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Título

Aceruloplasminemia: a severe neurometabolic disorder

RESUMO

Case report
59-year-old woman presented with recent onset depressed mood and emotional lability. After 6 months, forgetfulness, impairment of activities and speech difficulties were observed, followed by gait imbalance. On examination, she was dysarthric, disoriented in time, and also had saccadic intrusions, rigidity, oral dyskinetic movements, cervical dystonia, and ataxic gait.
Investigation included complete blood counts, liver, thyroid and kidney function tests, HIV, syphilis and hepatitis serologies; and they were unremarkable. Additional tests revealed elevated ferritin levels (2540ng/ml), low serum iron (27 µg/dL), reduced plasmatic ceruloplasmin and low urinary copper.
Brain MRI showed T2 hypointensity and SWI low signal on basal ganglia, thalamus and dentate nucleus. NGS-based gene panel testing was performed showing the pathogenic variant c.1149G>A (p.Tr383) as well as a variant of uncertain significance (VUS) c.31118T>C (p.Cys1040Arg) in the ceruloplasmin (CP) gene, in heterozygosity. The VUS is expected to disrupt CP protein function, although not yet reported on CP-related conditions. Despite not being able to determine if the CP variants are in cis or in trans, our final diagnosis was aceruloplasminemia (ACP). The patient initiated the treatment with deferoxamine combined with fresh frozen plasma (FFP) which controlled the disease progression.
Discussion
ACP is an adult-onset autosomal recessive disorder caused by homozygous or compound heterozygous mutations in the CP gene (responsible for iron homeostasis). This mutation can cause systemic and cerebral iron overload.
The clinical features are diabetes, retinopathy, liver disease and progressive neurological symptoms: movements disorders and cognitive dysfunction. An early sign of the disease is an atypical anemia with microcytosis, low transferrin saturation and hyperferritinemia.
Brain MRI can show dentate nuclei of cerebellum, basal ganglia and thalamus with diffuse hypointensity in T2 and SWI. The diagnosis of ACP is established with typical clinical findings and the identification of pathogenic CP gene variants.
The treatment is focused on iron chelators therapy (ICT). ICT is more effective in reducing systemic iron overload but less effective on neurological symptoms and it can be combined with FFP administration.
Final remarks
ACP is a severe neurometabolic disorder that needs a prompt diagnosis and therapy to prevent neurological complications.

Palavras Chave

Aceruloplasminemia Ceruloplasmin Dystonia Dyskinesia