Evidence for synergistic effects of PRNP and ATP7Bmutations in severe neuropsychiatric deterioration
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AbstractBackgroundWilson’s disease (WD), a rare cause of neuropsychiatric deterioration, is associated with mutations in theATP7Bgene. Prion diseases are also rare causes of neuropsychiatric deterioration that can occur sporadically without an identifiable cause, or can be attributed to mutations in thePRNPgene.Case presentationHere 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 twoATP7Bsequence 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 aPRNPvariant, 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 onATP7Bgenotype. Of particular interest was the observation that the patient’s older sister, who carried the sameATP7Bgenotype and laboratory evidence for biochemical WD but was clinically asymptomatic, lacked thePRNPvariant allele.ConclusionsWe propose that synergism may occur between at least some allelic variants ofATP7BandPRNP, possibly exerted through effects on cellular copper metabolism.
