Alternative titles; symbols
SNOMEDCT: 124224004; ORPHA: 48818; DO: 0050711;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 3q24-q25.1 | Aceruloplasminemia | 604290 | Autosomal recessive | 3 | CP | 117700 |
A number sign (#) is used with this entry because of evidence that aceruloplasminemia (ACEP), also designated here as neurodegeneration with brain iron accumulation-10 (NBIA10), is caused by homozygous or compound heterozygous mutation in the gene encoding ceruloplasmin (CP; 117700) on chromosome 3q23. Rare individuals with heterozygous mutations have hypoceruloplasminemia and may show mild symptoms.
Aceruloplasminemia (ACEP) is an autosomal recessive disorder characterized by mild anemia (often microcytic), diabetes mellitus, retinopathy, liver disease, and progressive neurologic symptoms due to iron accumulation in the pancreas, retina, liver, and brain. Anemia is often found in childhood or adolescence, whereas the neurologic and systemic features usually develop in middle age or later. The disorder shows clinical heterogeneity; all symptoms may not be present in every affected individual. Laboratory studies show high ferritin levels, low serum iron levels, and low or undetectable ceruloplasmin. Brain imaging usually shows iron accumulation in specific parts of the brain, particularly in the basal ganglia and thalami, as well as in visceral organs, such as the liver and pancreas. Many reported patients are from Japan, but patients have been reported worldwide (summary by Vila Cuenca et al., 2020).
Roy and Andrews (2001) reviewed disorders of iron metabolism, with emphasis on aberrations in hemochromatosis (235200), Friedreich ataxia (229300), aceruloplasminemia, and other inherited disorders.
For a discussion of genetic heterogeneity of NBIA, see NBIA1 (234200).
Miyajima et al. (1987) described a 52-year-old Japanese 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. Harris et al. (1995) reported follow-up of the family reported by Miyajima et al. (1987). The proband was then 61 years of age and had developed cogwheel rigidity and dysarthria over the intervening 10 years. Her 51-year-old sister, who was asymptomatic at the time of the original presentation despite low 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. Liver biopsy confirmed the presence of excess iron. 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.
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.
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.
Vila Cuenca et al. (2020) reported 13 patients from 11 unrelated non-Japanese families with ACEP. The patients originated from several different countries, including Spain, Lithuania, Poland, Italy, Brazil, India, and Pakistan. Most patients had symptoms or were diagnosed in middle age (median of 40 years). Many reported a history of anemia, often microcytic, since childhood or adolescence. The clinical presentations were variable and included neurologic symptoms, type 2 diabetes mellitus, mild anemia, and/or hepatic iron overload. Neurologic disturbances were characterized by cognitive decline, often with executive dysfunction, and movement abnormalities, such as bradykinesia, ataxia, choreoathetosis, dystonia, and/or tremor. Three patients had retinopathy. Laboratory studies showed mild anemia, low or undetectable ceruloplasmin, decreased serum iron (in most), increased ferritin, and decreased transferrin saturation. Brain imaging in most patients showed iron accumulation in the basal ganglia, thalami, and cerebellum; 2 patients had no iron overload on brain imaging.
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.
Treatments for ACEP are mainly based on iron-chelating agents, which are quite effective in reducing liver iron accumulation and may prevent further brain iron deposition. However, this treatment is poorly effective in patients with already established neurologic damage (summary by Vila Cuenca et al., 2020).
The transmission pattern of aceruloplasminemia in the family reported by Miyajima et al. (1987) was consistent with autosomal recessive inheritance. Okamoto et al. (1996) noted that consanguinity occurred in 3 of 4 affected pedigrees, suggesting autosomal recessive inheritance.
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.
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).
Di Meo and Tiranti (2018) suggested that lack of the CP protein results in the inability of astrocytes to oxidize ferrous iron that enters the CNS, causing abnormal iron accumulation. In vitro studies of some of the CP mutations have shown that mutant CP is retained in the ER, misincorporates copper atoms, and impairs ferroxidase activity, leading to cellular iron overload.
In a Japanese woman with aceruloplasminemia previously reported by Miyajima et al. (1987), Harris et al. (1995) identified a homozygous frameshift mutation in the CP gene (117700.0002). The patient's asymptomatic daughter, who had a 50% decrease in ceruloplasmin levels, was heterozygous for the mutation.
In 4 Japanese sibs with ACEP (Morita et al., 1992), Yoshida et al. (1995) demonstrated a homozygous splice site mutation in the ceruloplasmin gene (117700.0001).
In a 45-year-old Japanese woman, born of consanguineous parents, with ACEP, Takahashi et al. (1996) identified a homozygous nonsense mutation in the CP gene (W858X; 117700.0003). The patient's younger brother, who had diabetes and retinal degeneration without other neurologic deficits, was also homozygous for the mutation.
In the 2 brothers with ACEP reported by Logan et al. (1994), Harris et al. (1996) found homozygosity for a 1-bp deletion in exon 13 of the CP gene (c.2389delG; 117700.0004). The nucleotide sequence surrounding this deletion site (TGGAGA) corresponded to a consensus sequence 'hotspot' for nucleotide deletions (Krawczak and Cooper, 1991). The nucleotide deletion resulted in a frameshift with change of 11 amino acids and a premature stop codon at codon 789.
In a 56-year-old Japanese man, born of consanguineous parents, with ACEP, Okamoto et al. (1996) identified a homozygous frameshift mutation in the CP gene (117700.0005).
In 12 individuals from 10 non-Japanese families with ACEP, Vila Cuenca et al. (2020) identified homozygous or compound heterozygous mutations in the CP gene (see, e.g., 117700.0006). There were 6 missense mutations, 3 frameshifts, and 3 splice site mutations. An additional patient (a 40-year-old Polish woman, family 5) carried a heterozygous H130P variant; the authors noted that they could not exclude the presence of an additional CP mutation in this patient. Functional studies of the variants and studies of patient cells were not performed.
Heterozygous Variants
Daimon et al. (2000) reported a 72-year-old woman with a 1-year history of postural tremor in the hands, about a 50% decrease in serum ceruloplasmin and copper levels, and mild brain imaging abnormalities of the putamina associated with a heterozygous I28F variant in the CP gene. Her asymptomatic son also carried the heterozygous variant; he had hypoceruloplasminemia. Functional studies of the variant were not performed, and the authors stated that the variant may not be responsible for the disease, since structural analysis did not predict a structural change in the protein.
In 3 individuals from 2 unrelated Japanese families with cerebellar ataxia and hypoceruloplasminemia, Miyajima et al. (2001) identified a heterozygous W858X mutation in the CP gene (117700.0003). The patients had onset of cerebellar dysfunction in the fourth decade. Features included relatively nondisabling gait ataxia and dysarthria, as well as hyperreflexia. Brain and abdominal MRI showed cerebellar atrophy and no low-signal intensities in the basal ganglia, thalamus, and liver. The deficiency in serum ceruloplasmin was partial; protein concentrations and ferroxidase activities ranged from 36 to 41% of control values. Serum iron concentration and transferrin saturation levels were normal. At autopsy, pathologic and biochemical examinations showed marked loss of Purkinje cells, a large iron deposition in the cerebellum, and small depositions in the basal ganglia, thalamus, and liver. Cerebellar ataxia reflected the site of iron deposition. The authors concluded that heterozygosity for mutation of the CP gene can result in cerebellar ataxia.
Kuhn et al. (2005) reported a 16-year-old girl with a progressive, primarily right-sided disorder of coordination and precision movements, dysmetria, dysdiadochokinesia, hyperkinesia of the right lower limb, abnormal gait, hypometric horizontal saccades and abduction deficits, and personality changes associated with a heterozygous R701W missense variant in the CP gene. Brain imaging was normal, but PET scan showed reduced glucose metabolism in the basal ganglia and thalamus. Serum CP and ferroxidase activity were reduced by about 50% compared to controls and serum copper was decreased, whereas serum iron, transferrin, and ferritin were normal. Liver biopsy showed increased iron deposition. The heterozygous R701W variant was also present in her asymptomatic father who had low-normal serum CP levels.
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 aceruloplasminemia.
Edwards et al. (1979) studied a kindred in which 14 members were found to have low serum ceruloplasmin and low serum copper without the abnormalities of Wilson disease (277900) and without clinical manifestations. 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.
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