Cerebellar ataxia associated with heteroallelic ceruloplasmin gene mutation

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.

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.

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.

Cerebellar ataxia reflects the site of iron deposition. Being heterozygous for mutation of the ceruloplasmin gene may result in cerebellar ataxia.