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Background Arterial spin labeling, a magnetic resonance imaging modality that can evaluate cerebral perfusion without using a contrast material or ionizing radiation, is becoming increasingly accessible. However, only a few reports have used this method to assess the perfusion abnormalities observed in acute encephalopathy with biphasic seizures and late reduced diffusion. Patient description A 10-month-old Japanese girl presented with febrile status epilepticus (early seizures). Her convulsions ceased after the administration of intravenous phenobarbital, although her impaired consciousness was protracted. Five days later, diffusion-weighted imaging revealed slightly high signal intensity lesions in the bilateral posterior frontal areas. Arterial spin labeling revealed bilateral frontal-dominant hypoperfusion and posterior frontal hyperperfusion. On day 6, she had three convulsions (late seizures) and was diagnosed with acute encephalopathy with biphasic seizures and late reduced diffusion. She received treatment accordingly and recovered eventually. Discussion Based on previous reports, hypoperfusion within 1–2 days of early seizures and hyperperfusion accompanied by bright tree appearance on diffusion-weighted imaging within 1–2 days of late seizures are typical in acute encephalopathy with biphasic seizures and late reduced diffusion. In our patient, the first magnetic resonance imaging scan was performed one day prior to the onset of late seizures. We observed posterior frontal hyperperfusion accompanied by high signals on diffusion-weighted imaging, which leads us to speculate that this could be a predictive marker of late seizures.

Objectives Acute encephalopathy is an acute brain dysfunction after preceding infection, consisting of multiple syndromes. Some syndromes, such as acute encephalopathy with biphasic seizures and late reduced diffusion (AESD), are severe with poor outcome, whereas others, such as clinically mild encephalitis/encephalopathy with reversible splenial lesion (MERS), are mild with favorable outcome. Previous study reported the association of the thermolabile polymorphism in Carnitine Palmitoyltransferase 2 (CPT2) gene and severe syndromes of acute encephalopathy. To further explore the pathogenetic role of CPT2 in acute encephalopathy, we conducted a case-control association study of a typical thermolabile CPT2 polymorphism, rs2229291, in 416 patients of acute encephalopathy, including both severe and mild syndromes. Methods The case cohort consisted of 416 patients, including AESD, MERS, and other syndromes. The control subjects were 100 healthy Japanese. rs2229291 was genotyped by Sanger sequencing. Genetic distribution was compared between the patients and controls using Cochran-Armitage trend test. Results Minor allele frequency of rs2229291 was significantly higher in AESD (p = 0.044), MERS (p = 0.015) and entire acute encephalopathy (p = 0.044) compared to the controls. The polymorphism showed no significant association with influenza virus, or with outcome. Conclusions This study provided evidence that CPT2 is a susceptibility gene for overall acute encephalopathy, including both severe and mild syndromes, and suggested that impairment of mitochondrial metabolism is common to various syndromes of acute encephalopathy.

ObjectiveWe examined the clinical manifestations of acute encephalopathy (AE) and identify risk factors for AE in children with tuberous sclerosis complex (TSC).MethodsThe clinical data of 11 children with clinically diagnosed TSC associated with AE and 109 children with clinically diagnosed TSC alone aged 4 years or older were collected from 13 hospitals.ResultsOf the 11 children with AE, 5 had histories of febrile seizures (FS), and all had histories of febrile status epilepticus (FSE). AE developed within 24 h after fever onset in all children with seizures lasting 30 min or longer. All children developed coma after seizure cessation. Head magnetic resonance imaging (MRI) revealed widespread abnormalities in the cerebral cortex, subcortical white matter, corpus callosum, basal ganglia, and thalamus. One child died; seven had severe neurological sequelae; and the other three, mild sequelae. Logistic regression analysis revealed that a history of FSE was correlated with the development of AE.SignificanceAE in children with TSC was characterized by sudden onset after fever, followed by coma, widespread brain edema evident on MRI, and poor outcomes. A history of FSE was a risk factor for the development of AE.

Background Tuberous sclerosis complex (TSC)-associated neuropsychiatric disorders (TAND) have a large impact on patients and their families. Improving intellectual ability outcomes using preventive vigabatrin (VGB) treatment has recently been reported. Aim The aim of this study was to investigate the severity of behavioral problems and degree of distress among families of patients with TSC with and without a history of VGB treatment. Method The study enrolled 21 children and adolescents who were patients with TSC from four hospitals: 14 in the VGB group and 7 in the no-VGB group. To evaluate patients' psychiatric and neurological symptoms, we used the TAND Checklist, Aberrant Behavior Checklist (ABC), Social Communication Questionnaire (SCQ), and Social Responsive Scale–2nd edition (SRS-2). Results All VGB-group patients were administered VGB after the onset of epileptic seizures. No obvious differences were observed between the VGB and no-VGB groups in behavioral problem scores on the TAND Checklist, or on the ABC, SCQ, and SRS-2 total scores. Behavioral problem scores were lower in patients with normal intelligence than in those with mild intellectual disability (ID; P = 0.042). Degrees of family distress assessed with the TAND Checklist were not correlated with the intelligence quotient/developmental quotient (IQ/DQ) or seizure frequency but were correlated with the total SRS-2 scores (P = 0.022). For several patients, there were large discrepancies between familial and physician ratings of the TAND impact score. Conclusion Children and adolescents with TSC may present with significant behavioral difficulties and family distress, regardless of whether they were treated with VGB or not after the onset of seizures. Difficulties in social communication may have the strongest “TAND impact” on families.

Pyridoxine-dependent epilepsy (PDE) is a rare autosomal-recessive disorder typically presenting with neonatal seizures and is sometimes difficult to diagnose, because the clinical features mimic those of birth asphyxia. A Japanese newborn boy presented with pulmonary haemorrhage and convulsions on the day of birth. Brain computed tomography showed diffuse, but mild, low-density cerebral white matter and a thin subdural hematoma in the posterior fossa. He did not have thrombocytopenia or coagulopathy. His respiratory status improved with conservative treatment, but his convulsions were persistent even after prescription of several antiepileptic drugs. His serum and cerebrospinal fluid showed decreased vitamin B6 vitamers and increased upstream metabolites of α-aminoadipic semialdehyde dehydrogenase, strongly suggesting a diagnosis of PDE; the epileptic spasms ceased after administration of intravenous pyridoxal phosphate hydrate. Gene analysis revealed novel compound heterozygous mutations in ALDH7A1 that included NM_001182.4:[c.1196G > T] and [c.1200 + 1G > A]. Atypical birth asphyxia with persistent neonatal seizure should prompt vitamin B6/metabolite screening.

Background Mucolipidosis IV (MLIV; OMIM #252650) is an autosomal recessive lysosomal storage disorder, frequently observed in the Ashkenazi Jewish population. MLIV typically results in intellectual disability, corneal opacities, and delayed motor milestones during infancy, with a relatively static course. To date, reports of MLIV in other ethnic groups have been sparse. Patient The present study is a case report of a 9-year-old Japanese boy, diagnosed via whole-exome sequencing, with compound heterozygous mutations of MCOLN1 (OMIM * 605248): c.410T>C (p.Leu137Pro) and c.802_803delAG (p.Ser268Trpfs*17). Although his clinical course was mild (due to a lack of corneal clouding), other relevant features were present. These included strabismus, white matter signal abnormalities, and a hypoplastic corpus callosum at 2years of age. After a molecular diagnosis, a markedly elevated serum gastrin level (which is also common in MLIV) was confirmed. Discussion The present results suggest that MLIV could be added as a differential diagnosis for white matter disorders, regardless of ethnicity. Beyond neurological or ophthalmologic findings, serum gastrin could be a useful diagnostic marker for MLIV.

Background Mumps is a common childhood viral disease characterized by fever and swelling of the parotid gland. The prognosis is generally good, although some complications, such as encephalitis (0.1%), exist. Acute encephalopathy with biphasic seizures and late reduced diffusion is the most common type of acute encephalopathy. However, this type of encephalopathy has not been reported in association with mumps infection. Patient A previously healthy 3-year-old Japanese boy had a brief convulsion after fever for 3 days, and then had conscious disturbance and parotitis. After several days, he had a second brief convulsion and was admitted. Increased serum amylase levels and presence of anti-mumps immunoglobulin M antibody confirmed mumps parotitis. The patient had another brief seizure later the day of admission. He did not have status or cluster seizures, although the biphasic nature of his seizures, conscious disturbance between the seizures, no pleocytosis in cerebrospinal fluid, and brain magnetic resonance images were consistent with acute encephalopathy with biphasic seizures and late reduced diffusion. Discussion In Japan, the mumps vaccine is not administered as a part of routine immunizations. It thus has low coverage (30–40%), and as a result, mumps infections are still common. However, this is the first case of mumps-related acute encephalopathy with biphasic seizures and late reduced diffusion. This case may be representative of only a minority of patients with mumps-associated central nervous system involvement. Nevertheless, this diagnostic possibility may be considered. In order to prevent mumps-related complications, routine mumps vaccination might be warranted.

Background: There have been numerous reports regarding serum or cerebrospinal fluid (CSF) biomarkers in various disorders; however, the validities of such biomarkers for more precise diagnoses and prognosis estimates remain to be determined, especially in pediatric patients with neurological disorders. Methods: Serum/CSF S100B, neuron-specific enolase, and total tau (tTau) were measured in various acute pediatric neurological disorders, and their usefulness for diagnostic and prognostic predictions was validated using receiver operating characteristic curves and area under the curve (AUC) analysis. Results: A total of 336 serum and 200 CSF specimens from 313 patients were examined, and we identified statistically significant differences that were relevant from diagnostic and prognostic viewpoints. CSF and serum tTau levels could be good predictors for diagnosis (CSF tTau; AUC = 0.76) and prognosis (serum tTau; AUC = 0.78). Conclusions: Both CSF and serum tTau levels could be useful for precise diagnostic and prognostic estimations in acute pediatric neurological disorders. Further studies are needed to clarify the clinical significance of such biomarkers.

Introduction The ketogenic diet is a valuable therapy for patients with intractable epilepsy, but it can result in a variety of complications that sometimes limits its usefulness. Hypoproteinemia is one of the common adverse effects of this diet, although the underling mechanism is largely unknown except for the diet's reduced protein intake. Only one case of protein-losing enteropathy during the ketogenic diet has been reported. Patient Description A previously healthy 9-year-old girl experienced fever for 5 days then suddenly developed convulsive seizures that subsequently evolved to severe refractory status epilepticus. After multiple antiepileptic drugs failed to improve the patient's condition, we introduced the ketogenic diet. Although her seizures diminished, her course was complicated by hypoproteinemia. An abdominal dynamic scintigraphy and colonoscopy findings indicated protein-losing enteropathy with nonspecific mucosal inflammation. Her nutritional status deteriorated; thus, we discontinued the ketogenic diet. Her nutritional status gradually improved, whereas her seizures increased. Discussion Hypoproteinemia during the ketogenic diet is common, but the underlying etiologies are not well understood. Abdominal dynamic scintigraphy could be valuable for clarifying the etiology of hypoproteinemia during the ketogenic diet.

Objective: Acute encephalopathy with biphasic seizures and late reduced diffusion (AESD) is a childhood encephalopathy following severe febrile seizures, leaving neurologic sequelae in many patients. However, its pathogenesis remains unclear. In this study, we clarified that genetic variation in the adenosine A2A receptor ( ADORA2A ), whose activation is involved in excitotoxicity, may be a predisposing factor of AESD. Methods: We analyzed 4 ADORA2A single nucleotide polymorphisms in 85 patients with AESD. The mRNA expression in brain samples, mRNA and protein expression in lymphoblasts, as well as the production of cyclic adenosine monophosphate (cAMP) by lymphoblasts in response to adenosine were compared among ADORA2A diplotypes. Results: Four single nucleotide polymorphisms were completely linked, which resulted in 2 haplotypes, A and B. Haplotype A (C at rs2298383, T at rs5751876, deletion at rs35320474, and C at rs4822492) frequency in patients was significantly higher than in controls ( p = 0.005). Homozygous haplotype A (AA diplotype) had a higher risk of developing AESD (odds ratio 2.32, 95% confidence interval 1.32–4.08; p = 0.003) via a recessive model. mRNA expression was significantly higher in AA than AB and BB diplotypes, both in the brain ( p = 0.003 and 0.002, respectively) and lymphoblasts ( p = 0.035 and 0.003, respectively). In lymphoblasts, ADORA2A protein expression ( p = 0.024), as well as cellular cAMP production ( p = 0.0006), was significantly higher in AA than BB diplotype. Conclusions: AA diplotype of ADORA2A is associated with AESD and may alter the intracellular adenosine/cAMP cascade, thereby promoting seizures and excitotoxic brain damage in patients.

We describe a boy with Fisher syndrome. He presented the typical symptoms of Fisher syndrome, including external ophthalmoplegia, abnormality of convergence, and areflexia, after an episode of Campylobacter enterocolitis. Atypically, however, anti-GA1 antibody was detected in his serum, though anti-GQ1b and anti-GT1a antibodies were not. In addition, the tau protein level in his cerebrospinal fluid was elevated. Generally, Fisher syndrome is a self-limiting disease and has a good prognosis. In our patient, however, mild diplopia and areflexia persisted 6 months after their onset. Here, we report on the first Fisher syndrome patient with anti-GA1 antibody in the serum and elevated tau protein in the cerebrospinal fluid.

Background Congenital cytomegalovirus (CMV) infection causes various neurological sequelae. However, most infected infants are asymptomatic at birth, and retrospective diagnosis is difficult beyond the neonatal period. Objective This study aimed to investigate the aspects of neurological sequelae associated with asymptomatic congenital CMV infection. Methods We retrospectively analyzed 182 patients who were suspected of having asymptomatic congenital CMV infection with neurological symptoms in Japan. Congenital CMV infection was diagnosed by quantitative polymerase chain reaction amplification of CMV from dried umbilical cord DNA. Results Fifty-nine patients (32.4%) who tested positive for CMV were confirmed as having congenital CMV infection. Among 54 congenital CMV patients, major neurological symptoms included intellectual disability (n = 51, 94.4%), hearing impairment (n = 36, 66.7%) and cerebral palsy (n = 21, 38.9%), while microcephaly (n = 16, 29.6%) and epilepsy (n = 14, 25.9%) were less common. In a brain magnetic resonance imaging (MRI) study, cortical dysplasia was observed in 27 CMV-positive patients (50.0%), and all patients (100%) had cerebral white matter (WM) abnormality. Intracranial calcification was detected by CT in 16 (48.5%) of 33 CMV-positive patients. Cerebral palsy, cortical dysplasia and a WM abnormality with a diffuse pattern were associated with marked intellectual disability. Conclusions Brain MRI investigations are important for making a diagnosis and formulating an intellectual prognosis. Analysis of umbilical cord tissue represents a unique and useful way to retrospectively diagnose congenital CMV infection.

Background: Acute encephalopathy with biphasic seizures and late reduced diffusion (AESD) is characterized clini- cally by biphasic seizures and late magnetic resonance imaging abnormalities, such as reduced subcortical diffusion from day 3 onwards, often accompanied with some neurological sequelae. In the early stages of the disease, AESD closely resembles its far more prevalent and relatively benign counterpart, febrile seizure (FS). Methods: We measured and compared the serum or cerebrospinal fluid (CSF) levels of S100B, neuron-specific enolase (NSE), and total tau protein in 43 patients with FS and 18 patients withAESD, at any point during the disease. To assess early diagnostic validity, we compared these biomarkers in 43 FS and eight AESD patients, with whom the day 0-2 samples were available. We used the receiver-operator characteristic curve to evaluate the diagnostic values of these markers. Results: The levels of all biomarkers were significantly higher in AESD than FS patients. When only day 0-2 samples from AESD patients were used, the levels of all the measured biomarkers, except serum NSE, were still significantly higher in patients with AESD than in FS, suggesting that AESD could damage astrocytes, neurons, and axons, even in the early stages of the disease. According to the receiver-operator characteristic curve analyses, CSF S100B (cut-off value, 100 pg/mL) and CSF total tau protein (cut-off value, 100 pg/mL) were better predictors of AESD than other biomarkers. Conclusion: The combination of CSF S100B and CSF total tau protein resulted in a positive predictive value of AESD 83.3%, which could be helpful for early diagnosis, facilitating early therapeutic interventions.

We report sibling cases of aromatic L-amino acid decarboxylase (AADC) deficiency, which is a very rare congenital metabolic disorder. These patients were born to healthy and non-consanguineous parents, and presented oculogyric crises, paroxysmal dystonic attacks, and severe psychomotor retardation since early infancy. In cerebrospinal fluid the levels of homovanilic acid and 5-hydroxyindoleacetic acid were very low and the level of L-dopa was very high. The diagnosis was confirmed by the lack of AADC activity in plasma, and a point mutation in the AADC gene. MRI revealed a slightly small volume of the prefrontal areas and normal myelination in both patients. Positron emission tomography using 2-deoxy-2[(18)F] fluoro-D-glucose was performed in one patient, which revealed hypometabolism in the prefrontal cortex and bilateral basal ganglia with a little laterality. These findings suggested that the severe dystonic features were caused by abnormal function of bilateral basal ganglia and severe psychomotor retardation could be due to abnormalities in prefrontal cortical activity.

We report on a girl with early onset Huntington disease (HD). Her initial symptoms at 2 years of age included oral motor dysfunction and gait disturbance. Magnetic resonance imaging of the head revealed severe atrophy of both the vermis and the cerebellar cortex in addition to the common findings of basal ganglia including the caudate nuclei, putamen, and globus pallidus. Molecular analysis showed 160 CAG repeats in the HD gene. This mutation was inherited from her mother who was also affected, with a HD CAG expansion of 60 repeats. Cerebellar symptoms should be considered as a manifestation of early onset HD.

It is known that rotavirus gastroenteritis can accompany some neurological manifestations, including encephalitis/encephalopathy or seizures. However, the detailed pathogenesis involved has not been fully understood. To date, acute cerebellitis associated rotavirus gastroenteritis has not been previously reported, except for one case. Herein, we describe two cases of acute encephalitis/encephalopathy and concurrent cerebellitis, associated rotavirus gastroenteritis. Following vomiting and diarrhea, case 1 experienced convulsions and consciousness disturbance and case 2, transient loss of consciousness with eye deviation. After these symptoms subsided, cerebellar signs became evident and a brain MRI showed cerebellar involvement in both cases. Both cases showed speech disturbances, such as mutism, slow speech and dysarthria. In this report, we will discuss the possible pathogenesis of rotavirus associated acute encephalitis/encephalopathy and concurrent cerebellitis.

An 11-year-old boy presented with progressive walking disturbances. He exhibited severe equinovarus feet that together presented with hyperreflexia of the patellar tendon and extensor plantar, resembling spastic paraplegia or upper neuron disease. He showed mild distal muscle atrophy, as well. We did not observe signs of cognitive impairment, cerebellar signs, or brain magnetic resonance imaging abnormalities. Nerve biopsy showed giant axon swellings filled with neurofilaments. Gene analysis revealed novel compound heterozygous missense mutations in the gigaxonin gene, c.808G>A (p.G270S) and c.1727C>A (p.A576E). He was diagnosed with mild giant axonal neuropathy (GAN) without apparent central nervous system involvement. Patients with classical GAN manifest their symptoms during early childhood. Mild GAN, particularly in early stages, can be misdiagnosed because of lack of typical hair features and incomplete or indistinct peripheral and central nervous system symptoms. This case is important since it can aid to identify atypical and milder clinical courses of GAN. This report widens the mild GAN clinical spectrum, alerting physicians for correct diagnosis.

Acute encephalopathy with biphasic seizures and late reduced diffusion (AESD) at onset manifests an early seizure (ES) usually lasting more than 30 min. Following ES, some patients exhibit almost clear consciousness with no neurological symptoms, and no MRI abnormality for a few days, which may lead to an initial misdiagnosis of prolonged febrile seizures (PFS). To allow an early diagnosis of AESD, we retrospectively analyzed clinical manifestations, laboratory data, and radiologic and EEG findings in patients with AESD (n=62) having ES of over 30 min, and ones with PFS (n=54), using logistic regression analyses. Multivariate logistic regression analysis revealed that an age below 1.5 years and a Glasgow Coma Scale score of 14 or less than 14 (Japan Coma Scale score of 1 or higher) were high risk factors of developing AESD. We proposed an AESD prediction score system consisting of consciousness level, age, duration of convulsions, enforcement of mechanical intubation, and aspartate aminotransferase, blood glucose and creatinine levels (full score: 9), the mean scores in AESD and PFS being 5.9 and 1.8, which were significantly different (p

We describe a 5-year-old boy and a 33-year-old woman with spondyloepimetaphyseal dysplasia with joint laxity leptodactylic form (spondyloepimetaphyseal dysplasia with multiple dislocations) (MIM 6003546), and two 12-year-old girls with the disorder who were previously reported as examples of a variant of sponatrime dysplasia. Their clinical manifestations included midface hypoplasia, micromelic short stature, and generalized joint laxity that caused multiple joint problems, including thoracolumbar scoliosis, hip subluxation, progressive genu valgum with knee and patellar subluxation, elbow subluxation, and malalignment of the wrist. Laryngotracheomalacia was present in two individuals, and myopathy was noted in one. The radiological findings in the four individuals included mild platyspondyly most conspicuous in infancy, narrow interpediculate distances of the lumbar spine evident in infancy, retarded epiphyseal ossification that evolved to epiphyseal dysplasia and later to degenerative joint disease, metaphyseal irregularities and striations present in early childhood, and leptodactylic appearance (slender short tubular bones) of the hand. © 2002 Wiley-Liss, Inc.

We retrospectively collected three patients with clinically mild encephalitis with a reversible splenial lesion (MERS) after mumps vaccination, and reviewed five patients, including two patients previously reported. The five patients (all males, aged 1 to 9) presented with fever, vomiting, or headache as the initial symptoms (day 0), suggesting meningitis, at 13 to 21 days after mumps vaccination. Consciousness disturbance, delirious behavior, seizures, or dysarthria was observed on days 1 to 3, which had completely resolved before day 11. Hyponatremia was observed in all patients. A cerebrospinal fluid study showed pleocytosis, and confirmed the vaccine strain genome. MRI revealed reduced diffusion in the splenium of the corpus callosum on days 2 to 4, which had completely disappeared on the follow-up studies performed on days 7-15. EEG showed high voltage slow wave in three patients, which later normalized. These findings led to a diagnosis of MERS after mumps vaccination. MERS after mumps vaccination may be more common than previously considered. MERS is suspected when a male patient after mumps vaccination presents with neurological symptoms with hyponatremia, following symptoms of aseptic meningitis, and MRI would be performed to examine the splenium of the corpus callosum.

Background Pelizaeus–Merzbacher disease (PMD), a hypomyelinating leukodystrophy, and the related but less severe allelic spastic paraplegia 2 (SPG2) are caused by mutations in the proteolipid protein 1 (PLP1) gene. Magnetic resonance imaging (MRI) is pivotal for diagnosing these disorders. The severity of PMD/SPG2 varies, and for a milder form of PMD, there have been some reports of near-normal findings in T1-weighted images but abnormal findings in T2-weighted images. Patient We report the case of a 5-year-old boy diagnosed with a milder form of PMD caused by a novel PLP1 mutation in exon 3: c.300delC (p.I100IfsX13). He had delayed development from several months of age and was able to walk with support at 19 months in spite of the spasticity in his lower extremities. Hypomyelination was noted at 12 months by brain MRI. Motor nerve conduction studies showed decreased velocities with reduced amplitudes. Follow-up MRI at 1-year intervals from 18 months until 55 months of age showed gradual myelination progress. Discussion The single nucleotide deletion identified in this patient can cause a frameshift and premature termination of PLP1. Via the nonsense-mediated mRNA decay mechanism of this mutation will result in loss-of-function, leading to a milder form of PMD. The present case is compatible with previously reported cases of milder form of PMD. We incidentally identified progressive myelination in this patient by T1-weighted images obtained by serial MRI. This finding adds to our understanding of the pathological stages of a milder form of PMD.

This report describes a patient with Costello syndrome associated with moyamoya-like vasculopathy. His clinical findings were sparse, thin, and light-colored hair, bilateral ptosis, low-set ears, depressed nasal bridge, bulbous nose, short neck, loose pigmented skin with deep palmar and plantar creases, bilateral cryptorchidism, and delays in growth and development. Brain magnetic resonance imaging and cerebral angiography revealed moyamoya-like vasculopathy. A skin biopsy from the extensor surface of the right thigh revealed shortening and rupture of elastic fibers. Electron microscopy indicated reduced depositions of elastin. Formation of a stable elastic fiber system may be impaired in patients with Costello syndrome, and brain magnetic resonance imaging and magnetic resonance angiography would be recommended for these patients.

Division of Medical Genetics, Division of Neurology, Gunma Children’s Medical Center, Shibukawa, Department of Medical Genetics, Shinshu University School of Medicine, Matsumoto, Department of Pediatrics, Dokkyo Medical University Koshigaya Hospital, Koshigaya, Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan and Department of Child Neurology, VU University Medical Center, Amsterdam, The Netherlands Correspondence to Yoko Narumi, MD, PhD, Department of Medical Genetics, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto 390-8621, Japan Tel: + 81 263 37 2618; fax: + 81 263 37 2619; e-mail: ynarumi@shinshu-u.ac.jp

Galloway-Mowat syndrome (GMS) is a rare autosomal recessive disorder characterized by early onset nephrotic syndrome and microcephaly with various anomalies of the central nervous system. GMS likely represents a heterogeneous group of disorders with hitherto unknown genetic etiology. The clinical phenotype to some extent overlaps that of Pierson syndrome (PS), which comprises congenital nephrotic syndrome and distinct ocular abnormalities but which may also include neurodevelopmental deficits and microcephaly. PS is caused by mutations of LAMB2, the gene encoding laminin beta 2. We hypothesized that GMS might be allelic to PS or be caused by defects in proteins that interact with laminin beta 2. In a cohort of 18 patients with GMS or a GMS-like phenotype we therefore analyzed the genes encoding laminin beta 2 (LAMB2), laminin alpha 5 (LAMA5), alpha 3-integrin (ITGA3), beta 1-integrin (ITGB1) and alpha-actinin-4 (ACTN4), but we failed to find causative mutations in these genes. We inferred that LAMA5, ITGA3, ITGB1, and ACTN4 are not directly involved in the pathogenesis of GMS. We excluded LAMB2 as a candidate gene for GMS. Further studies are required, including linkage analysis in families with GMS to identify genes underlying this disease.

Acute cerebellar ataxia is usually a self-limited benign disease, which may develop in children after certain viral infections or vaccinations. There are several reports of acute cerebellar ataxia associated with autoantibodies. Glutamate receptor delta2, a member of the glutamate receptor family, is predominantly expressed in cerebellar Purkinje cells and plays a crucial role in cerebellar functions. To date anti-GluRdelta2 autoantibody was detected in a patient with chronic cerebellitis. Herein, an 18-month-old boy presented with cerebellar ataxia 9 days following a mild respiratory tract infection. Although cerebellar ataxia gradually improved, it worsened yet again following mumps and varicella virus infection. Cerebro-spinal fluid examination and magnetic resonance imaging of the brain demonstrated pleocytosis and meningeal enhancement, respectively. Furthermore, glutamate receptor delta2 autoantibody was detected in serum and cerebro-spinal fluid. Thus, we believe that the glutamate receptor delta2 autoantibody may play a role in cerebellar ataxia and consecutive cerebellitis.

We describe a 12-year-old girl, who had been medicated with theophylline for bronchial asthma and developed acute encephalopathy with refractory status epilepticus, showing bilateral mesial temporal and claustral lesions, which were evident on fluid-attenuated inversion recovery images, obtained with 1.5 T magnetic resonance imaging. To date, oxidative stress has been implicated in aging or various disorders, including inflammatory or degenerative neurological disorders. One of the oxidative stress markers, 8-hydroxydeoxyguanosine, was increased in our patient's cerebro-spinal fluid, plasma and urine. We speculate that augmented oxidative stress was associated with refractory status epilepticus in our patient, accompanying bilateral mesial temporal, claustral lesions and severe neuronal damage. Serial measurements of oxidative stress markers in acute encephalitis, encephalopathy, or status epilepticus could clarify the relationships between acute brain damage and free radicals.

We report on a family with dominantly inherited asymptomatic Alexander's disease due to a novel Glial fibrillary acidic protein (GFAP) mutation. The proband, a 16-month-old boy, presented with megalocephaly and brain magnetic resonance imaging (MRI) showing the typical findings of Alexander's disease. Molecular analysis showed that he was a heterozygote of the L331P mutation of GFAP. His mother and sister, without megalocephaly or other neurological abnormalities, were also heterozygotes of the mutation and their brain magnetic resonance imaging showed mild changes in the caudates and deep frontal white matters. These results suggest the existence of a forme fruste of Alexander's disease. The L331P mutation may be associated with the mild phenotype of Alexander's disease. To elucidate the genotype-phenotype correlation in Alexander's disease, molecular diagnosis and MRI examination are required for many patients and their families.

We report a 19-month-old boy with Menkes' syndrome that was complicated by a progressive sliding hiatal hernia. He presented with convulsions, developmental delay, elongation and tortuosity of major cerebral arteries, and diverticulae of the bladder at 4 months of age. Based on the diagnosis of Menkes' syndrome, treatment with intravenous or subcutaneous copper-histidine administration was initiated at 6 months of age. At 13 months of age, he vomited frequently owing to sliding hiatal hernia, which progressed rapidly and required surgical treatment. Connective tissue abnormalities are characteristic complications of Menkes' syndrome. Sliding hiatal hernia is probably one of the connective tissue manifestations and should be carefully evaluated in patients with Menkes' syndrome demonstrating recurrent gastrointestinal and/or respiratory symptoms. ( J Child Neurol 2002;17:401-402).

The case of a 3-year-old male with type 3 Gaucher's disease, whose genotype for the beta-glucosidase gene was D409H/unknown mutation, is presented. After the onset of visceral and neurologic signs during infancy, a radiologic investigation at 3 years of age revealed communicating hydrocephalus, an unusual complication of Gaucher's disease. A ventriculoperitoneal shunt operation led to clinical and radiologic improvement. The possibility of this complication should be considered in the treatment of patients with Gaucher's disease.

Sir: Huber et al. have reported the cases of three adolescents with opsoclonus–myoclonus syndrome (OMS) after Mycoplasma pneumoniae infection [2]. We report another such patient with OMS, who showed autoantibodies against glutamate receptors (GluR). A 12-year-old girl, otherwise healthy except for bronchial asthma, presented with a 5-day history of jerky movements of her extremities and eyes and inability to walk. One week earlier, she had suffered from a respiratory disease, and at that time, the particle agglutination test for M. pneumoniae antibody was strongly positive (>1:10,240; titers of ≥1:40 are regarded positive). Thorough examinations such as hematology, blood chemistry, electroencephalography, brain imaging, and cerebrospinal fluid (CSF) examination revealed normal findings; no signs of neuroblastoma were observed. Initially, the symptoms of OMS gradually improved. However, these symptoms worsened on day 28; therefore, intravenous immunoglobulin (IVIG) was administered at 2.0 g/kg. The symptoms of OMS began to improve within several days; however, they worsened around day 50. Therefore, IVIG was added at 1.0 g/kg, and intravenous methylprednisolone pulse therapy (30 mg/kg/day for three consecutive days) was administered three times at intervals of 1 week. The symptoms of OMS gradually disappeared by day 150 with no apparent sequelae. GluR δ2 is predominantly expressed in cerebellar Purkinje cells; it plays a crucial role in cerebellar functions and is reportedly associatedwith cerebellitis [3]. On day 30, the serum was positive, but CSF was negative for anti-GluR IgG-δ2 and IgM-δ2 antibodies. These findings indicate that the etiological role of these antibodies is uncertain; however, they may be a surrogate marker of autoimmunity. Autoimmunity may play a role in OMS. Further studies are required to detect specific autoantibodies in cases of M. pneumoniae-related OMS [1].

We report an 11-year-old girl with Chiari type I malformation and syringomyelia, who experienced isolated sleep apnea without other neurologic problems. Monitoring with oximetry and movement of thoracic and abdominal walls indicated mixed-type sleep apnea. Chiari type I malformation should be differentiated from other disorders causing sleep apnea.