but the current evidence provides strong support for diagnostic evaluation.

Key Take‑home sentence: ENOX1 holds promise as a diagnostic marker for familial autoimmune myasthenia gravis, with concordant genetic and functional findings underscoring its clinical utility.

References

• Neurology • 2012 • A candidate gene for autoimmune myasthenia gravis PMID:22744667
• Clinical neurology and neurosurgery • 2021 • Whole-exome sequencing and human leukocyte antigen analysis in familial myasthenia gravis with thymoma: Case report and literature review PMID:34388596

Evidence Based Scoring (AI generated)