Objective: To report an early onset parkinsonism in a family carrying a pathogenic variant in the ATP7A gene.

Background: ATP7A variants cause Menkes disease (MD), a rare X-linked recessive disorder mainly affecting males with onset in the first three month of life. Classical manifestations include regression of motor functions, seizures, pili torti and vascular tortuosity. The ATP7A protein is a copper transporter which carries copper outside enterocytes; thus, the MD phenotype probably results from reduced activity of copper-depending enzymes. A few affected females have been reported [1], most of them presenting an attenuated phenotype.

Method: Clinical assessment, Sanger sequencing.

Results: We report an Italian family carrying a pathogenic variant in the ATP7A gene. The proband, a 49-years-old woman, presented intellectual disability and epilepsy. She developed asymmetric parkinsonism with rest and postural tremor at 48 age, non-responsive to levodopa. Ceruloplasmin, serum and urinary copper were repeatedly normal. Brain MRI showed a high signal intensity of bilateral globus pallidus on T2-weighed images. The maternal grandmother and the mother were reported to be affected by tremor. Two brothers died for MD in early childhood. One 54-year-old sister developed non-levodopa-responsive parkinsonism with atypical tremor at 51 age. Brain SPECT showed bilateral asymmetric reduced uptake. Another 50-years-old sister is developing initial asymmetric parkinsonism. A third 43-years-old sister was not examined. All four sisters shared the ATP7A heterozygous intronic variant c.1946+5G>C. This variant has been previously reported in MD male patients [2], [3] and was shown to result in out-of-frame mRNA lacking exon 8 and premature protein truncation (p.Ser624MetfsX35).

Conclusion: We describe the association between a pathogenic variant in the ATP7A gene and early-onset parkinsonism in females from an Italian family with MD. We suggest that ATP7A haploinsufficiency may result in dysregulation of copper metabolism in basal ganglia. Whole exome sequencing and an X-inactivation assay are in progress to further understand the contribution of this variant to the parkinsonian phenotype.

References: [1] P. Smpokou, M. Samanta, G. T. Berry, L. Hecht, E. C. Engle, and U. Lichter-Konecki, “Menkes disease in affected females: The clinical disease spectrum,” Am. J. Med. Genet. Part A, vol. 167, no. 2, pp. 417–420, Feb. 2015. [2] Z. Tümer, C. Lund, J. Tolshave, B. Vural, T. Tønnesen, and N. Horn, “Identification of point mutations in 41 unrelated patients affected with Menkes disease.,” Am. J. Hum. Genet., vol. 60, no. 1, pp. 63–71, Jan. 1997. [3] M. P. Moizard et al., “Twenty-five novel mutations including duplications in the ATP7A gene,” Clin. Genet., vol. 79, no. 3, pp. 243–253, Mar. 2011.

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