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Introduction: Spinal muscular atrophy (SMA) is caused by a defect in the survival motor neuron 1 (SMN1) gene. The Cooperative Study of the natural history of SMA Type I in Taiwan is a retrospective, longitudinal, observational study that helps in further understanding SMA disease progression in patients who have not received disease-modifying therapeutic interventions., Methods: Case report forms were used to collect demographics; genetic confirmation; SMN2 copy number; treatment patterns; and clinical outcomes including ventilator use, endotracheal tube intubation, tracheostomy, gastrostomy, complications, and survival., Results: A total of 111 patients with SMA Type I were identified over the study period (1979-2015). Mean (median) age of onset and age at confirmed diagnosis were 1.3 (0.8) and 4.9 (4.4) months, respectively. SMN1 deletion/mutation was documented in 70 patients and SMN2 copy number in 32 (2 copies, n = 20; 3 copies, n = 12). At 240 months, survival probability for patients born during 1995-2015 versus 1979-1994 was significantly longer (p = 0.0057). Patients with 3 SMN2 copies showed substantially longer 240-month survival versus patients with 2 SMN2 copies. Over the 36-year period, mean (median) age at death was 31.9 (8.8) months. As of December 2015, 95 patients had died, 13 were alive, and 3 were lost to follow-up. The use of supportive measures (tracheostomy and gastrostomy) was associated with improved survival., Conclusions: These data describe the short survival of patients with SMA Type I in Taiwan in the pretreatment era, emphasizing the positive impact of supportive measures on survival., (Copyright © 2020 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.)

Background: Several studies on clinical practice for Duchenne muscular dystrophy (DMD) have been conducted in Western countries. However, there have been only a few similar studies in Asia and Oceania. Here, we investigate the steroid therapy-related clinical practice for DMD among the local experts. In 2015, we conducted a DMD expert survey in Asia and Oceania to acquire information regarding patients with DMD and to assess current clinical practice with the cooperation of Asian and Oceanian Myology Centre, a neuromuscular disease research network., Results: We obtained survey responses from 87 out of 148 clinicians (62%) from 13 countries and regions. In China, 1385 DMD patients were followed-up by 5 respondent neurologists, and 84% were between 0 and 9 years of age (15% were 10-19 years, 1% > 19 years). While in Japan, 1032 patients were followed-up by 20 clinicians, and the age distribution was similar between the 3 groups (27% were 0-9 years, 35% were 10-19 years, 38% were >19 years). Most respondent clinicians (91%) were aware of DMD standard of care recommendations. Daily prednisolone/prednisone administration was used most frequently at initiation (N = 45, 64%). Inconsistent opinion on steroid therapy after loss of ambulation and medication for bone protection was observed., Conclusions: Rare disease research infrastructures have been underdeveloped in many of Asian and Oceanian countries. In this situation, our results show the snapshots of current medical situation and clinical practice in DMD. For further epidemiological studies, expansion of DMD registries is necessary., (Copyright © 2020 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.)

Background and Purpose: Rotavirus was detected in 40-50% of patients with benign convulsions with mild gastroenteritis (CwG) before the rotavirus vaccine was introduced in late 2000. However, the rate of rotavirus positivity has decreased since 2010 while the prevalence of norovirus has gradually increased. We investigated the incidence of norovirus-associated CwG during a recent 3-year period and additionally compared the characteristics of norovirus-associated CwG with those of rotavirus-associated CwG., Methods: The medical records of CwG patients admitted to our hospital between March 2014 and February 2017 were reviewed, including the results of stool virus tests. For comparing norovirus- and rotavirus-associated CwG, data obtained between March 2005 and February 2014 that included sufficient numbers of patients with rotavirus-associated CwG were additionally reviewed. Data were collected on clinical characteristics (age, sex, seasonal distribution, enteric symptoms, and the interval to seizure onset), seizure characteristics (frequency, duration, type, and electroencephalographic findings), and laboratory findings., Results: CwG was diagnosed in 42 patients during the 3-year study period. Stool viruses were checked in 40 (95.2%) patients and were detected in 32 (80.0%) patients. Norovirus genogroup II was detected in 27 (67.5%) of the 40 patients, rotavirus was detected in 3 patients, and adenovirus was detected in 2 patients. In total, 140 CwG patients were enrolled between March 2005 and February 2017. The patients with norovirus-associated CwG (N = 44) and rotavirus-associated CwG (N = 26) were aged 18.66 ± 5.57 and 19.31 ± 7.37 months (mean ± standard deviation), respectively (P > 0.05). Norovirus-associated CwG was less prevalent than rotavirus-associated CwG during spring (13.6% vs. 34.6%, P = 0.04), while the prevalence of both types of CwG peaked during winter (63.6% and 46.2%, respectively). Vomiting was more prevalent in norovirus- than rotavirus-associated CwG (97.7% vs. 80.8%, P = 0.02) and the interval between enteric symptom onset and seizure onset was shorter in norovirus-associated CwG (2.00 ± 1.06 vs. 2.58 ± 1.21 days, P = 0.04). Most cases in both groups had seizures that lasted for less than 5 min (95.5% vs. 92.3%). Clustered seizures seemed to occur more frequently in the norovirus group (79.5% vs. 57.7%), although with borderline significance (P = 0.05). Posterior slowing was observed more frequently in norovirus-associated CwG (34.9% vs. 11.5%, P = 0.03)., Conclusion: The most common viral pathogen of CwG was norovirus during the analyzed 3-year period, with an incidence of 67.5%. In comparison with rotavirus-associated CwG, norovirus-associated CwG was less frequent during spring, more frequently seen with vomiting, had a shorter interval from enteric symptom onset to seizure onset, and more frequently showed posterior slowing in electroencephalography., (Copyright © 2018 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.)

Early-onset epileptic encephalopathies (EOEEs) are severe and intractable infantile-onset epilepsies with progressive intellectual disability and other associated neurologic comorbidities. Whole-exome sequencing (WES) was recently used to determine the causative gene mutations in individuals with unclassified EOEEs. The present study used WES to determine the causative variant in a family with X-linked, EOEE. One potential variant (c. 427A>G, NM_002641.3; p.Lys143Glu, NP_002632.1) of the gene encoding phosphatidylinositol glycan biosynthesis class A protein (PIGA; PIGA) was found, which was verified by Sanger sequencing. The functional effect of this PIGA mutation was assessed by the surface expression levels of glycosylphosphatidylinositol-anchored proteins on blood cells: CD16 on red blood cells was significantly decreased in the proband (by 11.0%) and his mother (by 15.6%). This is the second report of a less-severe form of PIGA deficiency., (Copyright © 2016 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.)

Doublecortin (DCX) and tubulin play critical roles in neuronal migration. DCX mutations usually cause anterior dominant lissencephaly in males and subcortical band heterotopia (SBH) in females. We used whole-exome sequencing to investigate causative gene variants in a large family with late-childhood-onset focal epilepsy and anterior dominant pachygyria without SBH in both genders. Two potential variants were found for the genes encoding DCX and beta tubulin isotype 1 (TUBB1). The novel DCX mutation (p.D90G, NP_000546.2) appeared to be a major causative variant, whereas the novel mutation of TUBB1 (p.R62fsX, NP_110400.1) was found only in patients with more-severe intellectual disability after gender matching. We report an unusual DCX-related disorder exhibiting familial pachygyria without SBH in both genders., (Copyright © 2015 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.)

Background and Purpose: Rotavirus was the most common virus in benign convulsions with mild gastroenteritis (CwG), with an incidence of 40-50%. As rotavirus gastroenteritis has decreased since introduction of rotavirus vaccine, we investigated the incidence of CwG and rotavirus positivity after introduction of the vaccine., Methods: We retrospectively reviewed the medical records of 987 patients aged between 3months and 3years who were admitted to the Chonnam National University Hospital between March 2005 and February 2014 due to their first seizures and enrolled 102 patients with CwG. The incidences of CwG among seizure patients and stool rotavirus positivity in CwG patients were compared between two periods: period I (March 2005-February 2010) and period II (March 2010-February 2014). Other viruses in stools were also reviewed., Results: The incidence of CwG were 8.47% (45 among 531 patients) in period I and 12.50% (57 among 456 patients) in period II (P=0.018). Stool rotavirus was checked in 85.29% (87 patients): 82.22% (37 patients) in period I and 87.72% (50 patients) in period II (P=0.166). The positivity of rotavirus was 40.54% (15 patients) in period I and 16.00% (8 patients) in period II (P=0.01). In the patients without rotavirus gastroenteritis, 30 patients were test for other viruses. Norovirus was the most common (56.67%, 17 patients) and was more frequent in period II than I (71.43% versus 22.22%, P=0.018)., Conclusion: After introduction of rotavirus vaccine, rotavirus-associated CwG has decreased but the incidence of CwG has increased due to an increase of norovirus., (Copyright © 2014 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.)

Objectives: To clarify the characteristics of brain magnetic resonance imaging (MRI) and magnetic resonance angiography (MRA) at symptom onset in patients with childhood moyamoya disease (MD) according to developmental stage., Methods: In 26 childhood MD patients who underwent brain MRI and MRA within 3 months from symptom onset, MRA scores and grades and MRI findings from symptomatic hemispheres were summarized according to developmental stage: infancy (0-1 years, three patients), toddlerhood/preschool age (2-5 years, nine patients), school age (6-10 years, seven patients), and adolescence (11-18 years, seven patients)., Results: Mean MRA score was 5.6, which was higher in adolescents (6.9). The most common MRA grade was grade 3, particularly in those under 10 years. Acute ischemic infarction presented in 17 patients (65%), was more common in patients below 5 years (83%) and was mainly in a gyral pattern (47%). Most hemorrhagic infarctions occurred in adolescents. Moyamoya vessels in the Sylvian valleys were apparent in 22 patients (85%), which were the most sensitive non-ischemic findings on T2 weighted images. The signal void in the distal internal carotid artery was diminished in 73% and apparent signal voids in basal ganglia were seen in three patients. The ivy sign was positive in 81% on fluid attenuated inversion recovery images and 69% on contrast-enhanced T1-weighted images in 21 and 16 patients, respectively., Conclusions: Brain MRIs and MRAs at symptom onset in childhood MD have characteristic findings, which differ in different developmental stage., (Copyright © 2014 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.)

Intranuclear rods myopathy (IRM), a variant of nemaline myopathy (NM), is characterized by rod structure in the myonuclei. Patients with IRM present with similar symptoms to those of severe infantile-type NM but have worse outcome. Several extramuscular manifestations have been reported in NM but no dysautonomia. We herein report a 2-year-old girl with IRM and a heterozygous mutation, c.430C>T (p.L144F) in ACTA1. During the infancy, the patient showed severe diaphoresis and facial flushing. Arrhythmia and hypertension with the precipitating factors of feeding, defecation, and urination were observed. Sympathetic antagonist was prescribed and showed some effectiveness. Our report may widen the clinical spectrum of IRM. It also reminds clinicians that autonomic dysfunction may occur in patients with IRM or other actinopathies and appropriate treatment may be necessary., (Copyright © 2012 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.)

The objective is to clarify the early clinical characteristics in childhood moyamoya disease (MD). Epidemiologic characteristics, symptoms and diagnostic rates were assessed in 64 children (0-18 years) with definite MD according to developmental stage: infancy (5; 0-1 years); toddlerhood/preschool age (22; 2-5 years); school age (29; 6-10 years); and adolescence (8; 11-18 years). The median ages at onset was 6.25 years and the female to male ratio was 1.9 (~2.5 in toddlerhood/preschool age and in adolescence, P=0.71). Previous headache was observed in 23% (14/64): frequently in school age (38%, P=0.02) and within 6 months before main symptoms (6/11). As an initial symptom, weakness was observed in 78% (50/64) mainly as transient ischemic attack (TIA, 61%) in limbs (90%) and unilaterally (82%). TIA was less frequent in infancy (40%, P=0.04). Seizure was observed in 27% (17/64): frequently in infancy (100%, P<0.01), as the focal type (71%), and in the right extremity (3:1). Isolated seizures without other symptoms was frequent in children ~5 years (P<0.01). Severe headache associated with MD was observed in 14% (9/64). Provoking events were positive in 42% (27/64): in school age, frequently during eating (28%); and in toddlerhood/preschool age, during crying (27%). The diagnostic rates at 3 and 12 months from symptom-onset were 39% (80% during infancy vs. 28% in school age, P=0.14) and 67%, respectively. Symptomatic progression at diagnosis was observed in 38% (24/64). Initial clinical characteristics in childhood definite MD differed according to developmental stage and from at diagnosis., (Copyright © 2012 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.)

Limb-girdle muscular dystrophy (LGMD) is a group of hereditary muscle diseases with preferential involvement of the shoulder and pelvic girdle muscles, but with no pathognomonic features as in facioscapulohumeral and congenital muscular dystrophies. We report 18-year-old female with progressive shoulder and pelvic muscle weakness. She had marked restrictive pulmonary dysfunction. Echocardiogram showed mild decrease in ejection fraction of 52% (normal: >55%). She was first seen in our hospital at age 2 years with progressive proximal muscle weakness and elevated creatine kinase (CK) level to 15,290 IU/L, with what clinically and pathologically appeared to be steroid-responsive inflammatory myopathy. She responded dramatically to steroid therapy. Progressive proximal muscle weakness began again at age 8 years. Serum CK was 14,910 IU/L. She was wheelchair-bound by age 12. Muscle biopsy showed dystrophic changes without inflammation with reduced immunoreactivity to an antibody against sugar chain (VIA4-1) of alpha-dystroglycan. On laminin overlay assay, there was a nearly complete loss of laminin-binding activity to alpha-dystroglycan. Genetic analysis of fukutin-related protein (FKRP) gene revealed a novel compound heterozygous mutation of c.823C>T (p.R275C) and c.948delC, confirming the diagnosis of LGMD2I, the first reported case in East Asia.

In this study, we longitudinally followed into childhood a cohort of preschool children, initially diagnosed as autistic or non-autistic with developmental delay, to evaluate the stability of cognitive assessments performed during the preschool period. The consistency in group means and intra-individual stability of developmental quotients (DQ) and non-verbal intelligence quotients (IQs) were compared for these two groups, which were matched by chronological age, initial non-verbal IQ/DQs, initial test given, and length of follow-up interval. The case group comprised 16 autistic children with average age at initial assessment of 3 years 8 months. The control group comprised 16 non-autistic developmental delayed children with average age at initial assessment of 3 years 11 months. Mean DQ/non-verbal IQ at initial assessment was 73.9+/-23.9 for the case group and 80.3+/-23.2 for the control group. ANOVA yielded no significant effect of time or time x diagnosis interaction (F=0.183, P=0.675). The absolute difference in scores and group means were equivalent for both groups of children, with no difference in patterns of change. Correlations between DQ/non-verbal IQs at initial assessment and follow-up were significant and high for the two groups (autistic group: r=0.87; control: r=0.77). Intellectual functioning can be a valid measure in Taiwanese preschool children with autism, and has an equivalent meaning for children with autism and for non-autistic children with developmental delay. Though the follow-up period is too short for definite prognostic conclusions to be drawn, we think that non-verbal intelligence should be an essential assessment for preschool oriental autistic children so that sound expectation and treatment plan can be made.

A 12-year-old girl with proximal muscle weakness and delayed psychomotor development from early infancy is presented. She had a myopathic face, high-arched palate, nasal tone vocalization, positive Gowers' sign, waddling gait and decreased deep tendon reflexes. Her IQ was 40 (PIQ = 39, VIQ = 51). The serum creatine kinase level and peripheral nerve conduction velocity as well as electrocardiogram were normal. The electromyogram showed myopathic changes. Magnetic resonance imaging (MRI) of thigh muscles revealed fatty infiltration of all muscle groups, the hypertrophic biceps femoris and semimembranous muscles being spared. A biopsy specimen from the left biceps brachii muscle revealed small caliber fibers, increased variability of fiber size and uniformity of type 1 fibers (greater than 99%). This case was diagnosed as having congenital nonprogressive myopathy with uniform type 1 fibers, and had a non-deteriorating clinical course as in most congenital nonprogressive myopathy cases.

A 28-month-old male with generalized hypotonia and muscle weakness, a myopathic face, skeletal dysmorphism and delayed motor milestones from birth is reported. He gradually developed the ability of sitting and rolling over, but could not stand without support until 28 months. There was no intellectual impairment or seizures. Deep tendon reflexes were absent. The serum CK value, peripheral nerve conduction velocity and EMG were within normal limits. A muscle biopsy specimen showed mild variation in fiber size, and an increased number of type 2C fibers on histochemical examination, but no apparent abnormalities on electron microscopy. The baby was tentatively diagnosed as having minimal change myopathy or nonspecific congenital myopathy which is thought to be one of the congenital nonprogressive myopathies.