Evidence for synergistic effects of PRNP and ATP7B mutations in severe neuropsychiatric deterioration
1 Department of Medicine, McMaster University, Hamilton, Canada
2 Department of Pediatrics, McMaster University, Hamilton, Canada
3 National Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, Canada
4 Neuromuscular and Neurometabolic Disease, Department of Pediatrics, McMaster University, 1200 Main St. W., HSC-2H26, Hamilton, ON L8N 3Z5, Canada
BMC Medical Genetics 2014, 15:22 doi:10.1186/1471-2350-15-22Published: 20 February 2014
Wilson’s disease (WD), a rare cause of neuropsychiatric deterioration, is associated with mutations in the ATP7B gene. Prion diseases are also rare causes of neuropsychiatric deterioration that can occur sporadically without an identifiable cause, or can be attributed to mutations in the PRNP gene.
Here we describe a biological “experiment of nature” in which a patient presented with severe neuropsychiatric decline and strong biochemical evidence of WD. Genetic analysis revealed that he was a compound heterozygote for two ATP7B sequence variants (c.2165dupT, p.Arg723Glufs*32; and c.4039G > A, p.Gly1347Ser), the first having been reported once previously, and the second being novel. In addition, the patient was heterozygous for a PRNP variant, c.160G > A, p.Gly54Ser, that has been reported in a neuropsychiatric patient only once previously in association with a similarly severe clinical course of neuropsychiatric disease and early age of onset, but no accompanying information on ATP7B genotype. Of particular interest was the observation that the patient’s older sister, who carried the same ATP7B genotype and laboratory evidence for biochemical WD but was clinically asymptomatic, lacked the PRNP variant allele.
We propose that synergism may occur between at least some allelic variants of ATP7B and PRNP, possibly exerted through effects on cellular copper metabolism.