Further Neurobiologic Studies

Based on the abundant reports of probable ChAc in Japan, basic scientific studies were performed in a number of institutions. A number of erythrocyte membrane studies were carried out [3, 24, 38]. A study using freeze-fracture electron microscopy showed a significant increase of the intramembranous particle free areas in both P and F faces [38]. The fluidity deep inside the red cell membrane in this disorder was studied using a spin labeling technique, and low fluidity was found when compared to that of normal red blood cells [24]. The same group also studied the capacity of self-digestion of red blood cells and reported easily self-digestible conformation of the red cell membrane in patients with probable ChAc [3]. Sakai et al. reported the abnormal membrane property of acanthocytes in patients with probable ChAc [29]. Analysis of covalently (tightly) bound fatty acids in erythrocyte membrane proteins after alkaline hydrolysis disclosed an increase of palmitic and docosahexaenoic (C22:6) acids and a decrease of stearic acid in this disease.

Muscle biopsy examination in the patients with distal amyotrophy due to probable ChAc revealed a typical neurogenic grouped atrophy with fibre-type grouping, suggestive of chronic polyneuropathy [11, 17]. Histological studies of the sural nerve biopsy showed axonal degeneration associated with secondarily demyelinat-ing changes. The density of total myelinated fibers was slightly decreased with more involvement of large myelinated fibers [22, 23].

In addition to neurogenic changes in muscle biopsy, evidence now supports a primary muscle fiber or membrane disorder to explain elevated CPK in this disease. Nemaline rods were noted in the subsarcolemmal and paranuclear locations of the muscle biopsy of probable ChAc [36]. This strongly suggests a primary disorder in the muscle membranous structure in this disease. Dilated cardiomyopathy with skeletal myopathy was also reported in a case of ChAc in which MLS was definitively excluded [13]. We also have an evidence of abnormally disrupted ChAc expression in the muscle membrane, stained histochemically with the anti-chorein antibody (in preparation).

Post mortem neuropathological studies of probable ChAc were reported by Iwata et al. [12] and Sato et al. [30]. These authors found atrophy and gliosis of the caudate nuclei and putamen, with no neuronal loss in the cerebral cortex or other parts of the brain, including the substantia nigra. Degeneration and gliosis was the most marked in the head of the caudate, followed in the body and the tail. The numbers of small neurons in the caudate nucleus and putamen were greatly reduced to 1% and 20% of each healthy control respectively. On the other hand, large neurons of the caudate decreased in diameter but not in number. The ventral portion of the putamen was also moderately degenerated. These findings are quite similar to those reported by Bird et al. [4] and Hardie et al. [7]. Sato's group also studied biochemical changes of the striatum in their autopsy case. They found marked a decrease of substance P (SP) level without any changes of choline acetyltransferase or glutamic acid decarboxylase (GAD) in both the caudate nucleus and putamen [30]. However, GAD and SP activity were decreased in the substantia nigra where there were no histopathological abnormalities.

Neurosurgical management of probable ChAc with posteroventral pallidotomy (PVP) was reported in one case with severe intractable involuntary movements [6] and see chapter by Yokochi and Burbaud. A 41-year-old man suffered from marked orolingual dyskinesia which gave him marked difficulty with eating and swallowing. A left PVP was done initially with a marked reduction of oro-lingual dyskinesia and chorea of the right limbs. Subsequently he had a PVP of the right side with reduction of the left-sided choreo-ballistic movements. The same authors have performed a bilateral PVP for another patient with ChAc with a complete remission of involuntary movements (see chapter by Yokochi and Burbaud). The exact mechanism of the effect by this surgical procedure has not yet been clearly explained.

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