Summary: A 63-year-old white female presented with a 5 year history of
progressive dementia, ataxia, and difficulty swallowing. The patient
also had diabetes mellitus. Neuropsychiatric evaluation revealed ataxic
gait, marked psychomotor slowing and severe dementia. Laboratory analysis revealed low serum iron (17 mg/dL), high serum
ferritin (1343 µg/mL), low serum transferrin saturation (6%),
undetectable serum ceruloplasmin (<4.0), normal serum transferrin
receptor concentration (25 µmol/L), normal 24 hour urine copper
excretion (0.6 µg/dL), high serum HbA1c (7.5), low hemoglobin (10.7).
Magnetic resonance imaging (MRI) of the head was performed (Figure 1).
An MRI study revealed marked T2 hypointensity consistent with
susceptibility effect involving the putamen, head of the caudate,
posterior thalami, and dentate nuclei compatible with iron deposition.
In addition, some minimal iron deposition was detected within the
cerebral and cerebellar cortices.
Iron plays a crucial role in the formation of toxic oxygen radicals.
Excess iron functions as a potent catalyst of biologic oxidation.
Homeostatic mechanisms are utilized to maintain appropriate serum iron
concentrations, thus preventing neuronal cell damage from ironmediated
free radicals. Several hereditary disorders, including
aceruloplasminemia, can disrupt this homeostasis. Ceruloplasmin is an
α2glycoprotein synthesized in hepatocytes that binds plasma copper and
has ferroxidase activity.
Aceruloplasminemia is an autosomal
recessive disorder characterized by a lack of ceruloplasmin ferroxidase
activity important for iron conversion and exportation. The lack of
ceruloplasmin results in the accumulation of ferrous iron leading to
parenchymal and reticuloendothelial iron overload. Missense mutations in
the ceruloplasmin gene (Cp), chromosome 3q, are associated with
aceruloplasminemia. Clinically, patients present with a triad of adult
onset neurodegeneration, retinal degeneration, and diabetes mellitus.1–3
Laboratory analysis, which is used to confirm the diagnosis, reveals
elevated serum ferritin with low serum iron, low transferrin saturation
and mild anemia. In addition, ceruloplasmin ferroxidase activity is
Neurological symptoms include ataxia, dementia, and involuntary movements, thus reflecting the sites of iron deposition.5 The
unique involvement of the central nervous system (CNS) distinguishes
aceruloplasminemia from other iron or paramagnetic element storage
disorders including hemochromatosis, HallervordenSpatz, and Wilson’s
disease.6 Autopsy series in aceruloplasminemia have
demonstrated severe iron deposition and extensive neuronal loss within
the neostriatum, dentate nucleus, and thalamus and marked loss of
Perkinje cells within the cerebellar cortex.7,8 MRI
demonstrates marked T2 hypointensity within the basal ganglia, with
greatest involvement of the putamina and caudate nuclei. T2
hypointensity has also been reported in the thalamic and dentate nuclei.2
contradiction, hemochromatosis preferentially deposits iron in the
pituitary gland. The basal ganglia are typically normal in
hemochromatosis. Hallervorden-Spatz syndrome is characterized by iron
deposition in the globus pallidus, red nuclei and substantia nigra. MRI
demonstrates T2 hypointensity within the basal ganglia with a
characteristic T2 high signal in the globus pallidus often referred to
as the “eye of the tiger” sign. Additionally, cortical and caudate
atrophy can be identified. Wilson’s disease is characterized by the
deposition of copper in the basal ganglia and thalami characterized by
T2 hypointensity in the lentiform nuclei and thalami. However, a
peripheral rim of T2 hyperintensity may surround the lentiform nuclei
and ventral mass of the thalami.2
Aceruloplasminemia is an autosomal recessive disorder characterized by
abnormal deposition of iron in the brain, resulting in progressive
neurological dysfunction. Abnormal deposition of iron and/or other
paramagnetic elements in the CNS also occurs in other hereditary
disorders such as hemochromatosis, Hallervorden-Spatz syndrome, and
Wilson’s disease. Aceruloplasminemia has unique involvement of the CNS
compared with the aforementioned disorders that can be demonstrated with
- Bosio S, De Gobbi M, Roetto A, et al. Anemia and iron
overload due to compound heterozygosity for novel ceruloplasmin
mutations. Blood. 2002;100:22462248.
- Grisoli M, Piperno A, Chiapparini L, et al. MR imaging of cerebral cortical involvement in aceruloplasminemia. AJNR Am J Neuradiol. 2005;26: 657661.
- Ponka P. Hereditary causes of disturbed iron homeostasis in the central nervous system. Ann of the New York Academy of Sciences. 2004;1012: 267281.
- Xu X, Pin S, Gathinji M, et al. Aceruloplasminemia: an inherited neurodegenerative disease with impairment of iron homeostasis. Annals of the New York Academy of Science.s 2004;1012:299305.
- Miyajima H, Takahashi Y, Kono S. Aceruloplasminemia, an inherited disorder of iron metabolism. Biometals. 2003;16:205213.
H, Kono S, Takahashi Y, Sugimoto M. Increased lipid peroxidation and
mitochondrial dysfunction in aceruloplasminemia brains. Blood, Cells, Molecules and Diseases 2002;29:433438.
K, Yoshida K, Arima K, et al. Astrocytic deformity and globular
structures are characteristic of the brain of patients with
aceruloplasminemia. Journal of Neuropathology and Experimental Neurology 2002;61:10691077.
- Miyajima H. Aceruloplasminemia, an iron metabolic disorder. Neuropathology 2003;23:345350.