The Neurological Presentation of Ceruloplasmin Gene Mutations

Abstract

Aceruloplasminemia is an autosomal recessive disorder of iron metabolism resulting from mutations of the ceruloplasmin gene. To better define the neurological phenotype of aceruloplasminemia we reviewed reports of published cases and sought details of unpublished ones. We identified 32 published reports and 1 unpublished case. The age at diagnosis ranged from 16 to 71 years with a mean of 51. For the 28 homozygous cases the most common presentation was with cognitive impairment (12/28, 42%) accompanied by craniofacial dyskinesia (8/28, 28%), cerebellar ataxia (13/28, 46%) and retinal degeneration (21/28, 75%). Four heterozygotes presented with cerebellar signs or tremor, whilst 1 had chorea-athetosis. There were no genotype-phenotype associations, but homozygotes tended to have severer disease.

A Cross-Sectional Community Study of Serum Iron Measures and Cognitive Status in Older Adults

“…There has been considerable speculation that both iron deficiency and excess affect cognitive or motor performance and contribute to neurodegenerative disease, leading to proposals that chelation or other approaches may be of therapeutic relevance in this context [3][4][5][6]. This is supported by a limited amount of intriguing, but largely circumstantial, evidence derived from animal models and small patient groups [1,[7][8][9][10].…”

Iron chelation in the treatment of neurodegenerative diseases

“…Since aceruloplasminemia is a rare orphan disease, effects of chelation therapy were reported only in several case studies (Table 1). Deferasirox and deferoxamine treatments lead to serum ferritin normalization, decrease of hepatic and cardiac iron loading, and symptomatic improvement of anemia and diabetes in the majority of patients [44][45][46][47]. However, neurological outcomes of iron removal therapy are variable.…”

En mann i 50-årene med høyt ferritinnivå og økende kognitiv svikt

“…Ceruloplasmin er et kobberbindende plasmaprotein som oksiderer jern før det kan bindes til transferrin og transporteres til erytropoetisk marg og andre kroppsvev. I likhet med ferroportinsykdom fører mutasjon i ceruloplasmingenet til nedsatt utskilling av jern fra cellene, med opptil 40 ganger økning av s-ferritin, lav transferrinmetning, tendens til anemi og intoleranse for intensiv årelating (15).…”

“…I en metastudie, som inkluderte 28 homozygote pasienter med gjennomsnittsalder 51 år, var de vanligste nevropsykiatriske symptomene cerebellar ataksi (46 %), kognitiv svikt (42 %) og dyskinesier i ansiktet (28 %) (15). Heterozygote baerere kan ha moderate endringer i laboratorieprøvene, uten eller med mild sykdom.…”

“…Tilstanden er meget sjelden, med en beregnet prevalens i Japan på én per to millioner innbyggere (15). Prevalensen i andre land er ukjent.…”