Rinsho Shinkeigaku (Clinical Neurology)

Case Report

An autopsy case of multiple system atrophy with a heteroallelic ceruloplasmin gene mutation

Harumi Yomono, M.D.1), Hiroshi Kurisaki, M.D.1), Shigeo Murayama, M.D.2), Akira Hebisawa, M.D.3), Hiroaki Miyajima, M.D.4) and Yoshiaki Takahashi, M.D.4)

1)Department of Neurology, Tokyo National Hospital
2)Department of Neuropathology, Tokyo Metropolitan Institute of Gerontology
3)Department of Pathology, Tokyo National Hospital
4)The First Department of Medicine, Hamamatu University School of Medicine

We reported a 69-year-old woman with multiple system atrophy (MSA), who had a heteroallelic missense mutation (G1874A, Gly→Glu) in the exon 11 of the ceruloplasmin (Cp) gene. At the age of 64, she began to complain of progressive gait disturbance, which was resistant to anti-Parkinsonian drug treatment. Neurological examination revealed parkinsonism such as rigidity, akinesia, mild tremor and postural instability, accompanying saccadic eye movement, dysarthria, dysphagia, orthostatic hypotension and bladder disturbance. She showed neither cerebellar signs nor dementia. Serum Cp and copper concentrations were 13-18 mg/dl and 38-56 μg/dl, respectively, which were decreased to about a half of normal values. Brain MRIs revealed high intensity areas in the bilateral putamens in the T2-weighted image, and mild pontine base atrophy. She died of respiratory failure due to laryngeal paresis after five years from the onset. Neuropathological examination revealed brown-colored putamens, where there was severe neuronal cell loss with gliosis. Though atrophy of the pontine base was mild, transverse myelinated fibers were pale in Klüver-Barrera stain. There were Purkinje cell loss of moderate degree and appearance of torpedos in the cerebellum. Both silver staining and immunohistochemical staining to α-synuclein showed glial cytoplasmic inclusions, which were found predominantly in the putamens. These clinical features and neuropathological findings were compatible with multiple system atrophy (MSA). Iron staining of the brain revealed iron deposition in the putamens and the substantia nigra, but not in the pontine base nor in the cerebellum. Furthermore, we failed to reveal it in both the liver and the pancreas as well as the thalamus and the caudate nucleus, which were common sites of iron deposition in the previous cases of Cp gene mutation. We have already reported three other MSA cases with a- or hypo-ceruloplasminemia with similar clinical and pathological features to this case. One of them, in which gene analysis was also available, did not have any mutations in its Cp gene. Therefore, the gene mutation of this case may not be a direct cause to MSA, but the fact that the most cases of MSA with hypoceruloplasminemia showed striatonigral degeneration (SND) type implies some relationship between hypoceruloplasminemia and SND.

(CLINICA NEUROL, 43: 398－402, 2003)
key words: ceruloplasmin gene mutation, hypoceruloplasminemia, multiple system atrophy

(Received: 1-Aug-02)