Thermolabile polymorphism of carnitine palmitoyltransferase 2: A genetic risk factor of overall acute encephalopathy.

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.

Identification of a rare homozygous SZT2 variant due to uniparental disomy in a patient with a neurodevelopmental disorder.

Because biallelic SZT2 variants have been reported in patients with neurodevelopmental disorders associated with various degrees of developmental delay, intractable seizures, and distinctive features; this condition is recognized as an autosomal recessive disorder. Previously, eleven patients have been reported and most of them have compound heterozygous SZT2 variants, leading to premature termination. In these patients, all reported variants were unique and there were no common pathogenic variants identified. In this study, we identified a paternal uniparental disomy of chromosome 1 in a patient with a neurodevelopmental disorder associated with severe intellectual disability, intractable epilepsy, autistic features, distinctive features, and transient macrocephaly. This resulted in homozygous patterns through chromosome 1. Among the variants in chromosome 1, a rare SZT2 variant, NM_015284.3:c.6553C>T (p.Arg2185Trp), was selected as a powerful candidate variant in this patient. Although the clinical features of this patient are relatively milder than that reported previously, it may be derived from genetic heterogeneity. This is the first report of a homozygous missense SZT2 variant.

Herpes zoster meningitis in immunocompetent children: Two case reports and a literature review.

We encountered two cases of Herpes zoster (HZ) meningitis, a rarely occurring complication of HZ, in previously healthy children. One patient treated with i.v. acyclovir (ACV, 31 mg/kg/day) did not recover. His symptoms were relieved somewhat by increased ACV dosage, but it caused transient renal dysfunction. Another patient treated with i.v. ACV (30 mg/kg/day) recovered. Treatment for HZ meningitis in immunocompetent children has not been established. In a literature review, 80% of 20 patients were treated with the usual dose of ACV 15-30 mg/kg/day. The present cases suggest that a high dosage of ACV up to 60 mg/kg/day should be considered (while monitoring for side-effects) unless symptoms improve. In the review, one of every three vaccine-strain Varicella zoster virus (VZV) cases was severe, whereas the present cases resulted from wild type. Further investigations must examine different clinical characteristics of HZ meningitis caused by wild-type and vaccine-strain VZV.

Two mild cases of Dravet syndrome with truncating mutation of SCN1A.

BACKGROUND: SCN1A is the gene that codes for the neuronal voltage-gated sodium-channel alpha-subunit 1. It is generally considered that an SCN1A truncating mutation causes the severe phenotype of Dravet syndrome. PATIENTS: We describe 11- and 4-year-old male patients presenting with mild Dravet syndrome with a truncating mutation of SCN1A. The former patient showed moderate mental retardation; however, seizure was controlled to almost one incident a year by levetiracetam and topiramate. Carbamazepine was also effective, which is atypical of Dravet syndrome. The latter patient showed a borderline developmental quotient and did not have episodes of afebrile seizure. CONCLUSION: Two patients presented with mild Dravet syndrome, even though they had a truncating mutation of SCN1A. Not all truncating mutations of SCN1A cause the severe phenotype of Dravet syndrome.

Comorbid Epilepsy and Developmental Disorders in Congenital Long QT Syndrome With Life-Threatening Perinatal Arrhythmias.

OBJECTIVES: Given the association of long QT syndrome (LQTS) and neurological disorders, we speculated that the more severe LQTS phenotype, perinatal LQTS, would exhibit more frequent comorbid neurodevelopmental anomalies than LQTS without perinatal arrhythmias (nonperinatal LQTS). BACKGROUND: Congenital LQTS with life-threatening perinatal arrhythmias (perinatal LQTS) has a poor life prognosis. METHODS: Twenty-one consecutive LQTS patients diagnosed before 1 year of age at our institution and 3 previously reported perinatal LQTS patients with neurological seizures were enrolled. In total, the clinical course was evaluated in 24 patients. RESULTS: Among 21 infantile LQTS patients, 5 of 6 with perinatal LQTS (83%) were diagnosed with epilepsy and 4 (67%) with developmental disorders, but none with nonperinatal LQTS were. The total development quotient by Kinder Infant Development Scale scores was 17 to 72 (median 67) in 5 epileptic perinatal LQTS. In the 8 perinatal LQTS patients with neurological disorders, including 3 previously reported cases, epileptic seizures occurred at 2 days to 2.5 years of age and 5 had developmental disorders. Mutations in these 8 patients were located in the transmembrane loop of KCNH2, and D3/S4-S5 linker, D4/S4, or the D4/S6 segment of SCN5A. CONCLUSIONS: A high comorbidity of neurodevelopmental anomalies was observed in perinatal LQTS. Mutations in patients with neurological comorbidities were in loci linked to LQTS with a severe cardiac phenotype. These observations indicate the possibility that neurological disorders in perinatal LQTS are manifested as neurological phenotypes associated with severe cardiac phenotypes, while we could not completely exclude another possibility that those were caused by a brain perfusion injury.

Severe Hemolytic Jaundice in a Neonate with a Novel COL4A1 Mutation.

We report our experience with a preterm infant with severe hemolytic jaundice who required exchange transfusion just after birth. The patient was negative for alloimmune hemolysis as a result of maternal-fetal blood type incompatibility, and tests for inherited defects in erythrocyte metabolism, membrane function, and hemoglobin synthesis were normal. We also performed a bone marrow examination, but could not identify the cause of hemolysis. The patient had several other complications, including porencephaly, epilepsy, elevated serum levels of creatine kinase, and persistent microscopic hematuria. Later, we detected a genetic mutation in COL4A1, which was recently found to be associated with hemolytic anemia. We therefore believe that all of the patient's clinical features, including hemolytic anemia, were due to the mutation in COL4A1. Genetic testing for COL4A1 mutations is recommended in neonates who exhibit hemolytic disease of unknown etiology, especially when other complications compatible with COL4A1-related disorders are present.

A haploinsufficiency of FOXG1 identified in a boy with congenital variant of Rett syndrome.

BACKGROUND: Forkhead box G1 gene (FOXG1) mutations and deletions are associated with a congenital variant of Rett syndrome (RTT). Nucleotide alterations of the coding region of FOXG1 have never caused dysmorphic features. PATIENT: An 8-year-old boy with the congenital variant of RTT who showed severe psychomotor deterioration, epilepsy, acquired microcephaly, and involuntary movements including jerky movements of the upper limbs and tongue protrusion. He showed dysmorphic features including round face, anteverted nostrils, and tented upper lips. Brain magnetic resonance imaging showed hypoplasia of the frontal lobes and the rostral part of the corpus callosum. The molecular cytogenetic analysis confirmed a de novo deletion of 14q12 including FOXG1 in this patient. CONCLUSION: We identified the smallest deletion of 14q12 involving FOXG1 among those previously reported. Dysmorphic facial features are a characteristic for the patients with chromosomal deletion including FOXG1. In our patient, C14orf23 is the only transcript other than FOXG1. Therefore, C14orf23 might be responsible for facial dysmorphism.

ADORA2A polymorphism predisposes children to encephalopathy with febrile status epilepticus.

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.

Phenotypic spectrum of COL4A1 mutations: porencephaly to schizencephaly.

OBJECTIVE: Recently, COL4A1 mutations have been reported in porencephaly and other cerebral vascular diseases, often associated with ocular, renal, and muscular features. In this study, we aimed to clarify the phenotypic spectrum and incidence of COL4A1 mutations. METHODS: We screened for COL4A1 mutations in 61 patients with porencephaly and 10 patients with schizencephaly, which may be similarly caused by disturbed vascular supply leading to cerebral degeneration, but can be distinguished depending on time of insult. RESULTS: COL4A1 mutations were identified in 15 patients (21%, 10 mutations in porencephaly and 5 mutations in schizencephaly), who showed a variety of associated findings, including intracranial calcification, focal cortical dysplasia, pontocerebellar atrophy, ocular abnormalities, myopathy, elevated serum creatine kinase levels, and hemolytic anemia. Mutations include 10 missense, a nonsense, a frameshift, and 3 splice site mutations. Five mutations were confirmed as de novo events. One mutation was cosegregated with familial porencephaly, and 2 mutations were inherited from asymptomatic parents. Aberrant splicing was demonstrated by reverse transcriptase polymerase chain reaction analyses in 2 patients with splice site mutations. INTERPRETATION: Our study first confirmed that COL4A1 mutations are associated with schizencephaly and hemolytic anemia. Based on the finding that COL4A1 mutations were frequent in patients with porencephaly and schizencephaly, genetic testing for COL4A1 should be considered for children with these conditions.

Low response to a monovalent inactivated unadjuvanted influenza A (H1N1) pdm09 vaccine in pediatricians of a general hospital in Japan.

Immunization of health care personnel (HCP) is critically important to reduce healthcare-associated influenza infections substantially. During 2009-2010, 74% of all HCP at Kitano Hospital, Osaka, Japan, including 94% of pediatricians, received the monovalent unadjuvanted influenza A (H1N1) pdm09 vaccine. We evaluated the vaccine's immunogenicity. Sixteen pediatricians received 15 µg hemagglutinin antigen subcutaneously. Antibody titer assays were conducted using hemagglutination-inhibition antibody assay on days 0 and 21, and at 5 mo after vaccination. Seroprotection rates, seroconversion rates, and geometric mean titer folds at 21 d were, respectively, 43.8%, 43.8%, and 5.4 in all subjects, 70.0%, 70.0%, and 8.0 in subjects aged 27-34 y, and 0.0%, 0.0%, and 8.0 in subjects aged ≥ 35 y. None of the latter group met the European Medicines Agency criteria. We hope to adopt intradermal routes and further the development of the influenza vaccine using new technology to improve immunogenicity in Japan.

Pandemic influenza A-associated acute necrotizing encephalopathy without neurologic sequelae.

We describe an 8-year-old girl with the mildest form of acute necrotizing encephalopathy, associated with pandemic influenza A. She manifested a convulsion engendering deterioration of consciousness, although cranial computed tomography and magnetic resonance imaging within 4 hours after the convulsion revealed no abnormalities. Cranial magnetic resonance imaging 20 hours after the convulsion revealed lesions of the thalamus bilaterally, brainstem tegmentum, internal capsule, and white matter. She was diagnosed with acute necrotizing encephalopathy. Typically, the prognosis of acute necrotizing encephalopathy with a brainstem lesion is poor. Nevertheless, she recovered almost completely, after early intervention with pulsed methylprednisolone and high-dose γ-globulin therapy. She manifested a thermolabile phenotype of carnitine palmitoyltransferase II variants such as cystine-isoleucine-methionine phenotype type 9 (FVM-CIM; Phe352Cys-Val388Ile-Met647Met alleles), resulting in a predisposition to encephalopathy during influenza infection. This case is the first, to the best of our knowledge, of pandemic influenza A-associated acute necrotizing encephalopathy with a good outcome despite severe magnetic resonance imaging findings.

Depressed levels of interferon-gamma and HLA-DR+CD3+ T cells in infants with transient hyperferritinemia.

Familial hemophagocytic lymphohistiocytosis (FHL), which typically has its onset during infancy, is uniformly fatal if not treated. It therefore requires prompt therapeutic intervention. Although hyperferritinemia has been emphasized as a useful marker for FHL, some nonfatal cases in infants with spontaneous remission also manifest with hyperferritinemia. However, distinguishing them is difficult because initial clinical features of these infants are similar. The authors encountered 14 infants with hyperferritinemia (serum ferritin >674 ng/mL), which normalized within 3 weeks following a benign clinical course. The authors compared the levels of HLA-DR+CD3+ T-cell subsets and interferon-gamma (IFN-γ) in the peripheral blood between these infants and FHL cases: one of the authors' own patients and others from the literature. Serum IFN-γ was not detected in infants with hyperferritinemia. Moreover, levels of HLA-DR+CD3+ T cells were extremely depressed. In contrast, serum IFN-γ was elevated and HLA-DR+CD3+ T cells were not depressed in FHL. Measurement of activated T cells and serum IFN-γ might help differentiate FHL in febrile infants with transient hyperferritinemia.

Diffusion-weighted imaging in preclinical Leigh syndrome.

We report on a preterm Japanese male baby with Leigh syndrome, i.e., intrauterine growth restriction, central apnea, and feeding difficulty. These signs improved at 41 weeks of corrected age. At that time, brain magnetic resonance imaging revealed increased signal in diffusion-weighted imaging in the parietal white matter, bilaterally and symmetrically not respecting vascular territory or boundaries. However, clinical improvement deterred us from further investigation. About 3 months later, he manifested frequent ictal apnea with myoclonic seizures and deterioration of consciousness to semicoma. Subsequent diffusion-weighted imaging revealed increased signal in the bilateral symmetric thalamus, internal segments of the globus pallidus, substantia nigra, and pontine tegmentum. Laboratory investigation indicated remarkable elevation of lactate levels in cerebrospinal fluid. The diagnosis was of Leigh syndrome. We think this is the first reported case of Leigh encephalopathy with transient abnormality of diffusion-weighted imaging of the white matter before apparent clinical onset. Leigh syndrome should be included in the differential diagnosis of abnormality of diffusion-weighted imaging in white matter without apparent clinical signs.

Hereditary spherocytosis in 3 children coexisting with UDP-glucuronyl transferase 1A1 deficiency.

Simultaneous presence of hemolytic anemia and bilirubin UDP-glucuronosyltransferase deficiency is a possible cause of misdiagnosis. Seven-year-old and 17-year-old brothers and a 15-year-old sister consecutively suffered from aplastic crises. Although few spherocytes were present, the siblings and their mother had diagnoses of hereditary spherocytosis with flow cytometric analysis of eosin-5'-maleimide-labeled red blood cells in addition to osmotic fragility test. However, inappropriately high values of bilirubin compared with mild hemolysis persisted. Further analysis of UDP-glucuronyltransferase 1A1 revealed all 3 siblings were heterozygous for A(TA)7TAA-P229Q. We report here the importance of careful evaluation of mild hereditary spherocytosis masking UDP-glucuronyltransferase 1A1 deficiency.

Novel de novo splice-site mutation of SCN1A in a patient with partial epilepsy with febrile seizures plus.

This report describes a 4-year-old male patient experienced prolonged febrile seizures after 1 year of age, multiple febrile seizures and complex partial seizures with secondary generalization. The gene encoding voltage-gated sodium channel alpha1-subunit: SCN1A analysis revealed a heterozygous de novo one-point mutation (IVS16+2 T>C) at a splice-acceptor site. This mutation was inferred to cause truncation of the alpha1-subunit molecule and, thereby, a loss of channel function. To date, truncation mutation has been found exclusively in patients with severe myoclonic epilepsy in infancy (SMEI), although only missense mutations have been found in generalized epilepsy with febrile seizures plus (GEFS+), partial epilepsy with FS+, FS+, and FS. The patient's phenotype is consistent with that of partial epilepsy with FS+, rather than SMEI, including borderline SMEI (SMEB). We present the first case report of partial epilepsy with FS+ associated with a truncation mutation of SCN1A. The possibility exists for concomitant involvement of multiple genes other than SCN1A for seizure phenotypes.

Split notochord syndrome with congenital unilateral Horner's sign.

A 2-year-old boy exhibited congenital right Horner's sign and right finger, wrist, and elbow flexion arthrogryposis. He had dyspnea and feeding difficulty 12 hours after birth. Radiologic examination revealed a thoracoabdominal intestinal tube and mediastinal cystic lesion at the right side, with vertebral anomaly at the cervical level. Histopathologically, the intestinal tube was diagnosed as bowel duplication. Because the mediastinal lesion could not be resected surgically, no histopathological diagnosis was made. Embryologically, the combination of transdiaphragmatic duplication, mediastinal cystic lesion, anterior spina bifida, and hemivertebra suggested notochord malformation. The diagnosis was split notochord syndrome, an extremely rare embryological malformation syndrome. Congenital unilateral Horner syndrome often has unknown etiology. In this case, cervical vertebral anomalies and mediastinal cystic lesion implied a compressed nerve root, resulting in Horner syndrome and right finger, wrist, and elbow flexion joint contracture. Split notochord syndrome should be included in differential diagnosis of congenital unilateral Horner syndrome.

Familial hemophagocytic lymphohistiocytosis with the MUNC13-4 mutation: a case report.

A 44-day-old male infant with familial hemophagocytic lymphohistiocytosis (FHL) associated with the MUNC13-4 mutation is reported. He presented with fever and poor feeding, lymphocytosis with thrombocytopenia and CSF pleocytosis without virological explanation. On the basis of progressive hyperferritinemia (1323 ng/ml), anemia (hemoglobin: 5.2 g/dl), hypertriglyceridemia (547 mg/dl) and increased LDH (1063 IU/l) with hemophagocytosis in the bone marrow, hemophagocytic lymphohistiocytosis was diagnosed. He showed a good response to corticosteroid therapy and the disease was stable for more than 5 months. Thereafter, he suffered from central nervous system complications, and successfully underwent unrelated cord blood stem cell transplantation. A remission was observed for more than 2 years, with mild mental retardation. Genetic analysis revealed that he had a compound heterozygous mutation of MUNC13-4; namely a novel 2163G>A mutation resulting in W721X, and 754-1G>C resulting in a premature stop codon in this gene. Western blot analysis showed the complete loss of the MUNC13-4 protein, whereas other molecules associated with the SNARE systems were detected at normal levels. Conclusion. FHL may have a broad clinical spectrum, and further analysis on its phenotype-genotype association is required to establish an appropriate treatment strategy, including immunochemotherapy and stem cell transplantation in the future.

[Intractable epilepsy (apneic seizure) in an infant with 18q deletion syndrome].

We report here an infant with 18q deletion syndrome, and intractable apneic seizures. He had intrauterine growth retardation and dysmorphic features. Chromosomal analysis demonstrated mosaicism of 18q interstitial deletion (q12.3-q22.3). From the age of 3 months, apneic attacks occurred from once a week to over 10 times a day despite many oral antiepileptic agents, and were diagnosed as complex partial seizures. Ictal electroencephalogram and 18F-fluorodeoxyglucose-positron emission tomography at the age of 10 months identified the epileptic focus in the right parieto-temporal region. He also had severe psychomotor retardation. Head MRI examination revealed diffuse cerebral atrophy and severe white matter dysmyelination, which was caused by the deletion of myelin basic protein gene at the locus of 18q22.3. This locus may be responsible for the clinical manifestations of 18q deletion syndrome. Detailed description of the onset, seizure types, and prognosis of epilepsy associated with 18q deletion syndrome is rare. It was suggested that the locus of 18q21.3-q22.3 was responsible for autonomic seizures in 18q deletion syndrome.