Akie Miyamoto

Serum melatonin kinetics and long-term melatonin treatment for sleep disorders in Rett syndrome

We studied the circadian rhythm of serum melatonin levels in two patients with classical Rett syndrome having severe sleep disorders; serum melatonin levels were measured before and during melatonin treatment using radioimmunoassay. Patient 1 had a free-running rhythm of sleep-wake cycle from 3 years of age. At the age of 4 years, the peak time of melatonin was delayed 6 h compared to normal control and the peak value was at the lower limit. Patient 2 had a fragmented sleep pattern accompanied by night screaming from 1 year and 6 months of age. At the age of 10 years, the peak time of melatonin secretion was normal but the peak value was at the lower limit. These patients were given 5 mg melatonin orally prior to bedtime. Exogenous melatonin dramatically improved the sleep-wake cycle in patient 1. In patient 2, exogenous melatonin showed a hypnotic effect but early morning awakenings occurred occasionally. When melatonin treatment was stopped, the sleep disorders recurred and re-administration of 3 mg melatonin was effective in both patients. The effect was maintained over 2 years without any adverse effects. These findings suggests that sleep disorders in patients with Rett syndrome may relate with an impaired secretion of melatonin.

The role of different X-inactivation pattern on the variable clinical phenotype with Rett syndrome

A gene for Methyl-CpG binding protein 2 (MECP2), which locates Xq28, was recently found to be responsible for Rett syndrome. Although mutational analyses of MECP2 in Rett syndrome have been extensively analyzed, the mechanism(s) by which variable clinical phenotype occurred between affected monozygotic twins or sisters have not been clarified. We hypothesized that the difference of X-inactivation pattern might explain this phenomenon. With the method based on methylation-specific PCR, we analyzed polymorphic trinucleotide repeat in the human andorogen receptor gene mapped on Xq11.2-12, using DNA samples derived from previously described monozygotic twins and sisters together with their parents. Their clinical phenotypes were reported to be significantly different between siblings. We found that (1) maternally derived allele is predominantly active than paternally derived one in three out of four patients analyzed, (2) remaining one twin patient, whose ratio of active paternal allele is almost the same level as maternal allele, showed far much severe phenotype when compared with her counterpart. Together with the finding that most of the alleles with de novo mutation are from paternal X chromosome in sporadic cases, the existence of a mechanism that suppresses mutated paternal allele activation, resulting skewed X-inactivation to make clinical phenotype milder, might be speculated. Thus, when this mechanism fails to work sufficiently by an unknown reason, severer clinical phenotype could occur.

ASSESSMENT OF VISUOPERCEPTUAL DISTURBANCE IN CHILDREN WITH SPASTIC DIPLEGIA USING MEASUREMENTS OF THE LATERAL VENTRICLES ON CEREBRAL MRI

The authors estimated perceptual disturbance in children with spastic diplegia from the difference between the visual and performance IQ scores (VIQ‐PIQ) on the Wechsler Intelligence Scale for Children‐Revised (WISC‐R), having found a strong negative correlation between this score and the PQ obtained on the Frostig Developmental Test of Visual Perception (DTVP). The ratio of the areas of the posterior horns to the anterior horns (P/A) correlated negatively with visuoperceptual disturbance. This ratio can therefore be used to assess perceptual disturbance at an early age in children with spastic diplegia.

Encephalopathy associated with haemophagocytic lymphohistiocytosis following rotavirus infection

Abstract A 2-year-old Japanese boy with a haemophagocytic lymphohistiocytosis (HLH) associated encephalopathy which developed after rotavirus infection is described. The neurological symptoms consisted of coma, seizures and spastic quadriplegia. On therapy with steroids, etoposide and cyclosporin A, the patient recovered without any neurological deficits. The interferon-gamma levels in serum and CSF were elevated at onset of the disease but had returned to normal at the time of clinical remission. Brain MRI revealed diffuse white matter abnormalities and parenchymal volume loss. Proton magnetic resonance spectroscopy revealed elevated lactate in the abnormal lesions observed on MRI, indicating that macrophages not exhibiting aerobic metabolism had infiltrated the CNS. At the time of clinical remission, the white matter abnormalities and brain lactate had disappeared. These findings suggested that the neurological symptoms resulted from the overproduction of cytokines by activated T-cells and macrophages. The pathophysiology of a HLH associated encephalopathy was considered to be a local immune response within the CNS, because interferon-gamma can induce the expression of major histocompatibility complex class I and II antigens on glial cells in the CNS. Conclusion Haemophagocytic lymphohistiocytosis associated encephalopathy should be considered early in the differential diagnosis of cases with acute onset neuropathy.

Serial neuroimages of acute necrotizing encephalopathy associated with human herpesvirus 6 infection

A previously healthy 8-month-old girl developed exanthem subitum and acute encephalopathy with status epilepticus, quadriplegia and bilateral abducens nerve palsies. Human herpesvirus-6 DNA was found in the cerebrospinal fluid by the polymerase chain reaction at the acute stage. Cranial computed tomography showed low density areas in the thalami and in the cerebellar and abducens nuclei. The distribution of the lesions was consistent with acute necrotizing encephalopathy. As for the thalamic lesions, a T2 weighted magnetic resonance image on the 24th day of the illness demonstrated low signal intensity surrounded by high intensity; 99mTc-ECD SPECT showed hypoperfusion, which suggested irreversible tissue damage. The patient is now 1 year 6 months old and has spastic quadriparesis with mental retardation and abducens nerve palsies.

Missense mutations in the DNA-binding/dimerization domain of NFIX cause Sotos-like features

Sotos syndrome is characterized by prenatal and postnatal overgrowth, characteristic craniofacial features and mental retardation. Haploinsufficiency of NSD1 causes Sotos syndrome. Recently, two microdeletions encompassing Nuclear Factor I-X (NFIX) and a nonsense mutation in NFIX have been found in three individuals with Sotos-like overgrowth features, suggesting possible involvements of NFIX abnormalities in Sotos-like features. Interestingly, seven frameshift and two splice site mutations in NFIX have also been found in nine individuals with Marshall–Smith syndrome. In this study, 48 individuals who were suspected as Sotos syndrome but showing no NSD1 abnormalities were examined for NFIX mutations by high-resolution melt analysis. We identified two heterozygous missense mutations in the DNA-binding/dimerization domain of the NFIX protein. Both mutations occurred at evolutionally conserved amino acids. The c.179T>C (p.Leu60Pro) mutation occurred de novo and the c.362G>C (p.Arg121Pro) mutation was inherited from possibly affected mother. Both mutations were absent in 250 healthy Japanese controls. Our study revealed that missense mutations in NFIX were able to cause Sotos-like features. Mutations in DNA-binding/dimerization domain of NFIX protein also suggest that the transcriptional regulation is abnormally fluctuated because of NFIX abnormalities. In individuals with Sotos-like features unrelated to NSD1 changes, genetic testing of NFIX should be considered.

Neuroradiological assessment of visuoperceptual disturbance in children with spina bifida and hydrocephalus

The intellectual status of twelve children with spina bifida and hydrocephalus was evaluated. Seven children were considered to have verbal and non‐verbal skill discrepancies. It was considered that the Verbal IQ‐Performance IQ score by WISC‐R could be used as an index of their visuoperceptual disturbance. The disturbance was closely related to the morphological characteristics of the lateral ventricles on cerebral MRI. The ratio of the areas of the posterior horns to the anterior horns (P:A) showed a negative correlation with visuoperceptual ability. The visual pathway, visual cortex, and the ventral system were thus considered to be the sites of the affected lesions. From P.A changes with time, it was evident that adequate shunting would prevent the perceptual disturbance.

Proton magnetic resonance spectroscopy to study the metabolic changes in the brain of a patient with Leigh syndrome.

Localized proton magnetic resonance spectroscopy (MRS) was performed to study the metabolic changes in the brain of a patient with Leigh syndrome, who had a T-->G point mutation at nt 8993 of mitochondrial DNA. In this patient, sodium dichloroacetate therapy normalized the lactate and pyruvate levels in both blood and cerebrospinal fluid (CSF). However, his psychomotor retardation did not improve and magnetic resonance imaging showed progressive cerebral atrophy. In the patients spectra, elevation of brain lactate was observed throughout the brain with regional variations, predominantly in the basal ganglia and brainstem with an abnormal MRI appearance. Although the lactate/creatine ratio observed on proton-MRS was related to the CSF lactate level, the ratio did not completely parallel the CSF lactate level, i.e. brain lactate was detected even when the CSF lactate level had become normalized. Furthermore, proton-MRS revealed a decrease in the N-acetylaspartate/creatine ratio and an increase in the choline/creatine ratio, representing neuronal loss and breakdown of membrane phospholipids. The clinical and MRI findings were well related to the changes in spectroscopically determined brain metabolites. These results indicate that the brain metabolites observed on proton-MRS are useful indicators of a response to therapy and prognosis in Leigh syndrome.

PCDH19 mutation in Japanese females with epilepsy

PURPOSE To determine the significance of PCDH19 mutations in Japanese females with epilepsy and to delineate their phenotypes. METHODS PCDH19 sequencing analysis was performed in 116 females with various epilepsies, including 97 with Dravet syndrome (83.6%). They were referred for SCN1A analysis, and 52 carried SCN1A mutations. RESULTS Seven heterozygous mutations in exon 1 were identified in 7 patients (6.0%): 2 frameshift, 2 nonsense, and 3 missense mutations. One patient was a monozygotic twin, and her sister with mild phenotype carried the same mutation. The main clinical features among these 8 patients included early seizure onset (≤25 months of age), seizure clusters (7/8), fever-associated seizures (7/8), single seizure type (6/8), and late deterioration of intellect (5/8). Seizure durations were generally up to a few minutes, and only one patient developed status epilepticus once. The main seizure types were generalized tonic-clonic (4/8), tonic (3/8) and focal seizures, with (2/8) or without secondary generalization (3/8). Myoclonic, atonic and absence seizures were extremely rare. Two patients had Dravet syndrome (25%), and this proportion was significantly smaller than that in the total subjects (p<0.01). CONCLUSION PCDH19 mutation is a relatively frequent cause of epilepsy in Japanese females. Dravet syndrome was rare in our cohort.

Kabuki make-up syndrome is not caused by microdeletion close to the Van der Woude syndrome critical region at 1q32-q41

We reported on a 5-year-old Japanese girl with clinical manifestations of Kabuki make-up syndrome (KMS) and van der Woude syndrome (VWS). Since the concurrence of the two syndromes is known in four patients, including ours, it suggests a common cause. Assuming that the association of the two syndromes was caused by a microdeletion involving the putative KMS/VWS genes, we carried out fluorescence in situ hybridization and microsatellite analyses using PAC clones and dinucleotide repeat markers spanning the VWS1 critical region at 1q32-q41. No deletion was detected at the VWS1 critical region.