Masao Ushiyama

Cerebral hemorrhage in Fabry's disease

Fabrys disease is an X-linked lysosomal storage disorder resulting from α-galactosidase A deficiency. Although ischemic stroke is recognized as an important manifestation of Fabrys disease, hemorrhagic stroke is considered to be rare. Here, we report our recent clinical experience with three hemizygous male patients with Fabrys disease who developed cerebral hemorrhage. One patient had classic type Fabrys disease with p.Ala37Val mutation and others had cerebrovascular variant with p.Glu66Gln mutation. Degeneration of the cerebral small arteries secondary to deposition of glycosphingolipids and aging, in addition to hypertension and antiplatelet/anticoagulant agents, are considered to be contributing factors for hemorrhage. Fabrys disease is frequently associated with not only ischemic but also hemorrhagic stroke, especially in elderly patients.

Late-onset spastic ataxia phenotype in a patient with a homozygous DDHD2 mutation

Autosomal recessive cerebellar ataxias and autosomal recessive hereditary spastic paraplegias (ARHSPs) are clinically and genetically heterogeneous neurological disorders. Herein we describe Japanese siblings with a midlife-onset, slowly progressive type of cerebellar ataxia and spastic paraplegia, without intellectual disability. Using whole exome sequencing, we identified a homozygous missense mutation in DDHD2, whose mutations were recently identified as the cause of early-onset ARHSP with intellectual disability. Brain MRI of the patient showed a thin corpus callosum. Cerebral proton magnetic resonance spectroscopy revealed an abnormal lipid peak in the basal ganglia, which has been reported as the hallmark of DDHD2-related ARHSP (SPG 54). The mutation caused a marked reduction of phospholipase A1 activity, supporting that this mutation is the cause of SPG54. Our cases indicate that the possibility of SPG54 should also be considered when patients show a combination of adult-onset spastic ataxia and a thin corpus callosum. Magnetic resonance spectroscopy may be helpful in the differential diagnosis of patients with spastic ataxia phenotype.

Noradrenergic nerve fibers of the rectal mucosa in autonomic disorders" comparison of histochemical study with clinical severity and changes in plasma noradrenaline induced by standing

A histochemical study was carried out on the rectal mucosae biopsied from 20 patients with autonomic dysfunctions and 13 controls using a catecholamine fluorescent staining method, and the rectal noradrenergic nerve fiber lesions were compared with the severity of autonomic symptoms and disturbance of plasma noradrenaline increase in response to standing in 17 patients. In 9 patients with type I familial amyloid polyneuropathy and 1 with acute pandysautonomia, the number of fluorescent nerve fibers was greatly reduced, and the degree of depletion correlated well with the other 2 parameters showing the severity of autonomic dysfunction. In contrast, rectal noradrenergic nerve fibers were normally preserved in 10 patients with multiple system atrophy, although they suffered from severe autonomic symptoms with poor noradrenaline response to the postural loading. It is concluded that noradrenergic nerve fiber lesions in the biopsied rectal mucosa may represent the systemic involvement of sympathetic post-ganglionic nerves.

ULTRASTRUCTURAL FINDINGS OF RECTAL AND SKIN BIOPSIES IN ADULT GM1-GANGLIOSIDOSIS

We report the ultrastructural findings in rectal and skin biopsies in four cases with adult GM1‐gangliosidosis. The rectal specimens taken under endoscopic control contained submucosal plexuses, which were easily identified on light‐microscopic and electron‐microscopic examination. In all cases the ganglion cells in submucosal plexus contained characteristic osmiophilic lamellar Inclusions, some of which were typical membranous cytoplasmic bodies, but others showed pleomorphism in shape and diameter. Lipofuscin bodies were commonly observed in the ganglion cells, Schwanns cells, vascular endothelial cells, and perithelial cells in rectal biopsy, and membrane‐bound clear vacuoles were occasionally seen in the cytoplasm of rectal and cutaneous fibroblasts. However, the axons of unmyelinated nerves in both biopsies showed a normal appearance, and there was no significant change in the eccrine glands in skin biopsy. Comparing rectal and skin biopsies, the former was found to be more valuable for morphological diagnosis of this disease, and our ultrastructural examination of rectal biopsy revealed that enteric nerve cells were involved even in adult GM1‐gangliosidosis with a benign course and restricted cerebral lesions.

Prealbumin type cerebral amyloid angiopathy in familial amyloid polyneuropathy

Immunocytochemical and electron-microscopic studies were performed on the central nervous system(CNS) in 10 cases with type I familial amyloid polyneuropathy. All cases showed CNS amyloid deposits, mainly on the leptomeningeal vessels and pia-arachnoid membranes, with arteries and arterioles in subarachnoidal space being the predominant site of cerebral amyloid accumulation. All of these amyloid deposits were specifically immunolabeled by an anti-human prealbumin antibody. However, there were no prealbumin deposits in the brain parenchyma. It is concluded that CNS prealbumin-type amyloid deposition with cerebral amyloid angiopathy is a common pathological finding in this disease.

Shinshu Brain Resource Net

“Shinshu Brain Resource Net” is a database of pathological reports, stained sections and paraffin blocks of brains, clinical information and images of nervous systems of patients with neurological diseases autopsied in core hospitals in Nagano prefecture, Japan (Fig. 1). The Net was established in August 2010 and is now managed by 17 Board Members. The total number of patients registered was 841 in February 2016. The materials of the registered patients autopsied have been used for various collaborative researches, and for education and enlightenment of medical students and doctors at lectures and clinical and pathological conferences (Shinshu NeuroCPC) which were held featuring particular neurological themes. Papers reported using the autopsy cases of the Net, ongoing researches and themes of the Shinshu NeuroCPC are noted below. All of the materials are kept in each hospital where the autopsies were done, and the principle data of each patient are gathered in the Division of Neuropathology, Department of Brain Disease Research, Shinshu University School of Medicine, Nagano, Japan. The “Shinshu Brain Resource Net” contains 63 sporadic amyotrophic lateral sclerosis (ALS), eight familial ALS containing L106 V and C111Y mutations of SOD1, 18 spinocerebellar ataxia containing SCA31, 21 familial amyloid polyneuropathy, four transthyretin amyloid angiopathy, three citrullinemia and two aceruloplasminemia. The “Shinshu Brain Resource Net” is open for collaborative studies by researchers as well as the members of the Board.