20.500.12556/DiRROS-24566 Novel ATP7A splice-site variant causing distal motor neuropathy and occipital horn syndrome: two siblings and literature review 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 ATP7Arelated 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. ATP7A splice-site variant distal hereditary motor neuropathy occipital horn syndrome copper metabolism neurogenetics true false true Angleški jezik Ni določen Neznano 2025-12-05 14:38:27 2025-12-05 14:38:28 2025-12-06 03:47:57 0000-00-00 00:00:00 2025 0 0 Nasl. z nasl. zaslona; Opis vira z dne 22. 9. 2025; str. 1-14 iss. 9, [article no.] 1077 Vol. 16 2025 0000-00-00 Zaloznikova Objavljeno apc 0000-00-00 0000-00-00 0000-00-00 575 2073-4425 10.3390/genes16091077 249818371 RAZ_Writzl_Karin_2025.pdf RAZ_Writzl_Karin_2025.pdf 1 0A1C60905408AB4C484BE6B4B56F1902 99243783b1f9b1662b8481f2b514d1f9faa8da8707ff9dae24efaab01ecc8680 d73700c1-d1df-11f0-94a7-001a4af901a5 https://dirros.openscience.si/Dokument.php?lang=slv&id=36648 https://www.mdpi.com/2073-4425/16/9/1077 1 b01ba79c-d1df-11f0-94a7-001a4af901a5 https://dirros.openscience.si/Dokument.php?lang=slv&id=36647 Univerzitetni klinični center Ljubljana 0 0 0