Genetic heterogeneity in 26 infants with a hypomyelinating leukodystrophy.

T2 hyperintensity of brain white matter lesions detected by magnetic resonance imaging (MRI) are characteristic of a heterogeneous group of diseases. Persistent T2 high intensity in combination with T1 iso- or high intensity of white matter in infants indicates a lack of normal myelination, that is, hypomyelination. However, the precise diagnosis of hypomyelinating leukodystrophy based solely on MRI findings can be difficult, especially in the early stage of the disease. We studied 26 patients who were diagnosed with hypomyelinating leukodystrophy according to MRI findings and clinical features to uncover their genetic etiology through chromosomal analyses, targeted gene analyses, and an array comparative genomic hybridization (aCGH) assay. Then, for the 17 patients with unexplained hypomyelination by traditional analyses, whole-exome sequencing (WES) was performed. The presumptive diagnoses were confirmed in 58 % of the enrolled patients (15/26) and involved 9 different genetic backgrounds. The most frequent backgrounds were 18q deletion syndrome and Pelizaeus-Merzbacher disease, with an incidence of 12 % (3/26) for both. The diagnostic rate of chromosomal analyses, targeted gene analyses, and aCGH was 31 % (8/26), and one patient was clinically diagnosed with Cockayne syndrome. Using WES, the following causative genes of hypomyelination were identified in six individuals (35 %, 6/17): TUBB4A, POLR3B, KCNT1, and MCOLN1, and some of those genes were pathogenic for not only hypomyelination but also dysmyelination or delayed myelination. Our findings suggested heterogeneous genetic backgrounds in patients with persistent white matter lesions. These data also indicate that WES may be a rapid and useful tool for identifying the underlying genetic causes of undiagnosed leukodystrophies.

De novo GABRA1 mutations in Ohtahara and West syndromes.

OBJECTIVE: GABRA1 mutations have been identified in patients with familial juvenile myoclonic epilepsy, sporadic childhood absence epilepsy, and idiopathic familial generalized epilepsy. In addition, de novo GABRA1 mutations were recently reported in a patient with infantile spasms and four patients with Dravet syndrome. Those reports suggest that GABRA1 mutations are associated with infantile epilepsy including early onset epileptic encephalopathies. In this study, we searched for GABRA1 mutations in patients with infantile epilepsy to investigate the phenotypic spectrum of GABRA1 mutations. METHODS: In total, 526 and 145 patients with infantile epilepsy were analyzed by whole-exome sequencing and GABRA1-targeted resequencing, respectively. RESULTS: We identified five de novo missense GABRA1 mutations in six unrelated patients. A p.R112Q mutation in the long extracellular N-terminus was identified in a patient with infantile epilepsy; p.P260L, p.M263T, and p.M263I in transmembrane spanning domain 1 (TM1) were identified in three unrelated patients with West syndrome and a patient with Ohtahara syndrome, respectively; and p.V287L in TM2 was identified in a patient with unclassified early onset epileptic encephalopathy. Four of these mutations have not been observed previously. SIGNIFICANCE: Our study suggests that de novo GABRA1 mutations can cause early onset epileptic encephalopathies, including Ohtahara syndrome and West syndrome.

Efficacy of vigabatrin therapy for tuberous sclerosis with infantile spasms.

Objective: To evaluate the effects and tolerability of vigabatrin (VGB) in children with tuberous sclerosis (TS) with infantile spasms or tonic seizures. Methods: We examined the impact of VGB on a series of 17 children with TS visiting Tohoku University Hospital in Japan during April 2010 and May 2015. To minimize potential adverse effects, VGB was given to the patients for limited 6 months with titration from 30 mg/kg/day as an initial dose. Results: Main seizure types were classified into spasms (n=10) or tonic seizures (n=7). Seizure reduction was positively associated with seizure type of infantile spasms, lower maximum dosage, younger age on VGB administration, and earlier VGB treatment after the diagnosis. Seizure type of infantile spasm was an independent favorable predictor and also associated with long-term seizure reduction. Major adverse events included psychiatric symptoms (n=7) and electroretinogram (ERG) abnormalities (n=2). All symptoms were recovered by reducing the dosage of VGB. Conclusion: VGB is effective and well tolerated as first-line treatment for TS children with infantile spasms. Our "low dosage and limited period" protocol is efficient for improving seizure control as well as minimizing the potential risks of VGB.

Genomic analysis identifies candidate pathogenic variants in 9 of 18 patients with unexplained West syndrome.

West syndrome, which is narrowly defined as infantile spasms that occur in clusters and hypsarrhythmia on EEG, is the most common early-onset epileptic encephalopathy (EOEE). Patients with West syndrome may have clear etiologies, including perinatal events, infections, gross chromosomal abnormalities, or cases followed by other EOEEs. However, the genetic etiology of most cases of West syndrome remains unexplained. DNA from 18 patients with unexplained West syndrome was subjected to microarray-based comparative genomic hybridization (array CGH), followed by trio-based whole-exome sequencing in 14 unsolved families. We identified candidate pathogenic variants in 50% of the patients (n = 9/18). The array CGH revealed candidate pathogenic copy number variations in four cases (22%, 4/18), including an Xq28 duplication, a 16p11.2 deletion, a 16p13.1 deletion and a 19p13.2 deletion disrupting CACNA1A. Whole-exome sequencing identified candidate mutations in known epilepsy genes in five cases (36%, 5/14). Three candidate de novo mutations were identified in three cases, with two mutations occurring in two new candidate genes (NR2F1 and CACNA2D1) (21%, 3/14). Hemizygous candidate mutations in ALG13 and BRWD3 were identified in the other two cases (14%, 2/14). Evaluating a panel of 67 known EOEE genes failed to identify significant mutations. Despite the heterogeneity of unexplained West syndrome, the combination of array CGH and whole-exome sequencing is an effective means of evaluating the genetic background in unexplained West syndrome. We provide additional evidence for NR2F1 as a causative gene and for CACNA2D1 and BRWD3 as candidate genes for West syndrome.

Magnetoencephalography reveals a unique neurophysiological profile of focal-onset epileptic spasms.

Epilepsy is defined as a disorder of the brain characterized by an enduring predisposition to experience epileptic seizures and the neurobiological, cognitive, psychological, and social difficulties relating to the condition. An epileptic spasm (ES) is a type of seizure characterized by clusters of short contractions involving axial muscles and proximal segments. However, the precise mechanism of ESs remains unknown. Despite the potential of magnetoencephalography (MEG) as a tool for investigating the neurophysiological mechanism of ESs, it has been difficult to use this methodology due to magnetic artifacts attributable to patient movement. We report on an 8-year-old girl suffering from intractable epileptic spasms from the age of 7 months. She was diagnosed with possible Aicardi syndrome [corrected] (AGS), characterized by the triad of callosal agenesis, infantile spasms, and chorioretinal lacunae. She is now intellectually delayed and suffers from intractable ES. We used both MEG and electroencephalography to investigate her epilepsy. The recording captured two series of spasm clusters. Spikes were clearly identified with MEG in about four-fifths of all spasms but were identified poorly or not at all in the remainder. MEG findings support previous studies that used intracranial electrodes to analyze patients with ESs and that showed variability in ES-associated spikes in terms of manner of cortical involvement and magnitude. Given the limitations of intracranial electrodes, such as sampling restrictions and invasiveness, MEG may be a helpful tool for non-invasively investigating the unique pathophysiological profile of focal-onset ESs.

Utility of thallium-201 scintigraphy in Tolosa-Hunt syndrome.

Tolosa-Hunt syndrome (THS) is a rare disorder, especially in the pediatric population, characterized by unilateral painful ophthalmoplegia with a relapsing-remitting course. Because the diagnosis of THS is based on the exclusion of other causes of painful ophthalmoplegia, attention should be paid to possible alternative diagnoses. Thallium-201 chloride ((201)Tl) scintigraphy has been used to evaluate tissue histology in clinical oncology with a marker, the retention index (RI). A higher value indicates histological malignancy. Although its utility in pediatric THS has not been discussed, we suggest that (201)Tl scintigraphy may be informative as a marker in the diagnosis. We present an 11-year-old boy with THS who was evaluated with (201)Tl scintigraphy before treatment with corticosteroids, when he had headache, photophobia, and diplopia. The RI of (201)Tl indicated that the lesion would be benign. Although his clinical symptoms did not fulfill the THS criteria completely, his eye symptoms disappeared 2 weeks after corticosteroid treatment, which was not within the 72 h as in the diagnostic criteria of THS. He has been symptom-free for more than 2 years with only an initial 4-week corticosteroid therapy. This report not only shows the potential of (201)Tl scintigraphy to contribute to the correct diagnosis of pediatric THS but also suggests the possibility that the diagnosis of THS could be supported uniquely even in a pediatric THS-suspicious patient who did not fulfill the current THS criteria completely. In conclusion, we suggest that (201)Tl scintigraphy may be useful for making the diagnosis of THS, especially in pediatric patients.

Functional hearing loss and developmental imbalances.

OBJECTIVE: Functional hearing loss (FHL) is a disorder in which there are abnormal values on a hearing test, despite the absence of organic abnormalities in the peripheral and central auditory pathways. Here, we examined the developmental characteristics of FHL and the importance of intervention by analyzing the clinical characteristics of children with this disorder. METHODS: We retrospectively examined 16 patients assessed under a diagnosis of FHL. After interventions such as psychological counseling by our pediatrics and psychiatry departments, we compared the clinical profiles of patients in which hearing was "improved/normalized" and "unimproved". RESULTS: Fourteen patients visited a pediatrician and two chose not to do so. A discrepancy between the maximum and minimum values of the four index scores was observed in all patients in which WISC-IV (the fourth version of the Wechsler Intelligence Scale for Children) was performed (n = 12). The discrepancy between the verbal comprehension index (VCI) and perceptual reasoning index (PRI) was significantly greater in "unimproved" patients than in "improved/normalized" patients. Hearing improved, or was normalized, after intervention in six of 16 patients. CONCLUSIONS: Developmental imbalances were suspected in all 12 children who visited a pediatrician and completed the WISC-IV. Cooperation with pediatricians, psychiatrists, and other health professionals is desirable in supporting patients diagnosed with FHL.

Myelin oligodendrocyte glycoprotein antibody-associated disease in a patient with symptoms of aseptic meningitis who achieved spontaneous remission: A case report and review of the literature.

BACKGROUND: A few case reports have described patients with myelin oligodendrocyte glycoprotein antibody (MOG-Ab)-associated demyelinating syndrome who presented with symptoms of aseptic meningitis. All such patients required immunotherapy. We report a patient with MOG-Ab-associated disorder (MOGAD) who presented with symptoms of aseptic meningitis and improved without treatment. CASE: A 13-year-old girl presented with fever, headache, decreased appetite, and neck stiffness. Cerebrospinal fluid (CSF) analysis revealed pleocytosis and magnetic resonance imaging (MRI) showed leptomeningeal enhancement. The patient was diagnosed with aseptic meningitis at admission. However, there were no signs of recovery 4 days after admission (i.e., 8 days after disease onset). Therefore, we performed extensive investigations to identify the cause of the underlying infection and inflammation. On day 14 after admission, the serum MOG-Ab test performed at admission came back positive (1:128) and she was diagnosed with MOGAD. She was discharged on day 18 after admission, because her symptoms, CSF pleocytosis, and MRI findings had improved. About 6 weeks after discharge, MRI revealed hyperintensity without gadolinium enhancement. However, her serum MOG-Ab test was negative. We did follow-ups for 11 months but found no new neurological symptoms. DISCUSSION AND CONCLUSION: To the best of our knowledge, this is the first ever report of a pediatric patient with MOGAD experiencing spontaneous remission with no demyelinating symptoms during an extended follow-up period.

Unusual ribbon-like periventricular heterotopia with congenital cataracts in a Japanese girl.

Periventricular heterotopia (PH), clumps of neurons mislocated beside the ventricle, is caused by failure to initiate migration during embryogenesis. We report on a 32-month-old Japanese girl with a unique subtype of PH, namely ribbon-like PH. The patient presented with severe psychomotor developmental delay, intractable epilepsy, and congenital cataracts and developed West syndrome phenotype. Brain magnetic resonance imaging revealed a unique undulating form of PH, categorized as ribbon-like PH, and other brain malformations including simplified gyri and dysgenesis of the corpus callosum. There was no evidence of prenatal TORCH infection or associated syndrome. Array-based comparative genomic hybridization revealed no chromosomal rearrangements. Genetic analyses of the FLNA, DCX, ARX, LIS1, and TUBA1A genes showed no mutations. Although little is known about ribbon-like PH, the clinical manifestations in our patient clearly differed from those in other reported patients.

Human herpes virus type 6 can cause skin lesions at the BCG inoculation site similar to Kawasaki Disease.

Kawasaki Disease (KD) is acute, febrile, multisystem vasculitis of early childhood, the detailed mechanism of which is still unclear. Skin symptoms occur in KD, such as edema of the hands and feet with subsequent desquamation and redness at the inoculation site of bacillus Calmette-Guerin (BCG). The change at the BCG inoculation site has been considered as a specific feature of KD, although its mechanism is not fully understood. We present an 11-month-old boy who developed fever with redness of the BCG site due to infection with human herpes virus type 6 (HHV6). At the age of 3 months, the patient received BCG. His fever remitted 7 days after the onset of skin redness, with sequential desquamation at the BCG site and extremities, which is not a common feature of HHV6 infection that typically lasts for 3 days. The final diagnosis was exanthema subitum. Characteristically, the HHV6 infection in our patient appeared to be associated with the invigoration of the T cell system, as represented by the elevated serum levels of soluble interleukin-2 receptor (3,490 U/ml vs. normal range 145-519 U/ml). This patient clearly showed redness and crusting at the BCG inoculation site, suggesting that HHV6 infection might cause skin changes similar to those of KD via an unknown mechanism. In addition, we suggest that the activation of the T cell system may account for the skin lesions in KD, characterized by redness and subsequent crusting of the BCG inoculation site and desquamation of the extremities.

Panax ginseng: a newly identified cause of gynecomastia.

Gynecomastia or benign proliferation of the male breast glandular tissue is not uncommon for adolescent males. Its pathogenesis has been attributed to a transient imbalance between estrogens and androgens. Ginseng is a popular herb with a long history of medicinal use. Oriental folk medicine describes it as both a tonic for restoring strength and a panacea. The term "ginseng" generally refers to a plant, Panax ginseng. Based on estrogen-like actions of Panax ginseng due to its structural similarity with estradiol, this agent could be speculated to cause gynecomastia. Here we report a 12-year-old Korean-Japanese boy with bilateral enlargement of the breasts with tenderness in the right breast, which was noticed about 1 month before his first visit to our outpatient clinic. He was diagnosed with gynecomastia based on physical, laboratory, and ultrasound examinations. Detailed questioning about his medications and supplements revealed that he had been given red ginseng extract daily to enhance his performance for 1 month before his clinical presentation. He wanted to make his body stronger as an athlete. He was recommended from his grandmother to take Panax ginseng for his purpose. After stopping this, there was no further growth of the masses and no pain when his right breast was pressed. In conclusion, physicians should consider ginseng in the investigation of gynecomastia.

[Clinical features of Japanese pediatric patients with anti-aquaporin 4 antibody].

Recently, a disease-specific antibody was found in serum from patients with neuromyelitis optica (NMO), and its target antigen was identified as aquaporin 4 (AQP4) water channel protein. There is no clinical picture of pediatric cases with anti-AQP4 antibody, except one report from North America. Here, we report the clinical features of 18 Japanese anti-AQP4-antibody-positive patients with childhood-onset of NMO. Of the 2000 patients who had been examined for anti-AQP4 antibody at Tohoku University Hospital up until 2008, 60 were under 15 years of age at onset, and 18 of them were positive for anti-AQP4 antibody. We analyzed the clinical information on those patients. There were 14 girls and 4 boys (M:F ratio = 1:3.5). The age of onset ranged from 3 to 15 years old (median 13). The clinical diagnoses of the 18 patients before the anti-AQP4 antibody tests were: NMO in 8 (44%), MS in 7 (39%), and opticospinal MS (OSMS) in 3 (17%). Nine patients developed only optic neuritis at onset. At the last follow-up, brain magnetic resonance imaging (MRI) was abnormal in 14 patients, nine had monocular or binocular blindness, and the expanded disability status scale score was 6.0 or higher (cannot walk without support) in eight patients. NMO has a poor prognosis, as seen in adult cases, suggesting the importance of an early diagnosis using the anti-AQP4 antibody test to institute effective immunosuppressive treatment.

[Case of a pharyngeal-cervical-brachial variant of Guillain-Barré syndrome without pharyngeal palsy].

We report a case of a 3-year-old boy with acute muscle weakness that initially affected neck and all four limbs but later vanished from the lower limbs. Pharyngeal palsy was not observed during the course. All deep tendon reflexes were absent. Peripheral nerve conduction studies showed a demyelination pattern in each limb. The patient received intravenous high-dose corticosteroid hormone, followed by two immunoglobulin therapies. His muscle strength gradually improved after treatment and was almost completely restored four months later. We ultimately diagnosed the condition as the pharyngeal-cervical-brachial variant of Guillain-Barré syndrome, in consideration of the patient's muscle weakness of the neck and four limbs, the greater degree of weakness of the upper limbs versus the lower limbs. His clinical presentation was atypical for the pharyngeal-cervical-brachial variant of Guillain-Barré syndrome, as he presented no pharyngeal muscle weakness or anti GT1a antibodies, typical manifestations of the condition.

A patient with a 6q22.1 deletion and a phenotype of non-progressive early-onset generalized epilepsy with tremor.

We report a patient with a 6q22.1 deletion, who presented with a rare syndrome of generalized epilepsy, myoclonic tremor, and intellectual disability. There was no clinical progression after follow-up for more than 10 years. Our report presents the genetic basis for a phenotype involving a non-progressive generalized epilepsy with tremor. The efficacy of valproic acid for seizure control and the partial efficacy of deep brain stimulation with propranolol for myoclonic tremor is detailed.

A 23-year follow-up report of juvenile-onset Sandhoff disease presenting with a motor neuron disease phenotype and a novel variant.

BACKGROUND: The clinical severity of Sandhoff disease is known to vary widely. Furthermore, long-term follow-up report is very limited in the literature. CASE PRESENTATION: We present a long-term follow-up report of a patient with juvenile-onset Sandhoff disease with a motor neuron disease phenotype. The patient had compound heterozygous variants of HEXB (p.Trp460Arg, p. Arg533His); the Trp460Arg was a novel variant. Long-term follow-up revealed no intellectual deterioration, swallowing dysfunction, or respiratory muscle dysfunction despite progressive weakness of the extremities and sensory disturbances. CONCLUSION: We need to be aware of Sandhoff disease in patients with juvenile-onset motor neuron disease.

Efficacy of long-term adrenocorticotropic hormone therapy for West syndrome: A retrospective multicenter case series.

OBJECTIVES: Long-term adrenocorticotropic therapy (LT-ACTH), which consisted of 2-4 weeks of daily injections of adrenocorticotropic hormone (ACTH) and subsequent months of weekly injections, was tried for relapsed West syndrome (WS) or other intractable epilepsies in small case reports. Our aim was to explore the efficacy of LT-ACTH for preventing WS relapse, as well as the prevalence of its adverse events. METHODS: This is a retrospective, nationwide, multicenter case series of patients with WS who underwent LT-ACTH. Clinical information of the patients and protocol of LT-ACTH were collected from participating institutes in this study. We defined clinical response to ACTH as achievement of hypsarrhythmia and epileptic spasms resolution. Patients who responded to daily ACTH injections were identified and assessed whether they experienced WS relapse during/after the weekly ACTH injection period. The outcome was measured by the nonrelapse rate at 24 months after daily ACTH injections using the Kaplan-Meier method. RESULTS: Clinical information of 16 children with WS was analyzed. The median age at LT-ACTH initiation was 14.5 months (range: 7-68 months). Thirteen (81%) patients had previously undergone conventional ACTH treatment. The LT-ACTH regimens comprised a median of 16 days of daily injections (range: 11-28 days) and 10 months of weekly injections (range: 3-22 months). Seven patients experienced WS relapse during/after subsequent weekly ACTH period, and the nonrelapse rate at 24 months after daily injections was estimated at 60.6% (95% confidence interval: 32.3%-80.0%). Height stagnation, hypertension, and irritability were observed; lethal adverse events were not reported. SIGNIFICANCE: Our study firstly explored the efficacy of LT-ACTH for preventing WS relapse. LT-ACTH might be a treatment option for patients with relapsed or intractable WS; however, we note that our study is limited by its small sample size and the lack of an appropriate control group.

Acute encephalopathy with a truncation mutation in the SCN1A gene: a case report.

A girl aged 1 year 9 months had recurrent episodes of febrile status epilepticus. She recovered completely after the first three episodes. However, at 9 months she developed acute encephalopathy resulting in severe neurologic sequelae. Diffusion-weighted magnetic resonance imaging revealed diffuse high-intensity signals over the cortex and subcortical white matter in the acute phase and severe diffuse cerebral atrophy in the chronic phase. Mutations were detected in the neuronal voltage-gated sodium channel alpha subunit type 1 (SCN1A) gene. SCN1A sequence analysis revealed a truncation mutation:e x1-c.126Adel (D43fs). Our patient was likely afflicted by severe myoclonic epilepsy in infancy, and the fourth episode of status epilepticus was similar to acute encephalopathy. This report provides further insight into the molecular pathophysiology underlying acute encephalopathy.

Efficacy of idebenone for respiratory failure in a patient with Leigh syndrome: a long-term follow-up study.

Respiratory failure can be the direct cause of death in patients with Leigh syndrome. Unfortunately, no effective treatment strategy is available. Here, we report successful treatment of a patient with Leigh syndrome using idebenone, a derivative of coenzyme Q-10. The patient's brainstem function, especially respiratory function, improved after idebenone treatment. Idebenone may be worth trying in patients with Leigh syndrome.