Characterization of a nonsense mutation in the ceruloplasmin gene resulting in diabetes and neurodegenerative disease.

We report here on the characterization of a mutation in the ceruloplasmin gene in a 45 year old woman with insulin-dependent diabetes mellitus who presented with the recent onset of gait disturbance and dysarthria. Physical examination revealed an ataxic gait, scanning speech and retinal degeneration. Magnetic resonance imaging of the brain was consistent with increased basal ganglia iron content and laboratory studies revealed a low serum iron concentration and no detectable serum ceruloplasmin. Nucleotide sequence analysis of the ceruloplasmin gene from this patient revealed a G to A substitution in exon 15 resulting in a nonsense mutation at amino acid 858 (Trp858ter). The patient's younger, neurologically asymptomatic brother was also found to be homozygous for this mutation. Taken together the clinical and genetic data support the concept of an essential and unique role for ceruloplasmin in human iron metabolism. Identification of this kindred extends the spectrum of ceruloplasmin gene mutations resulting in this autosomal recessive, late-onset neurodegenerative disease and highlights the importance of recognizing aceruloplasminemia as a genetic cause of diabetes and neurologic disease.