CONICET | Buscador de Institutos y Recursos Humanos

Wilson´s disease (WD) is a rare inborn error of copper metabolismcaused by mutations in ATP7B gene. Although there is no geneticheterogeneity in WD etiology, the widespread clinicalpresentation ofWDmakes its diagnosis not always straightforward,particularly when atypical symptoms are present and a number ofdifferential diagnoses must be considered [1]. Since it is a potentiallytreatable disorder, the prognosis of WD rests in a confirmatoryand timely diagnosis leading to prompt therapy [1,2]. Exomesequencing has proved to be useful for the diagnosis of several neurogeneticdisorders, enhancing the ability to identify the causativegenetic defect in patients with complex phenotypes. Moreover, thecost and time needed to reach a proper diagnosis is reduced [3]. Wereport the phenotype and genotype of a patient with WD who, bymeans of exome sequencing, was diagnosed with the disease, withtwo novel ATP7B mutations being identified.A 25- year-old woman, born of non-consanguineous parents,was admitted to our center with a 6-month history of progressiveirritability, personality changes, depression, emotional liability, unmotivatedlaughter and slow speech. Involuntary movements in theleft hand, abnormal posture of lower limbs and impairment of gaitwere also observed. On neurological examination, the patient wasalert, with Mini-Mental State of 23/30 and Montreal cognitiveassessment test (MOCA) of 20/30. Speech was slow; a moderateseveredysarthriawas present. Except for slow conjugate eye movementsand square wave jerks, cranial nerves were normal. Wefound increased deep tendon reflexes in lower limbs, bilateral Hoffman´ssign, left ankle clonus and a mild right brachio-crural paresis.She presented slow and rhythmic involuntary movements in theleft upper limb, suggestive of stereotyped movements and a dystonicposture in internal rotation of both lower limbs (video:segment 1).Supplementary video related to this article can be found athttp://dx.doi.org/10.1016/j.parkreldis.2015.09.031.A decreased ceruloplasmin (18 mg/dl) and a mildly increasedurinary copper excretion (84.80 ug/24 h) in the presence of normaltotal serum cooper levels (71.1 ug/dl) were found. The rest ofroutine laboratory tests were normal. Ophthalmologic evaluationdid not show the presence of Kayser-Fleischer´s rings. The MRIshowed increased signal intensity on T2/FLAIR bilaterally and symmetricallyin putamen, caudate nucleus, posterior limb of the internalcapsule, tectum mesencephalon, pons and red nucleus. Aremarkable diffusion restriction in both putamen and red nucleuswas observed (Fig. 1).Based on radiological findings - albeit atypical but suggestive ofWD- and the evidence of low serum cooper as well as an increasedurinary cooper excretion, a probable diagnosis of WD was postulated.Empirical treatment with D-Penicilamine was initiated. In orderto confirm the diagnosis, we performed a targeted ATP7Bsequencing, looking for the presence of the common His1069Glnmutation. However, the mutation remained undetected. Consequently,a so-called rapid exome sequencing was performed usingan ampliseq assay in an Ion Proton platform, revealing compoundheterozygosity for two ATP7B novel mutations (NM_000053:c.2165T > A:p.L722Q and c.3704G > A:p.G1235D). A month afterpenicillamine therapy onset, the patient showed an improvementin cognitive functions, gait and dysarthria in concordance with anadequate decoppering (video: segment 2).We have presented a WD patient with predominant psychiatricsymptoms and a wide spectrum of neurological manifestationswithout Kaiser Fleisher rings. The patient´s MRI showedatypical neuroimaging findings characterized by the so-calledgiant panda sign but with restriction in DWI. We illustratehow exome sequencing was useful for confirming a moleculardiagnosis, which allowed a prompt therapy. Previous reportshave shown the presence of restriction in the DWI of WD patients,correlating diffusion changes with clinical severity. Onthe other hand, restricted diffusion may be seen at early stagesof the disease, with a return to normal diffusivity after necrosisand spongiform degeneration have occurred [4]. The observedpattern on MRI, along with the absence of Kaiser-Fleisher rings,is likely to reveal early stages of the disease in our patient. Delaysin the diagnosis of WD are more frequent in patients withneuro-psychiatric presentations than in those with hepaticaffection. A mean time to diagnosis of about 3 years has been reportedin patients showing neuropsychiatric symptoms at onset.Early diagnosis leading to prompt therapy is crucial in stoppingthe progression of the disease [2]. Exome sequencing can be performedin a few days at a cost no greater than what it takes tosequence a small number of candidate genes [3,5]. In summary,we have highlighted the use of next generation sequencing as afast tool for confirming a WD diagnosis and have reported twonovel ATP7B mutations, thus expanding the spectrum of mutationscausing WD.