A 34-year-old man from the Punjab region of India, who had immigrated to Canada in 2010, having developed a gradual onset of a bilateral intention tremor, worsening over the course of 7 years. This was initially diagnosed as spinocerebellar ataxia. Over the previous 2 years he had experienced various progressive psychiatric disturbances including severe depression, anxiety and mood lability. This constellation of symptoms had been variously diagnosed as depression, bipolar disorder and bipolar affective disorder, for which trials of several mood stabilizers, antidepressants and antipsychotics had been attempted with limited, modest, short-term benefits. In the year following emigration, the patient experienced a rapid decline in overall function, marked by an incident involving a trip and a fall. He began experiencing gait instability and imbalance, rigidity, scanning speech, dysphagia, and eventually choking episodes. The neuropsychiatric symptoms worsened over several months as the patient concomitantly experienced restlessness, sexual disinhibition, aggression and social inappropriateness. By the summer of 2011, his balance and rigidity had further deteriorated preventing him from ambulating, and thus prompting his family to seek further medical assessment. His symptoms culminated in an in-hospital episode of acute dystonia in July of 2011, prompting admission. At the time of admission following this episode, the patient was on lithium, quetiapine, propranolol, and zopiclone. The patient’s family history revealed no known consanguinity and the only significant neurological disorder was in the now deceased proband’s maternal grandfather who developed a rapidly progressive gait disturbance and cognitive impairment at age 62 y and died ~ 8 months after the onset with a first generation CT scan showing “cerebral atrophy”. Neurological examinations of the proband’s mother (age 61 y), father (age 62 y) and older sister (age 39 y) were normal, aside from a mild intention tremor in the mother. Physical examination revealed normal vital signs but the patient was agitated, with labile mood and sporadic emotional outbursts. Detailed neurologic examination revealed the presence of scanning dysarthria, severe rigidity in both upper and lower extremities, hyperreflexia in arms and legs, appendicular dystonia, dysdiadochokinesia and truncal ataxia. Ophthalmologic examination did not reveal Kayser-Fleischer rings by fundoscopy; however, the patient was unable to be positioned for a slit-lamp examination because of severe rigidity and tremor. Cardiac, respiratory and abdominal examinations were unremarkable, with no evidence of hepatosplenomegaly or ascites. There were no stigmata of acute or chronic liver disease, and no asterixis. Brain MRI revealed generalized atrophy in addition to “giant panda sign” at the level of the midbrain, consistent with Wilson’s disease. Abdominal ultrasound showed coarse liver echogenicity and irregular contours with a height of 10.2 cm in the mid-clavicular line, suggestive of cirrhosis. Liver biopsy confirmed grade 2–3 fibrosis and bridging, with Orcein stain negative for copper deposition (no direct biochemical measurement). A complete biochemical and pathologic workup was negative for viral hepatitis, alpha-1 anti-trypsin disease, hemochromatosis, and autoimmune hepatitis. Echocardiogram showed normal ejection fraction with no hypertrophy or abnormal deposition. Routine biochemical investigations of blood and urine were within normal limits, including a complete blood count, extended electrolyte panel and tests of renal function. Liver enzymes were normal, as were tests of synthetic liver function. Tests of copper metabolism showed a markedly low serum ceruloplasmin of 0.05 (normal, > 0.21 g/L), low serum copper of 3.4 (normal, > 11 μmol/L), and high 24-hour urine copper of 1.8 (normal, < 0.6 μmol/24 h). The patient was then treated with standard chelating therapy and zinc supplementation. Initially, he was started on penicillamine, but experienced commonly described adverse effects of severe neurologic deterioration and fever, warranting a change to trientene, which he is still taking along with zinc. His 24-hour urine copper value rose ten-fold to 17.7 μmol after 3 weeks of chelation. The patient’s psychiatric issues largely resolved but he did remain on the aforementioned psychotropic medications. He has made small gains in terms of recovery of neurologic function, but remains mute, wheelchair bound and dystonic, in spite of modest cognitive recovery when assessed one year after initiation of treatment. Based upon the patient’s history of a severely progressive neurological disorder with basal-ganglia symptoms/signs, ataxia and a major antecedent psychiatric presentation, diagnoses of either WD or genetic prion disease were considered, and DNA sequence analysis of ATP7B and PRNP was requested. Analysis of the ATP7B gene was performed by the University of Chicago Genetic Services Laboratory in Chicago, Illinois through Sanger sequencing of all coding exons and intron/exon boundaries (reference sequence: GenBank NM_000053, transcript variant 1). Sanger sequencing of the single coding exon (exon 2) of the PRNP gene was performed by the Canadian Creutzfeldt-Jakob Disease Surveillance System, Public Health Agency of Canada (reference sequence: GenBank M13899). DNA sequencing revealed that the patient was a compound heterozygote for two different ATP7B sequence variants (c.2165dupT; c.4039G > A). His PRNP gene lacked known pathogenic sequence variants, but he was heterozygous for a non-synonymous sequence variant (c.160G > A, p.Gly54Ser), as well as homozygous (ATG/ATG) for a common, non-pathogenic single-nucleotide polymorphism (c.385A > G, p.Met129Val) at codon 129. A family study revealed that the parents of the proband were each carriers of one of the two different ATP7B mutations (c.2165dupT in the father, and c.4039G > A in the mother). His mother carried the PRNP c.160G > A variant and was heterozygous ATG/GTG (Met/Val) at codon 129, while his father did not carry the PRNP c.160G > A variant and was homozygous ATG/ATG (Met + Met) at codon 129. The sister of the proband was found to be a compound heterozygote for the same two ATP7B variants carried by her brother, while lacking the c.160G > A variant and being heterozygous ATG/GTG (Met + Val) at codon 129 of PRNP. However, despite exhibiting a classical biochemical phenotype for Wilson’s disease with a low serum copper level of 2.1 μmol/L, a low ceruloplasmin of 0.12 g/L, and a high 24 h urine copper level of 1.1 μmol (normal values as above), she was asymptomatic, with a normal MRI and neurological examination.