Hans-Jürgen Kühn

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.

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.

Mode of action of triethylenetetramine dihydrochloride on copper metabolism in Wilson's disease

The drug of choice for the initial treatment of “decoppering” in Wilsons disease, an inherited disorder of copper metabolism, is the chelating agent D‐penicillamine. In the case of harmful side‐effects an alternative drug is triethylenetetramine dihydrochloride (trien or trientine). Using the 24‐h‐urine excretion of copper and the oral copper loading test with copper‐64, a double function for trien was found: trien increases the urine copper excretion and decreases the intestinal copper absorption respectively.

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.

Serum neuron-specific enolase levels do not increase after electroconvulsive therapy

BACKGROUND Cognitive disorders occurring after electroconvulsive therapy (ECT) are regarded as an expression of brain damage, despite computed tomography (CT) and magnetic resonance imaging (MRI) showing no signs of structural brain damage. Serum neuron-specific enolase (NSE) is a sensitive marker of neuronal damage (i.e., after stroke or cardiac arrest). The objective of this study was to investigate whether ECT leads to a rise in the serum NSE level as an expression of neuronal damage. METHODS We investigated seven patients (four women, three men; mean age 6212 years) with major depressive disorder, who were treated with ECT for the first time. ECT was administered every 2 days, three times a week under standard conditions (anaesthesia: thiopental, succinylcholine, 100% oxygen, unilateral ECT, seizure duration more than 20 s). Blood samples were drawn at the following times. For the first ECT: 15 and 1 min before ECT, and 1, 5, 10, 15, 20, 25, 30, 45, 60, 75, 90, 105, 120 min, and 8, 12, 24 h after ECT. For all subsequent ECT: 1 min before and 4 h after every ECT. Serum NSE was measured by means of enzyme immunoassay (Cobas Core NSE, EIA, Hoffmann-La Roche). RESULTS On average, each patient underwent ECT 10 times (range 5-20). In the first ECT there was no difference in serum NSE levels before and at all times following ECT. A comparison of serum NSE levels before and after each subsequent bout of ECT revealed no differences. Moreover, comparing the baseline serum NSE levels (before the first ECT) with the values after final ECT showed no differences either. CONCLUSION ECT did not increase serum NSE values, indicating that electroconvulsive therapy does not cause neuronal damage.

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.

Classification of fine‐motoric disturbances in Wilson's disease using artificial neural networks

Patients suffering from Wilsons disease are divided into several types according clinical symptoms only at time of manifestation. Thereby two main subgroups exist: neurologic and non‐neurologic types. After long‐term therapy the neurological symptoms occurring in hepatolenticular degeneration may be improved but frequently with remaining fine‐motoric disturbances which should be used for evaluation of the actual patient state. These disturbances are difficultly to assess in an exact and objective manner by clinical examination. Therefore we measured fine‐motoric passive and active abilities based on a standardized test set using the VSCOPE‐system. The parallel evaluation of all fine‐motoric data using an artificial neural network leads to a reclassification of these patients based on actual fine‐motoric abilities but not reflecting the clinical classification at time of manifestation.

Long-Term Care and Management of Wilson’s Disease in the GDR

Diagnosis, long-term management and family investigations of Wilsons disease are provided by selected clinical institutions in the GDR. From 187 patients detected since 1949, 111 are alive. In spite of the principal effectiveness of penicillamine treatment, confirmed by the disappearance of most of the central nervous system symptoms and successful professional rehabilitation of many patients, insufficient therapeutic discipline, psychosocial disturbances and penicillamine side-effects forcing its substitution by zinc or triethylenetetramine dihydrochloride in 14 cases need our further attention.