Wilson's disease (WD) is an inherited disorder of copper metabolism. Despite being treatable, patients with WD suffer severe disabilities due to delay in initiation and difficulty in monitoring treatment. We propose a two tier, Global Assessment Scale for Wilson's Disease (GAS for WD) that grades the multisystemic manifestations of the disease. Tier 1 scores the global disability in four domains: Liver, Cognition and behavior, Motor, and Osseomuscular. Tier 2 is multidimensional scale for a fine grained evaluation of the neurological dysfunction. We prospectively validated this scale in 30 patients with WD. Both tiers had a high inter-rater reliability (Intraclass correlation coefficient ICC (A, 2) = 0.96-1.0). Tier 2 items were internally consistent (Cronbach's alpha = 0.89) and factorial analysis showed that 90.3% of the Tier 2 total score variance was determined by seven factors. Scores of both tiers were commensurate with the disease burden as assessed by standard disability scales (Child Pugh, UPDRS, SS3, and CGI) and satisfied criteria for validity. Longitudinal follow-up over 1.5 years showed that the scale was sensitive to clinical change. This suggests that GAS for WD is a practical tool with potential applications in management of patients, and in testing and comparison of treatment regimens.

We describe intermittent or sustained severe involuntary tongue protrusion in patients with a dystonic syndrome. Speech, swallowing, and breathing difficulties can be severe enough to be life threatening. Causes include neuroacanthocytosis, pantothenate kinase-associated neurodegeneration, Lesch-Nyhan syndrome, and postanoxic and tardive dystonia. The pathophysiology of intermittent severe tongue protrusion remains unknown. Tongue protrusion dystonia is often unresponsive to oral drugs but may benefit from botulinum toxin injections into the genioglossus muscle. Bilateral deep brain pallidal stimulation was beneficial in two cases.

Background: Wilson disease (WD) is an inherited neurometabolic disorder that results in excessive copper deposition in the liver and the brain, affecting children and young adults. Without treatment the disease is invariably fatal. Though treatments for WD have been available since the 1950s, the disease continues to be associated with considerable morbidity and mortality because of missed diagnosis, and delayed or inadequate treatment. In this paper we survey WD-related literature in order to review recent advances in WD treatment. Methods: We performed a literature search using the PubMed database for articles relating to WD and its medical treatment. We reviewed the articles, and crossreferences of relevant articles, to summarize the current practices for treatment of WD. Results: The survey shows that if WD is properly treated, in most patients the liver can be stabilized, even severe neurological disability reversed, and patients can resume normal lives. Discussion: Medical treatment for WD includes use of copper chelators (penicillamine, trientine, dimercaprol, dimercaptopropane sulfonate, and ammonium tetrathiomolybdate) and drugs that decrease gastrointestinal copper absorption. Our knowledge of the treatment approaches has benefited from the large systematic clinical studies that have been conducted over the last decade. For each drug used to treat WD, we surveyed its development, indication for use, dosing, efficacy, and adverse effects.

SummaryWilson disease (WD) is an autosomal recessive disorder resulting from mutations in the ATP7B gene, with over 600 mutations described. Identification of mutations has made genetic diagnosis of WD feasible in many countries. The heterogeneity of ATP7B mutants is, however, yet to be identified in the Indian population. We analyzed the mutational pattern of WD in a large region of Western India. We studied patients (n = 52) for ATP7B gene mutations in a cohort of families with WD and also in first-degree relatives (n = 126). All 21 exon-intron boundaries of the WD gene were amplified and directly sequenced. We identified 36 different disease-causing mutations (31 exonic and five intronic splice site variants). Fourteen novel mutations were identified. Exons 2, 8, 13, 14, and 18 accounted for the majority of mutations (86.4%). A previously recognized mutation, p.C271 * , and the novel mutation p.E122fs, were the most common mutations with allelic frequencies of 20.2% and 10.6%, respectively. Frequent homozygous mutations (58.9%) and disease severity assessments allowed analysis of genotype-phenotype correlations. Our study significantly adds to the emerging data from other parts of India suggesting that p.C271 * may be the most frequent mutation across India, and may harbor a moderate to severely disabling phenotype with limited variability.

Neurodegeneration with brain iron accumulation (NBIA) is etiologically, clinically, and by imaging a heterogeneous group including NBIA types 1 [pantothenate kinase-associated neurodegeneration (PKAN)] and 2 (PLA2G6-associated neurodegeneration), neuroferritinopathy, and aceruloplasminaemia. Data on genetically defined Indian-subcontinent NBIA cases are limited. We report 6 patients from the Indian-subcontinent with a movement disorder and MRI basal ganglia iron deposition, compatible with diagnosis of an NBIA syndrome. All patients were screened for abnormalities in serum ceruloplasmin and ferritin levels and mutations in NBIA-associated genes [pantothenate kinase 2 (PANK2), PLA2G6 and ferritin light chain (exon 4)]. We present clinical, imaging and genetic data correlating phenotype-genotype relations. Four patients carried PANK2 mutations, two of these were novel. The clinical phenotype was mainly dystonic with generalized dystonia and marked orobulbar features in the 4 adolescent-onset cases. One of the four had a late-onset (age 37) unilateral jerky postural tremor. His mutation, c.1379C>T, appears associated with a milder phenotype. Interestingly, he developed the eye-of-the-tiger sign only 10 years after onset. Two of the six presented with adult-onset levodopa (L-dopa)-responsive asymmetric re-emergent rest tremor, developing L-dopa-induced dyskinesias, and good benefit to deep brain stimulation (in one), thus resembling Parkinson's disease (PD). Both had an eye-of-the-tiger sign on MRI but were negative for known NBIA-associated genes, suggesting the existence of further genetic or sporadic forms of NBIA syndromes. In conclusion, genetically determined NBIA cases from the Indian subcontinent suggest presence of unusual phenotypes of PANK2 and novel mutations. The phenotype of NBIA of unknown cause includes a PD-like presentation.