Aceruloplasminemia

Aceruloplasminemia is a rare autosomal recessive neurodegenerative disorder caused by biallelic mutations in CP, the gene that encodes ceruloplasmin, a copper-containing ferroxidase essential for cellular iron export. Deficiency of ceruloplasmin leads to systemic iron overload and iron deposition in the brain and other organs.

Pathophysiology involves impaired oxidation of Fe2+ to Fe3+ required for ferroportin-mediated iron efflux. Without ceruloplasmin activity, iron accumulates in neurons and glia, promoting oxidative stress and cell injury. Laboratory testing typically shows very low or undetectable serum ceruloplasmin and reduced ferroxidase activity; serum copper may be normal or reduced. Aceruloplasminemia is extremely rare, with only a small number of cases reported.

Neurological features usually develop in adulthood and progress over years, with movement disorders such as tremor, dystonia, ataxia, and dysarthria, along with signs of parkinsonism, cognitive decline, and psychiatric symptoms. End-organ involvement may include retinopathy and diabetes mellitus from pancreatic iron deposition; liver iron can cause hepatic dysfunction.

Diagnosis relies on a combination of clinical findings, severely reduced serum ceruloplasmin and ferroxidase activity, brain iron deposition on MRI (symmetric T2*-weighted or susceptibility-weighted imaging abnormalities in basal ganglia, thalamus, and cerebellum), and confirmation by CP gene sequencing.

Treatment centers on managing iron overload and its manifestations. Iron chelation with deferiprone, which crosses the blood–brain barrier, has been reported to reduce brain iron and stabilize or improve neurological symptoms in some patients; deferasirox and deferoxamine are less consistently beneficial for brain iron. Supportive care includes monitoring for diabetes and liver disease and genetic counseling.