Associations of sleep bruxism with age, sleep apnea, and daytime problematic behaviors in children.

OBJECTIVES: The aims of this study were to investigate the prevalence of sleep bruxism in children in Japan, and its relationships with sleep-related factors and daytime problematic behavior. SUBJECTS AND METHODS: Guardians of 6023 children aged 2-12 years completed the Japanese Sleep Questionnaire. Multiple regression analysis and structural equation modeling were performed. RESULTS: Sleep bruxism was reported in 21.0% children (n = 1263): the prevalence was highest in the age group of 5-7 years (27.4%). Multiple regression analysis showed that sleep bruxism had significant correlations with age 5-7 years (OR: 1.72; P < 0.0001), 'Moves a lot during sleep' (OR: 1.47; P < 0.0001), 'sleeps with mouth open' (OR: 1.56; P < 0.0001), and 'snores loudly' (OR: 1.80; P < 0.0001). In structural equation modeling, sleep bruxism had a significant but weak direct effect on daytime problematic behavior, while sleep bruxism significantly correlated with obstructive sleep apnea, which had a higher direct effect on daytime problematic behavior. CONCLUSIONS: Sleep bruxism was reported in 21.0% of Japanese children and had independent relationships with age, movements during sleep, and snoring. A comorbidity of sleep-disordered breathing might be related to daytime problematic behavior in children with sleep bruxism.

Severe mandibuloacral dysplasia caused by novel compound heterozygous ZMPSTE24 mutations in two Japanese siblings.

Mandibuloacral dysplasia (MAD) is a rare autosomal recessive progeroid syndrome, characterized by mandibular hypoplasia, acroosteolysis affecting distal phalanges and clavicles, delayed closure of the cranial sutures, atrophic skin, and lipodystrophy. Recently, mutations in lamin A/C (LMNA) and zinc metalloprotease (ZMPSTE24), involved in post-translational processing of prelamin A to mature lamin A, have been identified in MAD kindreds. We now report novel compound heterozygous mutations in exon 1 (c.121C>T; p.Q41X) and exon 6 (c.743C>T; p.P248L) in ZMPSTE24 in two Japanese sisters, 7- and 3-year old, with severe MAD and characteristic facies and atrophic skin. The older sister had lipodystrophy affecting the chest and thighs but sparing abdomen. Their parents and a brother, who were healthy, had heterozygous mutations. The missense mutation, P248L, was not found in 100 normal subjects of Japanese origin. The mutant Q41X was inactive in a yeast halo assay; however, the mutant P248L retained near normal ZMPSTE24 activity. Immunoblots demonstrated accumulation of prelamin A in the patients' cell lysates from lymphoblasts. The lymphoblasts from the patients also revealed less intense staining for lamin A/C on immunofluorescence. We conclude that ZMPSTE24 deficiency results in accumulation of farnesylated prelamin A, which may be responsible for cellular toxicity and the MAD phenotype.

Neuronal intranuclear hyaline inclusion disease with rapidly progressive neurological symptoms.

This report describes a male patient who presented with symptoms suggestive of spinocerebellar degeneration and who died of respiratory failure at the age of 7 years but was diagnosed, at autopsy, as having neuronal intranuclear hyaline inclusion disease. Neuronal intranuclear hyaline inclusion disease is a progressive and degenerative disease; diagnosis is possible only by neuropathological analysis. This is a rare disorder; few cases with early childhood onset and rapidly progressive neurologic symptoms have been documented. According to previous reports, most neurons in the central nervous system exhibited intranuclear eosinophilic inclusion bodies; neuronal depletion appeared to be restricted to the cerebellar cortex and the medullary inferior olivary nuclei, consistent with the fact that clinical deficit appears to correspond to the site of neuronal depletion and not to where eosinophilic bodies are detected. Immunohistochemical analysis revealed that these inclusions were positive for ubiquitin. The case presented herein clearly indicates that neuronal intranuclear hyaline inclusion disease should be considered as a differential diagnosis of cases involving spinocerebellar degeneration with childhood onset.

Lipocalin-type prostaglandin D synthase (beta-trace) is upregulated in the alphaB-crystallin-positive oligodendrocytes and astrocytes in the chronic multiple sclerosis.

Lipocalin-type prostaglandin D synthase (L-PGDS), which is mainly synthesized in leptomeningeal cells and oligodendrocytes (OLs) in rodents and humans, is secreted into the human cerebrospinal fluid (CSF) as beta-trace. L-PGDS protects OLs and neurones against apoptosis in twitcher mice, a murine model of Krabbe's disease, and is the second only to a stress protein, alphaB-crystallin, as the most abundant gene product upregulated in the demyelinating focus of multiple sclerosis (MS). Here we report that although the CSF level of L-PGDS is not increased in MS patients, L-PGDS is increased in the white matter of MS patients, especially in the shadow plaque as compared with the normal white matter. L-PGDS immunoreactivity was intensely expressed in OLs within the shadow plaques and in hypertrophied astrocytes within the chronic plaques of MS patients. Both L-PGDS-positive OLs and astrocytes expressed a stress protein, alphaB-crystallin. These results suggest that the upregulation of L-PGDS occurs in OLs and astrocytes as a stress reaction.

Cellular localization of lipocalin-type prostaglandin D synthase (beta-trace) in the central nervous system of the adult rat.

We applied high-resolution laser-scanning microscopy, electron microscopy, and non-radioactive in situ hybridization histochemistry to determine the cellular and intracellular localization of lipocalin-type prostaglandin D synthase, the major brain-derived protein component of cerebrospinal fluid, and its mRNA in leptomeninges, choroid plexus, and parenchyma of the adult rat brain. Both immunoreactivity and mRNA for prostaglandin D synthase were located in arachnoid barrier cells, arachnoid trabecular cells, and arachnoid pia mater cells. Furthermore, meningeal macrophages and perivascular microglial cells, identified by use of ED2 antibody, were immunopositive for prostaglandin D synthase. In the arachnoid trabecular cells, the immunoreactivity for prostaglandin D synthase was located in the nuclear envelope, Golgi apparatus, and secretory vesicles, indicating the active production and secretion of prostaglandin D synthase. In the meningeal macrophages, prostaglandin D synthase was not found around the nucleus but in lysosomes in the cytoplasm, pointing to an uptake of the protein from the cerebrospinal fluid. Furthermore, the existence of meningeal cyclooxygenase (COX) -1 and COX-2 was investigated by Western blot, Northern blot, and reverse transcriptase-polymerase chain reaction (RT-PCR), and the colocalization of COX-2 and prostaglandin D synthase was demonstrated in virtually all cells of the leptomeninges, choroid plexus epithelial cells, and perivascular microglial cells, suggesting that these cells synthesize prostaglandin D(2) actively. Alternatively, oligodendrocytes showed prostaglandin D synthase immunoreactivity without detectable COX-2. The localization of lipocalin-type prostaglandin D synthase in meningeal cells and its colocalization with COX-2 provide evidence for its function as a prostaglandin D(2)-producing enzyme.

An apoptotic depletion of oligodendrocytes in the twitcher, a murine model of globoid cell leukodystrophy.

Morphological alterations of oligodendrocytes (OLs) leading to their depletion were studied in the genetic demyelinating mutant, twitcher, a murine model of globoid cell leukodystrophy (GLD). With pi-glutathione-S-transferase immunostaining, OLs with multiple varicose processes were recognized in the early stages and adjacent areas of demyelination and then the OLs cytoplasm as well as the processes became shrunken with progression of the disease. These shrunken OLs were labeled by the TUNEL method, indicative of apoptotic cell death. The ultrastructural features of apoptotic cells were noted in these OLs and DNA laddering was noted in the twitcher brain in advanced stages. This is the first report describing the gradual depletion of OLs by apoptosis in genetic demyelination.

A case of giant axonal neuropathy showing focal aggregation and hypophosphorylation of intermediate filaments.

We report here the clinicopathological features of a typical case of giant axonal neuropathy (GAN). Scanning electron microscopy of the hair of this case revealed an extraordinarily irregular cuticle. Focal accumulation of intermediate filaments in axons, Schwann cells, muscle fibers and skin fibroblasts were also found under an electron microscopy. When examined immunocytochemically, muscle fibers exhibited local disruption of the filamentous network in the subsarcolemmal space and in the central cytoplasm accompanied by focal accumulation of desmin. The intracellular network of vimentin was also disrupted, exhibiting global accumulation in some of the cultured skin fibroblasts. Decreased interneurofilament spacing was found in enlarged axons, suggesting the presence of hypophosphorylation of neurofilaments in this patient. These findings suggest general disorganization, abnormal distribution and possible defective phosphorylation of intermediate filaments in GAN.

A case of Kearns-Sayre syndrome showing a constant proportion of deleted mitochondrial DNA in blood cells during 6 years of follow-up.

Kearns-Sayre syndrome (KSS) and Pearson syndrome (PS) show quite different phenotypes despite the same underlying genetic defect, i.e. a large deletion of one population of mitochondrial (mt) DNA. The main feature of KSS is progressive encephalomyopathy; on the other hand, PS shows fatal hematological problems in early infancy. Through Southern blot analysis of mtDNA of blood cells, deletion has been consistently found in patients with PS but usually undetectable in KSS patients. Therefore, their different clinical phenotypes have been explained by the different tissue distribution of mutant mtDNA. Recently, a few cases were reported which had features of PS in infancy and later developed KSS. These observations suggest that phenotypes may also be modified by the selection process involving mtDNA within different tissues. We found a case of KSS, who initially presented endocrinological dysfunction such as insulin-dependent diabetes mellitus (IDDM) and growth hormone (GH) deficiency, and had not developed external ophthalmoplegia until the age of 17. Although he did not show any symptoms of PS, a marked proportion of mtDNA was deleted not only in muscle but also in blood cells. Analysis of his blood cells showed an unchanged proportion of deleted mtDNA at three estimations within 6 years of the follow-up period. This case provides evidence that deleted mtDNA in blood cells also has a stable replicative capacity and that a large proportion of deleted mtDNA in blood cells may not accompany hematological problems.