FINAL DIAGNOSIS: HEREDITARY CERULOPLASMIN DEFICIENCY WITH HEMOSIDEROSIS.
Ceruloplasmin deficiency is a newly recognized autosomal recessive disorder, first described in Japan in 1987 (4), linked to a mutation of the ceruloplasmin gene located on chromosome 3. This case is the first French case (6). Ceruloplasmin is an abundant serum glycoprotein, a copper-binding oxidase that carries more than 95% of the plasma copper (3). It is synthesized in hepatocytes and can oxidize several substrates and especially plays the role of a ferroxidase. In the few reported cases of aceruloplasminemia, patients presented with non specific symptoms, i.e. association of intellectual deterioration, extrapyramidal signs and, inconstantly, cerebellar ataxia. Associated diabetes mellitus and pigmentary degeneration of the retina are frequent. Biological tests show complete lack of ceruloplasmin in keeping with a homozygous mutation of the ceruloplasmin gene. All the patients had increased serum ferritin concentration and serum iron level. Cerebrospinal fluid (CSF) examination also showed significant increase of iron concentration (3).
There are only few neuropathological studies (2, 5). The pathological changes involve predominantly the basal ganglia, particularly the striatum and posterior thalamus, and the dentate nucleus; the cerebral cortex is less affected. They include necrosis with massive iron deposition, marked neuronal loss and gliosis. The neuropathological findings in our case are comparable to those in the previously reported pathological cases (2) except for the presence of Opalski cells and Alzheimer type II astrocytes, which were not found in the latter.
The main differential diagnosis includes 3 congenital entities sharing common clinical, biological, and pathological features.
Wilson disease (hepatolenticular degeneration) is an autosomal recessive disorder of copper excretion with variable phenotypic expression. It is related to mutations of the Wilson gene on chromosome 13 (more than 190 mutations). Its product is ATP7B, a cathion transporting P-type ATPase with 6 copper-binding domains, located in mitochondria. Hypoceruleoplasminemia is considered a characteristic feature of Wilson's disease; however it is only the consequence of copper deficiency and does not have any physiopathological role. Clinically, the disease include cirrhosis, progressive rigidity, tremor, dysarthria, dysphagia and, if untreated, dementia. A ring of brown pigmentation in the cornea (Kaiser Fleischer ring) is a pathognomonic sign. The clinical presentation is quite similar with aceruloplasminemia except for diabetes mellitus. In contrast, pathological examination in Wilson disease does not show iron deposition in tissues but excessive copper deposition in the liver (exceptionally associated with cirrhosis) brain and kidneys. At neuropathological examination, the topography of the lesions is superimposable to that in aceruloplasminemia and includes necrosis, gliosis with Alzheimer's type II astrocytes and microglial activation with Opalski cells. These cells have been originally described in Wilson disease and are considered characteristic of the condition. They are large cells with small nuclei and no obvious cytoplasmic processes. They have a finely granular or foamy cytoplasm (1). In Wilson disease, they contain copper deposits.
Pantothenate kinate-associated neurodegeneration (PKAN) (Hallervorden-Spatz syndrome) is an autosomal recessive disease linked to a mutation in the pantothenate kinase gene (PANK2). PKAN is clearly an iron deposition disease related to a reduction of the cysteine dioxigenase activity. The disease begins usually around the age of 15 and presents with gait disorders, rigidity of the lower limbs, dystonia, motor slowing, dysarthria, mental deterioration and a high incidence of choreoathetosis. Most patients die by the age of 35 years. In patients with longer survival, the disease usually presents as an extrapyramidal movement disorder associated with dementia. MRI, is usually diagnostic and shows "eye of the tiger sign" that is considered as a specific feature. The microscopic changes are roughly similar to those in aceruloplasminemia including iron deposition and numerous axonal spheroids, but are limited to the globus pallidus and pars reticularis of the substantia nigra. In these cases, the dentate nucleus, striatum, and thalamus are unaffected. There is no systemic extra-cerebral iron deposition.
Idiopathic hemochromatosis is an uncommon HLA-related genetic defect in the regulation of gastrointestinal iron absorption leading to excessive systemic iron deposition, particularly in the liver. The latter induces cirrhosis, which appears around 40 years of age. The cirrhosis is responsible for secondary neurological involvement i.e. hepatic encephalopathy. In the brain, iron deposition can only be found in areas in which the blood-brain barrier is absent (e.g. choroids plexus, area postrema).
Contributed by Fabrice Chrétien MD, Jérôme Servan MD, Jacqueline Mikol MD, PhD, Michèle Trierweiller MD, Dominique Elghozi MD, Françoise Gray MD, PhD.