Biomedical subjects
Publications and source records attributed to I H Scheinberg.
The authors used the MMPI to assess psychopathology in neurologically impaired and neurologically asymptomatic patients with Wilson's disease. Neurologically impaired patients showed more psychopathology on the schizophrenia and depression scales and had a significantly higher rate of severe depression.
To examine the neuropsychological deficits of patients with Wilson's disease (WD), 19 neurologically impaired patients with WD were administered the Wechsler Adult Intelligence Scale (revised), Wechsler Memory Scale, Dementia Rating Scale, Wisconsin Card Sorting Test, Boston Naming Test, Trail Making Test, and Animal Naming Test. Their test scores were compared with those of 12 neurologically asymptomatic patients with WD and 15 normal controls. The neurologically impaired patients scored lower than did the control group on the Performance IQ, Full-Scale IQ, Dementia Rating Scale, and Trail Making Test, and they scored lower on the Wechsler Memory Scale than did both the asymptomatic and control groups. The major areas of deficit for the neurologically impaired WD group were in motor and memory functioning. Computed tomographic and neurologic examinations of the neurologically impaired patients with WD generally reflected abnormalities of the basal ganglia.
Wilson disease (WD) is an autosomal recessive disorder resulting in an accumulation of copper in the liver, brain, and other organs. The WD locus (WND) has previously been linked to esterase D (ESD) and localized to 13q14-22. With the large Centre d'Etude Polymorphisme Humain cohort, a refined map of DNA markers from this region was constructed, with the following locus order: D13S1-D13S21-D13S22-D13S10-ESD-RB-WND-D 13S26-D13S12-D13S2. A significant excess of male recombination was observed between D13S21 and D13S22. Intervals distal to D13S22 showed an excess of female recombination. When these markers were tested on 19 WD families from a variety of ethnic backgrounds, the two closest loci were shown to be RB and D13S26. The retinoblastoma gene locus (RB) was shown to be proximal to WND at a distance of 4.4 centimorgans (cM), and D13S26 was placed distal to WND at a distance of 4.0 cM. ESD was assigned proximally at a distance of 9.4 cM. In all families studied WND was linked to one or more of the loci ESD, RB, or D13S26.
Penicillamine is known to be effective therapy for Wilson's disease. However, the clinical consequences of the abrupt and permanent withdrawal of penicillamine have not been investigated. We studied 11 patients who stopped their own treatment after having been treated successfully with penicillamine (1 to 2 g per day) for periods of 3 to 19 years. Eight died of hepatic decompensation or fulminant hepatitis after an average survival of only 2.6 years. In another 13 patients, penicillamine was discontinued by the physician because of serious adverse reactions. In these patients, penicillamine was replaced with trientine (1 to 1.5 g per day), a newer chelating agent. All but one of these patients (who was killed accidentally) are alive at this writing, from 2 to 15 years later. Our observations suggest that discontinuation of penicillamine in patients with Wilson's disease results in rapid clinical deterioration, which is often fatal. The replacement of penicillamine with trientine appears to prevent this adverse clinical course.
Explore the source record for details and available documents.
Deficiency of serum ceruloplasmin is a characteristic biochemical abnormality of Wilson's disease, although the mechanism of this finding is unknown. Ceruloplasmin messenger RNA (mRNA) levels were therefore examined in five patients with Wilson's disease and five controls with other types of hepatic disease. Northern and dot blot hybridizations showed that detectable ceruloplasmin mRNA was present in all of the patients with Wilson's disease, including one patient with no detectable serum ceruloplasmin. However, the ceruloplasmin mRNA levels in the Wilson's disease patients were only 33% that of controls (P less than 0.001). In contrast, albumin mRNA levels in the Wilson's disease patients averaged 161% that of controls. In an attempt to better delineate the level of gene expression responsible for this decrease in ceruloplasmin mRNA, the nuclear run-on assay was used to analyze transcriptional rates. The amount of ceruloplasmin gene transcription in four Wilson's patients was decreased to 44% that of three controls. These results indicate that the diminished serum ceruloplasmin levels in patients with Wilson's disease are due at least in part to a decrease in ceruloplasmin gene transcription.
Explore the source record for details and available documents.
Explore the source record for details and available documents.
Explore the source record for details and available documents.
Explore the source record for details and available documents.
Though myocardial alterations are well recognized in haemochromatosis, little attention has been paid to the cardiac changes in Wilson's disease. To define the extent of myocardial degeneration in newly diagnosed or chronically treated Wilson's disease, we reviewed the autopsy findings in 9 cases with this condition. We compared our observations with those in 3 control cases, selected for comparable age and with liver disease having no known association with cardiac degeneration. Our results revealed cardiac hypertrophy in 5 out of 9 cases of Wilson's disease. There was evidence of interstitial and replacement fibrosis, intramyocardial small vessel sclerosis and focal inflammatory cell inflammation to a variable degree in all cases. One case had AV nodal degeneration, and a 15 year old boy had severe atherosclerosis of the left main coronary artery. Two patients died suddenly, presumably secondary to an arrhythmia; one of these patients had the most marked myocardial alterations. We could not correlate these changes specifically with the tissue levels of copper, treatment with D-penicillamine, or the presence of cirrhosis. We conclude that there are definite morphological abnormalities in the hearts of patients with Wilson's disease consistent with a cardiomyopathy. Though the myocardial changes were non-specific, the fact that 2 patients died suddenly, suggests the need for a prospective study of cardiac function in these patients in the future.
To examine whether hepatic plasma membrane receptors for asialoglycoproteins are replaced or reutilized during endocytosis, receptors on the surface of isolated hepatocytes were uniquely labeled by neuraminidase treatment. This enzyme abolishes binding of asialo-orosomucoid, a galactose-terminated glycoprotein, and restricts the ligand specificity of the cell surface receptor protein to N-acetylgalactosamine-terminated glycoproteins such as desialylated ovine submaxillary mucin. Although a much larger intracellular pool of apparently identical receptor protein is unaffected by neuraminidase, endocytosis of asialo-orosomucoid does not occur in neuraminidase-treated cells, while endocytosis of desialylated ovine submaxillary mucin is unaffected. Endocytosis of desialylated ovine submaxillary mucin, in amounts far exceeding cell surface binding capacity, is not a consequence of replacement of neuraminidase-treated surface receptor by intracellular receptor. Binding and endocytosis of asialoglycoproteins appear, therefore, to be maintained through a continuous reutilization of plasma membrane receptors rather than through their replacement from an intracellular receptor pool.
Explore the source record for details and available documents.
Explore the source record for details and available documents.
Explore the source record for details and available documents.
In patients with normal serum concentrations of ceruloplasmin, measurement of the incorporation of radiocopper into this protein can aid in the clinically important differentiation of patients with hepatic illnesses that mimic Wilson's disease from patients with this disorder.
Removal of sialic acid from a specific hepatic binding protein virtually abolishes its capacity to bind certain asialoglycoproteins. The loss of this capacity is the result of competition for the binding sites by galactosyl residues, of hepatic binding protein, that become terminal after desialylation.
Explore the source record for details and available documents.