W. Hermann

High prevalence of the H1069Q mutation in East German patients with Wilson disease: rapid detection of mutations by limited sequencing and phenotype–genotype analysis

BACKGROUND/AIMS Wilson disease is caused by a large number of different mutations in the ATP7B gene. Wilson disease patients from a homogeneous ethnical background (Saxonia) were studied for distribution and phenotypes of ATP7B mutations. METHODS Eighty-two patients were analyzed. The H1069Q mutation was assayed by a polymerase chain reaction-based restriction fragment length polymorphism test. Exons 8 and 15 were sequenced in all, and the entire gene in 30, non-H1069Q-homozygotes. RESULTS Four novel and 12 known mutations were found. Thirty-two (39%) Wilson disease patients were homozygous and 39 (48%) heterozygous for the H1069Q mutation (allele frequency 63%). Together with sequence analysis of exons 8 and 15 mutations in both alleles were identified in 65% of patients. Only one patient had both mutations at other locations. In H1069Q homozygotes symptoms started later (21.3+/-7.2 years) than in H1069Q compound heterozygotes (14.6+/-5.8, P<0.001) or H1069Q negatives (10+/-4.4, P<0.001), and they had more frequently neurologic symptoms (93 vs. 47%, P<0.001) and Kayser-Fleischer rings (82 vs. 51%, P<0.001). Mutation status did not correlate with liver biopsy findings, serum ceruloplasmin levels or (64)Cu-assay results. CONCLUSIONS In spite of many known ATP7B mutations, only few occur in this homogeneous population. Limited genetic testing is useful to confirm Wilson disease in this population.

The degree of depression in Hamilton rating scale is correlated with the density of presynaptic serotonin transporters in 23 patients with Wilson's disease.

Abstract.Objective: One of the most frequent psychiatric symptoms in patients with Wilsons disease (WD) is depression. It has been suggested that depression is associated with deficits in serotonergic neurotransmission, but, hitherto, no measurements have been performed in WD. Methods: We prospectively examined 23 adult patients (12 women, 11 men, mean age 40 years) with WD for symptoms of depression using the Hamilton rating scale for depression (HAMD). We correlated the data with the presynaptic serotonin transporter density (SERT density) in the thalamus–hypothalamus and the midbrain–pons regions measured with high resolution single-photon emission computed tomography (SPECT) 24 hours after the application of 180 MBq 2β-carbomethoxy-3β-(4 [123I]iodophenyl)tropane ( [123I]b-CIT). The regions of interest were determined by coregistration with a standard MRI dataset. Results: A significant negative correlation was found between HAMD and SERT density in the thalamus–hypothalamus region (r = −0.49, p = 0.02), but not in the midbrain–pons (r = −0.31, p = 0.15). Conclusions: We conclude that depression in patients with Wilsons disease is correlated with alterations of serotonergic neurotransmission in the thalamus–hypothalamus region.

Comparison of clinical types of Wilson's disease and glucose metabolism in extrapyramidal motor brain regions

Abstract. In Wilsons disease a disturbed glucose metabolism especially in striatal and cerebellar areas has been reported. This is correlated with the severity of extrapyramidal motor symptoms (EPS). These findings are only based on a small number of patients. Up to now it is unknown whether EPS are caused by various patterns of disturbed basal ganglia glucose metabolism. We investigated 37 patients and 9 normal volunteers to characterize the disturbed glucose metabolism in Wilsons disease more precisely. The glucose metabolism was determined in 5 cerebellar and cerebral areas (putamen, caput nuclei caudati, cerebellum, midbrain and thalamic area) by using 18F-Fluorodesoxyglucose-Positron-Emission-Tomography ( [18F]FDG-PET). The database was evaluated by a cluster analysis. Additionally, the severity extrapyramidal motor symptoms were judged by a clinical score system. Three characteristic patterns of glucose metabolism in basal ganglia were obtained. Two of them may be assigned to patients with neurological symptoms whereas the third cluster corresponds to most patients without EPS or normal volunteers. The clusters can be identified by characteristic consumption rates in this 5 brain areas. The severity of EPS can not clearly be assigned to one of the clusters with disturbed glucose metabolism. However, the most severe cases are characterized by the lowest consumption in the striatal area. When there is marked improvement of EPS impaired glucose consumption reveals a persistent brain lesion. Finally, the neurological symptoms in Wilsons disease are caused by (at least) two different patterns of disturbed glucose metabolism in basal ganglia and cerebellum. The severity of EPS seems to be determined by a disturbed consumption in the striatal area.

Regional serotonin transporter availability and depression are correlated in Wilson's disease.

Summary. In patients with Wilson’s disease (WD), depression is a frequent psychiatric symptom. In vivo neuroimaging studies suggest that depression and other neuropsychiatric disorders are associated with central serotonergic deficits. However, in vivo measurements of serotonergic neurotransmission have not until now been performed in patients with this copper deposition disorder. The present prospective study revealed that depressive symptomatology is related to an alteration of presynaptic serotonin transporters (SERT) availability as measured by [123I]-2β-carbomethoxy-3β-(iodophenyl)tropane ([123I]β-CIT) and high-resolution single-photon emission computed tomography (SPECT). SERT imaging with [123I]β-CIT-SPECT could therefore become a useful tool for diagnosis and therapy monitoring in depressed WD patients.

Differential alteration of the nigrostriatal dopaminergic system in Wilson's disease investigated with [123I]ß-CIT and high-resolution SPET

Abstract. Wilsons disease (WD) is a copper deposition disorder which can result in a number of extrapyramidal motoric symptoms such as parkinsonism. Therefore, this study was carried out to investigate, for the first time, nigrostriatal dopaminergic function in WD in relation to different courses and severity of the disease. Using high-resolution single-photon emission tomography (SPET) after administration of 2ß-carbomethoxy-3ß-(4[123I]iodophenyl)tropane ([123I]ß-CIT), striatal dopamine transporters (DAT) were imaged in 43 WD patients and a control group of ten subjects. From the SPET images, specific [123I]ß-CIT binding ratios were obtained for the caudate heads, putamina and entire corpus striatum. In addition, to evaluate a putative dissociation between the caudate and putaminal [123I]ß-CIT binding ratios, the ratio between these binding ratios was calculated (CA/PU ratio). The SPET data were compared with clinical data on the course of the disease (CD), the severity of neurological symptoms and the degree of hepatic alteration. Whereas the specific regional [123I]ß-CIT binding ratios in patients with asymptomatic/hepatic CD did not differ from those in the control group (e.g. striatal ratios: 13.4±3.0 vs 11.7±2.8), in patients with neurological CD the ratios were significantly reduced for all striatal substructures (P=0.003 after one-factor ANOVA). For the different subgroups a tendency was detected towards a stepwise decrease in the specific [123I]ß-CIT binding ratios from pseudo-sclerosis CD (9.4±2.3), through pseudo-parkinsonian CD (9.1±2.1) to arrhythmic-hyperkinetic CD (8.5±1.6). However, these group differences reached significance only for the comparison with asymptomatic/hepatic CD (P=0.02). The CA/PU ratio was significantly higher in WD than in the control group (1.30±0.19 vs 1.11±0.08; P=0.003). Severity of neurological symptoms was significantly correlated with all specific regional [123I]ß-CIT binding ratios (r=–0.49 to –0.57). For degree of liver alteration, significant correlations were obtained with the putaminal binding ratio (r=–0.37) and the CA/PU ratio (r=0.44). From these results is concluded that in WD the nigrostriatal dopaminergic function is compromised to varying extents. The degree of this presynaptic alteration of dopaminergic neurotransmission depends on the clinical course and severity of this copper deposition brain disorder and also varies in the different striatal substructures.

Diabetic neuropathy in patients with “Latent Autoimmune Diabetes of the Adults” (LADA) compared with patients with type 1 and type 2 diabetes

Abstract.Objective: In previous studies, a lower incidence of diabetes-related complications such as diabetic neuropathy has been reported in patients with early stages of type 1 diabetes compared with type 2 diabetes. The aim of this study was to compare the prevalence of diabetic neuropathy in patients with manifestation of a slow onset type 1 diabetes in adulthood – latent autoimmune diabetes in adults (LADA) – with classical type 1 and type 2 diabetes patients. Research Design and Methods: Altogether, 37 patients (14 LADA, 9 type 1 and 14 type 2 diabetes) with short term diabetes (duration < 5 years) were investigated for diabetic neuropathy on the basis of clinical and neuroelectrophysiological evaluations. The neurological functions were evaluated by a standardized questionnaire and clinical examination. In electrophysiological evaluations the different nerve fibres were investigated using motor and sensory nerve conduction studies, quantitative thermotesting, vibratometry and autonomic function tests (heart rate variability). Results: LADA patients had a significantly lower clinical examination score (p = 0.008), cardiorespiratory reflex index (p = 0.009) and cold perception threshold index (p = 0.004). The neurological symptom score, the indices of motor and sensory nerve conduction, the index of thermotesting (warm perception threshold) and the vibratometry showed a trend to higher values in LADA patients than in type 2 diabetes patients. There were no significant differences between LADA and type 1 diabetes patients. Conclusions: LADA patients had fewer features of diabetic neuropathy than type 2 diabetes patients in the early stages of disease, thus being more similar to classical type 1 diabetes patients who normally develop diabetic neuropathy rather late.

The indication for liver transplant to improve neurological symptoms in a patient with Wilson's disease.

Sirs: Wilson’s disease is an autosomal recessive condition in which a defective copper-transporting P-Typ-ATPase causes a disorder in the excretion of copper from the liver. The resulting copper build-up affects first the liver and then the brain. The earlier medical therapy is started, the more effective it is. Should conservative therapy fail, another option is to perform a liver transplant. Accepted indications that a liver transplant is necessary in a patient with Wilson’s disease are fulminant hepatic failure and chronic, progressive liver disease in its final stage [3, 4, 7]. The good results of liver transplants with symptomatic improvement have generated increasing discussion over whether liver transplants are suitable for patients with progressive neurological symptoms [6, 8]. Wilson’s disease was diagnosed in a 19-year-old patient with behavioural disorder and progressive extrapyramidal motor symptoms (see Tab. 1) in 1994. The disease had manifested a year previously with epigastric discomfort, jaundice, ascites, hepatosplenomegaly and tissue oedema, but had not been recognised. As these findings were initially non-progressive, liver cirrhosis of uncertain genesis was assumed. Neurological symptoms occurred half a year later. Typical features included reduced ceruloplasmin and serum copper levels as well as a KayserFleischer corneal ring. The diagnosis of Wilson’s disease was confirmed by the intravenous radio copper test. Despite treatment with D-penicillamine being started immediately (initially 300 mg/d and gradually increased to 1,500 mg/d over a period of 8 months), the neurological symptoms – especially tremor, bradykinesia and dysarthrophonia – progressed during the following two years. In the end the patient was unable to dress himself. Oral food intake was impossible owing to a severe swallowing disorder. Symmetrical hypointense areas in the basal ganglia were observed in cerebral magnetic resonance imaging (T2 weighted) from 1994 (Fig. 1). In July 1996 an orthotopic liver transplant was carried out. Over the next few months, the neurological symptoms diminished. The patient regained his independence. The main residual symptoms were dysarthria and facial dystonia. Repeat MRI in 1999 indicated the reduction of the hypodense signals in the basal ganglia (Fig. 2). This case is characterised by a progressive deterioration of the neurological symptoms despite medical therapy. After the possible initial temporary deterioration of the symptoms owing to copper mobilisation caused by D-penicillamine, the extrapyramidal motor symptoms normally decline. Moreover, the gradually increasing dosage prevents rapid copper mobilisation. It was only after the liver transplant – which was carried out in response to the liver symptoms – that the neurological symptoms were reversed. Schumacher et al. also reported an improvement in the neurological symptoms of 13 patients with LETTER TO THE EDITORS

Correlation between automated writing movements and striatal dopaminergic innervation in patients with Wilson's disease

Abstract Handwriting defects are an early sign of motor impairment in patients with Wilsons disease. The basal ganglia being the primary site of copper accumulation in the brain suggests a correlation with lesions in the nigrostiatal dopaminergic system. We have analysed and correlated striatal dopaminergic innervation using [123I]β-CIT-SPECT and automated handwriting movements in 37 patients with Wilsons disease. There was a significant correlation of putaminal dopaminergic innervation with fine motor ability (p < 0,05 for NIV [number of inversion in velocity], NIA [number of inversion in acceleration], frequency). These data suggest that loss of dorsolateral striatal dopaminergic innervation has a pathophysiological function for decreased automated motor control in Wilsons disease. Furthermore analysis of automated handwriting movements could be useful for therapy monitoring and evaluation of striatal dopaminergic innervation.

Genotype Correlation with Fine Motor Symptoms in Patients with Wilson’s Disease

Wilson’s disease, an autosomal recessive disorder of copper metabolism, is caused by about 200 different mutations of the ATP7B gene. Using a genotype-phenotype correlation, 36 patients were examined to see whether the disorder of the automatic handwriting movement depends on the genotype. The findings of this study indicated that no such link exists. Neither the profile of the impairment of the fine motor parameters nor the severity and frequency of pathological findings were different among the three genotype groups (homozygous for H1069Q, compound homozygous for H1069Q and other mutations). By contrast, fine motor disorders were found to correlate with the clinical symptoms recorded when therapy began. The pathophysiology of the basal ganglia and the cerebellar loop therefore cannot be directly attributed to the genotype of the mutation in the ATP7B gene.

Hallervorden-Spatz-Krankheit Befundkonstellation am nigrostriatalen System

ZusammenfassungDie Diagnose der Hallervorden-Spatz-Krankheit (HSD), einer seltenen extrapyramidal-motorischen Erkrankung, konnte gewöhnlich erst postmortal gesichert werden. Bislang galt der typische MRT-Befund mit dem “Tigerauge-Zeichen” in Kombination mit der heterogen klinischen Symptomatik von Bewegungsstörungen als nahezu pathognomonisch und diente zur Diagnosestellung zu Lebzeiten. In der vorliegenden Kasuistik soll der diagnostische Beitrag von 123J-β-CIT und 123J-IBZM-SPECT bei einem akinetisch-rigiden Parkinsonsyndrom im Rahmen einer HSD dargestellt werden. Für beide Untersuchungen wurden im Gegensatz zum M. Parkinson und Multisystematrophien Normalbefunde gefunden. Diese Befundkonstellation zeigt einerseits, dass die Degeneration primär außerhalb des nigrostriatalen Systems liegt, und andererseits unterstützt sie die Diskussion der nosologischen Abgrenzung der HSD von anderen extrapyramidalen Erkrankungen.AbstractHallervorden-Spatz disease (HSD), a rare extrapyramidal motor illness, is usually only confirmed after death. In vivo diagnosis has relied hitherto on the combination of typical magnetic resonance imaging (MRI) findings (the “eye of the tiger” sign) and heterogeneous clinical symptoms of movement disorder which have been regarded as almost pathognomonic. We report on the diagnostic contribution of 123J-β-CIT single photon emission computed tomography (SPECT) and 123J-IBZM SPECT in akinetic-rigid Parkinsons syndrome occurring in a case of HSD. In contrast to Parkinsons disease and multisystem atrophies, the results of both tests were normal. This constellation of findings shows that the degeneration lies primarily outside the nigrostriatal system, supporting arguments for the nosologic distinction of HSD from other extrapyramidal illnesses.