Novel ATP7A Splice-Site Variant Causing Distal Motor Neuropathy and Occipital Horn Syndrome: Two Siblings and...

Background: Pathogenic hemizygous variants in ATP7A most commonly cause Menkes disease or occipital horn syndrome (OHS), whereas ATP7A-related distal hereditary motor neuropathy (dHMN) is rarely reported. Here, we describe two adult brothers with an overlapping dHMN/OHS phenotype caused by a novel ATP7A splice-site variant and review the clinical and genetic features of previously published patients with ATP7A-related dHMN. Methods: We performed detailed clinical, electrophysiological, and genetic evaluations of both siblings, including exome sequencing and RNA analysis. Additionally, we reviewed the clinical, electrophysiological, and genetic data of previously reported patients with ATP7A-related dHMN. Results: We identified a novel hemizygous ATP7A splice-site variant (NM_000052.7:c.1544-2A>T) in both brothers. The younger brother, who exhibited a more severe phenotype, presented in early childhood with mild global developmental delay, intellectual disability, and chronic diarrhea, while the older brother had childhood-onset chronic diarrhea without cognitive impairment. Both developed distal hereditary motor neuropathy later in life, and imaging revealed occipital horns. Serum copper and ceruloplasmin levels were mildly reduced. RNA sequencing revealed two aberrant transcript isoforms resulting from the splice-site variant, one of which may produce a partially functional protein. Review of previously reported patients shows that ATP7A-related dHMN may occur isolated or with overlapping features of OHS. In patients with the overlapping phenotype, chronic diarrhea was often the first symptom, followed by slowly progressive dHMN. Conclusions: Previously reported ATP7A-related dHMN has been mostly associated with missense variants. Our findings expand the mutational spectrum by identifying a splice-site variant. In patients with an overlapping OHS/dHMN phenotype, diagnosis was typically delayed for decades, suggesting this presentation remains underdiagnosed.