Copper Toxicity Associated With an ATP7A-Related Complex Phenotype.

Area of Science:

• Genetics
• Neuroscience
• Biochemistry

Background:

• The ATP7A gene is crucial for copper transport, and its mutations lead to Menkes disease, occipital horn syndrome (OHS), and ATP7A-related distal hereditary motor neuropathy (dHMN).
• This study investigates a family with OHS due to a novel ATP7A mutation, including a patient with co-occurring dHMN.

Observation:

• A novel ATP7A mutation (p.Lys1412AsnfsX15) was identified in affected family members.
• One patient exhibited both OHS and dHMN, demonstrating variable phenotypic expressivity.
• Copper replacement therapy exacerbated the dHMN in this patient, with improvement upon withdrawal.

Findings:

• Functional studies revealed reduced ATP7A and ATP7B expression and elevated mitochondrial superoxide levels.
• The patient presented with low levels of both copper transporters, ATP7A and ATP7B.
• High levels of superoxide ions in mitochondria were observed.

Implications:

• This research expands the known clinical spectrum of ATP7A-related disorders.
• The findings suggest that copper accumulation in motor neurons is the underlying pathogenic mechanism for ATP7A-related dHMN.
• The study highlights the potential risks of copper therapy in patients with specific ATP7A mutations.