RESUMEN
Angelman syndrome (AS) is caused by the functional absence of the maternal ubiquitin-protein ligase E3A (UBE3A) gene. Approximately 5% of AS is caused by paternal uniparental disomy of chromosome 15 (UPD(15)pat), most of which is considered to result from monosomy rescue. However, little attention has focused on how UPD(15)pat occurs. We suggest the mitotic nondisjunction mechanism as a cause of UPD(15)pat in a six-year-old patient presenting with distinctive characteristics in line with AS. DNA methylation screening of 15q11-q13 showed a paternal band and a faint maternal band, suggestive of mosaic status. By trio-based microsatellite analysis, we confirmed a large proportion of UPD(15)pat cells and a small proportion of cells of biparental origin. Single nucleotide polymorphism (SNP) microarray revealed isodisomy of the entire chromosome 15. These results suggest that the UPD(15)pat of the patient resulted from mitotic nondisjunction, which may also be the cause of other cases of AS with UPD(15)pat.
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Síndrome de Angelman , Disomía Uniparental , Humanos , Niño , Disomía Uniparental/genética , Síndrome de Angelman/genética , Polimorfismo de Nucleótido Simple , Metilación de ADN/genética , Análisis por MicromatricesRESUMEN
BACKGROUND: Variants in the type IV collagen gene (COL4A1/2) cause early-onset cerebrovascular diseases. Most individuals are diagnosed postnatally, and the prenatal features of individuals with COL4A1/2 variants remain unclear. METHODS: We examined COL4A1/2 in 218 individuals with suspected COL4A1/2-related brain defects. Among those arising from COL4A1/2 variants, we focused on individuals showing prenatal abnormal ultrasound findings and validated their prenatal and postnatal clinical features in detail. RESULTS: Pathogenic COL4A1/2 variants were detected in 56 individuals (n=56/218, 25.7%) showing porencephaly (n=29), schizencephaly (n=12) and others (n=15). Thirty-four variants occurred de novo (n=34/56, 60.7%). Foetal information was available in 47 of 56 individuals, 32 of whom (n=32/47, 68.1%) had one or more foetal abnormalities. The median gestational age at the detection of initial prenatal abnormal features was 31 weeks of gestation. Only 14 individuals had specific prenatal findings that were strongly suggestive of features associated with COL4A1/2 variants. Foetal ventriculomegaly was the most common initial feature (n=20/32, 62.5%). Posterior fossa abnormalities, including Dandy-Walker malformation, were observed prenatally in four individuals. Regarding extrabrain features, foetal growth restriction was present in 16 individuals, including eight individuals with comorbid ventriculomegaly. CONCLUSIONS: Prenatal observation of ventriculomegaly with comorbid foetal growth restriction should prompt a thorough ultrasound examination and COL4A1/2 gene testing should be considered when pathogenic variants are strongly suspected.
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Colágeno Tipo IV/genética , Mutación/genética , Síndrome de Dandy-Walker/genética , Femenino , Humanos , Masculino , Embarazo , Ultrasonografía Prenatal/métodosRESUMEN
BACKGROUND: Tuberous sclerosis complex (TSC)-associated neuropsychiatric disorders (TAND) have a large impact on patients and their families. Improving intellectual ability outcomes using preventive vigabatrin (VGB) treatment has recently been reported. AIM: The aim of this study was to investigate the severity of behavioral problems and degree of distress among families of patients with TSC with and without a history of VGB treatment. METHOD: The study enrolled 21 children and adolescents who were patients with TSC from four hospitals: 14 in the VGB group and 7 in the no-VGB group. To evaluate patients' psychiatric and neurological symptoms, we used the TAND Checklist, Aberrant Behavior Checklist (ABC), Social Communication Questionnaire (SCQ), and Social Responsive Scale-2nd edition (SRS-2). RESULTS: All VGB-group patients were administered VGB after the onset of epileptic seizures. No obvious differences were observed between the VGB and no-VGB groups in behavioral problem scores on the TAND Checklist, or on the ABC, SCQ, and SRS-2 total scores. Behavioral problem scores were lower in patients with normal intelligence than in those with mild intellectual disability (ID; Pâ¯=â¯0.042). Degrees of family distress assessed with the TAND Checklist were not correlated with the intelligence quotient/developmental quotient (IQ/DQ) or seizure frequency but were correlated with the total SRS-2 scores (Pâ¯=â¯0.022). For several patients, there were large discrepancies between familial and physician ratings of the TAND impact score. CONCLUSION: Children and adolescents with TSC may present with significant behavioral difficulties and family distress, regardless of whether they were treated with VGB or not after the onset of seizures. Difficulties in social communication may have the strongest "TAND impact" on families.
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Relaciones Familiares/psicología , Problema de Conducta/psicología , Distrés Psicológico , Esclerosis Tuberosa/psicología , Adolescente , Anticonvulsivantes/uso terapéutico , Lista de Verificación/métodos , Niño , Preescolar , Femenino , Humanos , Masculino , Anamnesis/métodos , Convulsiones/tratamiento farmacológico , Convulsiones/psicología , Esclerosis Tuberosa/tratamiento farmacológico , Vigabatrin/uso terapéuticoRESUMEN
BACKGROUND: In this study, we aimed to identify the gene abnormality responsible for pathogenicity in an individual with an undiagnosed neurodevelopmental disorder with megalencephaly, ventriculomegaly, hypoplastic corpus callosum, intellectual disability, polydactyly and neuroblastoma. We then explored the underlying molecular mechanism. METHODS: Trio-based, whole-exome sequencing was performed to identify disease-causing gene mutation. Biochemical and cell biological analyses were carried out to elucidate the pathophysiological significance of the identified gene mutation. RESULTS: We identified a heterozygous missense mutation (c.173C>T; p.Thr58Met) in the MYCN gene, at the Thr58 phosphorylation site essential for ubiquitination and subsequent MYCN degradation. The mutant MYCN (MYCN-T58M) was non-phosphorylatable at Thr58 and subsequently accumulated in cells and appeared to induce CCND1 and CCND2 expression in neuronal progenitor and stem cells in vitro. Overexpression of Mycn mimicking the p.Thr58Met mutation also promoted neuronal cell proliferation, and affected neuronal cell migration during corticogenesis in mouse embryos. CONCLUSIONS: We identified a de novo c.173C>T mutation in MYCN which leads to stabilisation and accumulation of the MYCN protein, leading to prolonged CCND1 and CCND2 expression. This may promote neurogenesis in the developing cerebral cortex, leading to megalencephaly. While loss-of-function mutations in MYCN are known to cause Feingold syndrome, this is the first report of a germline gain-of-function mutation in MYCN identified in a patient with a novel megalencephaly syndrome similar to, but distinct from, CCND2-related megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome. The data obtained here provide new insight into the critical role of MYCN in brain development, as well as the consequences of MYCN defects.
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Mutación con Ganancia de Función , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Megalencefalia/diagnóstico , Megalencefalia/genética , Proteína Proto-Oncogénica N-Myc/genética , Adolescente , Alelos , Animales , Encéfalo/anomalías , Análisis Mutacional de ADN , Modelos Animales de Enfermedad , Facies , Genotipo , Células HEK293 , Humanos , Imagen por Resonancia Magnética , Masculino , Ratones , Células-Madre Neurales/citología , Células-Madre Neurales/metabolismo , Linaje , Fenotipo , Radiografía , Síndrome , Secuenciación del ExomaRESUMEN
Since the publication of this article, it has been brought to our attention, that the identified mutation (NM_015277: c.2617 G > A; p.Glu873Lys) is identical with the mutation (NM_001144967: c.2677 G > A; p.Glu893Lys) reported by Broix et al (Nature Genetics 48, 1349-1358, 2016 https://doi.org/10.1038/ng.3676 ). Therefore the mutation is not novel but recurrent. Accordingly, the word "novel" should be deleted throughout the article including the title. Thus, the title should read "A missense mutation in the HECT domain of NEDD4L identified in a girl with periventricular nodular heterotopia, polymicrogyria, and cleft palate."
RESUMEN
TBC1D24-related disorders are rare neurodevelopmental disorders that show a broad range of neuropsychiatric deficits and are mostly inherited in an autosomal recessive manner. Here we describe a case with early-onset epileptic encephalopathy, in whom exome sequencing detected a novel pathogenic homozygous c.442G>A, p.(Glu148Lys) variant in TBC1D24. She showed severe developmental delay, congenital sensorineural hearing loss and seizures, but the combination of a high dose phenobarbital and potassium bromide was very effective for the seizures. Sanger sequencing revealed that her mother was a heterozygous carrier of the TBC1D24 variant, but her father showed only wild-type alleles. Homozygosity mapping analysis using exome data showed loss of the heterozygosity region at 16p13.3-p13.13 encompassing TBC1D24. Genotyping analysis using rare variants within loss of the heterozygosity region indicated that the patient has a homozygous haplotype inherited from her mother, indicating maternal segmental uniparental isodisomy (UPiD). These data clearly show that exome sequencing is a powerful tool to perform comprehensive genetic analysis.
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Proteínas Activadoras de GTPasa/genética , Homocigoto , Mutación , Espasmos Infantiles/etiología , Disomía Uniparental/patología , Exoma , Femenino , Humanos , Lactante , Pronóstico , Espasmos Infantiles/patología , Disomía Uniparental/genéticaRESUMEN
Microcephaly-capillary malformation syndrome is a congenital and neurodevelopmental disorder caused by biallelic mutations in the STAMBP gene. Here we identify the novel homozygous mutation located in the SH3 binding motif of STAMBP (NM_006463.4) (c.707C>T: p.Ser236Phe) through whole-exome sequencing. The case patient was a 2-year-old boy showing severe global developmental delay, progressive microcephaly, refractory seizures, dysmorphic facial features, and multiple capillary malformations. Immunoblot analysis of patient-derived lymphoblastoid cell lines (LCLs) revealed a severe reduction in STAMBP expression, indicating that Ser236Phe induces protein instability. STAMBP interacts with the SH3 domain of STAM and transduces downstream signals from the Jaks-STAM complex. The substitution of Ser236Phe found in the case patient was located in the SH3-binding motif, and we propose the mutation may block STAM binding and subsequently induce STAMBP degradation. Contrary to previously reported STAMBP mutations, the Ser236Phe mutation did not lead to constitutive activation of the PI3K-AKT-mTOR pathway in patient-derived LCLs, as indicated by the expression of phosphorylated S6 ribosomal protein, suggesting that it is not the major pathomechanism underlying the disorder in this patient.
Asunto(s)
Complejos de Clasificación Endosomal Requeridos para el Transporte , Homocigoto , Microcefalia , Mutación Missense , Transducción de Señal , Ubiquitina Tiolesterasa , Dominios Homologos src , Secuencias de Aminoácidos , Preescolar , Complejos de Clasificación Endosomal Requeridos para el Transporte/genética , Complejos de Clasificación Endosomal Requeridos para el Transporte/metabolismo , Humanos , Masculino , Microcefalia/genética , Microcefalia/metabolismo , Microcefalia/patología , Síndrome , Ubiquitina Tiolesterasa/genética , Ubiquitina Tiolesterasa/metabolismoRESUMEN
OBJECTIVE: To clarify longitudinal changes in white matter microstructures from the onset of disease in patients with West syndrome (WS) of unknown etiology. METHODS: Diffusion tensor imaging (DTI) was prospectively performed at onset and at 12 and 24 months old in 17 children with WS of unknown etiology. DTI was analyzed using tract-based spatial statistics (TBSS) and tract-specific analysis (TSA) of 13 fiber tracts, and fractional anisotropy (FA) and mean diffusivity (MD) were compared with those of 42 age-matched controls. Correlations of FA and MD with developmental quotient (DQ) at age 24 months were analyzed. Multiple comparisons were adjusted for using the false discovery rate (q-value). RESULTS: TBSS analysis at onset showed higher FA and lower MD in the corpus callosum and brainstem in patients. TSA showed lower MD in bilateral uncinate fasciculi (UF) (right: q < 0.001; left: q = 0.03) at onset in patients. TBSS showed a negative correlation between FA at onset and DQ in the right frontal lobe, whereas FA at 24 months old exhibited a positive correlation with DQ in the diffuse white matter. MD for bilateral UF at 24 months old on TSA correlated positively with DQ (q = 0.04, both). SIGNIFICANCE: These findings may indicate the existence of cytotoxic edema in the immature white matter and dorsal brainstem at onset, and subsequent alterations in the diffuse white matter in WS of unknown etiology. Microstructural development in the UF might play important roles in cognitive development in WS.
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Edema Encefálico/diagnóstico por imagen , Discapacidades del Desarrollo/fisiopatología , Espasmos Infantiles/diagnóstico por imagen , Sustancia Blanca/diagnóstico por imagen , Anisotropía , Encéfalo/diagnóstico por imagen , Tronco Encefálico/diagnóstico por imagen , Estudios de Casos y Controles , Preescolar , Discapacidades del Desarrollo/complicaciones , Imagen de Difusión Tensora , Femenino , Lóbulo Frontal/diagnóstico por imagen , Humanos , Lactante , Estudios Longitudinales , Masculino , Estudios Prospectivos , Espasmos Infantiles/complicaciones , Espasmos Infantiles/fisiopatologíaRESUMEN
BACKGROUND: Heterozygous mutations in CTCF have been reported in patients with distinct clinical features including intellectual disability. However, the precise pathomechanism underlying the phenotype remains to be uncovered, partly because of the diverse function of CTCF. Here we describe extensive clinical and genetic investigation for two patients with a microdeletion encompassing CTCF. METHODS: We performed genetic examination including comprehensive investigation of X chromosome inactivation and DNA methylation profiling at imprinted loci and genome-wide. RESULTS: Two patients showed comparable clinical features to those in a previous report, indicating that haploinsufficiency of CTCF was the major determinant of the microdeletion syndrome. Despite the haploinsufficiency of CTCF, X chromosome inactivation was normal. DNA methylation at imprinted loci was normal, but hypermethylation at CTCF binding sites was demonstrated, of which PRKCZ and FGFR2 were identified as candidate genes. CONCLUSIONS: This study confirms that haploinsufficiency of CTCF causes distinct clinical features, and that a microdeletion encompassing CTCF could cause a recognisable CTCF deletion syndrome. Perturbed DNA methylation at CTCF binding sites, not at imprinted loci, may underlie the pathomechanism of the syndrome.
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Factor de Unión a CCCTC/genética , Eliminación de Gen , Estudios de Asociación Genética , Factor de Unión a CCCTC/metabolismo , Preescolar , Hibridación Genómica Comparativa , Metilación de ADN , Epigénesis Genética , Facies , Femenino , Haploinsuficiencia , Humanos , Hibridación Fluorescente in Situ , Fenotipo , Análisis de Secuencia de ADN , Espectrometría de Masa por Láser de Matriz Asistida de Ionización Desorción , Síndrome , Inactivación del Cromosoma XRESUMEN
AIM: We developed quality-of-life (QOL) scales for patients receiving home medical care. The objective of this study was to examine the agreement between the scores of the scales answered by patients and those answered by their proxy, as cognitive decline may interfere with one's ability to understand complex topics, such as the QOL. METHODS: Participants were pairs of patients receiving home medical care and their proxy. The patients were asked to complete self-reported QOL scales (QOL-HC), and their proxies were asked to complete proxy-reported versions of the QOL scales (QOL-HC for caregivers). We then statistically examined the extent of agreement between the self- and proxy-reported QOL-HC scores using contingency tables and Spearman's rank correlation coefficient. The SPSS software program, version 24, was used for all statistical analyses. RESULTS: The concordance rate between patients and caregivers for questions 1 ( "Do you have peace of mind?" ), 2 ( "Do you feel satisï¬ed with your life when you reï¬ect on it?" ), 3 ( "Do you have someone that you spend time talking with?" ), and 4 ( "Are you satisï¬ed with the home care service system?" ) were 52.3%, 52.3%, 79.5%, and 81.8%, respectively. The total scores for the patients and caregivers were significantly correlated (Spearman's ρ=0.364*). CONCLUSIONS: We created the first QOL scale for patients receiving home-based medical care and for caregivers. The findings of this study suggest that the QOL-HC can be used in clinical practice for the assessment of patients receiving professional home care.
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Servicios de Atención de Salud a Domicilio , Calidad de Vida , Anciano , Anciano de 80 o más Años , Demencia/terapia , Femenino , Humanos , Masculino , Apoderado , AutoinformeRESUMEN
We analyzed the role of a heterotrimeric G-protein, Gi2, in the development of the cerebral cortex. Acute knockdown of the α-subunit (Gαi2) with in utero electroporation caused delayed radial migration of excitatory neurons during corticogenesis, perhaps because of impaired morphology. The migration phenotype was rescued by an RNAi-resistant version of Gαi2. On the other hand, silencing of Gαi2 did not affect axon elongation, dendritic arbor formation or neurogenesis at ventricular zone in vivo. When behavior analyses were conducted with acute Gαi2-knockdown mice, they showed defects in social interaction, novelty recognition and active avoidance learning as well as increased anxiety. Subsequently, using whole-exome sequencing analysis, we identified a de novo heterozygous missense mutation (c.680C>T; p.Ala227Val) in the GNAI2 gene encoding Gαi2 in an individual with periventricular nodular heterotopia and intellectual disability. Collectively, the phenotypes in the knockdown experiments suggest a role of Gαi2 in the brain development, and impairment of its function might cause defects in neuronal functions which lead to neurodevelopmental disorders.
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Corteza Cerebral/crecimiento & desarrollo , Corteza Cerebral/metabolismo , Subunidad alfa de la Proteína de Unión al GTP Gi2/fisiología , Discapacidad Intelectual/metabolismo , Heterotopia Nodular Periventricular/metabolismo , Animales , Reacción de Prevención/fisiología , Células COS , Corteza Cerebral/diagnóstico por imagen , Chlorocebus aethiops , Femenino , Subunidad alfa de la Proteína de Unión al GTP Gi2/deficiencia , Humanos , Discapacidad Intelectual/diagnóstico por imagen , Discapacidad Intelectual/genética , Ratones , Ratones Endogámicos ICR , Ratones Noqueados , Heterotopia Nodular Periventricular/diagnóstico por imagen , Heterotopia Nodular Periventricular/genética , EmbarazoRESUMEN
BACKGROUND: Constitutive activation of the PI3K-AKT-mTOR pathway (mTOR pathway) underlies megalencephaly in many patients. Yet, prevalence of the involvement of the PI3K-AKT-mTOR pathway in patients with megalencephaly remains to be elucidated, and molecular diagnosis is challenging. Here, we have successfully established a combination of genetic and biochemical methods for diagnosis of mTOR pathway-associated megalencephaly, and have attempted to delineate the clinical characteristics of the disorder. METHODS: Thirteen patients with an increased head circumference and neurological symptoms participated in the study. To evaluate the activation of the mTOR pathway, we performed western blot analysis to determine the expression levels of phosphorylated S6 ribosomal protein (phospho-S6 protein) in lymphoblastoid cell lines from 12 patients. Multiplex targeted sequencing analysis for 15 genes involved in the mTOR pathway was performed on 12 patients, and whole-exome sequencing was performed on one additional patient. Clinical features and MRI findings were also investigated. RESULTS: We identified pathogenic mutations in six (AKT3, 1 patient; PIK3R2, 2 patients; PTEN, 3 patients) of the 13 patients. Increased expression of phospho-S6 protein was demonstrated in all five mutation-positive patients in whom western blotting was performed, as well as in three mutation-negative patients. Developmental delay, dysmorphic facial features were observed in almost all patients. Syndactyly/polydactyly and capillary malformations were not observed, even in patients with AKT3 or PIK3R2 mutations. There were no common phenotypes or MRI findings among these patients. CONCLUSIONS: A combination of genetic and biochemical methods successfully identified mTOR pathway involvement in nine of 13 (approximately 70%) patients with megalencephaly, indicating a major contribution of the pathway to the pathogenesis of megalencephaly. Our combined approach could be useful to identify patients who are suitable for future clinical trials using an mTOR inhibitor.
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Megalencefalia/diagnóstico , Fosfohidrolasa PTEN/genética , Fosfatidilinositol 3-Quinasas/genética , Proteínas Proto-Oncogénicas c-akt/genética , Proteínas Quinasas S6 Ribosómicas/metabolismo , Adolescente , Línea Celular , Niño , Preescolar , Femenino , Humanos , Masculino , Megalencefalia/genética , Megalencefalia/metabolismo , Mutación , Fosfohidrolasa PTEN/metabolismo , Fosforilación , Proteínas Proto-Oncogénicas c-akt/metabolismo , Análisis de Secuencia de ADN/métodos , Transducción de Señal , Serina-Treonina Quinasas TOR/genética , Serina-Treonina Quinasas TOR/metabolismoRESUMEN
We identified a novel de novo heterozygous missense mutation in the NEDD4L gene (NM_015277: c.2617G>A; p.Glu873Lys) through whole-exome sequencing in a 3-year-old girl showing severe global developmental delay, infantile spasms, cleft palate, periventricular nodular heterotopia and polymicrogyria. Mutations in the HECT domain of NEDD4L have been reported in patients with a neurodevelopmental disorder along with similar brain malformations. All patients reported with NEDD4L HECT domain mutations showed periventricular nodular heterotopia, and most had seizures, cortex anomalies, cleft palate and syndactyly. The unique constellation of clinical features in patients with NEDD4L mutations might help clinically distinguish them from patients with other genetic mutations including FLNA, which is a well-known causative gene of periventricular nodular heterotopia. Although mutations in the HECT domain of NEDD4L that lead to AKT-mTOR pathway deregulation in forced expression system were reported, our western blot analysis did not show an increased level of AKT-mTOR activity in lymphoblastoid cell lines (LCLs) derived from the patient. In contrast to the forced overexpression system, AKT-mTOR pathway deregulation in LCLs derived from our patient seems to be subtle.
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Fisura del Paladar/diagnóstico , Fisura del Paladar/genética , Mutación Missense , Ubiquitina-Proteína Ligasas Nedd4/genética , Heterotopia Nodular Periventricular/diagnóstico , Heterotopia Nodular Periventricular/genética , Polimicrogiria/diagnóstico , Polimicrogiria/genética , Encéfalo/anomalías , Preescolar , Análisis Mutacional de ADN , Femenino , Estudios de Asociación Genética , Humanos , Imagen por Resonancia Magnética , Dominios Proteicos/genéticaRESUMEN
Bainbridge-Ropers syndrome (BRPS) is characterized by severe developmental delay, feeding problems, short stature, characteristic facal appearance including arched eyebrows and anteverted nares, and ulnar deviation of the hands. BRPS is caused by a heterozygous mutation in the additional sex combs-like 3 (ASXL3) gene. We describe a patient with severe developmental delay, feeding problems, short stature, autism, and sleep disturbance with a heterozygous de novo splicing mutation in the ASXL3 gene. Reported disease-causing mutations in ASXL3 are located mostly in the first half of exon 11, analogous to ASXL1 mutations of which result in Bohring-Opitz syndrome (BOS). Our findings suggest that the expression of the truncated ASXL3 protein, including ASXN and ASXH domains, give rise to BRPS, which is distinct from but overlaps with BOS. © 2016 Wiley Periodicals, Inc.
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Craneosinostosis/genética , Discapacidades del Desarrollo/genética , Discapacidad Intelectual/genética , Factores de Transcripción/genética , Preescolar , Craneosinostosis/complicaciones , Craneosinostosis/fisiopatología , Discapacidades del Desarrollo/complicaciones , Discapacidades del Desarrollo/fisiopatología , Exoma/genética , Femenino , Regulación de la Expresión Génica , Heterocigoto , Humanos , Discapacidad Intelectual/complicaciones , Discapacidad Intelectual/fisiopatología , Mutación , Fenotipo , Empalme del ARN/genéticaRESUMEN
Herein we report on three siblings with Leigh syndrome (LS) harboring a homoplasmic m.3697G>A mutation (G131S) in the MT-ND1 gene. The siblings' phenotypically normal mother had the same, albeit heteroplasmic, mutation. Complex I deficiency (8% of average control values) was demonstrated in a biceps brachii muscle from one of the patients. Heteroplasmic m.3697G>A has been reported in patients with Leber's hereditary optic neuropathy, mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes and Stüve-Wiedemann syndrome. Because all three patients in this series carried m.3697G>A in a homoplasmic manner and had LS, we suggest that homoplasmy of m.3697G>A may cause the LS phenotype.
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ADN Mitocondrial/genética , Enfermedad de Leigh/genética , Mutación , Secuencia de Aminoácidos , Sustitución de Aminoácidos , Encéfalo/patología , Niño , Preescolar , Análisis Mutacional de ADN , Proteínas del Complejo de Cadena de Transporte de Electrón/metabolismo , Activación Enzimática , Femenino , Genotipo , Humanos , Enfermedad de Leigh/diagnóstico , Enfermedad de Leigh/metabolismo , Imagen por Resonancia Magnética , Masculino , Datos de Secuencia Molecular , NADH Deshidrogenasa/genética , Fenotipo , HermanosRESUMEN
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.
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Encefalopatías/genética , Colágeno Tipo IV/genética , Hemiplejía/genética , Malformaciones del Desarrollo Cortical/genética , Mutación/genética , Fenotipo , Anemia Hemolítica/genética , Anemia Hemolítica/patología , Encefalopatías/patología , Niño , Preescolar , Colágeno Tipo IV/deficiencia , Hemiplejía/patología , Humanos , Lactante , Malformaciones del Desarrollo Cortical/patología , PorencefaliaRESUMEN
We encountered two children with acute encephalopathy associated with unique clinical manifestations. Both the patients had status epilepticus at onset and neuroimaging studies revealed marked brain edema and bilateral thalamic lesions. Although they were treated with steroids and immunoglobulin, their outcomes were very poor. A thermolabile variant of carnitine palmitoyltransferase II and an elevated interleukin-6 level in cerebrospinal fluid were observed in one patient each. The constellation of clinical and neuroimaging findings in our patients is apparently not consistent with any established subtype of acute encephalopathy/encephalitis.
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Edema Encefálico/diagnóstico , Encefalitis/diagnóstico , Núcleos Talámicos/patología , Enfermedad Aguda , Carnitina O-Palmitoiltransferasa/genética , Niño , Encefalitis/genética , Encefalitis/patología , Femenino , Humanos , Lactante , Interleucina-6/líquido cefalorraquídeo , MasculinoRESUMEN
BACKGROUND: Vici syndrome (VICIS) is a congenital disorder characterized by agenesis of the corpus callosum, cataracts, hypopigmentation, cardiomyopathy, combined immunodeficiency, microcephaly, and failure to thrive. This study aimed to elucidate the number of patients with VICIS, its clinical characteristics and relevant genetic information in Japan. METHODS: After developing diagnostic criteria for VICIS, we conducted a nationwide questionnaire-based survey of VICIS in Japan. In the initial survey, we investigated the number of VICIS patients who fulfilled definite or probable criteria. The second survey was used to obtain detailed clinical and genetic information of VICIS from institutions that responded to the initial survey. RESULTS: Clinical information was available for 15 patients (12 definite, three probable). As of October 2023, nine patients (60%) were alive and six (40%) had died. All patients presented with developmental delay, agenesis of the corpus callosum, elevated serum aspartate/alanine aminotransferase, hypopigmentation and hypotonia. Developmental delay was profound. Most patients developed recurrent infection, high-arched palate, epilepsy, failure to thrive, and microcephaly. Cardiomyopathy and cataracts, both initially described as principal features in VICIS, were notably uncommon in our study. Based on the information collected, all 14 patients for whom information was available received home medical care: 11 (79%) received tube feeding, three (21%) required noninvasive ventilation, four (29%) required tracheostomy, and four (29%) required home subcutaneous immunoglobulin administration. CONCLUSION: This study revealed for the first time the nationwide status of patients with VICIS in Japan. The mortality rate of patients with VICIS is as high as 40%, and almost all VICIS patients require various forms of home medical care, necessitating comprehensive management. Additionally, we identified one adult patient, underscoring the need for comprehensive medical management extending into adulthood for patients with VICIS.
RESUMEN
Angelman syndrome (AS) is a severe neurodevelopmental disorder caused by the loss of function of maternal UBE3A. The major cause of AS is a maternal deletion in 15q11.2-q13 and the minor causes are a UBE3A mutation, uniparental disomy (UPD) and imprinting defect (ID). Previous reports suggest that all patients with AS exhibit developmental delay, movement or balance disorders, behavioral characteristics and speech impairment. In contrast, a substantial number of AS patients with a UBE3A mutation, UPD or ID were reported not to show these consistent features and to show age dependent change of their features. In this study, we investigated 134 patients with AS, including 57 patients with a UBE3A mutation and 48 patients with UPD or ID. Although developmental delay was present in all patients, 20% of patients with AS caused by UPD or ID did not exhibit movement or balance disorders. Differences were also seen in hypopigmentation and seizures, depending on the causes. Moreover, patients with a UBE3A mutation, UPD or ID tended to show fewer of the specific phenotypes depending on their age. Especially, in patients with UPD or ID, easily-provoked laughter and hyperactivity tended to become more pronounced as they aged. Therefore, the clinical features of AS based on cause and age should be understood and genetic testing should not be limited to patients with the typical clinical features of AS.