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Cerebellar ataxia associated with heteroallelic ceruloplasmin gene mutation

From the First Department of Medicine (Drs. Miyajima, Kono, Takahashi, and Sugimoto), Hamamatsu University School of Medicine; Department of Neurology (Dr. Sakamoto), Hamamatsu Medical Center, Hamamatsu; and Department of Neurology (Dr. Sakai), Yaizu General Hospital, Yaizu, Japan.

Address correspondence and reprint requests to Dr. Hiroaki Miyajima, The First Department of Medicine, Hamamatsu University School of Medicine, 1-20-1 Handayama, Hamamatsu 431-3192, Japan; e-mail: miyajima{at}hama-med.ac.jp

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.

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