Aceruloplasminemia

Logan et al. (1994) reported 2 brothers with complete ceruloplasmin deficiency who presented in their late forties with dementia and diabetes mellitus. The proband had been admitted to hospital at the age of 49 years with a 6-week history of thirst and polyuria and a 2-week history of progressive confusion. Neurologic examination was normal. He was started on a diabetic diet and oral sulfonylurea. At the age of 52, he suddenly left his work one day and was found at home the next day sitting in a chair with the appearance of not having been to bed. When asked why he was not at work he replied, 'What work?' Dementia progressed thereafter, confusion occurring episodically. The younger brother, who worked as a railway laborer, developed diabetes and mental slowing at the age of 47 years. The symptoms seemed to have developed over a period of days and were progressive thereafter. Twelve relatives had partial ceruloplasmin deficiency. Both brothers had low serum iron and increased liver iron, and there was no copper overload. Transmission of the abnormality was autosomal recessive. The abnormal ceruloplasmin in this case was referred to as ceruloplasmin Belfast.

Morita et al. (1992) described a 55-year-old patient with complete ceruloplasmin deficiency who presented with dementia, diabetes, torticollis, chorea, and ataxia. A postmortem study of this proband demonstrated excessive iron deposition, mainly in the brain, liver, and pancreas. Morita et al. (1995) reported a clinical pathologic study of the family reported by Morita et al. (1992), which contained 3 affected sibs of consanguineous parents. Clinical symptoms were progressive dementia, extrapyramidal disorders, cerebellar ataxia, and diabetes mellitus, all of which appeared when they were between 30 and 50 years old. All had almost completely absent levels of serum ceruloplasmin and increased serum ferritin (see 134790) concentrations. The dentate nucleus, thalamus, putamen, caudate nucleus, and liver of each patient showed low signal intensities on T1- and T2-weighted MRIs. Autopsy revealed severe destruction of the basal ganglia and dentate nucleus with considerable iron deposition in neuronal and glial cells, whereas the cerebral cortex showed mild iron deposition in glial cells without neuronal involvement. Iron deposition in hepatocytes and in neural and glial cells of the brain was demonstrated by electron microscopy with energy-dispersive x-ray analysis.

Harris et al. (1995) reported a 61-year-old Japanese woman who had had retinal degeneration and blepharospasm for the previous 10 years. She had also developed cogwheel rigidity and dysarthria. Her 51-year-old sister, who was asymptomatic at the time of the original presentation despite undetectable CP, had recent onset of retinal degeneration and basal ganglia symptoms. In each case, the absence of serum CP was associated with mild anemia, low serum iron, and elevated serum ferritin. Magnetic resonance imaging studies demonstrated changes in the basal ganglia suggestive of elevated iron content in the brain. The patient's daughter was entirely asymptomatic but had a serum CP concentration that was 50% of normal, consistent with an obligate heterozygote. There was no consanguinity in the family. Liver biopsy confirmed the presence of excess iron.

Takahashi et al. (1996) reported a kindred with aceruloplasminemia. Their patient was a 45-year-old woman who came to attention after a several-month history of difficulty in walking and slurring of speech. She had previously been in excellent health with the exception of insulin-dependent diabetes mellitus beginning at age 31 years. Physical examination revealed ataxic gait, scanning speech, and retinal degeneration. MRI of the brain was consistent with increased basal ganglia iron content, and laboratory studies revealed a low serum iron concentration and no detectable serum ceruloplasmin.

Okamoto et al. (1996) reviewed the findings in 4 pedigrees with aceruloplasminemia. Clinical manifestations, which occurred after middle age, included extrapyramidal signs, cerebellar ataxia, dementia, and memory loss. Neuroimaging studies revealed iron deposition in the basal ganglia and in the red and dentate nuclei. Diagnostic laboratory findings included deficiency of ceruloplasmin, low serum iron, and high serum ferritin. The hepatic iron content was high, but cirrhosis was not usually present.

Hypoceruloplasminemia

Edwards et al. (1979) studied a kindred in which 14 members had low serum ceruloplasmin and low serum copper without the abnormalities of Wilson disease (277900). The phenotype segregated in a pattern suggesting heterozygosity for a mutant gene. One member of the family with low levels had been followed for over 25 years and had remained completely well.

Miyajima et al. (1987) described a 52-year-old woman with blepharospasm, retinal degeneration, and high density areas in the basal ganglia and liver by CT scan. Studies showed accumulation of iron, not copper, in liver and brain. Serum ceruloplasmin was less than 0.6 mg/dl (normal, 17-37 mg/dl) and serum apoceruloplasmin was undetectable. A sister and a brother demonstrated retinal degeneration and iron deposition in the basal ganglia and liver, respectively. Serum ceruloplasmin was less than 0.8 mg/dl in both cases.

Clinical Management

Logan et al. (1994) treated their index patient with ceruloplasmin-containing fresh-frozen plasma, resulting in an increase in serum iron that was dose dependent. Miyajima et al. (1997) reported favorable results with desferrioxamine in the treatment of aceruloplasminemia.

Inheritance

The study by Harris et al. (1995) (see MOLECULAR GENETICS) demonstrated the essential role of ceruloplasmin in human biology and identified aceruloplasminemia as an autosomal recessive disorder of iron metabolism. Okamoto et al. (1996) noted that consanguinity occurred in 3 of 4 affected pedigrees, suggesting autosomal recessive inheritance.

Mapping

Logan et al. (1994) performed DNA analysis on 2 affected brothers and showed genetic linkage between the ceruloplasmin deficiency and various polymorphic markers flanking the ceruloplasmin gene on 3q25.

Pathogenesis

Ceruloplasmin catalyzes the oxidation of ferrous iron to ferric iron or the peroxidation of Fe(II) transferrin to form Fe(III) transferrin (Logan et al., 1994). The molecular findings by Harris et al. (1995) supported previous studies that identified ceruloplasmin as a ferroxidase (Osaki et al., 1966) with a role in the ferric iron uptake by transferrin. Consistent with this concept, the anemia that develops in copper-deficient animals is unresponsive to iron but is correctable by ceruloplasmin administration (Lee et al., 1968). It is also consistent with the essential role of a homologous copper oxidase in iron metabolism in yeast.

Blepharospasm has been related to abnormality of the basal ganglia, as in blepharospasm-oromandibular dystonia (Meige syndrome); see Casey (1980) and Tanner et al. (1982).

Molecular Genetics

After the cloning of the Wilson disease gene, Harris et al. (1995) investigated a number of patients referred for molecular diagnosis with neurologic degeneration and low or absent serum ceruloplasmin. In the course of this analysis, they recognized several patients who did not have Wilson disease. One such patient identified in Japan and reported as a case of familial apoceruloplasmin deficiency (Miyajima et al., 1987) was found to have a mutation in the ceruloplasmin gene (117700.0002). The patient's daughter was heterozygous for the 5-bp insertion.

In the Japanese family reported by Morita et al. (1992), Yoshida et al. (1995) demonstrated a homozygous mutation in the ceruloplasmin gene (117700.0001) in 4 sibs with aceruloplasminemia, 3 of whom showed extrapyramidal disorders, cerebellar ataxia, progressive dementia, and diabetes mellitus.

Roy and Andrews (2001) reviewed disorders of iron metabolism, with emphasis on aberrations in hemochromatosis (235200), Friedreich ataxia (229300), aceruloplasminemia, and other inherited disorders.

Animal Model

To determine whether aceruloplasmin and its homolog hephestin (HEPH; 300167) are important for retinal iron homeostasis, Hahn et al. (2004) studied retinas from mice deficient in Cp and/or Heph. Mice deficient in both, but not each individually, had a striking, age-dependent increase in the iron content of retinal pigment epithelium and the retina. The iron storage protein ferritin was also increased in the double-null retinas. The pathology indicated that Cp and Heph are critical for central nervous system iron homeostasis and that loss of both in the mouse leads to age-dependent retinal neurodegeneration, thus explaining the retinal degeneration of aceruloplasiminemia.