Pediatric Wilson's disease: findings in different presentations. A cross-sectional study

ABSTRACT BACKGROUND: Wilson's disease (WD) may present with different manifestations: from an asymptomatic state to liver cirrhosis. Here, we aimed to evaluate clinical presentations and laboratory findings and prognoses among WD cases. DESIGN AND SETTING: Cross-sectional study based on patients' records from the university hospital, İnönü University, Malatya, Turkey. METHODS: The medical records of 64 children with WD were evaluated focusing on the clinical, laboratory and liver biopsy findings in different clinical presentations. RESULTS: The mean age at diagnosis was 8.6 ± 3.26 years (range 3.5-17) and mean length of follow-up was 2.49 years (range 0-9). There were 18 cases (28.1%), 12 (18.8%), 9 (14.1%) and 6 (9.4%) of chronic liver disease, fulminant liver failure, neurological WD and acute hepatitis, respectively. Nineteen (29.7%) were asymptomatic. The most common sign and laboratory finding were jaundice (45.3%) and hypertransaminasemia (85.9%), respectively. The lowest serum zinc level was found in the fulminant liver failure group (P = 0.035). Hepatosteatosis was detected in 35% of the 20 patients who underwent liver biopsy. Among those with hepatosteatosis, 57.1% were asymptomatic. While 35% had copper staining, 25% presented iron accumulation in liver biopsies. Nine cases underwent liver transplantation and seven of these presented fulminant liver failure (77.8%). CONCLUSION: The presentation, symptoms and signs of our cases were similar to those in previously reported series, except for the high proportion of fulminant WD cases. Further studies are needed to clarify the relationship between zinc levels and development of a fulminant course and between iron status and WD.

In vivo confocal microstructural analysis of corneas presenting Kayser-Fleischer rings in patients with Wilson's disease / Análise microestrutural confocal in vivo de córneas apresentando anel de Kayser-Fleischer em pacientes com doença de Wilson

ABSTRACT Purpose: To evaluate microstructural differences between corneas with and without Kayser-Fleischer rings in age-matched subjects with Wilson's disease with neurological symptoms, using confocal laser scanning microscopy. Methods: The study included 12 subjects with Wilson's disease with neurological symptoms. Twelve corneas presented clinically with classic Kayser-Fleischer rings, visible on slit lamp examination; the other 12 served as controls. The subjects underwent a comprehensive clinical examination. Microstructural analysis using confocal laser scanning microscopy evaluated increased corneal thickness, decreased number of cells, increased debris or specific deposits, and unusual microstructures. Results: Clinically, the subjects with Kayser-Fleischer rings had similar corneal findings and normal intraocular pressure; two had typical sunflower cataracts and decreased visual acuity. The control eyes all presented normal visual acuity, intraocular pressure, and corneal appearance. The microstructural analysis demonstrated similar findings in all the affected corneas. Compared with the control corneas, there were fewer keratocytes in the anterior stroma (17.380 vs. 22.380/mm3). Round, "hollow" dark areas were observed between the keratocytes; these were universal and similar in appearance in all affected corneas and all cornea layers. In the peripheral posterior stroma, there were dust-like, bright, granular deposits that tended to increase in number and density toward Descemet's membrane, masking the peripheral endothelium. The control corneas presented a normal microstructure apart from dust-like granular deposits in the periphery. Conclusions: In vivo confocal microscopy is a useful tool for evaluating the corneal microstructure when a Kayser-Fleischer ring is clinically present. The ring consists of granular, bright particles that increase in density toward Descemet's membrane, and is associated with a decreased number of keratocytes and peculiar dark, round areas in all stromal layers, probably a sign of corneal damage. When the ring is not visible in subjects with Wilson's disease, changes to the corneal microstructure are insignificant.

RESUMO Objetivo: Avaliar, ao nível microestrutural, através de microscopia confocal in vivo a lazer, 12 córneas com anel de Kayser-Fleischer visível ao exame da lâmpada de fenda e compará-las com 12 córneas clinicamente normais de indivíduos com idades correspondentes aos pacientes com doença de Wilson e sintomas neurológicos. Métodos: O estudo incluiu 12 indivíduos com doença de Wilson e sintomas neurológicos (24 córneas). Doze córneas apresentavam clinicamente o anel clássico de Kayser-Fleischer e as outras 12 serviram como controle. Todos os pacientes foram submetidos a um exame clínico abrangente e a uma análise microestrutural subsequente utilizando microscopia confocal in vivo de varredura a laser. Os principais resultados observados foram: aumento da espessura da córnea, diminuição do número de células, aumento de resíduos/depósitos específicos e microestrutura atípica. Resultados: Clinicamente, todos os indivíduos com anel de Kayser-Fleischer (12 olhos) apresentaram achados similares da córnea e pressão intraocular normal. Dois indivíduos também apresentaram uma catarata de girassol típica e diminuição da acuidade visual. Todos os olhos do grupo controle apresentaram acuidade visual, pressão intraocular e aparência corneana normais. A microscopia confocal in vivo com varredura a laser revelou achados semelhantes em todas as córneas afetadas. O número de ceratócitos no estroma anterior era menor, 17.380/mm3 (22.380/mm3 no grupo controle), e entre eles foram identificadas áreas escuras arredondadas "vazias". Essas zonas escuras eram generalizadas e similares em todas as córneas examinadas e em todas as camadas da córnea. No estroma posterior periférico, havia presença de depósitos granulares brilhantes e com aparência de pó que tendiam a aumentar em número e densidade no sentido da membrana de Descemet, mascarando o endotélio periférico. As córneas controle apresentaram estrutura normal, com exceção de depósitos granulares com aparência de pó na periferia. Conclusões: A microscopia confocal in vivo é uma ferramenta útil para a avaliação da microestrutura da córnea quando o anel de Kayser-Fleischer está clinicamente presente. O anel é constituído de partículas granulares brilhantes com densidade aumentada no sentido da membrana de Descemet. Sua presença está associada com uma diminuição do número de ceratócitos e com áreas circulares escuras "peculiares" em todas as camadas estromais, que representam, provavelmente, um sinal de dano da córnea. Quando o anel não está clinicamente visível, a estrutura da córnea in vivo encontra-se insignificantemente alterada.

Wilson?s disease presenting as rapid eye movement sleep behavior disorder: a possible window to early treatment / Doença de Wilson apresentando-se com transtorno comportamental do sono REM: uma janela possível para instituição de tratamento precoce

Objective To describe characteristics of REM sleep behavior disorder in Wilson’s disease. Method Questionnaire-based interviews (patients and relatives), neurological examinations, two-week prospective dream-diary, video-polysomnography, transcranial sonography, MRI. Results Four Wilson’s disease cases with REM sleep behavior disorder were described; three had REM sleep behavior disorder as initial symptom. All showed mesencephalic tegmental/tectal sonographic hyperechogenicities and two presented ponto-mesencephalic tegmental MRI hyperintensities. Conclusion This first description of REM sleep behavior disorder in Wilson’s disease in literature documents REM sleep behavior disorder as a possible presenting symptom of Wilson’s disease and adds further evidence to the parallelism of Parkinson’s disease and Wilson’s disease in phenotype and brainstem topography, which ought to be further studied. REM sleep behavior disorder has prognostic relevance for neurodegeneration in α-synucleinopathies. In Wilson’s disease, usefulness of early diagnosis and treatment are already well established. REM sleep behavior disorder in Wilson’s disease offers a possible theoretical model for potential early treatment in this extrapyramidal and brainstem paradigm syndrome, previewing the possibility of neuroprotective treatment for REM sleep behavior disorder in “pre-clinical” Parkinson’s disease. .

Objetivo Descrever características do transtorno comportamental do sono REM (TCSR) na doença de Wilson (DW). Método Aplicação de entrevistas, vídeo-polissonografia, sonografia transcraniana (STC), ressonância magnética (RM), diário de sonhos. Resultados Descrevemos quatro casos de DW com TCSR. Três apresentaram o TCSR como primeira manifestação. Todos mostraram hiperecogenicidades mesencefálicas na STC, dois apresentaram hiperintensidades ponto-mesencefálicas na RM. Conclusão Esta é a primeira descrição do TCSR na DW. Relatamos o TCSR como um sintoma inicial da DW. Acrescentamos prova para o paralelismo entre a doença de Parkinson e DW, com relação aos fenótipos e localização das lesões cerebrais. Nas alfa-sinucleinopatias, o TCSR tem relevância prognóstica quanto à neurodegeneração. Na DW, já conhecemos a importância de diagnóstico e tratamento precoces. O TCSR na DW oferece um modelo para antecipar o tratamento desta síndrome de acometimento dos núcleos basais e tronco, vislumbrando a possibilidade de tratamento neuroprotetor para a fase “pré-clínica” da DP. .

Bilateral Hypertrophic Olivary Degeneration in Wilson Disease

Hypertrophic olivary degeneration resulting from lesions of the dento-rubro-olivary pathway, also called Guillain-Mollaret-triangle, has been described previously in a number of cases. Reports about bilateral hypertrophic olivary degeneration of the inferior olivary nuclei are very limited, and the magnetic resonance imaging findings of hypertrophic olivary degeneration in Wilson disease have not yet been described to the best of our knowledge. Herein, we present the first report of bilateral hypertrophic olivary degeneration diagnosed by magnetic resonance imaging in a patient suffering from Wilson disease.

Analysis of clinical and biochemical spectrum of Wilson Disease patients.

Background and Aims: Wilson disease (WD) is autosomal recessive disorder of copper metabolism. Wilson disease patients usually suffer from hepatic or neuropsychiatric complications. The symptoms appear between ages five to 35 but it can vary from two years to 72 years. Materials and Methods : Study was carried out from June 2008 to November 2010. This study included nine families with eleven cases of WD to determine clinical presentation, diagnostic findings (including laboratory results) and liver histology. It included 11 patients who presented with hepatic manifestations and/or Neuropsychiatric manifestations and/or family history suggesting features of WD. Patients with hepatitis B and C and those with history of taking antipsychotic drugs were excluded from the study. Patient's data was included in a well designed performa. Liver function test, serum ceruloplasmin, serum copper, 24 hour urinary copper, blood complete picture were analyzed. Quantitative data such as age, hemoglobin etc were expressed as mean with ± SD and quantitative variables such as sex, movement disorders, hepatic involvement etc were expressed as frequency and percentage. Results: There were five male and six female patients with evidence of various manifestations here (i) hepatic in which they had only liver dysfunction (ii) hepatic and neurological (iii) neurological. The mean age of presentation was 8.7±3.92 years (range 4-19 years) and 45% were male patients. Decreased serum ceruloplasmin, enhanced 24-h urinary copper excretion and signs of chronic liver damage were confirmed in all patients and Kayser-Fleischer rings (KF rings) in 72% of patients. In severe WD patients, serum prothrombin activity was less than 50%, serum ceruloplasmin were low and serum copper levels were high than those in non-severe WD patients. High degree of suspicion leads to early treatment with good outcome. Conclusions: The WD is rare but important cause of chronic liver disease. Clinical and biochemical analysis in cases of patients with unexplained liver disease with high degree of suspicion can lead to early treatment with good outcome.

Wilson's disease in southern Brazil: a 40-year follow-up study

BACKGROUND: Long-term data on the clinical follow-up and the treatment effectiveness of Wilson's disease are limited because of the low disease frequency. This study evaluated a retrospective cohort of Wilson's disease patients from southern Brazil during a 40-year follow-up period. METHODS: Thirty-six Wilson's disease patients, diagnosed from 1971 to 2010, were retrospectively evaluated according to their clinical presentation, epidemiological and social features, response to therapy and outcome. RESULTS: Examining the patients' continental origins showed that 74.5 percent had a European ancestor. The mean age at the initial symptom presentation was 23.3 ± 9.3 years, with a delay of 27.5 ± 41.9 months until definitive diagnosis. At presentation, hepatic symptoms were predominant (38.9 percent), followed by mixed symptoms (hepatic and neuropsychiatric) (30.6 percent) and neuropsychiatric symptoms (25 percent). Kayser-Fleischer rings were identified in 55.6 percent of patients, with a higher frequency among those patients with neuropsychiatric symptoms (77.8 percent). Eighteen patients developed neuropsychiatric features, most commonly cerebellar syndrome. Neuroradiological imaging abnormalities were observed in 72.2 percent of these patients. Chronic liver disease was detected in 68 percent of the patients with hepatic symptoms. 94.2 percent of all the patients were treated with D-penicillamine for a mean time of 129.9 ± 108.3 months. Other treatments included zinc salts, combined therapy and liver transplantation. After initiating therapy, 78.8 percent of the patients had a stable or improved outcome, and the overall survival rate was 90.1 percent. CONCLUSION: This study is the first retrospective description of a population of Wilson's disease patients of mainly European continental origin who live in southern Brazil. Wilson's disease is treatable if correctly diagnosed, and an adequate quality of life can be achieved, resulting in a long overall survival.

Enfermedad de Wilson: revisión del tema / Wilson's disease: a review

La Enfermedad de Wilson es un trastorno autosómico recesivo causado por mutaciones en el genATP7B que producen anormalidad en el metabolismo del cobre, con acumulación de este elementoen distintos órganos y tejidos. El diagnóstico se basa en la combinación del cuadro clínico con diversaspruebas bioquímicas, pues ninguna de ellas, aisladamente, es diagnóstica. En la actualidad se cuentacon un tratamiento efectivo para esta enfermedad, basado en la utilización de quelantes del cobre,para movilizarlo de los sitios donde se acumula y promover su excreción, así como de zinc parabloquear su absorción intestinal. El trasplante hepático es el tratamiento de elección en los pacientescon hepatopatía fulminante, así como en los que llegan a la cirrosis descompensada. En esta revisiónse incluyen aspectos bioquímicos, genéticos, clínicos, diagnósticos y terapéuticos de esta enfermedad.

Wilson’s disease: a reviewWilson’s disease is an autosomal recessive disorder caused by mutations in the ATP7B gene thatlead to an abnormal metabolism of copper, resulting in the accumulation of this element inseveral organs and tissues. Its diagnosis is based on the combination of the clinical picture withvarious biochemical tests, neither one of which is, by itself, diagnostic of the disease. Presentlythere are effective treatments for EW based on the administration of chelating agents to promotemobilization of copper from the accumulation sites and its excretion. Zinc is also used in orderto block the intestinal absorption of copper. Liver transplantation is the treatment of choice inpatients with fulminating hepatitis, as well as in those with decompensated cirrhosis. This reviewincludes the following aspects of Wilson‘s disease: biochemical, genetic, clinical, diagnostic, andtherapeutic.

Clinicopathologic findings in 35 children with Wilson disease

Wilson disease is a rare autosomal recessive disorder of copper metabolism. Wilson disease is the most common metabolic cause of fulminant hepatic failure in children over the age years. The aim of this study was to find the major clinical and pathologic findings of Wilson disease in children in Tehran. This retrospective study was carried out in the Mofid children's hospital. Thirty five patients suffering from Wilson disease were studied. Ceruloplasmin level below 20 mg/dl and urinary copper excretion level above 100 micro g/24hr were considered as the inclusion criteria. Of the patients, 20 cases were males and 15 were females with average age of 9 years. The most patients were in 8-9 and 10-11 years age group with 37% and 20%, respectively. Hepatic invoIvement was confirmed in 100% of patients. Jaundice was seen in 20 patients [57%], abdominal enlargement together in 20 patients [57%], and encephalopathy in 9 patients [26%]. Serum copper was reduced in 100% and low-serum ceroluplasmin in 100%, increased urinary copper excretion in%97, increased AST and ALT in 100%, increased PT was in 94% patients, anemia was found in 100%, leucopenia in 14%, and thrombocytopenia was seen in 71% of patients. In this study, 37% of patients had neurological symptoms such as tremor, ataxia, difficulty in speech and delayed education. 32 patients had undergone ophthalmic examination and 62% showed KF ring in their ophtalmoscopy. According to this study, hepatic and neurologic involvement is the most consistent finding in the Wilson disease. Most patient were in the age's group of 8-9 and 10-11

Doença de Wilson com sinal da face do panda gigante na ressonância magnética de encéfalo / WilsonÆs disease with the face of giant panda sign on magnetic resonance imaging

A Doença de Wilson (DW), é uma desordem hereditária de transmissão genética autossômica recessiva, que altera o metabolismo hepático do cobre e ocasiona seu acúmulo em órgãos e tecidos. Embora alterações na Ressonância Magnética de Encéfalo (RM) não façam parte dos critérios diagnósticos as mesmas podem ser sensíveis para detectar alterações em pacientes com a doença. Os autores descrevem o caso de uma paciente de 22 anos com manifestações neurológicas progressivas cujo diagnóstico de DW foi suspeitado pelas manifestações clínicas associadas as anormalidades na RM. Paciente apresentava alterações no putamen, caudato e tálamo além do chamado sinal do face do panda gigante no mesencéfalo. Um sinal considerado característico da DW

Anéis de Kayser-Fleisher / Kayser-Fleisher rings

Os anéis de Kayser-Fleischer (K-F) säo alteraçöes pigmentadas localizadas na membrana de Descemet, principalmente na regiäo perilímbica na córnea. Estäo associadas à doença de Wilson, sendo a manifestaçäo oftalmológica mais comum da mesma e se correlacionam diretamente ao tempo de evoluçäo desta doença. Os anéis de K-F caracterizam-se pela deposiçäo de granulaçöes de cobre de tamanhos e formas variadas na córnea e predominam na periferia corneana. A doença diretamente ligada ao aparecimento dos anéis de K-F, a doença de Wilson, caracteriza-se por distúrbio metabólico com acúmulo de cobre nos tecidos humanos, principalmente no fígado. A presença de anéis pigmentados na córnea nem sempre é diagnóstico de anéis de K-F, devendo ser diferenciados de outras alteraçöes pigmentadas da córnea näo ligadas à doença de Wilson. Estas englobam a vasta maioria de doenças hepato-biliares que podem ocasionar acúmulo de cobre, além de corpos estranhos intraoculares contendo cobre, mieloma múltiplo, entre outras. O objetivo do presente artigo é revisar alguns aspectos desta alteraçäo pigmentada corneana, os anéis de K-F, além de descrever algumas características da principal doença ligada ao seu aparecimento.

'Face of the giant panda' sign in Wilson's disease: revisited.

We report a patient, with Wilson's disease, who showed the characteristic radiological sign known as 'Face of the giant panda sign' on magnetic resonance imaging (MRI) of the brain.

Somatometria craneofacial en pacientes adultos con enfermedad de Wilson / Craniofacialsomatometry in adult patients presenting with Wilson's

Al diagnosticar, estudiar y tratar de forma cotidiana, los pacientes con enfermedades de Wilson notamos que presentaban rasgos en la morfologia craneofacial diferentes a los de la poblacion atendida, sin este padecimiento. Para verificar esta hipotesis se estudiaron 31 pacientes masculinos adultos, europoides, con el padecimiento. Se les midio el largo de la cabeza, anchura cefalica, altura auricular del craneo, anchura frontal minima, altura morfologica de la cara, anchura de la cara, altura de la nariz, anchura de la nariz, altura de la oreja, anchura de la oreja, anchura mandibular y circunferencia cefalica. Se calcularon los indices cefalico horizontal, facial morfologico, yugo mandibular, nasal y auricular. Todas las mediciones fueron realizadas por el Profesor Manuel Rivero de la Calle. Se observaron diferencias significativas (p<0,05) conrespecto a la poblacion general en el largo de la cabeza, altura morfologica de la cara, anchura de la nariz y oreja, circunferencia cefalica horizontal asi como en los indices facial morfologico y auricular. Todo hace pensar que los pacientes con enfermedad de Wilson, debido a su componente genetico, tienen caracterisiticas diferentes de la poblacion general

Doença de Wilson: uma atualizaçäo / Wilson's disease: a review

A doença de Wilson, enfermidade transmitida de forma autossômica recessiva, deve sempre fazer parte do diagnóstico diferencial de hepatopatias agudas e, sobretudo, crônicas, tendo em vista constituir-se em uma condiçäo progressiva e fatal quando näo tratada estando seu prognóstico intimamente ligado à precocidade com que é feito seu diagnóstico e tratamento. Os autores abordam, na presente revisäo, diferentes aspectos desta doença, enfocando de forma abrangente o metabolismo e a patogênese do cobre que é, muitas vezes, de difícil compreensäo. Ressalvam que, histológicamente, näo há dados patognomômicos para o seu reconhecimento e que a doença se exterioriza clinicamente através do predomínio de manifestaçöes hepáticas ou neuro-psiquiátricas. O diagnóstico é feito pelo achado de níveis baixos de ceruloplasmina, níveiselevados de cobre "livre" plasmático, elevada cupriúria de 24 horas e pelo aumento da concentraçäo do cobre hepático. Concluem salientando a importância de um tratamento precoce com agentes quelantes farmacológicos

Wilson's disease: magnetic resonance imaging (MRI) with clinical correlations in 16 cases

The purpuse of this study was to evaluate MRI findings in a group of patients with Wilson's disease, trying to establish possible correlations between clincial and image data. Sixteen patients (8 males and 98 females), with ages ranging from 11 to 50 years, and duration of illness ranging from 5 months to 32 years, were submitted to MRI in a 1.5T System. Four patients were asymptomatic, 4 had mild neurological findings, 2 were moderatedly affected and the remaining 6 had a severe form of the disease. All patients were receiveing D-penicillamine by the time of the study. The most symptomatic patients presented five or more sites of abnormalities on MRI. the putamen was affected in all symptomatic individuals and one asymptomatic and 11 of them presented dystonia on neurological examination. A striking feature was the peripheral localization of putaminal hyperintense lesions on T2 weighted images. In eight cases, striatum or "substantia nigra lesions explained parkinsonism observed on neurological examination. MRI seems to be an efficient method to study neurological involvement of Wilson's disease allowing some interesting anatomo-clincial correlations