BackgroundMutations in GDAP1 are responsible for heterogeneous clinical and electrophysiological phenotypes of Charcot-Marie-Tooth disease (CMT), with autosomal dominant or recessive inheritance pattern. The aim of this study is to identify the clinical and mutational spectrum of CMT patients with GDAP1 variants in Japan.Materials and MethodsFrom April 2007 to October 2014, using three state-of-art technologies, we conducted gene panel sequencing in a cohort of 1,030 patients with inherited peripheral neuropathies (IPNs), and 398 mutation-negative cases were further analyzed with whole-exome sequencing.ResultsWe identified GDAP1 variants from 10 patients clinically diagnosed with CMT. The most frequent recessive variant in our cohort (5/10), c.740C>T (p.A247V), was verified to be associated with a founder event. We also detected three novel likely pathogenic variants: c.928C>T (p.R310W) and c.546delA (p.E183Kfs*23) in Case 2 and c.376G>A (p.E126K) in Case 8. Nerve conduction study or sural nerve biopsy of all 10 patients indicated axonal type peripheral neuropathy.ConclusionWe identified GDAP1 variants in approximately 1% of our cohort with IPNs, and established a founder mutation in half of these patients. Our study originally described the mutational spectrum and clinical features of GDAP1-related CMT patients in Japan.

Joubert syndrome (JS) is rare recessive disorders characterized by the combination of hypoplasia/aplasia of the cerebellar vermis, thickened and elongated superior cerebellar peduncles, and a deep interpeduncular fossa which is defined by neuroimaging and is termed the ‘molar tooth sign’. JS is genetically highly heterogeneous, with at least 29 disease genes being involved. To further understand the genetic causes of JS, we performed whole‐exome sequencing in 24 newly recruited JS families. Together with six previously reported families, we identified causative mutations in 25 out of 30 (24 + 6) families (83.3%). We identified eight mutated genes in 27 (21 + 6) Japanese families, TMEM67 (7/27, 25.9%) and CEP290 (6/27, 22.2%) were the most commonly mutated. Interestingly, 9 of 12 CEP290 disease alleles were c.6012‐12T>A (75.0%), an allele that has not been reported in non‐Japanese populations. Therefore c.6012‐12T>A is a common allele in the Japanese population. Importantly, one Japanese and one Omani families carried compound biallelic mutations in two distinct genes (TMEM67/RPGRIP1L and TMEM138/BBS1, respectively). BBS1 is the causative gene in Bardet–Biedl syndrome. These concomitant mutations led to severe and/or complex clinical features in the patients, suggesting combined effects of different mutant genes.

Objectives To characterize the epileptic encephalopathy in patients with IQSEC2 mutations. Methods 270 patients with early-onset epileptic encephalopathies were analyzed by whole exome sequencing. Two patients with novel IQSEC2 de novo mutations were identified. A detailed clinical history was obtained from the referring physicians describing patients with IQSEC2 mutations. Results 16 patients with IQSEC2 mutations and epilepsy were identified and studied. This includes 6 (of 36) familial cases from 4 families with X linked inheritance, and 10 (of 12) sporadic cases with de novo mutations. 13 patients were males and 3 were females. Mutations types included: missense, truncating, disruption duplications and translocations. Epileptic encephalopathy was diagnosed in 8 patients, only one of them was a familial case. Seizure onset ranged from 1 day to 4 years of age; seizure types included spasms, astatic, myoclonic, tonic, absence, complex partial and generalized tonic clonic seizures; epileptic syndromes were infantile spasm (3), myoclonic epilepsy (3), astatic epilepsy (1) and Lennox-Gastaut (1); seizures were refractory to medical treatment and the ketogenic diet in 7 of the 8 patients. EEG findings included hypsarrhythmia, generalized spikes and waves, polyspikes and waves, slow spikes and waves, multi focal spikes as well as background slowing. In 5 of the 6 familial cases seizure onset ranged from infancy to 6 years; seizure types included GTC and absence seizures; epileptic syndromes were infantile or childhood generalized epilepsy; seizures were partially controlled in most cases. All 16 patients suffered from moderate to profound intellectual disability. Developmental regression, stereotypic hand movements and strabismus were prominent features. Conclusions Mutations in the IQSEC2 gene have been associated with non syndromic X linked intellectual disability, however an epileptic encephalopathy is the main clinical feature in sporadic cases with IQSEC2 mutations. IQSEC2 mutations should be evaluated in patients with an epileptic encephalopathy. To characterize the epileptic encephalopathy in patients with IQSEC2 mutations. 270 patients with early-onset epileptic encephalopathies were analyzed by whole exome sequencing. Two patients with novel IQSEC2 de novo mutations were identified. A detailed clinical history was obtained from the referring physicians describing patients with IQSEC2 mutations. 16 patients with IQSEC2 mutations and epilepsy were identified and studied. This includes 6 (of 36) familial cases from 4 families with X linked inheritance, and 10 (of 12) sporadic cases with de novo mutations. 13 patients were males and 3 were females. Mutations types included: missense, truncating, disruption duplications and translocations. Epileptic encephalopathy was diagnosed in 8 patients, only one of them was a familial case. Seizure onset ranged from 1 day to 4 years of age; seizure types included spasms, astatic, myoclonic, tonic, absence, complex partial and generalized tonic clonic seizures; epileptic syndromes were infantile spasm (3), myoclonic epilepsy (3), astatic epilepsy (1) and Lennox-Gastaut (1); seizures were refractory to medical treatment and the ketogenic diet in 7 of the 8 patients. EEG findings included hypsarrhythmia, generalized spikes and waves, polyspikes and waves, slow spikes and waves, multi focal spikes as well as background slowing. In 5 of the 6 familial cases seizure onset ranged from infancy to 6 years; seizure types included GTC and absence seizures; epileptic syndromes were infantile or childhood generalized epilepsy; seizures were partially controlled in most cases. All 16 patients suffered from moderate to profound intellectual disability. Developmental regression, stereotypic hand movements and strabismus were prominent features. Mutations in the IQSEC2 gene have been associated with non syndromic X linked intellectual disability, however an epileptic encephalopathy is the main clinical feature in sporadic cases with IQSEC2 mutations. IQSEC2 mutations should be evaluated in patients with an epileptic encephalopathy.

This is a case report that describes 2 sisters with microcephaly, simplified gyri, and enlarged extraaxial space. Clinical features of the cases include dysmorphic features, congenital microcephaly, failure of postnatal brain growth, neonatal onset of seizures, quadriplegia, and severe psychomotor delay. Neuroradiological imaging demonstrated hypoplasia of bilateral cerebral hemispheres with enlarged extraaxial spaces, simplified gyral patterns without a thickened cortex, hypoplastic corpus callosum, and enlarged lateral ventricles, with a reduction in gray and white matter volume during the prenatal and neonatal periods. Repeat MRI revealed progressive atrophy of the cerebral gray and white matter, with enlarged lateral ventricles, although the sizes of the bilateral basal ganglia, thalamus, and infratentorial structures were relatively preserved. These neuroradiological findings imply that this disease is caused by the gene involved in neuronal and glial proliferation in the ventricular zone and in tangential neuronal migration from the ganglionic eminence. The nature of the progressive degeneration of the hemispheric structures should be clarified.

We have successfully eliminated herpes simplex virus-2 from the central nervous system in a case of neonatal herpes simplex virus encephalitis with a continuous acyclovir infusion. A male infant delivered from a healthy 22-year-old woman without genital or systemic herpes symptoms around delivery began to develop fever and intractable seizures. He was started on intermittent intravenous acyclovir (20 mg/kg every 8 h) based on the diagnosis of herpes encephalitis. The virus was not eliminated with intermittent acyclovir and vidarabine, while continuous acyclovir was ultimately effective in eliminating herpes simplex virus from his central nervous system. This report demonstrates the efficacy of continuous acyclovir infusion in neonatal herpes simplex virus encephalitis.

This report describes a patient with Gaucher disease type II who developed severe rhabdomyolysis. We treated him successfully and measured various cytokine and chemokine levels sequentially to elucidate the pathophysiology of rhabdomyolysis. The serum levels of interleukin-6, -8, -10, granulocyte colony-stimulating factor, interferon-gamma, and monocyte chemoattractant protein-1 were markedly elevated in the early phase of rhabdomyolysis. These findings indicate that cytokines and chemokines are related to the massive myolysis and regenerating process. A viral infection may have triggered rhabdomyolysis through exaggerated activation of macrophages in our patient. The profiles of cytokines and chemokines should be examined in further cases to increase our understanding of the pathophysiology of rhabdomyolysis.

BACKGROUND AND OBJECTIVE:Hypomyelination with atrophy of the basal ganglia and cerebellum is a recently defined disorder. Only a few patients have been described. We report on 11 additional patients and new MRI findings and provide histopathologic confirmation of the MRI interpretation.METHODS:We reviewed the patients' clinical history and present findings. We scored the MRI abnormalities. The histopathology of one patient was re-examined.RESULTS:The patients' early psychomotor development was normal or delayed, followed by increasing extrapyramidal movement abnormalities, ataxia, and spasticity. Mental capacities were variably affected. MRI showed hypomyelination with, on follow-up, evidence of further myelin loss and variable white matter atrophy. The putamen was small or, more often, absent; the head of the caudate nucleus was decreased in size. In contrast, the thalamus and globus pallidus remained normal. Cerebellar atrophy was invariably present. Histopathology confirmed the myelin deficiency, probably related to both lack of deposition and low-grade further loss. The degeneration of putamen was subtotal. The cerebellar cortex was affected, particularly the granular layer.CONCLUSION:Hypomyelination with atrophy of the basal ganglia and cerebellum is a syndrome diagnosed by distinctive MRI findings. Histopathology confirms hypomyelination, low-grade further myelin loss, subtotal degeneration of the putamen, and cerebellar cortical atrophy. All known patients are sporadic, and the mode of inheritance is unclear.

We evaluated the ability of Cry1Aa9, Cry1Ab4, and Cry1Ac1 insecticidal toxins from Bacillus thuringiensis to destroy liposomes. Cry1A toxins are thought to form pores in midgut apical cell membranes (BBMV), thereby disrupting midgut cells. Liposomes containing fluorescent calcein were prepared using phosphatidylcholine (PC) and phosphatidylserine (PS) (PC/PS-Liposomes) or PC alone (PC-Liposomes). Cry1Ab (1.4 μM), but not Cry1Aa or Cry1Ac, disrupted PC/PS-Liposomes and PC-Liposomes. PC/PS-Liposomes containing cholesterol and oligosaccharylceramide from Plutella xylostella midgut were damaged even more extensively by Cry1Ab, but the inclusion of either lipid alone had no effect. The initial velocity of Cry1Ab-mediated liposome disruption increased 17-fold when liposomes were prepared with Triton X-100-soluble proteins from Bombyx mori BBMV and PC (PC/Proteo-Liposomes), and Cry1Aa and Cry1Ac also caused slight disruption. These data suggest that Cry1Ab achieves higher penetration into PC/PS-Liposomes, PC-Liposomes, and PC/Proteo-Liposomes compared with Cry1Aa or Cry1Ac and that Cry1Ab may interact with membrane proteins.

A boy had the clinical features of congenital muscular dystrophy with a very mild mental deficit. A muscle biopsy at one year of age showed the typical findings of Fukuyama-type congenital muscular dystrophy, including selective loss of immunoreactions for alpha dystroglycan. Magnetic resonance imaging showed no findings suggestive of migration disorders. The diagnosis of Fukuyama-type congenital muscular dystrophy was confirmed by a molecular assay at 8 years of age, and his haplotype analysis was heterozygous. At 9 years of age, his FIQ on the Wechsler Scale for Children revealed 69, while his IQ on the Tanaka Binnet scale of intelligence was 97. In this report the relationship between mild clinical condition of the studied case and its genotype is discussed.

We report on metabolic changes in the brain of a boy with Menkes disease. He was treated with parenteral copper (Cu)-histidine supplementation, from 5 months of age, and assessed with proton magnetic resonance spectroscopy (1H-MRS). The single-voxel 1H-MRS before treatment revealed an accumulation of lactate and a reduced N-acetyl aspartate (NAA)/total creatine (tCr) ratio with a z-score of −3.0. During treatment, the lactate signal faded away, whereas the NAA signal gradually increased to a z-score of −1.5 at 120 days of treatment. The choline/tCr ratio did not deviate much initially (z-score +0.5), but the ratio increased markedly during treatment (z-score +4.8). Consequently, the Cu-histidine therapy initiated after the critical period still improved the neuronal metabolism, suggesting that some Cu was delivered to neurons. Nevertheless, the brain atrophy, impaired myelination, and severe neurological symptoms were not ameliorated.

Postmarketing data about the effectiveness of zonisamide in childhood epilepsy was collected from 759 children with various forms of epilepsy (ages 3 months-15 years) to compare the tong-term efficacy of zonisamide in the treatment of epilepsy in intellectually normal versus intellectually disabled children. The follow-up period was 6 months-3 years; 291 children (245 intellectually normal, 46 intellectually disabled) received zonisamide as monotherapy. The remaining patients received additional antiepilepsy drugs (AEDs); mean numbers of additional AEDs were 1.6 and 2.9 for intellectually normal and intellectually disabled groups, respectively. Effectiveness could not be evaluated in 30 of the 759 patients because of very rare or irregular seizure frequency. In the 729 patients evaluated, 78% of intellectually normal patients and 43% of intellectually disabled patients showed >50% reduction in the number of seizures (P < 0.001). Improvement rates seen in the intellectually normal group were almost the same for patients with generalized (82%) and partial (77%) epilepsies, whereas in the intellectually disabled group, the improvement rate was higher for partial (50%) than generalized (36%) epilepsies (P < 0.01).These results are consistent with the known phenomenon that intellectually disabled children are likely to have more intractable seizures than children with normal intelligence. (C) 2004 Published by Elsevier Ltd on behalf of BEA Trading Ltd.