Cerebellar ataxia associated with heteroallelic ceruloplasmin gene mutation.

摘要

BACKGROUND: Aceruloplasminemia, an autosomal recessive disorder that affects human iron metabolism, is caused by mutation of the ceruloplasmin gene. Heterozygous individuals with a partial ceruloplasmin deficiency may have normal iron metabolism and no clinical symptoms. METHODS: The authors clinically characterized three Japanese patients from two families who had cerebellar ataxia with hypoceruloplasminemia from the fourth decade of life. Genetic analysis, restriction fragment length polymorphism analysis, and a pathologic study were performed. RESULTS: All three patients presented with cerebellar dysfunction that included relatively nondisabling gait ataxia and dysarthria, as well as hyperreflexia. Brain and abdomen MRI showed cerebellar atrophy and no low-signal intensities in the basal ganglia, thalamus, and liver. Direct mutational analysis excluded SCA-1, SCA-2, SCA-3, SCA-6, SCA-7, SCA-8, SCA-12, and DRPLA. The patients partially lacked serum ceruloplasmin, and the protein concentrations and ferroxidase activities ranged from 36% to 41% of the control values; moreover, they were heterozygous for a nonsense mutation of the ceruloplasmin gene (Trp858ter). Serum iron concentration and transferrin saturation were normal. At autopsy, pathologic and biochemical examinations showed marked loss of Purkinje cells, a large iron deposition in the cerebellum, and small depositions in the basal ganglia, thalamus, and liver. CONCLUSION: Cerebellar ataxia reflects the site of iron deposition. Being heterozygous for mutation of the ceruloplasmin gene may result in cerebellar ataxia.