Yoshiyuki Suzuki

β-Galactosidase deficiency in juvenile and adult patients

SummarySix juvenile and adult patients with progressive neurological diseases and β-galactosidase deficiency were reported. Any diseases known to date were denied. These cases together with ten case reports in the literature were reviewed and were classified into three groups from clinical and biochemical points. Group 1 patients were characterized by progressive ataxia and myoclonus with gargoyle changes and macular cherry-red spots. In this syndrome β-galactosidase activity seems to be secondarily affected by other biochemical defects. A group 2 patient showed similar neurological manifestations without gargoyle changes or macular cherry-red spots. Patients with these clinical features not associated with β-galactosidase deficiency have also been described in the literature. Group 3 patients had progressive pyramidal and extrapyramidal disease without gargoyle changes or macular cherry-red spots. These cases may represent juvenile and adult type GM1-gangliosidosis. Accumulation of GM1 has not yet been demonstrated.

High expression of L-type amino-acid transporter 1 (LAT1) in gastric carcinomas: Comparison with non-cancerous lesions

Amino acid transporters are essential for maintenance and proliferation of both normal and transformed cells. In the present study, L‐type amino‐acid transporter 1 (LAT1) immunoreactive expression was investigated in gastric carcinomas, in comparison with gastric adenomas and non‐neoplastic lesions, using our recently developed novel monoclonal antibody. In a total of 87 cases of advanced gastric cancer, high LAT1 expression was observed in carcinoma cells, predominantly at plasma membranes with greater intensity in non‐scirrhous than scirrhous carcinomas. Gastric carcinoma cases with lymph node metastasis showed significantly higher LAT1 expression than cases without lymph node metastasis. A positive correlation with Ki‐67 LI was observed and the highly expressing non‐scirrhous carcinomas showed a significantly poorer prognosis than the low LAT1 group. Cox hazard test revealed that TNM stage and LAT1 expression were independent prognostic factors in non‐scirrhous carcinoma group. Further, a significant poor prognosis was confirmed in high LAT1 expression group, when limited to undifferentiated carcinoma cases excluding scirrhous carcinoma. Lower levels were found in adenomas. In conclusion, LAT 1 expression may be linked with cell proliferation and prognosis of gastric carcinomas, and offers a potential target for future anticancer therapy by inhibitors.

Cardiovascular manifestations in Fabry's disease. A high incidence of mitral valve prolapse in hemizygotes and heterozygotes

Cardiovascular manifestations of Fabrys disease were studied clinically in 10 hemizygous males and 13 heterozygous females. Mitral valve prolapse was found in 5 of 9 hemizygotes and in 5 of 13 heterozygotes examined by echocardiography. Ordinary medical examinations revealed cardiomyopathy in some asymptomatic females, and the diagnosis of the Fabry heterozygote was established by demonstration of specific inclusion bodies in the biopsied myocardium and low a‐galactosidase activity in leukocytes. Renovascular hypertension of juvenile onset and thromboembolism were also found in 7 patients. It was concluded that Fabrys disease should always be considered in cases of mitral valve prolapse, cardiomyopathy, renovascular hypertension and thrombosis of unknown etiology, and that the Fabry patients should be followed carefully for the early detection of cardiovascular involvements in this disease.

GM1-gangliosidosis: accumulation of ganglioside GM1 in cultured skin fibroblasts and correlation with clinical types.

SummaryUptake of radioactivity from 14C-galactose into gangliosides by cultured skin fibroblasts was studied. GM3 was the major ganglioside in control human fibroblasts. An increase of GM1 was demonstrated in GM1-gangliosidosis fibroblasts. The degree of GM1 accumulation was correlated with the clinical types of this disease. The fibroblasts from an infantile-type patient showed a marked increase of GM1. In late-onset types the amount of total gangliosides was only slightly increased, but the distribution of individual gangliosides was definitely abnormal; a relative increase of GM1 was demonstrated in these cases. GM1 β-galactosidase activities were not detectable in either infantile or late-onset cases.

β-Galactosidase-neuraminidase deficiency in adults: Deficiency of a freeze-labile neuraminidase in leukocytes and fibroblasts

Summary4-Methylumbelliferyl neuraminidase activity was studied in fibroblasts, leukocytes, and frozen tissues from adult patients with β-galactosidase-neuraminidase deficiency and specific clinical manifestations. This enzyme was almost completely deficient in fibroblasts, but the residual activity was relatively high (20% of the control mean) in the leukocytes from the patients. The frozen liver from one patient showed the enzyme activity as high as controls.This enzyme consisted of two components, freeze-labile and freeze-stable, and it was demonstrated that only the labile enzyme was deficient in fibroblasts and leukocytes. The apparently normal activity of neuraminidase in frozen autopsy tissues of a patient may be explained by the loss of the labile component in control tissues after a long-term freezing. The neuraminidase activity was variable in parents and no definite conclusion was drawn on the hereditary nature of the disease.

SANFILIPPO B SYNDROME — A CASE REPORT —

An autopsy case of a 9 years and 5 months old gargoyle girl diagnosed as Sanfilippo B syndrome by the biochemical demonstration of a large amount of heparan sulfate in urine and some organs and of deficiency of α‐N‐acetyl‐D‐glucosaminidase in the liver and brain was reported. The morphological changes characterized by cytoplasmic swelling and vacuolization were more generalized than those which had been described in previously reported cases. Histochemically, accumulation of variable amounts of acidic glycosaminoglycans and compound lipids, presumably gangliosides and phospholipids, was substantiated in the vacuolated cells of various visceral organs and in the ballooned neuronal cells. Ultrastructurally, numerous inclusions found in these cells were largely divided Into two types; flocculent reticulogranular and osmiophilic, mostly laminated materials, many of which were bound by a single unit membrane. Enzyme cytochemistry proved acid phosphatase activity in the majority of the inclusions in fibroblasts and nbrocytes biopsied from the skin. Rough endoplasmic reticulum in these cells was markedly dilated with reticulogranular materials. The morphological changes of the present case and their pathogenesis were discussed.

MORPHOLOGICAL AND BIOCHEMICAL STUDIES OF A CASE OF MUCOPOLYSACCHARIDOSIS II (HUNTER'S SYNDROME)

An autopsy case of a 19‐year‐old boy who had shown typical gargoyle features, strictly consistent with mucopolysaccharidosis type II (Hunters syndrome) was reported. Histologically, cytoplasmic vacuolar change was found In hepatocytes, sinusoidal epithelium of spleen, follicular cells of thyroid, Sertoli cells of testis, chromophobe cell of pituitary and generalized fibroblast‐like cells including meninges, cardiac valve and periosteum. The vacuoles consisting of membrane‐bound structures with flocculus protein‐like material and occasional electron dense bodies on electron microscopy, were considered to be the site of mucopolysaccharide deposition by histochemical analysis. Deposition of lipid material consistent with so‐called membranous cytoplasmic body was observed in the neurons of central, peripheral and autonomic nervous system. Hepatosplenomegaly could be explained by cytoplasmic deposition, but the cause of cardiomegaly remained further to be studied. Biochemically hepatic mucopolysaccharide was identified as heparan sulfate, while in the kidney dermatan sulfate and heparan sulfate were detected. The correlation between morphology and biochemistry, and between deposition and degeneration was discussed.

Effect of vitamin E and ticlopidine on platelet aggregation in Fabry's disease.

Thromboembolism, increased platelet aggregation and high plasma concentration of /?‐throm‐boglobulin were observed frequently in hemizygotes and heterozygotes of Fabrys disease. The administration of vitamin E and ticlopidine could improve the increased platelet aggregation in this disease. The platelet activation, probably induced by vascular endothelial damages, would accelerate atherosclerotic and thromboembolic vascular changes. Antiplatelet therapy will be effective for the prevention of these vascular complications in this disease.

Farber's disease (disseminated lipogranulomatosis)--a pathological, histochemical and ultrastructural study--.

The first case of Farbers disease in Japan was reported, which was confirmed clinically, biochemically and pathologically. Soon after birth, the patient started developing hoarseness, stridor, fever, muscle hypotonous with retarded psychomotor functions including incapability of sitting alone and head control, joint swelling, subcutaneous nodules, albuminocytologic dissociation in cerebrospinal fluid, nodular corneal opacity, and abnormal findings in electroencephalogram. Lipid analysis on the material obtained from a subcutaneous nodule confirmed the presence of ceramide. Pathologically, the subcutanoues nodules were made up of granulomatous lesions displaying varied histological pictures, i.e., from cellular to fibrous areas depending on the disease progress. In the beginning, cells were mostly spindle‐shaped, and as these cells were getting more round and larger, cells manifested the morphology of foam cells. Spindle‐shaped cells were positive for periodic acid‐Schiff and acid mucopolysaccharide stainings. This particular substance disappeared almost entirely in typical foam cells. Electron microscopically, the cytoplasm of foam cells was filled with membrane‐bound storage inclusions which consisted of so‐called curvilinear tubular structures. Morphogenesis of the granulomatous lesions and histochemical and ultrastructural correlation of storage cells in this disorder were discussed.

LIPID STORAGE DISEASE: PART III: Ultrastructural Evaluation of Cultured Fibroblasts in Sphingolipidoses

For the purpose of evaluating electron microscopy of tissue culture in making the diagnosis of Sphingolipidoses, an ultrastructural study was made on the cultured fibroblasts from 23 patients with the disorders. The characteristic cytoplasmic inclusions were observed in the cultured cells of Fabry disease, Tay‐Sachs disease, Sandhoff disease, generalized gangliosidosis, Niemann‐Pick disease, metachromatic leukodystrophy, and multiple sulfatase deficiency, and differ in fine structure with these diseases. All these cytoplasmic inclusions were surrounded by a single limiting membrane and enzyme cytochemically showed acid phosphatase activity, indicating their lysosomal origin. Ultrastructurally, the cytoplasmic inclusions showed pleomorphic osmiophilic inclusions in Fabry disease, membranous cytoplasmic bodies (MCB) in Tay‐Sachs disease and Sandhoff disease, MCB and vacuolar inclusions containing finely reticulogranular materials in generalized gangliosidosis, myelin‐like inclusions in Niemann‐Pick disease, concentric lamellar inclusions in metachromatic leukodystrophy, and polymorphic cytoplasmic Inclusions in multiple sulfatase deficiency. In the heterozygous carriers of Fabry disease, pleomorphic osmiophilic inclusions were also detected. However, any specific inclusions were not detectable in the cultured fibroblasts of Gaucher disease and Krabbe disease. Availability of electron microscopy in the cultured fibroblasts of Sphingolipidoses is discussed.