Rare SMA Patients: A Comprehensive Look at Clinical Features, Genetic Profiles and Therapeutic Approaches

Area of Science:

• Genetics
• Neurology
• Molecular Biology

Background:

• Spinal muscular atrophy 5q (5q SMA) is a prevalent autosomal recessive disorder caused by variants in the SMN1 gene.
• Rare cases of 5q SMA involve subtle SMN1 variants of unknown clinical significance, with limited data on gene-based therapy outcomes.

Purpose of the Study:

• To investigate the molecular genetic and clinical characteristics of patients with 5q SMA associated with intragenic SMN1 variants and heterozygous deletion.
• To report the outcomes of gene-based therapy in this specific patient cohort.

Main Methods:

• Retrospective analysis of 10 patients with 5q SMA and intragenic SMN1 variants combined with heterozygous SMN1 deletion.
• Detailed molecular genetic analysis, including identification of known pathogenic and novel variants.
• Clinical data collection and assessment of gene-based therapy outcomes.

Main Results:

• Identified previously reported pathogenic SMN1 variants (e.g., c.*3+1del, c.815A>G, c.821C>T).
• Discovered a novel, recurrent variant c.80A>C (p.Gln27Pro) of unknown clinical significance.
• Reported detailed molecular and clinical data for 9 patients, with gene-based therapy results consistent with homozygous SMN1 deletion cases.

Conclusions:

• Subtle SMN1 variants, including novel ones, contribute to 5q SMA.
• Gene-based therapy appears effective in patients with complex SMN1 genetic profiles, similar to those with homozygous deletions.
• Further research is warranted to understand the clinical significance of novel SMN1 variants and optimize gene therapy strategies.