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Biomedical subjects

Masaya Segawa

Publications and source records attributed to Masaya Segawa.

17 recordsLinked to original sources
PubMed2005

Early motor disturbances in Rett syndrome and its pathophysiological importance.

Assessment of the development of motor function of Rett syndrome (RTT) revealed hypotonia with failure of crawling and disturbance in skillful hand manipulation are shown as early motor signs. Clinical evaluation has revealed the former as postural hypotonia with failure in locomotion and neurophysiological examinations have showed this to be due to hypofunction of the aminergic neurons of the brainstem. The latter signs are considered to indicate dysfunction of the corticospinal tract at higher levels. As the signs appear along with deceleration of head growth, dysfunction of the noradrenergic neuron, which is involved in synaptogenesis in the cerebral cortex, is postulated as the cause. The characteristic stereotyped hand movements appear in early childhood after loss of purposeful hand use and are underlain by rigid hypertonus. Neurophysiological examinations have indicated that these are due to hypofunction of the nigrostriatal (NS) dopamine (DA) neuron. By comparison with animal experimental work the neurohistochemical changes in the substantia nigra of the autopsied brain of RTT suggest a lesion caused by the dysfunction of the pedunculopontine nucleus, induced by dysfunction of the brainstem aminergic neurons which modulate postural tone and locomotion. Hypofunction of the aminergic neurons also cause 'leakage' of atonia into non-REM stages which lead to disturbances in the autonomic nervous system through inhibition of the reflex system. The grade of disturbance of locomotion closely matches the grade in abnormalities of higher cortical function as indicated by the development of meaningful words. The loci of missense mutation of methyl CPG binding domain of MECP 2gene which affect locomotion severely also markedly impaired their effects on the formation of the heterochromatin. Thus, dysfunction of the aminergic neurons of the brainstem which regulate postural tone and locomotion is proposed as the primary lesion.

Early Diagnosis↗
PubMed2005

A missense mutation in SCN1A in brothers with severe myoclonic epilepsy in infancy (SMEI) inherited from a father with febrile seizures.

Severe myoclonic epilepsy in infancy (SMEI) is an age-dependent epileptic encephalopathy occurring in the first year of life and is one of the intractable epilepsies. Heterozygous mutations in the voltage-gated sodium channel alpha subunit type1 gene (SCN1A) are frequently identified in patients with SMEI; two-thirds of these mutations are truncation mutations (non-sense and frameshift), and one-third are missense mutations. Although most reported SMEI cases arise as sporadic mutations, close relatives of SMEI patients have also been shown to manifest other types of epilepsies at a higher rate than that in the general population. Here, we report a familial case of SMEI, in which two brothers were affected with SMEI while their father had previously experienced simple febrile seizures. A gene-based analysis identified a novel missense mutation in the SCN1A gene (c.5138G>A, S1713N) in both brothers and in their father. Clinically, both siblings showed failure in locomotion, an impairment of the sleep-wake cycle after late infancy, and the subsequent appearance of frontal foci. The similarity in clinical manifestations in both brothers suggests that the impairment of elements of the brainstem, particularly aminergic neurons, develops after late infancy in SMEI. However, the siblings differed in age at onset of SMEI and of myoclonic seizures, as well as in the severity of speech delay. Our molecular and clinical findings suggest that different genetic backgrounds and/or environmental factors may critically affect the clinical features of patients with SCN1A mutations, consistent with the heterogeneity prevalent in this disorder.

Adult↗
PubMed2005

Rett syndrome.

PURPOSE OF REVIEW: Nearly 70 reports on Rett syndrome were published in 2004. We have selected 51 articles, including clinical reports, on pathophysiology, genotype-phenotype correlation, and clinical and basic molecular biology studies. These articles explain how mutation of the gene (MECP2) for methyl-CpG-binding protein 2 causes the particular disorders of Rett syndrome, and also induces other neurodevelopmental disorders, clarifying the situation for future studies. RECENT FINDINGS: The role of X-chromosome inactivation has been clarified in animal experiments. New isoforms of MeCP2 have been discovered and its functional characteristics are under research. Understanding of the influence of the MECP2 mutation on other neurodevelopmental disorders has increased. However, there is no apparent progress in neurophysiological studies. SUMMARY: Clinical studies included the pathophysiology of stereotyped movement, and cardiac and respiratory disturbances, and there were four therapeutic trials including one for epilepsy. For genotype-phenotype correlation the role of X-chromosome inactivation was looked at and its basic mechanisms were studied extensively in animals. Characteristics of mutations in the C-terminus and the biological function of the new isoform, exon 1, were introduced. In studies on related neurodevelopmental disorders, a relationship is suggested between the MECP2 gene and autism-related gene, with overlapping pathways, but this is not common to other neurodevelopmental disorders. Developmental studies suggest an important role for MeCP2 in the formation and/or maintenance of synapses, and clarify the molecular biological aspects of Rett syndrome. However, early involvement of the aminergic neurons, suggested as the basic, pathognomonic lesion of Rett syndrome, has unfortunately not been investigated with the MECP2 mutation.

Animals↗
PubMed2005

Natural history of Rett syndrome.

Rett syndrome is a unique neurodevelopmental disorder, with onset of hypotonia, autistic tendency, and abnormalities of fine finger movements and gross movements of the arms in early infancy. Clinical features include specific age-dependent symptoms. Studies of early and late signs correlated locomotive dysfunction to language disability and stereotypy to regression of higher cortical functions. Studies of sleep parameters revealed early hypofunction of brainstem aminergic neurons and late occurrence of hypofunction of dopaminergic neurons, followed by receptor supersensitivity. The syndrome's pathophysiology suggests that early hypofunction of aminergic neurons interferes with the development of higher neuronal systems. Particular symptoms surface at different ages throughout the natural course of Rett syndrome, with regressional and static periods.

Age Factors↗
PubMed2004

A variant of childhood-onset myasthenia gravis: HLA typing and clinical characteristics in Japan.

To investigate the correlation between clinical features and HLA DR/DQ genetic variability in myasthenia gravis (MG), we evaluated HLA DR/DQ allele frequencies in 87 Japanese patients with childhood-onset disease. HLA genotypes DRB1*1302/DQA1*0102/DQB1*0604 and DRB1*0901/DQA1*0301/DQB1*0303 were significantly higher in patients than in healthy controls (P(c) < 0.0001, RR = 5.5; P(c) < 0.0001, RR = 8.5, for two genotypes, respectively). Patients who had a significantly higher likelihood of the HLA types DRB1*1302/DQA1*0102/DQB1*0604 or DRB1*0901/DQA1*0301/DQB1*0303 belonged to the latent general type (LG) of MG; this is clinically ocular type, but shows myasthenic electromyographic findings in extremity muscles. The LG type of MG was observed in 78% of patients exhibiting the clinically ocular type; this group comprised approximately 75% of patients with childhood-onset MG. These date suggest that LG type of MG may present a particular subset of childhood-onset MG, which is associated with the specific HLA subtypes DRB1*1302/DQA1*0102/DQB1*0604 and DRB1*0901/DQA1*0301/DQB1*0303.

Adolescent↗
PubMed2004

Familial juvenile hyperuricemic nephropathy: detection of mutations in the uromodulin gene in five Japanese families.

BACKGROUND: Familial juvenile hyperuricemic nephropathy (FJHN) is an autosomal-dominant disease characterized by hyperuricemia of underexcretion type, gout, and chronic renal failure. We previously reported linkage on chromosome 16p12 in a large Japanese family designated as family 1 in the present study. Recent reports on the discovery of mutations of the uromodulin (UMOD) gene in families with FJHN encouraged us to screen UMOD mutations in Japanese families with FJHN, including family 1. METHODS: Six unrelated Japanese families with FJHN were examined for mutations of the UMOD gene by direct sequencing. To confirm the results of the mutation screening, parametric linkage analyses were performed using markers in 16p12 region and around other candidate genes of FJHN. RESULTS: Five separate heterozygous mutations (Cys52Trp, Cys135Ser, Cys195Phe, Trp202Ser, and Pro236Leu) were found in five families, including family 1. All mutations were co-segregated with the disease phenotype in all families, except for family 1, in which an individual in the youngest generation was found as a phenocopy by the genetic testing. Revised multipoint linkage analysis showed that the UMOD gene was located in the interval showing logarithm of odds (LOD) score above 6.0. One family carrying no mutation in the UMOD gene showed no linkage to the medullary cystic kidney disease type 1 (MCKD1) locus, the genes of hepatocyte nuclear factor-1beta (HNF-1beta), or urate transporters URAT1 and hUAT. CONCLUSION: Our results gave an evidence for the mutation of the UMOD gene in the majority of Japanese families with FJHN. Genetic heterogeneity of FJHN was also confirmed. Genetic testing is necessary for definite diagnosis in some cases especially in the young generation.

Amino Acid Sequence↗
PubMed2003

Autosomal dominant guanosine triphosphate cyclohydrolase I deficiency (Segawa disease).

Autosomal dominant guanosine triphosphate cyclohydrolase I (GCH-I) deficiency (Segawa disease) is a dopa-responsive dystonia caused by mutation of the GCH-I gene located on 14q22.1-q22.2. Neurohistochemical examination revealed a decrease of the tyrosine hydroxylase protein as well as its activity in the striatum and decrease of dopamine content, particularly in its ventral portion rich in D1 receptors (striatal direct pathways). Neuroimaging, clinical neurophysiological, and biochemical studies showed preservation of the structure and function of the terminal of the nigrostriatal DA neuron. Clinical neurophysiological studies showed no progressive decrement of DA activities. As the enzymatic activity of pteridine metabolism is highest in the early developmental course, it may modulate dopamine receptors maturing early in the developmental course. Its product, tetrahydrobiopterin, has higher affinity to tyrosine hydroxylase among hydroxylases. Thus, partial deficiency of tetrahydrobiopterin caused by heterozygous mutation of the GCH-I gene decreases dopamine activity rather selectively. This affects the DA receptors that mature early and demonstrates characteristic symptoms age-dependently along with the developmental decrement of the tyrosine hydroxylase activities at the terminals and the maturational processes of the projecting neurons of the basal ganglia. A difference in the ratio of mutant/wild-type GCH-I mRNA that depends on the locus of mutation may explain intrafamilial and interfamilial variation of phenotype.

Age of Onset↗
PubMed2003

Neurology of Tourette's syndrome (TS) TS as a developmental dopamine disorder: a hypothesis.

The favorable effect of dopamine (DA) depletors or DA receptor blockers suggested the state of increased transmission of DA system as the pathophysiology of Tourette's syndrome (TS). We have analysed the neurological signs of TS and evaluated the role of levodopa on the symptoms of TS. The data were compared with age-matched patients with Hereditary Progressive Dystonia (HPD) with marked diurnal fluctuation. Neurological examination of 81 drug naive TS patients revealed the clumsiness of rapid alternating pronation-supination movements of the arms and induced rigidity in the contralateral arm, which responded to the oral levodopa, and suggested hypofunction of the nigrostriatal (NS)-DA system. Postural asymmetry or scoliosis and abnormal tilting response suggested the asymmetric involvement of DA. The rotation to the side of less affected DA neuron on stepping with closed eyes suggested DA receptor supersensitivity. The favourable effects of a small dose of levodopa on these signs suggest the existence of DA receptor supersensitivity, because a small dose of levodopa is considered to alleviate the supersensitized DA receptors.

Adolescent↗
PubMed2003

Abnormalities of voluntary saccades in Gilles de la Tourette's syndrome: pathophysiological consideration.

Gilles de la Tourette's syndrome (TS) is a neurobehavioral disorder. Although the etiology and the pathophysiology of TS are still unknown, the involvement of the basal ganglia has long been postulated. On the other hand, saccadic eye movement was shown to be a useful measure to assess order and disorder of the function of the basal ganglia. To investigate the dysfunction of the basal ganglia of TS, we examined voluntary saccades in children with TS in comparison with the saccades in age-matched control children. Two kinds of saccades, visually-guided saccades (VGS) and memory-guided (MGS) saccades were evaluated. During the MGS, distracted saccades (DS), which indicate the distractibility, were examined. The results revealed the abnormalities in the parameters of the MGS, i.e. longer latencies and hypometric amplitudes, and decrease in the frequency of MGS. Whereas, the frequency of DS, the saccade to the predicted cue was significantly lower in younger patients (6-<9-years) than normal, but it was higher in the older TS children (9-<12-years). In addition, some of the patients showed large involuntary saccades, usually associated with eye blinks, during the task performance. These results suggest that in TS the basal ganglia fails to disinhibit the saccade neuron in the superior colliculus with the input of the frontal eye field to the striatum, and later allow the neurons to evoke non-goal directed saccades. In reference to abnormal saccades in other basal ganglia disorders with dopamine deficiency and to animal experiments with MPTP monkeys, these findings postulate primary hypodopaminergic state followed by upward regulation of dopamine receptors later in TS.

Age Factors↗
PubMed2003

Neurophysiology of Tourette's syndrome: pathophysiological considerations.

At present the neurophysiology of Tourette's syndrome (TS) has been investigated largely from two perspectives; one for evaluation of the dysfunction of the cerebral cortex and the other for clarification of the neuronal mechanisms that underlie tics and related symptoms. For the former the following examinations have been conducted: quantitative analyses of scalp electroencephalography (EEG), premovement EEG potentials, contingent negative variation, transcranial magnetic stimulation, and neuroimaging studies, including echo-planar images and positron emission tomography scans. These explorations have revealed the likely involvement of the subcortical and the cortical structures, particularly of the basal ganglia, in the pathophysiology of TS. For the latter, surface electromyography, evoked potentials, saccadic eye movements, and polysomnographies have been performed, and again have suggested a dysfunction of the basal ganglia and the brainstem neurons in TS patients. These neurophysiological studies suggest dysfunction of both motor and non-motor basal ganglia-thalamocortical circuitries in TS patients, which is hypothesized to be caused by hypofunction of the dopamine (DA) neurons associated with DA receptor supersensitivity, a well as hypofunction of the serotonergic neurons of the brainstem. Polysomnographical examination suggests that the dysfunction of the nigrostriatal (NS)-DA neurons is not a progressive process, but that the dysfunction is closely associated with an early occurrence of the developmental decrement of the activities of the NS-DA system to mature in a normal fashion. The associated DA receptor supersensitivity is assumed to be a consequence of this developmental abnormality and not due to denervation supersensitivity.

Basal Ganglia↗
PubMed2003

[Visual child neurology].

In neurodevelopmental disorders, the characteristic symptoms appear age-dependently along with the functional and morphological development of the affected neurons and the neuronal pathways. Most of them have the primary lesion in the subcortical structures as these mature earlier, which include the aminergic neurons of the brainstem and the midbrain having important roles for development of the higher cortical function (HCF). Thus, to clarify the pathophysiologies of the symptoms appearing age-dependently makes it possible to demonstrate the process of development of the HCF. Here, I reviewed the characteristic symptoms and their pathophysiologies of Rett syndrome, DYT-1, autosomal dominant GTP cyclohydrolase I (ADGCH I) deficiency, Tourette syndrome (TS) and Early-onset ataxia with ocular motor apraxia and hypoalbuminemia (EAOH), and suggested that the brainstem aminergic neurons modulating the locomotion have roles for development of the frontal cortex, the dopaminergic neurons and basal ganglia pathways involving in the action dystonia for motor execution and the serotonergic and the dopaminergic neurons projectioning to the nonmotor basal ganglia thalamocortical circuits for development of the frontal area, the targets of the circuits. While, postural dystonia, tics in GTS and symptoms in EAOH reflect the development of the causative neurons and the neuronal systems.

Age Factors↗
PubMed2002

[Rett syndrome: correlation of clinical symptoms and the mutations in the gene of methyl CPG binding protein 2 (MeCP2): introductory remarks].

Pathophysiology of Rett syndrome is discussed in relation to the MeCP2 gene. The brainstem aminergic neurons are affected in early infancy, resulting in failure in locomotion, head growth and language. The severity of symptoms is related to the specific loci of a mutation on the methylbinding domain which shows correlation with the degree of heterochronation disturbance. The secondary involvement of dopamine neurons together with dysfunction of cholinergic neurons, causes stereotyped movements and regression. In the normal fetus brain MeCP2 is expressed diffusely, and subsequently disappears early in the cortex and later in the brainstem. Abnormalities in the MeCP2 gene may alter these processes and cause age-dependent symptoms.

Chromosomal Proteins, Non-Histone↗
PubMedDate not supplied

Effects of phototherapy in neonates on circadian sleep-wake and saliva cortisol level rhythms.

The influence of phototherapy treatment during the neonatal period on sleep-wake rhythm, and its long-term effects on biological rhythms, was evaluated in preterm and full-term infants. Forty-three infants treated with phototherapy during the neonatal period and 47 untreated infants were examined for entrainment of sleep-wake rhythms between 16 and 52 weeks and for sleep-wake and saliva cortisol rhythms at 2.5 years of age. The age of sleep-wake rhythm entrainment was not significantly different between the 2 groups. No correlations between duration of exposure to phototherapy and corrected age of entrainment of sleep-wake rhythm were observed. At follow-up, no significant differences in sleep-wake and saliva cortisol rhythms were observed between the 2 groups, indicating that circadian variations were similar to those in adults.

Case-Control Studies↗