Non-SMN-linked Spinal Muscular Atrophy: From Genes to Clinical Phenotypes via Diagnostic Implications; A Systematic...

Spinal muscular atrophies are a group of genetically and clinically heterogeneous neuromuscular disorders characterized by progressive loss of lower motor neurons, muscle weakness, and atrophy. Approximately 95% of spinal muscular atrophy cases are associated with a deletion of exons 7 and 8 in the survival motor neuron 1 (SMN1) gene, resulting in insufficient levels of SMN protein. The remaining 5% of cases involve mutations in approximately 30 different genes, collectively referred to as non-SMN-related spinal muscular atrophies. These variants often present with distinct clinical features beyond typical spinal muscular atrophy symptoms, including arthrogryposis, extraocular movement abnormalities, brainstem signs, or cardiomyopathy. This review aims to provide an updated genetic landscape of non-SMN-linked spinal muscular atrophy phenotypes and propose a diagnostic protocol to assist clinicians in cases where SMN1 gene sequencing yields no conclusive findings.