Ceruloplasmin Deficiency Research Articles

Role of ceruloplasmin in cellular iron uptake.

Individuals with hereditary ceruloplasmin (Cp) deficiency have profound iron accumulation in most tissues, which suggests that Cp is important for normal release of cellular iron. Here, in contrast to expectations, Cp was shown to increase iron uptake by HepG2 cells, increasing the apparent affinity for the substrate by three times. Consistent with its role in iron uptake, Cp synthesis was regulated by iron supply and was increased four- to fivefold after iron depletion. Unlike other iron controllers that are posttranscriptionally regulated, Cp synthesis was transcriptionally regulated. Thus, iron-deficient cells could increase Cp synthesis to maintain intracellular iron homeostasis, so that defects would lead to global accumulation of iron in tissues.

Hereditary ceruloplasmin deficiency: A cerebro‐retino‐diabetic disease

Hereditary ceruloplasmin deficiency (HCD) is a recently recognized neurodegenerative disease of an autosomal recessive inheritance. This disease is caused by the defect of the ceruloplasmin gene. The initial manifestation of HCD is usually adult‐onset diabetes mellitus. Neurological symptoms occur 10 to 20 years thereafter, between 40 and 60 years of age. These include dementia, abnormal involuntary movements, and cerebellar ataxia. Retinal degeneration is also present. The cardinal pathological change is a massive iron deposition to the brain, liver and pancreas. A marked loss of neurons is observed in the caudate nucleus and putamen of the brain. The number of insulin cells is decreased in the islets of the pancreas. In the clinical settings, it seems that HCD patients may exist among the population of adult‐onset diabetic patients.

Islet changes in hereditary ceruloplasmin deficiency

Diabetes mellitus (DM) is the important initial symptom of hereditary ceruloplasmin deficiency (HCD). We examined the pancreas of an autopsy case of HCD and revealed a marked reduction in insulin-containing cells in the islets despite no massive iron deposition, degeneration, nor necrosis. Non-insulin-containing cells in the islets had glucagon or somatostatin. This study indicates that DM in HCD results from depletion of insulin cells and this depletion does not seem to be caused by the direct effect of iron deposition. The present observation suggests that the defect of the ceruloplasmin gene may influence the population of islet cells.

Hereditary ceruloplasmin deficiency with hemosiderosis

Hereditary ceruloplasmin deficiency with hemosiderosis (aceruloplasminemia) is a new disease characterized by systemic hemosiderosis, diabetes mellitus, neurological abnormalities and pigment degeneration of the retina. Loss of the ferroxidase activity of ceruloplasmin results in systemic iron deposition and tissue damage. Neuroimaging studies reveal iron deposition in basal ganglia and in the red and dentate nuclei. Cerebellar ataxia, extrapyramidal signs and dementia develop after middle age. We report a patient with undetectable serum ceruloplasmin levels and the above clinical manifestations. Sequence analysis of the cDNA of ceruloplasmin from this patient revealed an insertion of adenine in exon 3; this produced a premature stop codon.

Hereditary ceruloplasmin deficiency with hemosiderosis

Hereditary ceruloplasmin deficiency with hemosiderosis

A Nonsense Mutation of the Ceruloplasmin Gene in Hereditary Ceruloplasmin Deficiency with Diabetes Mellitus

A novel mutation of the ceruloplasmin (Cp) gene was found in a patient with hereditary ceruloplasmin deficiency (HCD) with diabetes mellitus (DM). The patient had been treated for DM for about 13 years, and then his illness was diagnosed as HCD. One year later, he was found dead in his home. A decrease in insulin-immunostained cells was observed in the islets of the patient′s pancreas tissue, which accounted for his DM. The polymerase chain reaction (PCR)-direct sequencing analysis of the Cp gene of his daughter revealed a novel point mutation, G to A, at nucleotide 2630 in exon 15. This mutation changes the Trp858 codon (TGG) to a stop codon (TAG) (nonsense mutation). PCR-restriction analysis for the mutation revealed that the patient as well as his daughter was a heterozygote for the mutation, indicating that the patient was a compound heterozygote.

Evidence for serum factors modulating antibody production in normal and macular mice.

The macular mutant mouse is a model of Menkes' kinky hair disease, which is characterized by a deficiency of ceruloplasmin in the serum. In hemizygotic mice (ml/y), the antibody production against sheep red blood cells (SRBC) was decreased. Treatment with normal (+/y) mouse serum increased in a dose-dependent manner the antibody response of ml/y mouse spleen cells in vitro. However, +/y mouse serum had no effect on +/y mouse spleen cells, even at high doses up to 5%. In contrast, ml/y mouse serum decreased antibody production in +/y mouse spleen cells in a dose-dependent manner. Antibody production in +/y mouse spleen cells decreased with time, after pretreatment with ml/y mouse serum. However, serum from ml/y mice injected with ceruloplasmin did not decrease antibody production in +/y mouse spleen cells but rather increased it in ml/y mouse spleen cells. Ceruloplasmin had no effect on the production of antibodies against SRBC in ml/y and +/y mouse spleen cells in vitro. These findings suggest that one or more enhancers of antibody production exist in normal mouse serum and that one or more suppressors of normal antibody production exist in ml/y mouse serum. It is proposed that the activities of these factors in serum may be regulated by ceruloplasmin.

Molecular studies of ceruloplasmin deficiency in Wilson's disease.

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.

Letter: Doubt Wilson disease.

To the Editor..— Although the patient described by Schraeder et al 1 seems to have suffered from polymyositis, perhaps a reaction to penicillamine, it is very probable that she does not have disease. On the basis of the evidence presented, she is more likely to be a heterozygous carrier of one Wilson disease Deficiency, or absence, of ceruloplasmin in the serum is seen in about 95% of individuals with disease—abnormal homozygotes — but is also noted in at least 10% of heterozygous carriers of this gene. About one in 200 individuals in the general population is such a carrier 2 so that one would expect to find about one in 2,000 individuals whose deficiency of ceruloplasmin is a consequence of this heterozygosity. Since the prevalence of disease itself is of the order of one in 200,000, 2 only one of every 100 patients with hyperceruloplasminemia will be a

Investigations on the nature of ceruloplasmin deficiency in the newborn.

Enzymatic and immunoassaies of serum ceruloplasmin were undertaken on serum samples from 100 newborn infants, their mothers, and 100 unrelated women who served as controls. The results indicate that the remarkably low levels of ceruloplasmin oxidase activity observed in the serum of neonates are not due to deficient ceruloplasmin protein synthesis but to defective copper incorporation in the synthesized protein, resulting in excess apoceruloplasmin concentration. Furthermore, serum copper studies involving both total and free copper corroborated this conclusion.

The diagnosis of Wilson's disease in asymptomatic patients.

The authors established the diagnosis of hepatolenticular degeneration (HLD, Wilson's disease) in eight out of nine asymptomatic subjects suspected of being destined to develop the disease because of the finding of decreased serum ceruloplasmin concentration. Deficiency or absence of ceruloplasmin (less than 20 mg/ 100 ml of serum) is a necessary condition, and elevation of hepatic copper concentration above 100 μg/gm of dry weight is a sufficient condition, for a diagnosis of HLD in asymptomatic persons. The finding of nonspecific histologic changes in the livers of the eight subjects serves to confirm the presence of the disease. If the diagnosis is made, prompt adoption of an anticopper therapeutic regimen is recommended.

A rapid screening test for deficiency of plasma ceruloplasmin and its value in the diagnosis of Wilson's disease

A spot test is described which makes it possible to determine simply and with a satisfactory degree of certainty whether or not an individual has more or less than about 20 mg. of ceruloplasmin per 100 ml. of plasma or serum. The test should be applicable as a screening procedure to detect asymptomatic children with hypoceruloplasminemia in whom Wilson's disease may subsequently develop. Based on current knowledge, and with available pharmacologic agents, it may be practicable to prevent or delay the onset of symptoms and signs of Wilson's disease in such children. The test may also be used in the study of patients suspected of having Wilson's disease.