Jiro Fujiyama

Cerebrotendinous xanthomatosis: Clinical and biochemical evaluation of eight patients and review of the literature

We present the clinical and laboratory findings of 8 patients with cerebrotendinous xanthomatosis. The clinical features consisted of a combination of bilateral Achilles tendon xanthomas, cataracts, low intelligence, pyramidal signs, cerebellar signs, convulsions, peripheral neuropathy, foot deformity, cardiovascular disease or atherosclerosis, EEG abnormality, and increased CSF protein. Increased cholesterol was present in the serum, CSF and red cell membrane of all 8 patients. The bile of one patient with late age onset of the disease showed an attenuated production of bile acids and bile alcohols. Three of the 7 had obstruction and/or marked narrowing of the coronary arteries. Data on 136 patients reported throughout the world are reviewed.

Mechanism of methylmercury efflux from cultured astrocytes

To study the mechanism of methylmercury (MeHg) efflux from the central nervous system cells, cultured astroglia obtained from neonatal rats were incubated with 10 microM MeHg-cysteine (CySH) for 30 min. After being washed four times, cells were incubated in Hg-free medium, and the release of MeHg from the cells was monitored. The amount of MeHg released in the medium approached a plateau level (ca. 31% of the loaded amount) at 4 hr. Treatment of the cells with a CySH precursor, 2-oxothiazolidine-4-carboxylic acid (OTC), resulted in a significant increase of cellular levels of CySH and glutathione (GSH). OTC also increased 1.5-fold the MeHg efflux from the loaded cells. Another GSH enhancer, GSH isopropyl ester, also stimulated MeHg export from the cells. Ion-exchange column chromatography using DEAE-Sephadex revealed that the MeHg metabolite thus released was exclusively MeHg-GSH conjugate, both with and without OTC. Since the MeHg efflux was suppressed significantly by the presence of probenecid, the efflux occurred via the probenecid-sensitive organic acid transport system. Even though the cellular GSH levels were depleted drastically by treatment with L-buthionine-(S,R)-sulfoximine (BSO), a considerable level (90% of the control) of Hg efflux was detected. Since neither GSH- nor CySH-MeHg was detected in the culture medium of the BSO-treated cells, GSH depletion may trigger some other secretion system(s) in the cells. These results suggest that conjugation with GSH is the major pathway for MeHg efflux in rat astroglia, and that elevation in the cellular GSH level would possibly be a logical therapy for MeHg poisoning, promoting the accelerated elimination of MeHg from the critical tissues.

Epidemiology of Progressive Muscular Dystrophy in Okinawa, Japan

We studied the prevalence of various types of progressive muscular dystrophy (PMD) in Okinawa, Japan on December 31, 1989 and the incidence of Duchenne muscular dystrophy (DMD) in 5-year periods from 1957 to 1985. We classified patients with PMD clinically, electrophysiologically, molecular biologically and immunohistochemically with antidystrophin antibody, especially for sporadic cases of DMD, Becker muscular dystrophy (BMD) and limb-girdle muscular dystrophy (LG). The prevalence for all PMD in Okinawa was 7.13 X 10(-5) for DMD, 1.82 X 10(-5) for BMD in the male population, 1.55 X 10(-5) for LG, 1.14 X 10(-5) for congenital muscular dystrophy, 2.03 X 10(-5) for facioscapulohumeral muscular dystrophy (FSH), and 9.13 X 10(-5) for myotonic dystrophy (MD) in the total population. The incidence of DMD in the period 1957-1985 was 15.41 X 10(-5) live-born males (LBM) and 3.21 X 10(-5) LBM for BMD. The incidence has apparently declined in Okinawa since 1975. The prevalence of BMD, FSH and MD was rather high in Okinawa compared with previous reports. Molecular biological techniques for classifying patients were indispensable for the epidemiological study of PMD.

Cerebrotendinous xanthomatosis : cranial CT and MRI studies in eight patients

SummaryWe report the findings on cranial computed tomography (CT) and magnetic resonance imaging (MRI) and their correlation with the clinical manifestations, disease severity and biochemical abnormalities in eight patients with cerebrotendinous xanthomatosis. CT revealed cerebral atrophy in seven cases, cerebellar atrophy in four and focal low density lesions in the cerebral white matter in two. T2-weighted MRI showed high signal lesions in the cerebral white matter, focal in four cases and diffuse in one, and in the globus pallidus in three patients, two of whom also had lesions in the cerebellar white matter. While severely affected patients showed variable CT and MRI abnormalities, our cases did not show the dramatic findings expected from the neurological manifestations. Diffuse lesions in the cerebral and cerebellar white matter have been emphasized in previous reports, but in our study the focal lesions in the cerebral white matter were also present; the globus pallidus was frequently involved.

Treatment of cerebrotendinous xanthomatosis with low-density lipoprotein (LDL)-apheresis

We studied the effects of LDL-apheresis on the biochemical and clinical abnormalities of 5 patients with cerebrotendinous xanthomatosis (CTX). Levels of both cholestanol and cholesterol decreased to approximately 60% of those of pretreatment after one perfusion and gradually returned to their initial levels within 2 weeks. Improvement of clinical manifestations and regression of Achilles tendon xanthomas were detected after several perfusions, though dramatic changes could not be recognized. EEG abnormalities were improved immediately after LDL-apheresis in one patient. We conclude that LDL-apheresis may affect the serum cholestanol level and clinical manifestations in patients with CTX.

Histopathological and ultrastructural features of feline hereditary cerebellar cortical atrophy: a novel animal model of human spinocerebellar degeneration

Abstract Human spinocerebellar degeneration is one of the intractable diseases. We studied the detailed neuropathology of cats with hereditary cerebellar degeneration obtained from the experimental breeding. The findings included almost total loss of Purkinje cells with an increase in Bergmann’s glia in the cerebellar hemisphere, preservation of some Purkinje cells in the vermis and moderate neuronal depletion of the olive nucleus. Cerebellar and pontine nuclei were normal. The cerebrum and spinal cord as well as the peripheral nervous system appeared normal. Electron microscopic examination revealed swelling of the distal dendrites of Purkinje cells in the less-affected nodule of the vermis, and clusters of presynaptic boutons without any synaptic contact in the severely affected folia where Purkinje cell bodies and dendrites disappeared. Prolonged existence of presynapses in the molecular and Purkinje cell layers was confirmed by positive immunoreactivity to anti-synaptophysin. Quantitative analysis using electron microscopy demonstrated an apparent increase in the density and mean size of presynapses in the molecular layer of the severely affected folia. These findings indicate that degeneration of Purkinje cells started at the most distal part of the dendrite in this animal model of cerebellar degeneration, and that presynapses, axon terminals of the granular cells and basket cells can exist for a long time even after complete degeneration of the Purkinje cells. Further investigation of this novel animal model may promote a better understanding of pathogenesis of human hereditary cerebellar degeneration.

Muscle MRI findings of HTLV-1-associated myelopathy

We report here the muscle MRI findings in two patients with human T-cell lymphotropic virus type I-associated myelopathy (HAM). It is known that thigh muscles are vulnerable in HAM patients, but detailed information about the affected muscles has not been available. Muscle MRI findings of these patients showed that thigh muscles, especially adductor magnus, and semimembranosus muscles were severely affected, but lower leg muscles were comparatively preserved. In these affected muscles, neurogenic changes were observed by EMG. We concluded that muscle MRI is very useful to estimate the affected muscles in HAM patients.

Spontaneous Echo Contrast in Descending Aorta Correlates with Low Blood-Flow Velocity in Carotid Arteries and Hemostatic Abnormalities

Spontaneous echo contrast in the descending aorta (DA-SEC) was examined as a possible risk factor for cerebral thromboembolism. In 19 patients (10 males, 9 females) in the chronic stage of cerebral infarction, abnormal findings by transesophageal echocardiography, flow dynamics of the common carotid artery (CCA), and hemostatic factors including blood coagulation and fibrinolysis were investigated. In nine patients, DA-SEC was detected, and SEC in left atrium (LA-SEC) was detected in nine patients. The DA-SEC positive group showed decreased blood- flow velocity (BFV) in bilateral CCA, high levels of thrombin-antithrombin III complex (TAT) and prothrombin fragment 1.2 (F1+2), a decrease in platelet count and a slight increase in D- dimer, which means an activated state of thrombin generation and resulting fibrinolysis, compared to the DA-SEC negative group. On the other hand, the LA-SEC positive group showed normal BFV in CCA and only a slight increase in D-dimer. We conclude that the condition producing DA-SEC is a stronger risk factor for cerebral infarction than that producing LA-SEC.

Blood Dolichols in a Patient with Abetalipoproteinaemia

Dolichol and dolichyl derivatives have an important function as glycosyl carriers in the assembly of the N-asparaginyllinked oligosaccharide core region of glycoproteins. Dolichols are synthesized through the cholesterol biosynthesis pathway in all mammalian organs and are present in all tissues, and are also associated with lipoproteins in the blood circulation. However, the origin and metabolic pathway of blood dolichols remain unknown. Abetalipoproteinaemia is a disorder of the secretion of very low-density lipoprotein (VLDL) from the liver and of chylomicrons from the intestine into the blood circulation. Therefore, examination of blood dolichols in this disorder may provide valuable information on their origin and metabolic pathway. Dolichols were exclusively associated with the high-density lipoprotein (HDL) fraction (80·7±6·3% of total dolichols) in control human blood. Serum from a patient also contained dolichols in the HDL fraction (82·8% of total dolichols). The total amount of dolichols was higher in the patient (207·0 ng/mL) than in the controls (106·2±22·7 ng/mL, n = 14). The compositions of dolichols were very similar to each other. These results indicated that, at least in the patient with abetalipoproteinaemia, the HDL-associated dolichols were possibly derived from the liver not through other lipoproteins but through dolichol transfer protein, or were possibly taken up and carried by HDL from peripheral tissues.

Glycoproteins from Teratocarcinomas and Organs of Adult Mice: Analysis by Affinity Chromatography on Lectin-conjugated Agarose1

Glycoproteins were isolated from particulate fraction of four teratccarcinomas and several organs of adult mice by affinity chromatography on lectins conjugated with agarose [concanavalin A (Con A), wheat germ agglutinin (WGA), Ricinus communis agglutinin (RCA), peanut agglutinin (PNA) and Dolichos biflorus agglutinin (DBA)] and were compared by SDS gel electrophoresis. Glycoprotein components were found to be very similar in three lines of solid teratocarcinoma, namely F9, STT‐2 and OTT‐10A. Teratocarcinoma OTT6050, which is an ascitic form called embryoid bodies, also gave glycoprotein profiles somewhat similar to those of other teratocarcinomas. However, glycoprotein profiles of most adult organs were significantly different from those of teratocarcinomas. The following points were of special interest. 1) RCA receptors from the four teratocarcinomas gave a strong band with an apparent molecular weight 145,000 daltons, which was either weak or absent in the receptors from adult organs. 2) The WGA receptors of all adult organs except muscle and small intestine gave more intense bands than those of the teratocarcinomas. 3) Glycoproteins with molecular weights of more than 240,000 daltons were present in WGA receptors, RCA receptors and PNA receptors of teratocarcinoma OTT 6050, but not in the receptors of other teratocarcinomas.