A family with X-linked dystonia-deafness syndrome with a novel mutation of the DDP gene.

BACKGROUND: X-linked dystonia-deafness syndrome (DDS) is characterized by early-onset deafness followed by progressive dystonia in adulthood. Only 4 families with the syndrome have been reported, and all were white. OBJECTIVE: To describe the first nonwhite family with X-linked DDS, involving 5 affected males in 4 generations. RESULTS: Clinical features of the family members, who were Japanese, were mostly consistent with reports of DDS in whites except for a lack of visual disturbances. Whereas microdeletions in the deafness-dystonia peptide (DDP) gene were found in 2 white DDS families, our patients showed a novel mutation (arg80ter) in exon 2 of the DDP gene. CONCLUSION: The existence of a DDS family of Japanese origin with a new kind of mutation in the DDP gene provides additional evidence that the DDP gene is a causative gene for X-linked DDS.

Familial amyotrophic lateral sclerosis with a novel Leu126Ser mutation in the copper/zinc superoxide dismutase gene showing mild clinical features and lewy body-like hyaline inclusions.

BACKGROUND: Mutations in the SOD1 gene are responsible for approximately 25% of all familial amyotrophic lateral sclerosis (ALS) cases. However, the correlation between the clinical and pathological features and the various SOD1 gene mutations has not been well characterized. OBJECTIVES: To screen the SOD1 gene in search of potential mutations and to obtain clinical and pathological data for 2 Japanese families with ALS. DESIGN: Clinical histories and neurological findings, gross and microscopic pathological features, and DNA analysis of the SOD1 gene. RESULTS: The 2 families with ALS showed a novel missense mutation in the SOD1 gene, which was heterozygous for point mutation TTG to TCG, causing substitution of leucine for serine at codon 126 (Leu126Ser) in exon 5. Clinically, patients showed slower disease progression and lack of upper motor neuron signs. Neuropathologically, the autopsied patient showed the form of familial ALS with posterior column involvement, and the pontocerebellar tract and the dentate nuclei of the cerebellum were also involved. Furthermore, abundant Lewy body-like hyaline inclusions were observed in the affected motor and nonmotor neurons. CONCLUSIONS: Familial ALS with a novel Leu126Ser mutation in the SOD1 gene showed mild clinical features and lack of upper motor neuron signs. We believe that Leu126Ser might be associated with the clinical features and that the mutation site in the SOD1 gene and disease duration might be associated with the formation of Lewy body-like hyaline inclusions.

Does homozygosity advance the onset of dentatorubral-pallidoluysian atrophy?

We confirmed a homozygous type of relatively small expansion of CAG triplet repeats (57 repeats) in the short arm of chromosome 12 in a male patient with dentatorubral-pallidoluysian atrophy (DRPLA) by polymerase chain reaction. He showed early onset (age, 17 years) of DRPLA. There was good correlation of the age of onset with the number of triplet repeats. The homozygous state of the expansion of the triplet repeats was responsible for the early onset and severity of his DRPLA.

Temporal pattern of AP-1 DNA-binding activity in the rat hippocampus following a kindled seizure.

DNA binding by transcripton factor AP-1 was enhanced remarkably following kindling stimulation in rat amygdala. Maximum increase occurred 2 h after stimulation with return to baseline within 24 h. Supershift and western analyses revealed that 38,000 mol. wt Fos-related antigen and JunD were the main components of the evoked AP-1 complexes at the time their induction reached maximum. AP-1 induction 2 h after the last kindling stimulation was more prominent in samples from previously kindled rats than in those from non-kindled rats. This study sought to establish the role of AP-1 in plastic changes of the hippocampus associated with kindling. Male Sprague-Dawley rats were kindled from the left amygdala until they exhibited Racine15 class 5 generalized seizures. Nuclear proteins were extracted from dorsal hippocampi obtained from 0 to 24 h after final stimulations. From these, we evaluated the temporal pattern of DNA binding by AP-1 using a gel mobility-shift assay with a 32P-labelled AP-1 probe. Supershift and western analyses were added to investigate components of the seizure-evoked AP-1 complexes. Our results suggest that the basal level of AP-1 complexes is not associated with the seizure susceptibility in kindling. However, development of kindling appears to facilitate stimulus-evoked AP-1 induction, probably via plastic changes in the central nervous system. AP-1 may mediate such changes by regulating expression of certain genes.

NBQX, a selective antagonist of the AMPA receptor, affects neither field potentials nor long-term potentiation in vivo.

NBQX (2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(F)quinoxaline), a selective antagonist of AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate) receptors, at an anticonvulsant dose of 40 mg/kg (i.p.), was shown in vivo to have no effects on either the field potentials in the piriform cortex or those in the dentate gyrus of the hippocampus. The same dose of NBQX also exerted no significant effects on long-term potentiation in the hippocampus. These results suggest that the mechanism underlying the anticonvulsant action of NBQX in vivo does not involve a suppressive action on physiological synaptic transmission. The possible clinical usefulness of AMPA receptor antagonists as antiepileptic drugs is suggested.

Time-dependent changes in rat hippocampal synapsin I mRNA expression during long-term potentiation.

We studied the time-dependent changes in synapsin I mRNA levels after hippocampal long-term potentiation (LTP) in rats in vivo. Following LTP induction by stimulating the perforant path, synapsin I mRNA expression in the granule cell layer of the dentate gyrus ipsilateral to stimulation increased significantly in a time-dependent manner. From 2 to 8 h after stimulation, the synapsin I mRNA levels in the ipsilateral dentate gyrus were significantly higher than those of controls subjected to a sham procedure. The synapsin I mRNA level (157.4+/-7.1% of the control level, mean+/-SEM) was at a maximum 8 h after stimulation. The synapsin I mRNA level of animals that received only test pulses did not increase significantly, compared with the control level. These results suggest that the increased level of synapsin I mRNA is related to persistent enhancement of synaptic activity within the neural networks in which dentate granule cells participate in LTP.

Free radicals, lipid peroxides and antioxidants in blood of patients with myotonic dystrophy.

We studied the levels of free radicals, lipid peroxides and antioxidants, as well as superoxide dismutase (SOD) activity in the blood of six patients with myotonic dystrophy (MyD) (mean age 52.8, SD 5.0 years) and seven controls (mean age 48.8, SD 6.3 years). Electron spin resonance was used to assess the free radicals by the spin-trapping method using 5,5-dimethyl-1-pyrroline-1-oxide. The levels of C centre radical (P < 0.05) and H radical (P < 0.05) in blood from the six MyD patients were significantly higher than those in the seven controls. The SOD activities in red blood cells and serum from the six MyD patients showed no significant difference from those in the seven controls. The serum lipid peroxide concentration was increased in five of the MyD patients and tended to increase further as the disease progressed. The serum vitamin E level was low in two patients and in the low normal range in three. Serum coenzyme Q10 was decreased in four patients. The serum selenium level was decreased in two patients and that of serum albumin was decreased in three. Therefore we conclude that increased levels of free radicals and lipid peroxides and decreased antioxidant levels play an important role in the pathogenesis of MyD.

Hydroxyl radical and superoxide dismutase in blood of patients with Parkinson's disease: relationship to clinical data.

Hydroxyl radical (.OH) levels in blood, superoxide dismutase (SOD) activity in plasma (plasma-SOD) and in red blood cells (RBC) relative to Cu,Zn-SOD (SOD1) protein (RBC-SOD/SOD1), SOD1 protein in RBC (SOD1/RBC) and plasma (SOD1/plasma), and Mn-SOD protein in plasma (SOD2/plasma) were measured in patients with Parkinson's disease (PD), multiple-system atrophy (MSA) with parkinsonism, and in control subjects. Patients with PD had significantly higher.OH and plasma-SOD values and significantly lower RBC-SOD/SOD1 and SOD1/RBC values than the corresponding MSA and control values. In PD, RBC-SOD/SOD1 values were significantly lower in older patients and were negatively correlated with age.OH levels were significantly higher in PD patients with early onset, a long period of illness or severe Yahr stage, and were negatively correlated with onset and positively correlated with duration of illness. RBC-SOD/SOD1 values in PD patients who received pergolide therapy were significantly higher than those in PD patients who received neither pergolide nor bromocriptine therapy. Therefore, the higher.OH level and the lower SOD1 activity may play a role in the onset and progression of PD, and pergolide may act neuroprotectively by inducing SOD1 activity.

Superoxide dismutase and free radicals in sporadic amyotrophic lateral sclerosis: relationship to clinical data.

We studied the relationships between the superoxide dismutase (SOD) activity, free radical (FR) levels and clinical data in patients with sporadic amyotrophic lateral sclerosis (SALS). The SOD activities and blood FR levels of 16 patients with SALS (mean age 58.6 +/- 10.2 years), 11 with other neurological disease, including myotonic dystrophy (ND, mean age 53.5 +/- 9.1 years), and 15 normal control subjects (mean age 56.2 +/- 7.3 years) were measured. The mean levels of FR in blood from the patients with SALS and ND and the SOD activities in red blood cells (RBC) from those with ND were significantly higher than the corresponding control values. There was a positive correlation between the SOD activities in RBC and blood hydroxyl radical levels in the patients with ND, but neither the patients with SALS nor the controls showed such a correlation. The SALS patients without pyramidal signs showed slow disease progression and their mean RBC SOD activity was significantly higher than the corresponding control value. We compared the FR levels and SOD activities of 8 patients who needed a respirator within 40 months after the onset of SALS (SALS40, mean age 58.7 +/- 9.4 years), 3 who needed a respirator over 100 months after the onset of SALS (SALS100, mean age 58.3 +/- 15.9 years) and the controls. The mean blood FR levels of the SALS40 and SALS100 patients were significantly higher than the corresponding control values. The mean SOD activity in RBC from the SALS100 group was significantly higher than the SALS40 and control group values. Therefore, we concluded that elevated blood FR levels do not induce RBC SOD in SALS patients and that the disease progressed more rapidly in SALS patients with low than high RBS SOD activities.

Free radicals and superoxide dismutase in blood of patients with Alzheimer's disease and vascular dementia.

We measured hydroxyl radical (.OH) levels in blood, superoxide dismutase (SOD) activity in red blood cells (RBC) relative to both total protein (RBC-SOD/P) and Cu,Zn-SOD protein (RBC-SOD/SOD), SOD activity in plasma (plasma-SOD), and Cu,Zn-SOD protein relative to total RBC protein (Cu,Zn-SOD/P) in 22 patients with probable dementia of the Alzheimer type (DAT group, mean age 74.8+/-9.4 years), 16 with probable vascular dementia (VAD group, mean age 76.9+/-6.7 years) and 19 non-demented controls (control group, mean age 73.5+/-6.2 years). Levels of .OH in the DAT and VAD groups were significantly (P<0.01 and P<0.001, respectively) higher, whereas the values of RBC-SOD/P and RBC-SOD/SOD in these two groups (both P<0.001) and Cu,Zn-SOD/P in the DAT group (P<0.001) were significantly lower than the corresponding control values. Members of the VAD group with risk factors for stroke (RF+ group) showed significantly higher .OH levels than members of the VAD group without risk factors (RF- group; P<0.01) and the control group (P<0.001). RBC-SOD/P and RBC-SOD/SOD values in the RF+ group were significantly (both P<0.01) lower than the corresponding control values. There were no significant differences among the VAD, RF+ and control groups with respect to Cu,Zn-SOD/P values, or between the RF- and control groups for any measured parameter. We conclude that oxidative stress plays a role in the brain damage seen in both DAT and VAD, and that the causes of decreased SOD activity in RBC differ between DAT and VAD patients.

Increased levels of mRNA for beta- but not alpha-subunit of calmodulin kinase II following kindled seizures.

We studied levels of mRNA for the alpha- and beta-subunits of calmodulin (CaM) kinase II using the amygdaloid kindling model of epilepsy. There were significant increases in mRNA for the beta-subunit of CaM kinase II in the hippocampus 4-24 h after stage 5-kindled seizures. Moreover, this mRNA was significantly increased by 20.0-26.5% in the bilateral dentate gyrus 8 to 24 h after kindled seizures. The beta-subunit mRNA was also significantly increased by 13.5-19.0% in the CA3 on the side ipsilateral to the stimulation, 4 to 8 h after kindled seizures. mRNA for the alpha-subunit of CaM kinase II was not significantly changed in the regions examined for up to 24 h after the kindled seizures. These results suggest that CaM kinase II mediates the molecular processes that follow kindled seizures. It is possible that increases in CaM kinase II-dependent protein phosphorylation are associated with the plastic changes in kindling.

Time-dependent changes in neurotrophic factor mRNA expression after kindling and long-term potentiation in rats.

We compared the time-dependent changes in messenger ribonucleic acid (mRNA) levels for two neurotrophic factors after amygdala-kindled seizures and hippocampal long-term potentiation (LTP) in rats in vivo. The brain-derived neurotrophic factor (BDNF) mRNA levels in the bilateral granule cell layer of the dentate gyrus, increased significantly 1-4 h after stage 5 kindled seizures. Nerve growth factor (NGF) mRNA levels increased throughout the bilateral limbic regions more gradually than those of BDNF mRNA. The maximum levels in the dentate gyrus ipsilateral to stimulation (BDNF mRNA: 493%, NGF mRNA: 199% of control levels) occurred 2 h after seizures. As observed with kindling, BDNF and NGF mRNA expression increased in the dentate gyrus ipsilateral to stimulation also increased following LTP induced by the perforant path stimulation, with maximum levels occurring 2 h and 4 h, respectively, after stimulation, when they reached 284% and 189% of the control levels, respectively. These results suggest that BDNF and NGF are involved in enhancement of synaptic efficacy in the granule cells of the dentate gyrus in the hippocampus in kindling, not related to the neuronal excitability associated with seizure activity.

The effects of perinatal anoxia or hypoxia on hippocampal kindling development in rats.

The effects of anoxia and hypoxia (3% oxygen) at 10-12 post days of age on the development of ventral hippocampal kindling and its transfer to the contralateral ventral hippocampus were studied in adult male Sprague-Dawley rats. During oxygen deprivation, the heart rate decreased to 15% of the prehypoxic value in the animals exposed to anoxia and 40% in those exposed to hypoxia. As is observed in asphyxia of human newborns, our study included both ischemia and hypoxia. The susceptibility to kindling, which was measured by kindling rate, afterdischarge threshold, generalized seizure threshold, and total afterdischarge duration to stage 5, had a tendency to be enhanced in rats exposed to hypoxia compared with controls. The facilitating effects on primary site kindling were enhanced in the animals exposed to hypoxia compared with those exposed to anoxia. Transfer, which was indicated by kindling rate and afterdischarge threshold, was also slightly facilitated in the rats exposed to anoxia or hypoxia in the perinatal period. These results reveal that perinatal oxygen deficiency may not be sufficient to lead to the development of temporal lobe epilepsy. However, it is possible that perinatal hypoxia results in some pathophysiological change in the brain which leads to greater seizure susceptibility in adulthood.

Temporal profile of CRE DNA-binding activity in the rat hippocampus following a kindling stimulation.

This study was designed to establish a role for cAMP-responsive element (CRE) binding protein (CREB) in signal transduction cascade in the hippocampus associated with kindling. Male Sprague-Dawley rats were kindled from the left amygdala until they exhibited Racine's class 5 generalized seizures [Racine (1972). EMBO J. 11, 3337-3346] Nuclear proteins were extracted from dorsal hippocampi obtained from 0 to 24 h after final kindling stimulation. From these, we evaluated the temporal pattern of CRE DNA-binding activity by use of a gel mobility-shift assay with a 32P-labeled CREB oligonucleotide probe. CRE-binding activity in the hippocampus was enhanced significantly at 2 h and returned to baseline level within 4 h after the stimulation. Our results suggest that CREB may be involved in the hippocampal signal transduction pathway of rats activated in response to a kindling stimulation to the amygdala. However, the transient elevation of CRE-binding activity following a seizure in a kindled animal also suggests that persistent activation of CREB may not be required for maintenance of the kindling phenomenon.

Increases in mRNA levels for synapsin I but not synapsin II in the hippocampus of the rat kindling model of epilepsy.

We studied brain synapsin I and II mRNA levels using the amygdala kindling model of epilepsy. There were significant increases in the synapsin I mRNA level in the granule cell layer of the hippocampal bilateral dentate gyrus. One to 8 h after seizures, the level in the dentate gyrus ipsilateral to stimulation increased by 44.2-73.2%, compared with the control level. Of the time points investigated, the greatest increase in expression was observed 8 h after the kindled seizures. Furthermore, the synapsin I mRNA levels in the dentate gyrus contralateral to stimulation increased by 28.0% and 51.1%, 2 and 8 h, respectively, after the kindled seizures. Expression of this mRNA, however, did not change significantly in other areas examined, including CA1, CA2, CA3 and the polymorphic layer of the hippocampus and the perirhinal and temporal cortices. Synapsin II mRNA levels did not change significantly in any of the regions studied for up to 24 h after the seizures and synapsin II was presumed to have little involvement in kindling. We considered the locally elevated synapsin I mRNA levels in the bilateral dentate gyrus associated with kindling indicate that excitatory changes occur in the synaptic circuit in which the dentate granule cells participate. Synapsin I may be involved in the presynaptic molecular mechanisms underlying the neuronal plasticity in kindling.

Autonomic nervous disorder in motor neuron disease: a study of advanced stage patients.

Autonomic functions were studied in 10 respiratory-support patients with motor neuron disease (MND) at its most advanced stage by means of hemodynamic function tests. The mean duration of disease was 83.4 months (SD 28.0, range 50-140 months). All the patients in this study had lost their ability to breathe spontaneously and were ventilated by respirator. Hemodynamic function tests were performed in 8 out of 10 patients. These patients showed exaggerated sympathetic vasomotor reflexes, increased reflex hypertension and tachycardia in response to the cold pressor test and increased response to administration of adrenaline. However, the responses to both the Aschner eyeball pressure test and injection of atropine were normal, indicating normal parasympathetic nervous system function. Plasma and urine levels of norepinephrine, epinephrine and their metabolites were almost normal in all 10 patients, as were serum dopamine-beta-hydroxylase levels. In patients with the most advanced stage of MND, hyperfunction of the adrenergic sympathetic nervous system was observed, and this was considered to be a symptom characteristic of MND.

Influence of age and gender on iodine-123 MIBG kinetics in normal lung.

UNLABELLED: Iodine-123 MIBG is a biochemical marker that can be used to monitor pulmonary norepinephrine (NE) metabolism. The purpose of this study was to characterize pulmonary I-123 MIBG kinetics in relation to age and gender. MATERIALS AND METHODS: Seventeen healthy volunteers and 14 patients with no cardiac or pulmonary disorders were included in this study (age range: 24 to 88 years, mean age 50.2 +/- 17.6 years; 16 males, 15 females). Planar images were obtained 15 min (early) and 3 h (delayed) after injection of I-123 MIBG (111 MBq). Pulmonary uptake of I-123 MIBG was quantified based on the lung-to-mediastinum ratio (LMR) on early and delayed images. The lung clearance rate (LCR) was calculated form both the early and delayed images. RESULTS: Both early and delayed LMR values increased slightly, although they showed no significant correlations with age. There was a significant inverse correlation between LCR and age (r = -0.57, p < 0.001). Neither LCR nor LMR differed significantly between male and female patients, but the mean age of the men was lower than that of the women. CONCLUSIONS: Pulmonary I-123 MIBG kinetics may reflect age-dependent changes in NE metabolism. The effects of age should be taken into account when assessing pulmonary NE metabolism with I-123 MIBG.

Improved cardiac iodine-123 metaiodobenzylguanidine accumulation after drug therapy in a patient with Parkinson's disease.

A 72-year-old woman with Parkinson's disease and autonomic dysfunction underwent I-123 MIBG cardiac imaging to study sympathetic neuronal integrity. This revealed a defect in the infero-posterior wall. Tc-99m sestamibi myocardial perfusion imaging revealed no abnormalities. On follow-up I-123 MIBG SPECT, the defect was less prominent and the parkinsonian symptoms were ameliorated by drug therapy. Cardiac I-123 MIBG imaging may be a promising new method for evaluating drug therapy in patients with Parkinson's disease.

Epidemiological surveys of senile dementia in Japan.

Epidemiological surveys of senile dementia at home were carried out on 3,754 subjects for two consecutive years, 1987 and 1988. The prevalence and incidence rates were 4.1% and 1.01%, respectively. Concerning the incidence rate, the sample populations of previous reports were small in number--less than 1,000. If we suppose that the incidence were to be approximately 1%, then it follows that dementia would be noted yearly in no more than one out of 100 senile subjects. A difference in subject number leads to a great difference in the incidence. Therefore, it is necessary that the number of subjects should be more than 1,000 for a comprehensive epidemiological survey of incidence rate of senile dementia. Accordingly, the present study is a better representation of the true picture as it was obtained by a more accurate method accompanied by less errors.

[Convulsions observed during administration of antidepressants].

We investigated the incidence of convulsions observed during treatment with antidepressants. Among the patients observed in this department, 582 cases received the antidepressants for more than 2 months were selected. 8 cases (1. 4%) of these patients showed convulsions. Detailed evaluation revealed a high incidence of convulsions occurred in patients who were administered more than two kinds of antidepressants. Among tetracyclic antidepressants, viz. maprotiline and clomipamine, and tricyclic antidepressants, viz. amitriptyline indicated a high incidence rate of convulsions. On the contrary, mianserin and imipramine tended to show a lower incidence. In 4 cases, acute toxic symptoms were seen before the convulsion, and the serum concentration of antidepressants in these patients was high. If toxic symptoms and elevated level of serum concentration are useful indicator for prediction of convulsion by treatment with antidepressants, these might be a noteworthy clinical findings. At present, if doctors are required to administer more than moderate amounts of more than two antidepressants, careful administration is desirable. With the accumulation of such cases, it is necessary to obtain further evaluation of the relationship between toxic symptoms and serum concentration of antidepressants.