Maternal fermented food intake and infant neurodevelopment: The Japan Environment and Children's Study.

BACKGROUND AND OBJECTIVES: Fermented foods play an important role in establishing intestinal bacterial flora, and the composition of the intestinal bacterial flora might be associated with neurodevelopment. This study investigated the association between maternal intake of fermented foods during pregnancy and early neuro-development in offspring. METHODS AND STUDY DESIGN: Data were analyzed for 73,522 pregnant women participating in the Japan Environment and Children's Study. Their intake of four common fermented foods during pregnancy was assessed using a semi-quantitative FFQ. Neurodevelopment in their infants at 1 year of age was estimated using the Ages and Stages Questionnaires. RESULTS: Multivariable logistic regression analysis showed that maternal intake of miso soup and fermented soybeans was each associated with a significantly reduced risk of delay in infant communication skills. Maternal intake of fermented soybeans and cheese was each associated with a significantly reduced risk of delay in fine motor skills in the third and fourth quartiles. For problem-solving, preventive associations were observed with maternal intake of fermented soybeans in the second and third quartiles and with maternal intake of cheese in the third and fourth quartiles. Maternal intake of yogurt was associated with a significantly reduced risk of delay in personal-social skills in the third and fourth quartiles, while that of cheese was associated with a reduced risk in the third quartile. No reductions in risk were observed for gross motor skills. CONCLUSIONS: Our results suggest that fermented food intake during pregnancy may have beneficial associations with several areas of psychomotor development in children.

MODY3, renal cysts, and Dandy-Walker variants with a microdeletion spanning the HNF1A gene.

Heterozygous hepatocyte nuclear factor-1-α gene (HNF1A) mutations are the most common cause of maturity-onset diabetes of the young (MODY), but they rarely involve extrahepatic manifestations. Renal cysts and diabetes syndrome can be caused by HNF1B mutations. No association between MODY3 and Dandy-Walker variants (DWV) has been reported. HNF1A mutations might be responsible for renal malformations. In a Japanese girl with glycosuria, developmental delay, mental retardation, renal cysts, and DWV, the HNF1B gene had no mutations. Array comparative genomic hybridization analysis identified a de-novo interstitial 12q24.22-q24.31 deletion of 5.6 Mb encompassing the HNF1A gene, which is compatible with a diagnosis of MODY3. The variety of phenotypes suggests a novel microdeletion syndrome spanning the HNF1A gene. Because HNF1B functions as an HNF1A/HNF1B heterodimer, haploinsufficient HNF1A interacts with a certain HNF1B haplotype. The resulting truncated heterodimer might engender renal cysts. More patients with well-defined deletion within 12q.24.31 must be evaluated to produce a detailed genotype-phenotype correlation and to elucidate this emerging microdeletion syndrome.
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Human bocavirus in patients with encephalitis, Sri Lanka, 2009-2010.

We identified human bocavirus (HBoV) DNA by PCR in cerebrospinal fluid from adults and children with encephalitis in Sri Lanka. HBoV types 1, 2, and 3 were identified among these cases. Phylogenetic analysis of HBoV1 strain sequences found no subclustering with strains previously identified among encephalitis cases in Bangladesh.

An unmasked mutation of EIF2B2 due to submicroscopic deletion of 14q24.3 in a patient with vanishing white matter disease.

Leukodystrophy with vanishing white matter (VWM) is a neurodegenerative disorder with autosomal recessive traits that is caused by alteration of the eukaryotic translation initiation factor-2B (EIF2B). An 11-month-old patient with distinctive features began to exhibit progressive developmental deterioration associated with intractable epilepsy, which was triggered by recurrent acute infectious diseases. Brain magnetic resonance imaging (MRI) revealed abnormal white matter intensity. Chromosomal microarray testing identified a submicroscopic deletion at 14q24.3 that included EIF2B2, the gene encoding one of the subunits of EIF2B. Because the patient's clinical findings were distinctive for VWM, compound heterozygous mutations of EIF2B2 were suspected, and subsequent sequencing analysis of the remaining allele unmasked the existence of a novel missense mutation of EIF2B2 (V85W). Some distinctive features including small palpebral fissures, bushy eyebrows, ear abnormalities, small upturned nose, downturned corners of the mouth, and micrognathia may be the common features of the patients with 14q24.3 deletions.

Deciphering the premature mortality in PIGA-CDG - An untold story.

OBJECTIVE: Congenital disorder of glycosylation (CDG) due to a defective phosphatidylinositol glycan anchor biosynthesis class A protein (PIGA) is a severe X-linked developmental and epileptic encephalopathy. Seizures are often treatment refractory, and patients have intellectual disability and global developmental delay. Previous reports have suggested that patients with PIGA-CDG have a high risk of premature mortality. This study aimed to evaluate the observed high mortality and the causes of death in PIGA-CDG patients. METHODS: We reviewed the literature and collected additional unpublished patients through an international network. RESULTS: In total, we reviewed the data of 88 patients of whom 30 patients born alive were deceased, and the overall mortality before the age of 20 years was 30 % (26/88). Age at death ranged from 15 days to 48 years of life. The median age at death was two years and more than half of the patients deceased in early childhood. The PIGA-specific mortality rate/1000 person-years was 44.9/1000 person-years (95 %, CI 31.4-64.3). There were no cases of definite or probable sudden unexpected death in epilepsy (SUDEP) and half of the patients died due to respiratory failure (15/30, 50 %) or possible SUDEP (3/30, 10 %). Three patients (10 %) died from severe cardiomyopathy, liver failure and gastrointestinal bleeding, respectively. The cause of death was unclassified in nine patients (30 %). Autopsies were rarely performed and the true cause of death remains unknown for the majority of patients. SIGNIFICANCE: Our data indicate an increased risk of premature death in patients with PIGA-CDG when compared to most monogenic developmental and epileptic encephalopathies.

Learning difficulties in Japanese schoolchildren with focal epilepsy.

BACKGROUND: Children with epilepsy often show some degree of cognitive impairment. In this study, we investigated their learning skills to clarify the characteristics of the difficulties related to learning in Japanese-speaking children with focal epilepsy. METHODS: The study included 13 boys and 17 girls of mean age 9.7 years (standard deviation 2.61; range 6-14 years) with focal epilepsy and a normal magnetic resonance brain scan. None of the patients had any other neurological disorder. RESULTS: Twenty-two children had "learning difficulties", i.e., an intellectual disability or low scores on a learning abilities task. Significant differences were found in age (P = 0.030), age at onset of epilepsy (P = 0.033), and electroencephalographic findings, as well as between bilateral vs. unilateral (P = 0.028) and right-localized vs. left-localized or bilateral (P = 0.014) involvement between subjects with and without learning difficulties. Seven (88%) of eight children with low scores on a learning abilities task showed abnormalities in reading speed. DISCUSSION: More than half of Japanese-speaking children with focal epilepsy need learning assistance. This finding points to a need for learning support in children with focal epilepsy regardless of language. Measurement of reading speed is useful in children with learning difficulties to identify those who require early intervention.

Toddler Neurodevelopmental Outcomes Are Associated With School-Age IQ in Children With Single Ventricle Physiology.

To examine whether neurodevelopment at preschool age predicts IQ levels and needs for special education services in school-age children with single ventricle (SV) physiology. Thirty-five patients with SV physiology were assessed using the Bayley Scale of Infant and Toddler Development (BSID) II or III at 3 years and the Wechsler Intelligence Scale for Children-Fourth Edition (WISC) at 8 years. Whether the children were receiving special education services was also determined. Factors associated with the mental developmental index (MDI) of the BSID, the full-scale IQ (FSIQ) of the WISC, and special education services were also analyzed. The MDI and FSIQ of children with SV physiology were significantly lower than the values in healthy children (P < 0.01). The MDI at 3 years was moderately correlated with FSIQ at 8 years (P < 0.01, R2 = 0.41). Ten patients (28.6%) received special education services in their school. Children with MDI <85 were more likely than those with MDI ≥85 to require special education services at school age (53% and 10%, respectively, P < 0.01). Weight at birth and stage II were correlated with the MDI, extracorporeal circulation time at stage II was correlated with FSIQ, and age at Fontan operation was correlated with FSIQ and special education services. The toddler neurodevelopment index may predict not only IQ levels but also the need for special education services in school-age children. Children with low neurodevelopmental scores need to be followed closely for a long time.

PRRT2 mutations in Japanese patients with benign infantile epilepsy and paroxysmal kinesigenic dyskinesia.

PURPOSE: This study was performed to clarify the clinical features of Japanese patients with PRRT2 mutations. METHODS: The PRRT2 gene was analyzed in 135 patients with benign infantile epilepsy (BIE) or paroxysmal kinesigenic dyskinesia (PKD) using a direct sequencing method: 92 patients had BIE alone, 25 had both BIE and PKD, and 18 had PKD alone. Of the cases, 105 were familial, and 30 were sporadic. Clinical information was collected using a structured questionnaire. RESULTS: PRRT2 mutations were identified in 104 patients. Among the familial cases, PRRT2 mutations were found in at least one individual in 21 of 28 families with BIE alone, in 26 of 27 families with infantile convulsions and choreoathetosis, and in 2 of 3 families with PKD alone. Among the sporadic cases, PRRT2 mutations were observed in 7 of 25 patients with BIE alone, in 1 of 1 patient with BIE and PKD, and in 3 of 4 patients with PKD alone. The c.649dupC mutation was the most frequent, followed by the c.981C > G mutation. Among the patients with epilepsy, the median age at BIE onset was 5 months, the median age at the last seizure was 6 months, and the median number of seizures was 5. CONCLUSION: PRRT2 mutations were found in 68% of Japanese probands with BIE or PKD. The phenotypes of BIE associated with PRRT2 mutations were consistent with those of BIE diagnosed clinically.

Epileptic apnea in a patient with inherited glycosylphosphatidylinositol anchor deficiency and PIGT mutations.

We report an 11-month-old boy with acetazolamide-responsive epileptic apnea and inherited glycosylphosphatidylinositol (GPI)-anchor deficiency who presented with decreased serum alkaline phosphatase associated with compound PIGT mutations. The patient exhibited congenital anomalies, severe intellectual disability, and seizures, including epileptic apnea with epileptiform discharges from bilateral temporal areas. Brain magnetic resonance imaging revealed delayed myelination and progressive atrophy of the brainstem, cerebellum, and cerebrum. Whole-exome sequencing revealed compound heterozygous mutations in PIGT (c.250G>T, p.Glu84X and c.1096G>T, p.Gly366Trp), which encodes a subunit of the GPI transamidase complex. Flow cytometry revealed decreased expression of CD16 (a GPI anchor protein) on granulocytes, supporting the putative pathogenicity of the mutations. Phenobarbital, clonazepam, and potassium bromide decreased the frequency of tonic seizure and acetazolamide decreased epileptic apnea. To our knowledge, this is the first reported case of intractable seizures accompanied by epileptic apnea associated with GPI anchor deficiency and a compound PIGT mutation.

IgA nephropathy associated with X-linked thrombocytopenia.

X-Linked thrombocytopenia (XLT) is characterized by congenital thrombocytopenia with small platelets and absence of immunodeficiency; XLT is an allelic variant of Wiskott-Aldrich syndrome (WAS). Both entities are caused by mutations in the same gene. This study presents the case of an 8-year-old boy with XLT. He developed immunoglobulin A (IgA) nephropathy at the age of 4 years. Genetic analysis confirmed the XLT diagnosis. His maternal uncle also had thrombocytopenia from early infancy and developed end-stage renal failure as a result of IgA nephropathy. The maternal uncle was inferred to be affected with XLT because of the carrier status of the patient's mother. Abnormal glycosylation has a role in pathogenesis in IgA nephropathy; moreover, sialophorin glycosylation is defective in WAS. Altered glycosylation may contribute to renal involvement in patients with WAS/XLT despite different defective glycosylation patterns in IgA nephropathy and WAS/XLT.

Anti-NMDAR autoimmune encephalitis.

The N-methyl-D-aspartate receptor (NMDAR) is involved in normal physiological and pathological states in the brain. Anti-NMDAR encephalitis is characterized by memory deficits, seizures, confusion, and psychological disturbances in males and females of all ages. This type of encephalitis is often associated with ovarian teratoma in young women, but children are less likely to have tumors. Anti-NMDAR encephalitis is a neuroimmune syndrome in patients with autoantibodies recognizing extracellular epitopes of NMDAR, and the autoantibodies attenuate NMDAR function through the internalization of NMDAR. Following the initial symptoms of inflammation, the patients show the various symptoms such as memory loss, confusion, emotional disturbances, psychosis, dyskinesis, decrease in speech intelligibility, and seizures. About half of these patients improved with immunotherapy including high-dose intravenous corticosteroids and intravenous immunoglobulins is administrated to these patients, but the patients who had no improvement with these therapy require further treatments with rituximab or cyclophosphamide. It is necessary to detect anti-NMDAR antibodies at early stages, because the prognosis of these patients may be improved by early treatment. Recovery is slow, and the patients may have some disturbances in their motor function and cognition. The pathologic mechanism underlying the development of anti-NMDAR encephalitis has been elucidated gradually, but the optimal treatment has not yet been clarified. Further studies are required to clarify in detail the mechanism underlying anti-NMDA encephalitis and to develop effective treatments.

An autopsy case of infantile-onset vanishing white matter disease related to an EIF2B2 mutation (V85E) in a hemizygous region.

We report a rare autopsy case of early infantile-onset vanishing white matter disease, with a submicroscopic deletion of 14q24.3, which included EIF2B2 and a missense mutation of EIF2B2 (V85E) of the remaining allele. The patient was a 4-year-old boy, who was found to have suddenly died during sleep. Physical and mental development began to deteriorate after convulsions at 10 month of age, and did not recover to baseline measurements. At autopsy, the brain showed a marked decrease in volume of white matter, with no typical cystic rarefaction. Histopathologically, the affected white matter showed diffuse loss of myelin fibers, meager astrogliosis with dysmorphic astrocytes, and loss of oligodendrocytes. Proliferative and apoptotic markers were negative for oligodendrocytes in the severely affected area. These findings may be related to the severity of the disease, and might be a feature of the EIF2B2 mutation pattern of the patient. Additionally, unusual fatty infiltration of both ventricles of the heart was found. These findings were suspected as early pathology of arrhythmogenic right ventricular cardiomyopathy due to characteristic gene mutation in the present case. In the present case, the defect EIF2B2 caused by hemizygosity may be related to early onset of the disease and the unusual pathological changes with vulnerability of oligodendrocytes and astrocytes, as well as cardiac abnormalities and sudden unexpected death.

Deep sequencing detects very-low-grade somatic mosaicism in the unaffected mother of siblings with nemaline myopathy.

When an expected mutation in a particular disease-causing gene is not identified in a suspected carrier, it is usually assumed to be due to germline mosaicism. We report here very-low-grade somatic mosaicism in ACTA1 in an unaffected mother of two siblings affected with a neonatal form of nemaline myopathy. The mosaicism was detected by deep resequencing using a next-generation sequencer. We identified a novel heterozygous mutation in ACTA1, c.448A>G (p.Thr150Ala), in the affected siblings. Three-dimensional structural modeling suggested that this mutation may affect polymerization and/or actin's interactions with other proteins. In this family, we expected autosomal dominant inheritance with either parent demonstrating germline or somatic mosaicism. Sanger sequencing identified no mutation. However, further deep resequencing of this mutation on a next-generation sequencer identified very-low-grade somatic mosaicism in the mother: 0.4%, 1.1%, and 8.3% in the saliva, blood leukocytes, and nails, respectively. Our study demonstrates the possibility of very-low-grade somatic mosaicism in suspected carriers, rather than germline mosaicism.

PIGA mutations cause early-onset epileptic encephalopathies and distinctive features.

OBJECTIVE: To investigate the clinical spectrum caused by mutations in PIGA at Xp22.2, which is involved in the biosynthesis of the glycosylphosphatidylinositol (GPI) anchor, among patients with early-onset epileptic encephalopathies (EOEEs). METHODS: Whole-exome sequencing was performed as a comprehensive genetic analysis for a cohort of 172 patients with EOEEs including early myoclonic encephalopathy, Ohtahara syndrome, and West syndrome, and PIGA mutations were carefully investigated. RESULTS: We identified 4 PIGA mutations in probands showing early myoclonic encephalopathy, West syndrome, or unclassified EOEE. Flow cytometry of blood granulocytes from patients demonstrated reduced expression of GPI-anchored proteins. Expression of GPI-anchored proteins in PIGA-deficient JY5 cells was only partially or hardly restored by transient expression of PIGA mutants with a weak TATA box promoter, indicating a variable loss of PIGA activity. The phenotypic consequences of PIGA mutations can be classified into 2 types, severe and less severe, which correlate with the degree of PIGA activity reduction caused by the mutations. Severe forms involved myoclonus and asymmetrical suppression bursts on EEG, multiple anomalies with a dysmorphic face, and delayed myelination with restricted diffusion patterns in specific areas. The less severe form presented with intellectual disability and treatable seizures without facial dysmorphism. CONCLUSIONS: Our study confirmed that PIGA mutations are one genetic cause of EOEE, suggesting that GPI-anchor deficiencies may be an underlying cause of EOEE.

Cortical contribution to scalp EEG gamma rhythms associated with epileptic spasms.

The cortical contribution for the generation of gamma rhythms detected from scalp ictal EEG was studied in unique cases of epileptic spasms and a review of the related literature was conducted. Ictal scalp gamma rhythms were investigated through time-frequency analysis in two cases with a combination of focal seizures and spasms and another case with spasms associated with cortical dysplasia. In the two patients with combined seizures, the scalp distribution of ictal gamma rhythms was related to that of focal seizure activity. In the third patient, an asymmetric distribution of the ictal scalp gamma rhythms was transiently revealed in correspondence to the dysplasic cortex during hormonal treatment. Therefore, the dominant region of scalp gamma rhythms may correspond to the epileptogenic cortical area. The current findings have reinforced the possibility of the cortical generation of ictal scalp gamma rhythms associated with spasms. The detection of high frequencies through scalp EEG is a technical challenge, however, and the clinical significance of scalp gamma rhythms may not be the same as that of invasively recorded high frequencies. Further studies on the pathophysiological mechanisms related to the generation of spasms involving high frequencies are necessary in the future, and the development of animal models of spasms will play an important role in this regard.

A de novo interstitial deletion of 8p11.2 including ANK1 identified in a patient with spherocytosis, psychomotor developmental delay, and distinctive facial features.

The contiguous gene syndrome involving 8p11.2 is recognized as a combined phenotype of both Kallmann syndrome and hereditary spherocytosis, because the genes responsible for these 2 clinical entities, the fibroblast growth factor receptor 1 (FGFR1) and ankyrin 1 (ANK1) genes, respectively, are located in this region within a distance of 3.2Mb. We identified a 3.7Mb deletion of 8p11.2 in a 19-month-old female patient with hereditary spherocytosis. The identified deletion included ANK1, but not FGFR1, which is consistent with the absence of any phenotype or laboratory findings of Kallmann syndrome. Compared with the previous studies, the deletion identified in this study was located on the proximal end of 8p, indicating a pure interstitial deletion of 8p11.21. This patient exhibited mild developmental delay and distinctive facial findings in addition to hereditary spherocytosis. Thus, some of the genes included in the deleted region would be related to these symptoms.

Delayed onset adenosine deaminase deficiency associated with acute disseminated encephalomyelitis.

Acute disseminated encephalomyelitis (ADEM) is a monophasic, immune-mediated demyelinating disorder that can appear after either immunizations or, more often, infections. Magnetic resonance imaging of patients shows inflammatory lesions in the brain and spinal cord. An immune-mediated mechanism may play a role in this disease, although its precise pathogenesis remains unclear. In this study, a 2-year-old boy presented with ADEM, and he showed improvement on treatment with high-dose intravenous corticosteroids. At the age of 3 years, the presence of recurrent bronchitis, bronchiectasia, and lymphopenia suggested that the patient was suffering from combined immunodeficiency. The patient was finally diagnosed with delayed onset adenosine deaminase deficiency. Delayed onset adenosine deaminase deficiency is frequently associated with autoimmune diseases, including thyroiditis and cytopenia, both of which were observed in the patient. The ADEM in this patient may be a presentation of delayed onset adenosine deaminase deficiency.

Serine racemase is predominantly localized in neurons in mouse brain.

D-Serine is the endogenous ligand for the glycine binding site of the N-methyl-D-aspartate (NMDA)-type glutamate receptor (GluR) channel and is involved in the regulation of synaptic plasticity, neural network formation, and neurodegenerative disorders. D-Serine is synthesized from L-serine by serine racemase (SR), which was first reported to be localized in astrocytes. However, recently, SR mRNA and its protein have been detected in neurons. In this study, we examined the SR distribution in the brain during postnatal development and in cultured cells by using novel SR knockout mice as negative controls. We found that SR is predominantly localized in pyramidal neurons in the cerebral cortex and hippocampal CA1 region. Double immunofluorescence staining revealed that SR signals colocalized with those of the neuron-specific nuclear protein, but not with the astrocytic markers glial fibrillary acid protein and 3-phosphoglycerate dehydrogenase. In the striatum, we observed SR expression in gamma-aminobutyric acid (GABA)ergic medium-spiny neurons. Furthermore, in the adult cerebellum, we detected weak but significant SR signals in GABAergic Purkinje cells. From these findings, we conclude that SR is expressed predominantly in many types of neuron in the brain and plays a key role in the regulation of brain functions under physiological and pathological conditions via the production of the neuromodulator D-serine.