The gene copy ratios of SMN1/SMN2 in Japanese carriers with type I spinal muscular atrophy.

Spinal muscular atrophy is an autosomal recessive neurodegenerative disorder with progressive weakness and atrophy of voluntary muscles. The survival motor neuron gene (SMN) is present in two highly homologous copies (SMN1 and SMN2) on chromosome 5q13. Homozygous deletion of exons 7 and 8 of SMN1 is responsible for spinal muscular atrophy. In spinal muscular atrophy patients, SMN2 partially compensates for the lack of SMN1. Previously, we reported the relatively high incidence of a large deletion including the SMN1 region in Japanese spinal muscular atrophy type I patients. In order to further establish the genetic background of Japanese spinal muscular atrophy type I patients, we investigated the SMN1/SMN2 ratio in the carriers. In normal individuals, there is one copy of each gene on the chromosome (the SMN1/SMN2 ratio was 1). Among 15 carriers (14 parents and one carrier sibling of Japanese type I spinal muscular atrophy patients with homozygous deletion of exons 7 and 8 of SMN1), we found that the SMN1/SMN2 ratio was 0.5 or 1 in 11 (73.3%) carriers. The remaining four carriers had an SMN1/SMN2 ratio of 1/3. This finding supports the idea that deletion rather than conversion is the main genetic event in type I spinal muscular atrophy. In addition, the ratio of SMN1/SMN2 among Japanese carriers, which was thought to be higher than that of the Western population, was compatible with the results obtained in Western populations. For further insight into the characteristic genetic background of spinal muscular atrophy in Japanese, determination of the gene copy number is essential.

Enhanced expression of a-series gangliosides in fibroblasts of patients with peroxisome biogenesis disorders.

Peroxisome biogenesis disorders (PBD) are classified into Zellweger syndrome (ZS), infantile Refsum disease (IRD) and neonatal adrenoleukodystrophy. Disturbances in the differentiation of neural cells such as migration arrest are characteristic of PBD. So far the pathogenesis of these disturbances is not clearly understood. We describe an altered metabolism of glycosphingolipids in PBD which has not yet been investigated. We observed an increased amount of a-series gangliosides, GM2, GM1 and GD1a, in the fibroblasts of patients with ZS and IRD. Gangliosides GM1 and GD1a were not present in detectable amounts in normal subjects. A key step in the synthesis of a-series gangliosides is a transfer of GalNAc to ganglioside GM3, so we determined the level of ganglioside GM3 by immunohistochemical methods. We found a granular structure, which was positive toward anti-ganglioside GM3 antibody in the cytoplasm of the patients' fibroblasts. In control cells, the cell membrane was slightly positive toward anti-GM3 antibody. These results may help to clarify the pathogenesis of PBD with respect to the functional roles of glycosphingolipids in cell differentiation, proliferation and apoptosis.

[Regional cerebral blood flow in status epileptics measured by single photon emission computed tomography (SPECT)].

Status epileptics (SE) due to a cerebral vascular accident can cause a change for the worse in the quality of life of patients. We have performed single photon emission computed tomography (SPECT) with 99mTc-hexamethylpropylene amineoxim (HM-PAO) to evaluate regional cerebral blood flow (rCBF) in SE caused by a cerebral vascular accident. In addition, we have discussed the neurophysiology of SE based on the SPECT findings. A total of sixteen patients (5 males and 11 females, average age; 78.2 years old) with SE who were suffering from prolonged consciousness disturbance were investigated. When SPECT was performed in the ictal state, there was a remarkable increase in Radio Isotope (RI) uptake at the focus which correlated well with EEG findings. However, in other cortical regions, basal ganglia and thalamus, there was a relatively demonstrated decrease in RI uptake compared with that of the focus. Additionally in the interictal state, we found a decrease in RI uptake in the epileptic foci and normal recovery of the RI uptake level in other cerebral regions. We speculate that these characteristic patterns of cerebral blood flow distribution shown by SPECT scans in the ictal state reflect the state of consciousness disturbance due to SE. In general, in the elderly, it is difficult to make a differential diagnosis between prolonged consciousness disturbance due to nonconvulsive SE and other diseases such as cardiovascular, dehydration, metabolic disorder, etc. Nevertheless, nonconvulsive SE causes diffuse cell loss and irreversible brain damage. Therefore the elderly who have suffered from prolonged consciousness disturbance due to SE need an exact diagnosis and immediate medical treatment. When we diagnose a nonconvulsive SE, the characteristic findings of SPECT scans in the ictal state are very clear and useful. In conclusion, SPECT is a very simple and non-invasive method that demonstrates abnormalities of brain function exactly. Therefore, we should perform not only EEG but also SPECT scans when making a diagnosis of SE.

[Alterations of hemostatic markers in elderly patient with atrial fibrillation without a history of stroke].

To evaluate whether hemostatic abnormalities contribute to the increased risk of stroke, the authors prospectively studied the hemostatic markers (HM) (beta-TG, PF4, FPA, TAT, PIC, D-dimer) in 34 elderly patients with atrial fibrillation (Af) without a history of stroke (mean age 79.2) and 14 age-matched controls. In the Af group FPA was significantly higher than in the control group (p < 0.05). Among them, 8 patients showed a similar abnormal HM pattern as in cardioembolic is chemic stroke and in these, 4/8 patients had valvular disease (VD), 2/8 had hypertension (HT), 2/8 had congestive heart failure (CHF), 1/8 had diabetes mellitus (DM) and 1/8 had hyperlipidemia (HL). Eight patients showed the same abnormal HM pattern as atherothrombotic is chemic stroke and of these, 2/8 had HT as complications. Five patients showed combination of a HM abnormal pattern, that was observed in cardioembolic and atherothromboic ischemic stroke. The other 13 patients showed a normal HM pattern, were in these patients, 4/13 had HT, 1/13 had DM, 1/13 had VD, and 1/13 had CHF. The patients with VD complication tended to have embolic HM abnormality. Contrary to previous reports, nonvalvular Af patients do not necessarily tend to have high risk of cardioembolic stroke. Our data suggest difficulties in clinical diagnosis among Af patients with ischemic stroke whether it is cardio embolic or atherothrombotic.

[Serum alpha 1-antichymotrypsin in senile dementia].

To evaluate the clinical significance of serum alpha 1-Antichymotrypsin (ACT) as an early diagnostic marker of senile dementia of Alzheimer type (SDAT), we measured 333 healthy and not demented elderly subjects, 27 cases SDAT and 25 cases of vascular dementia (VD). For the measurement, a new high-sensitivity method, double antibody radioimmunoassay method was developed. In healthy elderly subjects, the mean value of serum ACT was 0.229 mg/ml. A tendency towards increase of ACT with aging was noted but was not significant. The serum level of ACT in the SDAT patients was significantly higher (0.309 mg/ml) compared with the healthy elderly subjects and the VD patients (0.226 mg/ml) (p < 0.01). We concluded that in the patients with SDAT, there was an overproduction of ACT and the serum value of ACT was markedly elevated. The measurement of serum ACT is very useful (sensitivity = 88.9%, specificity = 68.7%; cut-off value = 0.250 mg/ml) for the early differential diagnosis of senile dementia.