RESUMEN
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.
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Mutación Missense/genética , Receptores de GABA-A/genética , Espasmos Infantiles/diagnóstico , Espasmos Infantiles/genética , Secuencia de Aminoácidos , Niño , Preescolar , Electroencefalografía , Femenino , Humanos , Lactante , Masculino , Datos de Secuencia Molecular , Espasmos Infantiles/fisiopatologíaRESUMEN
Charcot-Marie-Tooth disease type 4C (CMT4C) is an autosomal recessive demyelinating form of CMT characterized clinically by early onset and severe spinal deformities, and is caused by mutations in SH3TC2. We describe the case of a 10-year-old Japanese girl diagnosed with CMT4C. The patient developed progressive foot deformities such as marked pes cavus and ankle contracture, with mild muscle weakness in both legs, and generalized areflexia. On electrophysiological studies, motor nerve conduction velocity ranged from 22.3 m/s in the tibial nerve to 48.2 m/s in the median nerve. Sensory nerve conduction velocity ranged from 30.3 m/s in the sural nerve to 52.8 m/s in the median nerve. Sequence analysis of candidate genes identified two novel heterozygous mutations, c.229C>T and c.2775G>A, in SH3TC2. The patient was diagnosed as having CMT4C with novel mutations, making this the first documented Japanese pediatric case.
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Enfermedad de Charcot-Marie-Tooth/genética , ADN/genética , Mutación , Proteínas/genética , Enfermedad de Charcot-Marie-Tooth/diagnóstico , Niño , Análisis Mutacional de ADN , Femenino , Pruebas Genéticas , Genotipo , Humanos , Péptidos y Proteínas de Señalización Intracelular , Fenotipo , Proteínas/metabolismoRESUMEN
X-linked lissencephaly with ambiguous genitalia (XLAG) syndrome is a disorder associated with severe intellectual disability and intractable epilepsy. Intractable diarrhea is also observed frequently. At present, pathogenic background of diarrhea is not revealed and the essential treatment has not yet established. We encountered a patient with XLAG, who showed intractable diarrhea. Lactose removed hypoallergenic milk and somatostatin analogs were ineffective. For enteral nutrition was impossible, a tunneled central venous catheters was inserted to obtain a sustained parenteral nutrition management. However, catheter-related bloodstream infections were repeated in a short period of time. Thus, we introduced ethanol lock therapy for infectious disease prevention purposes. As a result, we succeeded continuous treatments with preserving the catheter.
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Catéteres Venosos Centrales , Lisencefalias Clásicas y Heterotopias Subcorticales en Banda/terapia , Etanol , Humanos , Lactante , MasculinoRESUMEN
BACKGROUND: Acute encephalopathy with biphasic seizures and late reduced diffusion (AESD) is the most common syndrome among the acute encephalopathies, and is associated with a high incidence of neurologic sequelae. This study examined the efficacy of cyclosporine (CsA) for the treatment of AESD. METHODS: Fourteen children with AESD were recruited and categorized as group A (not receiving CsA) and group B (receiving CsA). Clinical course, laboratory data, magnetic resonance imaging (MRI), and outcome were analyzed retrospectively. We divided the patients into three types according to the distribution of abnormalities on MRI: frontal lobe predominant type, unilateral cerebral hemisphere type, and diffuse type. We used the Pediatric Cerebral Performance Category scale (PCPC) and the Pediatric Overall Performance Category scale (POPC) as prognostic measures. RESULTS: Of the 14 children, five were boys (age range, 9-32 months). PCPC score was: 1 for seven patients, 2 for three patients, and 3 for four patients. There was no significant difference in PCPC between groups A and B (P = 0.293). POPC score was: 1 for six patients, 2 for five patients, and 3 for three patients. There was a significant difference in POPC between groups A and B when patients with the frontal lobe predominant type were excluded (P = 0.020). CONCLUSIONS: CsA could improve the neurological prognosis of patients with AESD, except for those with frontal lobe predominant type.
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Encefalopatías/tratamiento farmacológico , Ciclosporina/uso terapéutico , Inmunosupresores/uso terapéutico , Convulsiones/tratamiento farmacológico , Enfermedad Aguda , Preescolar , Femenino , Humanos , Lactante , Imagen por Resonancia Magnética , Masculino , Estudios Retrospectivos , SíndromeRESUMEN
OBJECTIVES: Cryopyrin-associated periodic syndrome (CAPS), a rare hereditary auto-inflammatory disease, is associated with mutations in the NLRP3 gene resulting in elevated interleukin-1ß (IL-1 ß) release. CAPS generally occurs in early childhood with most patients presenting with periodic fever, skin rash, osteoarthropathy, aseptic meningitis, sensorineural hearing loss and optic neuritis. Canakinumab, a fully human anti-IL-1ß monoclonal antibody which binds selectively to IL-1ß, has demonstrated good efficacy with CAPS. This is the first study to evaluate the safety and efficacy of canakinumab in Japanese patients with CAPS. METHODS: In this open-label study, 19 Japanese CAPS patients aged ≥2 years received canakinumab either 150 mg s.c. or 2 mg/kg for patients with a body weight ≤ 40 kg every 8 weeks for 24 weeks. The primary objective was to assess the proportion of patients who were free of relapse at week 24. RESULTS: A complete response was achieved in 18 (94.7%) patients with some requiring a dose and/or a frequency adjustment to attain full clinical response. The majority of patients (14/18; 77.8%) were in remission, i.e. free of relapse at week 24. Auto-inflammatory disease activity as assessed by physician's global assessment declined from baseline to end of the study (score of absent in 10.5% at baseline versus 31.6% at end of the study). Two patients had serious adverse events (SAEs), which resolved with standard treatment. One patient reported a mild injection-site reaction. No malignancies or deaths were reported during the study. CONCLUSIONS: Canakinumab 150 mg s.c. every 8 weeks was well-tolerated, highly efficacious and offered a convenient dosing regimen for treating Japanese patients with CAPS.
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Anticuerpos Monoclonales/uso terapéutico , Síndromes Periódicos Asociados a Criopirina/tratamiento farmacológico , Inmunosupresores/uso terapéutico , Adolescente , Adulto , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales Humanizados , Biomarcadores/sangre , Niño , Preescolar , Síndromes Periódicos Asociados a Criopirina/sangre , Síndromes Periódicos Asociados a Criopirina/diagnóstico , Síndromes Periódicos Asociados a Criopirina/inmunología , Esquema de Medicación , Femenino , Humanos , Inmunosupresores/administración & dosificación , Inmunosupresores/efectos adversos , Mediadores de Inflamación/sangre , Inyecciones Subcutáneas , Japón , Masculino , Persona de Mediana Edad , Recurrencia , Inducción de Remisión , Factores de Tiempo , Resultado del Tratamiento , Adulto JovenRESUMEN
We describe the case of a 3-year-old boy diagnosed with the fulminant form of acute disseminated encephalomyelitis (ADEM). He developed general fatigue, fever, drowsiness and difficulty in walking. He had extensive multiple high-intensity lesions in the white matter of the cerebrum and cerebellum, which are typical findings of ADEM. He became comatose and developed decerebrate rigidity with severe brain edema despite high-dose methylprednisolone therapy, and then was subjected to mild hypothermia therapy, and given i.v. immunoglobulin. The patient recovered remarkably with the sequela of only mild action tremor. The patient was considered to have acute hemorrhagic leukoencephalitis (AHLE), an extremely severe form of ADEM, in terms of the rapidly deteriorating clinical course and neuroimaging features. It was speculated that AHLE and ADEM might be a continuous disease spectrum. It is considered that the severe brain edema associated with ADEM or AHLE is a suitable indication for mild hypothermia therapy.
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Encefalomielitis Aguda Diseminada/terapia , Hipotermia Inducida/métodos , Preescolar , Humanos , Masculino , Índice de Severidad de la EnfermedadRESUMEN
During her first year of junior high school, a 12-year-old Japanese girl with Down syndrome experienced dizziness, gait disruption, paroxysmal weakness in her hands, and sluggish speaking. Regular blood tests and a brain MRI revealed no abnormalities, and she was tentatively diagnosed with adjustment disorder. Nine months later, the patient experienced a subacute sickness of chest pain, nausea, sleep problem with night terrors, and delusion of observation. Rapid deterioration then developed with simultaneous fever, akinetic mutism, loss of facial expression, and urine incontinence. These catatonic symptoms improved after a few weeks after admission and treatment with lorazepam, escitalopram, and aripiprazole. After discharge, nonetheless, daytime slumber, empty eyes, paradoxical laughter, and declined verbal communication persisted. Upon confirmation of the cerebrospinal N-methyl-D-aspartate (NMDA) receptor autoantibody, methylprednisolone pulse therapy was tried, but it had little effect. Visual hallucinations and cenesthopathy, as well as suicidal thoughts and delusions of death, have predominated in the following years. Cerebrospinal IL-1ra, IL-5, IL-15, CCL5, G-CSF, PDGFbb, and VFGF were raised in the early stage of initial medical attention with nonspecific complaints, but were less prominent in the later stages of catatonic mutism and psychotic symptoms. We suggest a disease concept of progression from Down syndrome disintegrative disorder to NMDA receptor encephalitis, based on this experience.
RESUMEN
Autism spectrum disorder (ASD) is caused by combined genetic and environmental factors. Genetic heritability in ASD is estimated as 60-90%, and genetic investigations have revealed many monogenic factors. We analyzed 405 patients with ASD using family-based exome sequencing to detect disease-causing single-nucleotide variants (SNVs), small insertions and deletions (indels), and copy number variations (CNVs) for molecular diagnoses. All candidate variants were validated by Sanger sequencing or quantitative polymerase chain reaction and were evaluated using the American College of Medical Genetics and Genomics/Association for Molecular Pathology guidelines for molecular diagnosis. We identified 55 disease-causing SNVs/indels in 53 affected individuals and 13 disease-causing CNVs in 13 affected individuals, achieving a molecular diagnosis in 66 of 405 affected individuals (16.3%). Among the 55 disease-causing SNVs/indels, 51 occurred de novo, 2 were compound heterozygous (in one patient), and 2 were X-linked hemizygous variants inherited from unaffected mothers. The molecular diagnosis rate in females was significantly higher than that in males. We analyzed affected sibling cases of 24 quads and 2 quintets, but only one pair of siblings shared an identical pathogenic variant. Notably, there was a higher molecular diagnostic rate in simplex cases than in multiplex families. Our simulation indicated that the diagnostic yield is increasing by 0.63% (range 0-2.5%) per year. Based on our simple simulation, diagnostic yield is improving over time. Thus, periodical reevaluation of ES data should be strongly encouraged in undiagnosed ASD patients.
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Acute autonomic and sensory neuropathy is a rare disorder that has been only anecdotally reported. We characterized the clinical, electrophysiological, pathological and prognostic features of 21 patients with acute autonomic and sensory neuropathy. An antecedent event, mostly an upper respiratory tract or gastrointestinal tract infection, was reported in two-thirds of patients. Profound autonomic failure with various degrees of sensory impairment characterized the neuropathic features in all patients. The initial symptoms were those related to autonomic disturbance or superficial sensory impairment in all patients, while deep sensory impairment accompanied by sensory ataxia subsequently appeared in 12 patients. The severity of sensory ataxia tended to become worse as the duration from the onset to the peak phase of neuropathy became longer (P<0.001). The distribution of sensory manifestations included the proximal regions of the limbs, face, scalp and trunk in most patients. It tended to be asymmetrical and segmental, rather than presenting as a symmetric polyneuropathy. Pain of the involved region was a common and serious symptom. In addition to autonomic and sensory symptoms, coughing episodes, psychiatric symptoms, sleep apnoea and aspiration, pneumonia made it difficult to manage the clinical condition. Nerve conduction studies revealed the reduction of sensory nerve action potentials in patients with sensory ataxia, while it was relatively preserved in patients without sensory ataxia. Magnetic resonance imaging of the spinal cord revealed a high-intensity area in the posterior column on T(2)*-weighted gradient echo image in patients with sensory ataxia but not in those without it. Sural nerve biopsy revealed small-fibre predominant axonal loss without evidence of nerve regeneration. In an autopsy case with impairment of both superficial and deep sensations, we observed severe neuronal cell loss in the thoracic sympathetic and dorsal root ganglia, and Auerbach's plexus with well preserved anterior hone cells. Myelinated fibres in the anterior spinal root were preserved, while those in the posterior spinal root and the posterior column of the spinal cord were depleted. Although recovery of sensory impairment was poor, autonomic dysfunction was ameliorated to some degree within several months in most patients. In conclusion, an immune-mediated mechanism may be associated with acute autonomic and sensory neuropathy. Small neuronal cells in the autonomic and sensory ganglia may be affected in the initial phase, and subsequently, large neuronal cells in the sensory ganglia are damaged.
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Enfermedades del Sistema Nervioso Autónomo/patología , Dolor/patología , Polineuropatías/patología , Nervio Sural/patología , Adulto , Anciano , Enfermedades del Sistema Nervioso Autónomo/diagnóstico , Enfermedades del Sistema Nervioso Autónomo/fisiopatología , Niño , Electrodiagnóstico , Femenino , Humanos , Masculino , Persona de Mediana Edad , Conducción Nerviosa , Examen Neurológico , Dolor/fisiopatología , Polineuropatías/diagnóstico , Polineuropatías/fisiopatología , Pronóstico , Estudios Retrospectivos , Índice de Severidad de la Enfermedad , Estadísticas no Paramétricas , Nervio Sural/fisiopatologíaRESUMEN
BACKGROUND: Marked decreases in serum creatine kinase levels have been noted in Duchenne and Becker muscular dystrophies as rare complications of autoimmune or autoinflammatory diseases. SUBJECTS AND METHODS: The influence of systemic inflammation on serum creatine kinase levels was reviewed from the charts of three subjects with Fukuyama congenital muscular dystrophy. RESULTS: A total of 30 infectious events were identified. Elevated serum C-reactive protein levels coincided with decreased creatine kinase levels on 19 occasions. In one subject, administration of 2 mg/kg/d prednisolone for bronchial asthma resulted in a decrease in creatine kinase level on six other occasions. CONCLUSION: Apart from an increase in endogenous cortisol secretion, certain inflammation-related molecules could play a role in mitigating muscle cell damage in Fukuyama congenital muscular dystrophy during febrile infectious episodes. Corticosteroids may be a promising agent for the treatment of muscular symptoms in this disorder.
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Creatina Quinasa/sangre , Infecciones/enzimología , Síndrome de Walker-Warburg/sangre , Síndrome de Walker-Warburg/enzimología , Adolescente , Proteína C-Reactiva/metabolismo , Niño , Femenino , Fiebre , Humanos , Infecciones/sangre , Masculino , Adulto JovenRESUMEN
AIM: To describe beneficial effects of callosotomy on KCNQ2-related intractable epilepsy. CASE REPORT: Our patient was a 10-year-old girl who had developed epilepsy during the neonatal period, accompanied by a suppression-burst pattern on the electroencephalography (EEG). The patient showed profound psychomotor developmental delay since early infancy. Daily seizures of versive posturing and ocular deviation were transiently controlled by carbamazepine and valproate at the age of 1 year; however, the seizures gradually increased to up to 50 times per day. Ictal EEG and positron emission tomography revealed an epileptic focus in the left frontal lobe at age 5 years. Total callosotomy resulted in marked reduction of epileptic seizures thereafter, as well as improved responses to external auditory and visual stimuli. Whole exome sequencing at age 9 identified a de novo missense variant in KCNQ2 (NM_172107.3:c.563A > C:p.(Gln188Pro)). CONCLUSION: This case supports that epilepsy surgery could benefit children with epileptic encephalopathy, even with the etiology of channelopathy.
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Cuerpo Calloso/cirugía , Epilepsia Refractaria/cirugía , Canal de Potasio KCNQ2/genética , Carbamazepina/uso terapéutico , Niño , Epilepsia Refractaria/genética , Electroencefalografía , Femenino , Humanos , Hipoxia-Isquemia Encefálica/diagnóstico , Mutación Missense , Ácido Valproico/uso terapéuticoRESUMEN
BACKGROUND: We aimed to demonstrate the biochemical characteristics of vitamin B6-dependent epilepsy, with a particular focus on pyridoxal 5'-phosphate and pyridoxal in the cerebrospinal fluid. METHODS: Using our laboratory database, we identified patients with vitamin B6-dependent epilepsy and extracted their data on the concentrations of pyridoxal 5'-phosphate, pyridoxal, pipecolic acid, α-aminoadipic semialdehyde, and monoamine neurotransmitters. We compared the biochemical characteristics of these patients with those of other epilepsy patients with low pyridoxal 5'-phosphate concentrations. RESULTS: We identified seven patients with pyridoxine-dependent epilepsy caused by an ALDH7A1 gene abnormality, two patients with pyridoxal 5'-phosphate homeostasis protein deficiency, and 28 patients with other epilepsies with low cerebrospinal fluid pyridoxal 5'-phosphate concentrations. Cerebrospinal fluid pyridoxal and pyridoxal 5'-phosphate concentrations were low in patients with vitamin B6-dependent epilepsy but cerebrospinal fluid pyridoxal concentrations were not reduced in most patients with other epilepsies with low cerebrospinal fluid pyridoxal 5'-phosphate concentrations. Increase in 3-O-methyldopa and 5-hydroxytryptophan was demonstrated in some patients with vitamin B6-dependent epilepsy, suggestive of pyridoxal 5'-phosphate deficiency in the brain. CONCLUSIONS: Low cerebrospinal fluid pyridoxal concentrations may be a better indicator of pyridoxal 5'-phosphate deficiency in the brain in vitamin B6-dependent epilepsy than low cerebrospinal fluid pyridoxal 5'-phosphate concentrations. This finding is especially helpful in individuals with suspected pyridoxal 5'-phosphate homeostasis protein deficiency, which does not have known biomarkers.
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Epilepsia/metabolismo , Fosfato de Piridoxal/líquido cefalorraquídeo , Piridoxal/líquido cefalorraquídeo , 5-Hidroxitriptófano/metabolismo , Adolescente , Niño , Preescolar , Epilepsia/diagnóstico , Epilepsia/etiología , Femenino , Humanos , Lactante , Recién Nacido , Masculino , Ácidos Pipecólicos/metabolismo , Estudios Retrospectivos , Tirosina/análogos & derivados , Tirosina/metabolismo , Vitamina B 6 , Adulto JovenRESUMEN
BACKGROUND: Myelin oligodendrocyte glycoprotein antibodies (MOG Abs) are frequently detected in pediatric acquired demyelinating syndrome (ADS), and MOG-Ab-positive ADS differs from multiple sclerosis (MS) and aquaporin-4 (AQP4)-Ab-positive neuromyelitis optica spectrum disorder (NMOSD) in terms of age distribution, therapeutic response, and prognosis. METHODS: Based on medical records, we retrospectively evaluated patients with MOG-Ab-positive NMOSD treated in the acute phase who were followed up in the chronic phase at our hospital from January 2011 to December 2017. RESULTS: The patients comprised two boys and two girls aged 3-12 (median, 8) years. Peak MOG-Ab titers were 1:2048 to 1:32768 (median, 1:10240), and the relapse rate ranged from 0 to 1.25 times/year (median, 0.59 times/year); no sequelae were observed in any cases. Lesions other than those of optic neuritis were distributed at the cortex in one patient, subcortical white matter in four, deep white matter in three, and brainstem in one, all of which were disseminated lesions. No lesions were found in the corpus callosum, periventricular white matter, diencephalon, and regions adjacent to the third and fourth ventricles. The lesions tended to be asymptomatic, and two patients aged >5â¯years had well-demarcated lesions. CONCLUSION: All the patients showed disseminated lesions in the subcortical region to deep white matter, which were different from those found in MS and AQP4-Ab-positive NMOSD and were consistent with the characteristics of brain lesions in MOG-Ab-positive ADS, including other disease types.
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Glicoproteína Mielina-Oligodendrócito/análisis , Glicoproteína Mielina-Oligodendrócito/inmunología , Neuromielitis Óptica/diagnóstico por imagen , Autoanticuerpos , Encéfalo , Tronco Encefálico , Niño , Preescolar , Femenino , Humanos , Imagen por Resonancia Magnética/métodos , Masculino , Neuritis Óptica/fisiopatología , Estudios RetrospectivosRESUMEN
Although there are many known Mendelian genes linked to epileptic or developmental and epileptic encephalopathy (EE/DEE), its genetic architecture is not fully explained. Here, we address this incompleteness by analyzing exomes of 743 EE/DEE cases and 2366 controls. We observe that damaging ultra-rare variants (dURVs) unique to an individual are significantly overrepresented in EE/DEE, both in known EE/DEE genes and the other non-EE/DEE genes. Importantly, enrichment of dURVs in non-EE/DEE genes is significant, even in the subset of cases with diagnostic dURVs (P = 0.000215), suggesting oligogenic contribution of non-EE/DEE gene dURVs. Gene-based analysis identifies exome-wide significant (P = 2.04 × 10-6) enrichment of damaging de novo mutations in NF1, a gene primarily linked to neurofibromatosis, in infantile spasm. Together with accumulating evidence for roles of oligogenic or modifier variants in severe neurodevelopmental disorders, our results highlight genetic complexity in EE/DEE, and indicate that EE/DEE is not an aggregate of simple Mendelian disorders.
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Variación Genética , Espasmos Infantiles/genética , Proteínas Adaptadoras del Transporte Vesicular/genética , Pueblo Asiatico/genética , Estudios de Casos y Controles , ADN (Citosina-5-)-Metiltransferasas/genética , Epilepsias Mioclónicas/genética , Factores de Intercambio de Guanina Nucleótido/genética , Humanos , Lactante , Japón , Síndrome de Lennox-Gastaut/genética , Modelos Logísticos , Mutación , Neurofibromina 1/genética , Polimorfismo de Nucleótido Simple , Análisis de Componente Principal , Canales Catiónicos TRPM/genética , Secuenciación del ExomaRESUMEN
Eleven children with gait disturbance due to cerebral palsy (mean age, 5.6 years, ranging from 2.4 to 11.5) were treated with Botulinum toxin A (BTA, BOTOX, Allergan) for improvement of spasticity and walking difficulty. BTA was injected into the gastrocnemius, adductors, and hamstring muscles with an initial total dose up to 8 units/kg or 100 units. Spasticity and gait disturbance were significantly improved in all patients 4 weeks after the treatment. Their parents also reported that BTA was helpful for brace tolerance and assistance of caregivers. No side effects including worsening of gait or signs of systemic adverse effects were observed. Management of leg spasticity with BTA is thought to be useful and safe, and approval for this use in Japan is recommended.
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Toxinas Botulínicas Tipo A/uso terapéutico , Parálisis Cerebral/complicaciones , Pierna , Espasticidad Muscular/tratamiento farmacológico , Niño , Preescolar , Trastornos Neurológicos de la Marcha/tratamiento farmacológico , HumanosRESUMEN
OBJECTIVE: Vitamin B6-dependent epilepsies are treatable disorders caused by variants in several genes, such as ALDH7A1,PNPO, and others. Recently, biallelic variants in PLPBP, formerly known as PROSC, were identified as a novel cause of vitamin B6-dependent epilepsies. Our objective was to further delineate the phenotype of PLPBP mutation. METHODS: We identified 4 unrelated patients harboring a total of 4 variants in PLPBP, including 3 novel variants, in a cohort of 700 patients with developmental and epileptic encephalopathies. Clinical information in each case was collected. RESULTS: Each patient had a different clinical course of epilepsy, with seizure onset from the first day of life to 3 months of age. Generalized tonic-clonic seizures were commonly noted. Myoclonic seizures or focal seizures were also observed in 2 patients. Interictal electroencephalography showed variable findings, such as suppression burst, focal or multifocal discharges, and diffuse slow activity. Unlike previous reports, all the patients had some degree of intellectual disability, although some of them had received early treatment with vitamin B6, suggesting that different mutation types influence the severity and outcome of the seizures. SIGNIFICANCE: PLPBP variants should be regarded as among the causative genes of developmental and epileptic encephalopathy, even when it occurs after the neonatal period. Early diagnosis and proper treatment with pyridoxine or pyridoxal phosphate is essential to improve the neurologic prognosis in neonates or young children with poorly controlled seizures.
RESUMEN
Recent studies have established important roles of de novo mutations (DNMs) in autism spectrum disorders (ASDs). Here, we analyze DNMs in 262 ASD probands of Japanese origin and confirm the "de novo paradigm" of ASDs across ethnicities. Based on this consistency, we combine the lists of damaging DNMs in our and published ASD cohorts (total number of trios, 4,244) and perform integrative bioinformatics analyses. Besides replicating the findings of previous studies, our analyses highlight ATP-binding genes and fetal cerebellar/striatal circuits. Analysis of individual genes identified 61 genes enriched for damaging DNMs, including ten genes for which our dataset now contributes to statistical significance. Screening of compounds altering the expression of genes hit by damaging DNMs reveals a global downregulating effect of valproic acid, a known risk factor for ASDs, whereas cardiac glycosides upregulate these genes. Collectively, our integrative approach provides deeper biological and potential medical insights into ASDs.
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Trastorno del Espectro Autista/genética , Mutación/genética , Trastorno del Espectro Autista/patología , Predisposición Genética a la Enfermedad , HumanosRESUMEN
Norovirus is a common cause of gastroenteritis. We describe the case of a 23-month-old girl with encephalopathy possibly associated with norovirus infection. The viral genome was detected in stool, serum and cerebrospinal fluid (CSF) by reverse transcription polymerase chain reaction. This is the first report of encephalopathy potentially caused by norovirus as indicated by the presence of the virus genome in CSF.
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Infecciones por Caliciviridae/virología , Encefalitis Viral/virología , Norovirus/genética , Infecciones por Caliciviridae/sangre , Infecciones por Caliciviridae/líquido cefalorraquídeo , Encefalitis Viral/sangre , Encefalitis Viral/líquido cefalorraquídeo , Femenino , Gastroenteritis/virología , Genoma Viral , Humanos , LactanteRESUMEN
Migrating partial seizures in infancy (MPSI) are an age-specific epilepsy syndrome characterized by migrating focal seizures, which are intractable to various antiepileptic drugs and cause severe developmental delay. We report a case of MPSI with heterozygous missense mutation in KCNT1, which was successfully managed by ketogenic diet. At age 2months, the patient developed epilepsy initially manifesting focal seizures with eye deviation and apnea, then evolving to secondarily generalized clonic convulsion. Various antiepileptic drugs including phenytoin, valproic acid, zonisamide, clobazam, levetiracetam, vitamin B6, and carbamazepine were not effective, but high-dose phenobarbital allowed discontinuation of midazolam infusion. Ictal scalp electroencephalogram showed migrating focal seizures. MPSI was suspected and she was transferred to our hospital for further treatment. Potassium bromide (KBr) was partially effective, but the effect was transient. High-dose KBr caused severe adverse effects such as over-sedation and hypercapnia, with no further effects on the seizures. At age 9months, we started a ketogenic diet, which improved seizure frequency and severity without obvious adverse effects, allowing her to be discharged from hospital. Ketogenic diet should be tried in patients with MPSI unresponsive to antiepileptic drugs. In MPSI, the difference in treatment response in patients with and those without KCNT1 mutation remains unknown. Accumulation of case reports would contribute to establish effective treatment options for MPSI.
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Dieta Cetogénica , Epilepsias Parciales/dietoterapia , Anticonvulsivantes/uso terapéutico , Encéfalo/fisiopatología , Terapia Combinada/métodos , Electroencefalografía , Epilepsias Parciales/tratamiento farmacológico , Epilepsias Parciales/genética , Epilepsias Parciales/fisiopatología , Femenino , Estudios de Seguimiento , Humanos , Lactante , Proteínas del Tejido Nervioso/genética , Canales de Potasio/genética , Canales de potasio activados por Sodio , Resultado del TratamientoRESUMEN
OBJECTIVE: We aimed to investigate the possible association between SCN2A mutations and early-onset epileptic encephalopathies (EOEEs). METHODS: We recruited a total of 328 patients with EOEE, including 67 patients with Ohtahara syndrome (OS) and 150 with West syndrome. SCN2A mutations were examined using high resolution melt analysis or whole exome sequencing. RESULTS: We found 14 novel SCN2A missense mutations in 15 patients: 9 of 67 OS cases (13.4%), 1 of 150 West syndrome cases (0.67%), and 5 of 111 with unclassified EOEEs (4.5%). Twelve of the 14 mutations were confirmed as de novo, and all mutations were absent in 212 control exomes. A de novo mosaic mutation (c.3976G>C) with a mutant allele frequency of 18% was detected in one patient. One mutation (c.634A>G) was found in transcript variant 3, which is a neonatal isoform. All 9 mutations in patients with OS were located in linker regions between 2 transmembrane segments. In 7 of the 9 patients with OS, EEG findings transitioned from suppression-burst pattern to hypsarrhythmia. All 15 of the patients with novel SCN2A missense mutations had intractable seizures; 3 of them were seizure-free at the last medical examination. All patients showed severe developmental delay. CONCLUSIONS: Our study confirmed that SCN2A mutations are an important genetic cause of OS. Given the wide clinical spectrum associated with SCN2A mutations, genetic testing for SCN2A should be considered for children with different epileptic conditions.