Noboru Kawano

Increased body movements during sleep in gilles de la tourette syndrome

Overnight sleep polygrams were recorded form 9 patients with Gilles de la Tourette syndrome (GTS). Six of 9 patients had abnormal electroencephalograms, but no specific abnormalities were detected. Body movements and twitch movements during sleep were analyzed. At all stages of sleep, body movements during sleep were more frequent in cases of GTS than those in normal controls. Twitch movements in stage REM of sleep were significantly increased in GTS. These results are consistent with the idea that GTS is due to an imbalance between the central neurotransmitters, catecholamine and serotonin.

Characteristic evoked potentials in childhood-onset dentatorubral-pallidoluysian atrophy

To determine the characteristics of multimodal evoked potentials (MEPs) in childhood-onset dentatorubral-palli-doluysian atrophy (DRPLA) we studied three DRPLA patients with progressive myoclonus epilepsy. Brainstem auditory evoked potentials showed reduced or absent brainstem components as well as delayed latencies. In addition, short latency somatosensory evoked potentials (S-SEPs) had prolonged central conduction time and reduced amplitude of cortical components. Two patients with symptom onset in the first decade of life had extremely enlarged flash visual evoked potentials with shortened latency even in the absence of giant SEPs. Therefore, children with progressive myoclonus epilepsy and the above MEP findings are likely candidates for childhood-onset DRPLA and should undergo DNA analysis for DRPLA.

Proton magnetic resonance spectroscopy on childhood-onset dentatorubral-pallidoluysian atrophy (DRPLA)

To evaluate brain dysfunction of childhood-onset dentatorubral-pallidoluysian atrophy (DRPLA), three children with progressive myoclonus epilepsy, who were diagnosed as having DRPLA by DNA analysis, for the first time, underwent a study of proton magnetic resonance spectroscopy (1H-MRS). 1H-MRS obtained from both the parietal and basal ganglia regions disclosed markedly reduced ratios of N-acetylaspartate to both choline and creatine. Especially regarding the basal ganglia region, the latter (ratio of N-acetylaspartate to creatine) closely correlated to severity of genetic abnormality, i.e. number of expanded CAG repeats, suggesting that the degree of neuronal loss in the region strongly depends on genetic factors. 1H-MRS must be a valuable tool to clarify the pathophysiology of DRPLA.

Studies on the gonadotropin secretion during sleep in patients with abnormal sexual development — The role of the CNS in the onset of puberty—

In order to evaluate the secretory patterns of luteinizing and follicle-stimulating hormones in various forms of abnormal sexual development, plasma levels of these hormones were measured every 20-30 minutes during sleep in 9 patients with true precocious puberty and 2 patients with primary hypogonadism. Seven patients with idiopathic precocious puberty and 2 patients with organic CNS lesion-related precocious puberty exhibited fluctuating plasma concentrations of these hormones that resembled findings in normal pubertal subjects who had significantly increased concentrations of plasma luteinizing hormone during sleep. Two patients with primary hypogonadism also showed episodic fluctuation of both hormones and augmented luteinizing hormone concentrations during sleep. These results suggest that the pubertal sleep-related gonadotropin secretion is dependent on the sleep-entrained CNS mechanism, and that the central nervous system plays an important role in sexual maturation.

Hypothalamic-pituitary function in patients with congenital malformations accompanied by central nervous system disorders

In 20 patients with congenital brain disorders, the influence of the CNS maldevelopment on the neuroendocrine system was investigated by assessment of the hypothalamic-pituitary function through measurements of the secretory reserve of pituitary hormones (GH, PRL, TSH, LH and FSH) in response to injections of insulin, TRH and LH-RH, and of the secretion of sleep-dependent pituitary hormones with polygraphic recording. The subjects consisted of 9 patients with midline anomalies of the brain and face, 3 patients with hydrocephalus, hydroencephalodysplasia or microcephalus, and 8 patients with the malformation syndrome associated with mental retardation. Ten of the 18 patients examined showed normal responses of GH secretion in the loading test (secretory peaks: greater than 10 ng/ml). But only 4 of these patients were found normal in respect of GH secretory peaks of more than 10 ng/ml during sleep. Of these 17 children, 5 showed abnormal values for basal secretion of PRL, and/or the secretory peak of PRL on injection of TRH. Two children showed hypersecretion of PRL during sleep. One patient out of the 19 examined was unresponsive in gonadotropin secretion to injection of LH-RH and 2 patients displayed excessive responses. During sleep, 4 of the 13 patients studied were found to be hypersecretory and 2 hyposecretory of gonadotropin. These results suggest that abnormalities in pituitary hormone secretion are frequently present in patients with CNS maldevelopment, and growth disturbances and abnormal sexual development may in some instances be due to endocrine abnormalities.

HISTOLOGICAL OBSERVATION OF THE BRAIN OF TAY-SACHS DISEASE WITH SEIZURE AND CHRONIC DPH INTOXICATION

The patients was a 3‐year‐old boy with psychomotor retardation and attacked by seizures since 8 months of age. On funduscopy, the maculla presented a cherry‐red spot. Serum hexosaminidase A activities were as low as 8.2%. Both parents were carriers. The patient was diagnosed as classical Tay‐Sachs disease by neurological examination. Diphenylhydantoin was continuously given for 2 years and 2 months till his death. Autopsy revealed swelling of the cerebrum, atrophy and sclerosis of the cerebellum, hepatomegaly and mild enlargement of the lymph nodes. Histologically, the cerebrum showed ballooned swelling of nerve cells, slight gliosis and demyelination, while cerebellar Purkinjes cells and granular cells were degenerated and disappeared. The cerebellar cortex showed small focal spongy degeneration. By electron microscopy, membranous cytoplasmic bodies were found in the nerve cells. The change of brain observed in this case were interpreted as a combined result of (i) essential change to classical Tay‐Sachs disease, (ii) ischemic change due to frequently repeated seizures, (iii) chronic toxicity by long‐term anticonvulsant administration.

Menkes' Kinky Hair Disease

Menkes et al.1) (1962) reported a new Xlinked syndrome of neurodegenerative changes with clinical features of motor and mental retardation, seizures, hypothermia and peculiar hair. Aguilar et al.2) (1966) reported the third family with 9 patients who have the same clinical symptoms as the patient reported by Menkes et al. They called it “kinky hair disease” and regarded it as a new clinical entity. Dankes et al.3~4) (1972-73) carried out metabolic studies on kinky hair disease and established that all patients had a marked deficiency of serum copper and ceruloplasmin as well as defect of copper transfer through the intestinal epithelium. They recommended a treatment with parenteral copper administration. A number of reports5-8) of copper therapy have recorded increases in serum copper and ceruloplasmin. Goka et al.0) and Hornlo) (1976) reported that the copper concentration in cultured skin fibroblasts and the copper uptake by the skin fibroblasts and the cultured amniotic fluid cells were markedly increased in the patients with Menkes’ kinky hair disease. Nishikawa and Miyao et al.11) (1980) reported that the protein nature of apoceruloplasmin from a patient with Menkes’ kinky hair disease was not different enzymologically and immunologically from that of normal control and both increased accumulation of copper and reduced efflux of copper from cells were found in Menkes fibroblasts. Beratis et a1.12) (1978) demonstrated that copper incorporated by cultured skin fibroblasts of Menkes’ syndrome was preferentially bound to a molecule with a molecular weight of about 10,OOO. Garnica et al.13) (1978) reported a defect of cadmium metabolism and storage with an abnormality of copper efflux in Menkes fibroblasts, and they speculated abnormal copper transport in mutant fibroblasts due to abnormality in metallothionein function.

Hypothalamic Syndrome in Childhood

Clinical symptoms were studied in 39 cases which had organic or functional lesions in hypothalamus. 1 ) Of the etiologies the percentage of congenital malformation was as high as 41 percent. 2) Ophthalmological abnormalities were seen in 12 cases. Of them, only three cases showed the peak of GH secretion more than 10 ng/ml in a loading test or during sleep. 3) Of 17 cases which showed the secondary sex characters, 6 showed peculiar manifestation and development of secondary sex characters. Of them, 4 cases were detarded in the sexual maturity, while 2 cases showed a paradoxical response of GH to TRH. Clinical pictures peculiar to the hypothalamic disturbance in the childhood were discussed. As a result, it was suggested (1) that among birth defects, microphallus, cleft lip and/or palate and ophthalmological abnormality are sometimes complicated with hypothalamicpituitary dysfunction and (2) that the organic or functional abnormality in hypothalamus should be suspected in children showing peculiar physical and mental development.

Effects of Cyproterone Acetate on Gonadotropin Secretion during Sleep in Children with True Precocious Puberty

Four girls with true precocious puberty (idiopathic 3 and cerebral 1) were treated with cyproterone acetate (CA) and its effect on the secretion of gonadotropin (Gn) during sleep was studied. A dose from 53 to 100 mg CA/m2/day was orally given as divided into 1 or 2 doses for 27.827.5 months on an average. The chronoIogical age at the time of examination was between 7-3/12 years and 10-3/12 years. Gn secretion during sleep before CA administration was excessive in terms of their age, but plasma G n levels (LH: 11.4f8.9 mIU/mZ (n=95), FSH: 11.0f4.4 mIU/mZ (n=95)) and the pattern of episodic secretion corresponded to their stage of puberty. The increment of plasma LH after the LHRH administration was suppressed by the therapy. On the other hand, plasma Gn levels (LH: 12.1&4.9 mIU/mZ (n=80), FSH: 9.9f. 2.4 mIU/mZ (n=80)) and the pattern of episodic secretion during sleep were similar before and after the CA treatment. There was no significant difference in the mean plasma LH levels during sleep before and after the CA treatment. These results indicate that LH secretion during sleep in patients with true precocious puberty who have reached pubertal age is dependent on the pubertal LH “program” in the central nervous system and not affected by the CA administration. (Acta Paediatr Jpn 23(2): 245 1981)

Studies on the Pituitary Harmones Secretion during Sleep in Children Associated with Precious Puberty

Plasma levels of anterior pituitary hormones (GH, PRL, LH and FSH) during sleep were determined to study the etiology of precosity in patients with precocious puberty. The subjects included 3 of idiopathic precocious puberty, 2 of cerebral precocious puberty, 1 of McCune-Albright syndrome and 1 of premature thelarche. All cases were girls, aged from 2-8 years at the time of examination. During sleep, plasma GH showed a peak of more than 10.0 ng/ml (19.1 & 8.7 ng/ml, mean ? SD) in all cases except a patient with cerebral precocious puberty, being similar to the control values of 18.0 & 8 .3 ng/ml . Hypersecretion of PRL was observed in a case of idiopathic precocious puberty in which the mean plasma PRL level (53.4 4 13.8 ng/ml) was more than +2SD of the control value, while each of idiopathic precocious puberty, hydrocephalus and McCune-Albright syndrome also showed higher values than the control. As to the Gn levels, three types of Gn release were observed in the patients with respect to the age and the stage of puberty. 1) Gn secretion was suppressed (e.g. premature thelarche). 2) Gn secretion corresponded to the chronological age, but showed lower values judging from the stage of puberty (e.g. McCuneAlbright syndrome). Gn secretion was excessive in terms of age, but plasma Gn levels and the pattern of pediodic secretion corresponded to the stage of puberty (e.g. idiopathic precocious puberty and cerebral precocious puberty). When comparison was made of plasma LH and FSH levels in true precocious puberty having an excessive secretion of Gn, plasma LH was predominant in 3 out of 5 cases. Gn responses to LH-RH in idiopathic and cerebral precocious puberty were varied from normal to excessive reaction. However, plasma Gn levels during sleep were higher in terms of age, corresponding to the stage of puberty. A case of cerebral precocious puberty and a case of McCune-Albright syndrome showed a peculiar onset of the secondary sex characters different from that in a case of normal sexual matulity. These results indicate that the episodic secretion of Gn during sleep represents CNS puberty and thus determination of plasma levels of anterior pituitary hormones during sleep is useful for elucidating pathophysiology of various types of precocious puberty. 3)