Clinical and Genetic Analysis in Neurological Wilson’s Disease Patients With Neurological Worsening Following Chelator Therapy

Abstract

Objectives: None of the previous studies have focused on the genetic effect on neurological worsening in neurological Wilson’s disease (WD) patients following chelator therapy. We aimed to evaluate the clinical and genetic role in the occurrence of neurological worsening.Methods: We retrospectively reviewed the medical records of neurological WD patients who received initial chelator therapy and genetic test. Clinical, laboratory, and genetic data were collected. The genotype was classified into two types: 1) severe mutation genotype: patients who carried at least one of the following three types of mutations: frameshift mutation, splicing mutation, or nonsense mutation; 2) non-severe mutation genotype: patients who only carried missense mutations. Then, the clinical features and genotype of the patients with and without neurological worsening were investigated.Results: Forty-seven neurological WD patients were identified with a median age at onset of 16.17 years (range 7.75–47 years) and 35 (74.5%) males. The mean interval from onset to diagnosis was 0.6 years (range: 0.5 months-6.25 years). Neurological deterioration was observed in 29 patients (61.7%) and the other 18 patients (38.3%) were stable or improved during anti-copper treatment. The neurological worsening was completely irreversible in 6 cases (20.7%) and partially irreversible in 16 cases (55.2%). The common deteriorated symptoms were as follows: rigidity in 20 cases (69%), speech difficulties in 20 cases (69%)), walking difficulties in 13 cases (44.8%), dysphagia in 9 cases (31%), and salivation in 9 cases (31%). The patients with neurological worsening had significantly younger age (p = 0.028), shorter delayed diagnosis time (p = 0.011), higher rate of dystonia (p = 0.003), and severe mutation genotype (p = 0.036), compared to those without neurological worsening.Conclusion: We found that younger age of onset, the presence of dystonia, and genotype with severe mutations may be predictive of neurological worsening in the neurological WD patients that received chelator therapy. For those patients, chelator therapy should be given with caution and needs closer observation during follow-up.

Serum neurofilament light chain and initial severity of neurological disease predict the early neurological deterioration in Wilson’s disease

“…In our study, we found only statistically significant trend towards longer disease latency (time from symptoms onset to treatment introduction in WD) as a predictor of neurological deterioration. Previous study by Litwin et al [14] did not find such effect, and other studies evaluating predictors of early neurological deterioration did not include this parameter in analysis [24,31,32]. Lack of positive results in this topic may be due to possible problems with definition of age at symptoms onset, which mainly depends on treating physicians' decision and patients' data availability [33,34].…”

“…At baseline, the mean acute toxicity score was non-significantly greater in patients that worsened after 6 months. Because the deterioration was observed only in patients with neurological symptoms at diagnosis, and only initial sNfL concentrations predicted the neurological deterioration in this subgroup, higher UWDRS and brain MRI scores reflected a greater severity of neurological disease [ 14 , 23 , 24 , 31 ].…”

“…Initially (in retrospective clinical registries), authors reported just subjective information about worsening or not [ 6 , 10 , 12 ]. As discussion about treatment superiority or no-inferiority in WD started and new therapies and drugs were studied, several methods of neurological deterioration in WD were proposed [ 24 , 31 , 32 ]. They included modified Young scale (scoring more than 2 additional points defined deterioration; used in Chinese studies, not adapted for other countries) [ 31 , 32 ], Burke–Fahn–Marsden scale (increase of more than 10% of points defined worsening; Indian studies and scales dedicated mainly to asses dystonia) [ 24 ].…”

“…Finally, in the available literature, there are few papers which aimed to analyse the risk factors of early neurological deterioration. Those available mainly focussed on WD clinical symptoms as risk factors [ 14 , 24 , 31 ]. Litwin et al found that concomitant anti-dopaminergic medications, severity of WD neurological disease as well as localization of brain MRI lesions in pons and thalami are risk factors of neurological worsening [ 14 ].…”

“…Kalita et al analysed mainly symptomatic neurological WD patients treated with d-penicillamine and found association between deterioration and drooling, evidence of chronic liver disease, splenomegaly, leukopenia and thrombocytopenia [24]. Finally, Hou et al analysed 47 neurological WD patients treated with d-penicillamine and described the younger age, shorter delay of diagnosis, dystonia and severe mutation genotype as risk factors of deterioration [31]. These observations did not include different types of treatment of the symptomatic WD patients, and were based just on clinical data like age, neurological phenotype, presence of liver cirrhosis and their symptoms, type of mutations, which factors generally affected outcome in several studies with long follow-up [5][6][7].…”