ATP7A – X-linked distal spinal muscular atrophy type 3

ATP7A encodes a copper-transporting P-type ATPase whose allelic mutations cause Menkes disease, occipital horn syndrome (OHS), and X-linked distal spinal muscular atrophy type 3 (SMAX3), a continuum dependent on residual ATP7A function. SMAX3 is inherited in an X-linked recessive manner and is characterized by distal motor neuropathy without the severe neurodegeneration of Menkes disease. A single male proband presented with both classic OHS occipital horns and distal motor neuropathy, carrying a hemizygous missense variant c.2576A>G (p.Asp859Gly) in ATP7A, confirming allelism of OHS and SMAX3 (PMID:33137485). This one case constitutes the sole report of ATP7A in SMAX3, yielding limited genetic evidence, with no additional segregation data. Mechanistically, pathogenic ATP7A variants disrupt copper transport via haploinsufficiency, but functional studies specific to SMAX3 are lacking, leaving only mechanistic plausibility based on residual ATP7A activity. Further case series and biochemical assays are needed to strengthen the gene–disease association. Key Take-home: Identification of c.2576A>G (p.Asp859Gly) expands the ATP7A allelic spectrum to include SMAX3, informing diagnostic evaluation of distal motor neuropathies in males.

References

• European journal of medical genetics • 2020 • ATP7A mutation with occipital horns and distal motor neuropathy: A continuum. PMID:33137485

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