SMN1 – Spinal Muscular Atrophy Type 1

Spinal Muscular Atrophy Type 1 (SMA I), also known as Werdnig–Hoffmann disease, is a severe, infantile-onset neuromuscular disorder characterized by generalized hypotonia, profound muscle weakness, and early respiratory failure. It is caused by biallelic loss-of-function of the survival motor neuron gene SMN1 (Gene Symbol), leading to degeneration of anterior horn motor neurons.

Inheritance follows an autosomal recessive pattern, with >95% of patients harboring homozygous deletions of SMN1 exons 7 and 8 (PMID:9748045). Compound heterozygous cases with one deletion and a second SMN1 point mutation, such as c.306G>A (p.Trp102Ter), represent ~4% of cases (PMID:9719377). Affected relatives have been documented in sibships, confirming segregation of pathogenic alleles.

The variant spectrum is dominated by large deletions; rare intragenic point mutations and small indels have been reported to segregate with disease (PMID:9719377, PMID:14968368). Example: c.306G>A (p.Trp102Ter).

Functional studies demonstrate that SMN protein is essential for snRNP assembly and pre-mRNA splicing. Wild-type SMN stimulates splicing in vitro, while patient-derived mutants fail to do so (PMID:9845364). In zebrafish, SMN knockdown leads to motor axon outgrowth defects that are rescued by human SMN mRNA (PMID:17065443). Antisense oligonucleotides targeting SMN2 exon 7 restore full-length SMN expression in patient fibroblasts (PMID:12642665).

Clinically, affected infants present with severe hypotonia (HP:0001252), generalized muscle weakness (HP:0001324), respiratory insufficiency (HP:0002093), multiple joint contractures (HP:0002828), and fetal akinesia sequence (HP:0001989). The natural history is characterized by failure to achieve motor milestones and death typically before two years of age.

No conflicting evidence disputing the SMN1–Disease Name association has been reported. Taken together, the robust genetic and experimental data establish a Definitive gene–disease relationship.

Key take-home: Early SMN1 genetic testing—including exon 7/8 deletion analysis and sequencing—is critical for accurate diagnosis, prognostication, carrier screening, and timely initiation of emerging therapies.

References

• Neurology • 1998 • Congenital cytoplasmic body myopathy with survival motor neuron gene deletion or Werdnig-Hoffmann disease. PMID:9748045
• Journal of medical genetics • 1998 • Diagnosis of spinal muscular atrophy in an SMN non-deletion patient using a quantitative PCR screen and mutation analysis. PMID:9719377
• Acta neuropathology • 2004 • Neonatal spinal muscular atrophy with multiple contractures, bone fractures, respiratory insufficiency and 5q13 deletion. PMID:14968368
• Cell • 1998 • A novel function for SMN, the spinal muscular atrophy disease gene product, in pre-mRNA splicing. PMID:9845364
• The Journal of neuroscience • 2006 • Survival motor neuron function in motor axons is independent of functions required for small nuclear ribonucleoprotein biogenesis. PMID:17065443
• Proceedings of the National Academy of Sciences of the United States of America • 2003 • Bifunctional antisense oligonucleotides provide a trans-acting splicing enhancer that stimulates SMN2 gene expression in patient fibroblasts. PMID:12642665
• Neuroscience letters • 2008 • A SMNDelta7 read-through product confers functionality to the SMNDelta7 protein. PMID:18601974

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