Masayuki Shimono

Genotype–phenotype correlations in alternating hemiplegia of childhood

Objective: Clinical severity of alternating hemiplegia of childhood (AHC) is extremely variable. To investigate genotype–phenotype correlations in AHC, we analyzed the clinical information and ATP1A3 mutations in patients with AHC. Methods: Thirty-five Japanese patients who were clinically diagnosed with AHC participated in this study. ATP1A3 mutations were analyzed using Sanger sequencing. Detailed clinical information was collected from family members of patients with AHC and clinicians responsible for their care. Results: Gene analysis revealed 33 patients with de novo heterozygous missense mutations of ATP1A3: Glu815Lys in 12 cases (36%), Asp801Asn in 10 cases (30%), and other missense mutations in 11 cases. Clinical information was compared among the Glu815Lys, Asp801Asn, and other mutation groups. Statistical analysis revealed significant differences in the history of neonatal onset, gross motor level, status epilepticus, and respiratory paralysis in the Glu815Lys group compared with the other groups. In addition, 8 patients who did not receive flunarizine had severe motor deteriorations. Conclusions: The Glu815Lys genotype appears to be associated with the most severe AHC phenotype. Although AHC is not generally seen as a progressive disorder, it should be considered a disorder that deteriorates abruptly or in a stepwise fashion, particularly in patients with the Glu815Lys mutation.

Clinical study of childhood acute disseminated encephalomyelitis, multiple sclerosis, and acute transverse myelitis in Fukuoka Prefecture, Japan.

Acute disseminated encephalomyelitis (ADEM) has recently been studied in several countries owing to the development and wide spread use of imaging technology, but few epidemiological studies of childhood ADEM have been undertaken in Asian countries. To perform a comprehensive survey of ADEM and related diseases in Japanese children, we conducted a multicenter, population-based study on childhood ADEM, multiple sclerosis, and acute isolated transverse myelitis in Fukuoka Prefecture, Japan. We identified 26 children with ADEM, 8 with multiple sclerosis, and 4 with acute transverse myelitis during 5 years between September 1998 and August 2003. The incidence of childhood ADEM under the age of 15 years was 0.64 per 100,000 person-years, mean age at onset was 5.7 years, and male-female ratio was 2.3:1. The prevalence of childhood multiple sclerosis was 1.3 per 100,000 persons. The mean age at onset of multiple sclerosis, 9.3 years, was significantly higher than that of ADEM. Nineteen (73%) and four (15%) patients with ADEM experienced antecedent infectious illnesses and vaccinations, respectively, within 1 month before the onset. Clinical and radiological findings of ADEM revealed that the frequency of seizures, mean white blood cell counts in cerebrospinal fluid, and the frequency of subcortical lesions in Fukuoka study, seemed to be higher than those in previous non-Asian studies. These findings suggest that there are ethnic or geographical differences in the incidence and clinical features of ADEM, and that there might be potent genetic or environmental risk factors for ADEM distinct from those for multiple sclerosis.

Girl with nephrotic syndrome after peripheral blood stem cell transplantation

Allogenic hematopoietic stem cell transplantation (allo-HCT) is developed as the therapeutic tool for intractable hematopoietic diseases and also certain metabolic disorders. However, Graft-versus-host disease (GVHD), a representative severe complication, is relatively common. Recently, there have been several reports of nephrotic syndrome (NS) after allo-HCT. Membranous nephropathy (MN) is the renal pathology for most cases, but minimal change NS (MCNS) is also found. In general, the NS after HCT responds to immunosuppressant drugs fairly well and the prognosis is relatively good. As another type of renal complication, acute renal failure secondary to allo-HCT usually occurs within 120 days after transplantation. This can be due to antibiotics, cyclosporine A (CsA), total body irradiation, multiple organ failure following severe infection, or GVHD. 1

Successful risperidone treatment for behavioral disturbances in Prader–Willi syndrome

Prader–Willi syndrome (PWS) is characterized by perinatal muscular hypotonia, dysmorphic features and infancy feeding problems, followed by overeating and being excessively overweight and other symptoms related to hypofunctioning of the hypothalamus (i.e. hypogonadism, short stature and hypopigmentation) including learning disorders. PWS represents the most common diagnosable genetic obesity syndrome. It occurs in approximately one in 15 000 births, and it is associated with chromosomal paternal deletion or maternal disomy at 15q11–q13. In addition to physical features such as obesity, PWS also includes behavioral disturbances such as stubbornness, impulsiveness, aggressiveness, self-mutilation, skin picking, and temper tantrums. Behavioral disturbances (i.e. hyperphagia, morbid obsession, reduced satiety, stealing money to buy food), decreased energy expenditure and reduced physical activity may lead to morbid obesity accompanied by life-threatening cardiacrespiratory complications. Therefore, various modes of psychotropic medications have been suggested, among them selective serotonin reuptake inhibitors, central nervous system stimulators, lithium, anticonvulsant medications (valpro acid, carbamazepine, etc.) and classical neuroleptics. However, to date, no proven and efficient management modality for the behavioral manifestations in PWS has yet been established. Risperidone, an atypical antipsychotic agent, is a highly potent antagonist against both dopamine D2 and serotonin 2A receptors. Our decision to choose risperidone for the treatment of PWS was motivated by a recent report that described risperidone as being effective for children suffering from autism with behavioral disturbances including stubbornness and impulsiveness, which are similar to those of PWS. We herein report a case of PWS, in which risperidone improved the behavioral disturbances and also resulted in weight loss due to the introduction of cognitive behavioral therapy without any side-effects. Case report

Recurrent autonomic and sensory neuropathy in a patient with anti-ganglionic acetylcholine receptor antibodies

We report a case of recurrent neuropathy with predominant autonomic and sensory involvement whose serum was positive for anti-ganglionic acetylcholine receptor (anti-gAChR) antibodies, a diagnostic marker of autoimmune autonomic ganglionopathy. An 11-year-old girl complained of numbness and limb pain after gastroenteritis. Although hyperalgesia and autonomic dysfunctions, such as orthostatic intolerance and gastrointestinal dysmotility subsequently developed, these symptoms faded after a few days. Similar sensory and autonomic impairments recurred three times within 12 months after the first episode. The sensory and autonomic symptoms were rapidly ameliorated by the administration of intravenous immunoglobulin (IVIg) at the second and third relapse; however, the symptoms persisted even after the administration of IVIg at the fourth relapse. The residual symptoms disappeared after methylprednisolone pulse therapy. The patients serum was found to be positive for anti-gAChR antibodies at the second relapse, and was negative after methylprednisolone pulse therapy. Further studies are needed to clarify the efficacy of treatment and the nosological position in the spectrum of neuropathies that are associated with autonomic and sensory impairments.

Inability of infants to push up in the prone position and subsequent development

During routine health screening, some infants cannot maintain the prone position with extended arm support at 6 months. Little is known, however, about the development of full‐term infants with this developmental deviation. We investigated the developmental course of infants with this characteristic.

A recurrent homozygous NHLRC1 variant in siblings with Lafora disease

We report a case of two siblings with progressive myoclonus epilepsy whose parents were not consanguineous. Their clinical symptoms were typical of Lafora disease (LD), but skin biopsies revealed no Lafora bodies. Whole-exome sequencing identified a recurrent homozygous frameshift variant in the NHLRC1 gene in both siblings. The genetic analysis was useful for the diagnosis of LD, as neither consanguinity nor Lafora bodies were found.

Successful, Short-Term Drug Exchange Protocol in Epilepsy: Transient Addon of Intravenous Anti-Epileptic Drugs

Newer antiepileptic drugs (AEDs) are supposed to be more beneficial at controlling seizures than older AEDs. We substituted newer AEDs for older AEDs while conducting a transient add-on of an intravenous (IV) antiepileptic drug (AED) as a base therapy (AED adjustment), and in the present paper we evaluate the efficacy and safety of this method. The study participants were 40 consecutive referral patients with intractable epilepsy who had been treated with two or more AEDs but had epileptic seizure which spoiled their quality of life. Five of the patients were excluded because any IV AEDs exacerbated their clinical seizures and electro-encephalography (EEG). The mean age of the remaining 35 patients was 7.5 (range: 1.2 - 20.5). The patients had been on two to five AEDs (mean 3.3), and experienced seizures ranging from 0.2 to 100 times/day (mean 13.0). We kept the patients on one or two key oral AEDs and terminated the other oral AEDs simultaneously while they were treated with a base IV AED. After adjusting their dose, the patients were on two to four oral AEDs (mean 2.8) two years later, and the frequency of seizures was reduced to 0 to 10 times/day (mean 1.4). It took about one month of hospitalization to adjust the AEDs, and both seizure frequency and the number of drugs decreased significantly after AED adjustment (p<0.001). There were no serious side effects of clinical seizures or in their blood and chemistry tests. The adjusted AEDs included newer ones, and the older ones were still necessary. AED adjustment was possible and useful for epileptic patients once a transient add-on of intravenous antiepileptic drugs was done.

Two Cases of Tuberous Sclerosis Complex Suggestive of Complicating Multifocal Micronodular Pneumocyte Hyperplasia: A Case Report

Multifocal micronodular pneumocyte hyperplasia (MMPH) is pathologically characterized by multifocal nodular hyperplasia of type Ⅱ pneumocyte-like cells. MMPH is usually complicated with tuberous sclerosis complex (TSC). MMPH patients tend to be asymptomatic or only slightly symptomatic. MMPH tends to progress slowly and needs no treatment. We herein describe two cases of MMPH with its characteristic radiological features and clinical manifestations of TSC. Case 1: a 20-year-old female with definitive TSC in infancy. Chest CT at the age of 18 revealed multiple nodular opacities and ground-glass attenuations in a scattered and random distribution in the bilateral lungs. Case 2: a 44-year-old female with probable TSC at 36 years of age. Chest CT at the age of 43 showed random areas of small ground-glass attenuations, predominantly in the upper lung fields. Case 1 and Case 2 have had no respiratory symptoms or radiographic changes in the recent two years and four years, respectively. Although pathological examinations of the lung were not performed because consent for surgical lung biospies was unobtainable, we considered that these pulmonary manifestations were most likely MMPH with TSC because of these characteristic radiographical findings of multiple nodular opacities and ground-glass attenuations of 10 mm or less in size and their scattered distribution, and because there have been no abnormal laboratory data or changes in their chest radiological findings for years. Neither patient is under treatment for pulmonary lesions. Although MMPH is a rare disease, multiple nodules and ground-glass attenuations on lung imaging findings should be considered as pulmonary manifestations in patients with TSC.

A Short Commentary of Neuronal Ceroid Lipofuscinoses; Phenotypes inCongenital to Preschooler

The classification of neuronal ceroid lipofuscinoses (NCLs) had been clinically divided according to the age at the onset of symptoms: infantile, late infantile, juvenile and adult NCLs. However, this classification cannot always predict the causative gene; i.e., CLN1, for example, causes not only infantile NCL but also late onset infantile and adult NCLs. In 2012, a new classification for the NCLs that takes into account recent genetic and biochemical advances. This short review commentary focuses on the NCLs which might cause symptoms in children from neonate to preschooler age: CLN10 (neonatal), CLN1 (6-48 months), CLN14 (8-24 months), CLN2 (1-6 years), CLN3 (4-7 years), CLN5 (4-6 years), CLN6 (18 months-8 years), CLN7 (2-7 years) and CLN8 (5-10 years). There is no fundamental therapy, but there is the trial of some cures.