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1.
Am J Hum Genet ; 110(1): 120-145, 2023 01 05.
Artículo en Inglés | MEDLINE | ID: mdl-36528028

RESUMEN

Eukaryotic initiation factor-4A2 (EIF4A2) is an ATP-dependent RNA helicase and a member of the DEAD-box protein family that recognizes the 5' cap structure of mRNAs, allows mRNA to bind to the ribosome, and plays an important role in microRNA-regulated gene repression. Here, we report on 15 individuals from 14 families presenting with global developmental delay, intellectual disability, hypotonia, epilepsy, and structural brain anomalies, all of whom have extremely rare de novo mono-allelic or inherited bi-allelic variants in EIF4A2. Neurodegeneration was predominantly reported in individuals with bi-allelic variants. Molecular modeling predicts these variants would perturb structural interactions in key protein domains. To determine the pathogenicity of the EIF4A2 variants in vivo, we examined the mono-allelic variants in Drosophila melanogaster (fruit fly) and identified variant-specific behavioral and developmental defects. The fruit fly homolog of EIF4A2 is eIF4A, a negative regulator of decapentaplegic (dpp) signaling that regulates embryo patterning, eye and wing morphogenesis, and stem cell identity determination. Our loss-of-function (LOF) rescue assay demonstrated a pupal lethality phenotype induced by loss of eIF4A, which was fully rescued with human EIF4A2 wild-type (WT) cDNA expression. In comparison, the EIF4A2 variant cDNAs failed or incompletely rescued the lethality. Overall, our findings reveal that EIF4A2 variants cause a genetic neurodevelopmental syndrome with both LOF and gain of function as underlying mechanisms.


Asunto(s)
Proteínas de Drosophila , Epilepsia , Discapacidad Intelectual , Trastornos del Neurodesarrollo , Animales , Humanos , Drosophila/genética , Drosophila melanogaster/genética , Drosophila melanogaster/metabolismo , Proteínas de Drosophila/genética , Epilepsia/genética , Factor 4A Eucariótico de Iniciación/genética , Discapacidad Intelectual/genética , Hipotonía Muscular/genética , Trastornos del Neurodesarrollo/genética , ARN Mensajero/genética , ARN Mensajero/metabolismo
2.
Nat Chem Biol ; 18(1): 91-100, 2022 01.
Artículo en Inglés | MEDLINE | ID: mdl-34931062

RESUMEN

Glutathione peroxidase 4 (GPX4), as the only enzyme in mammals capable of reducing esterified phospholipid hydroperoxides within a cellular context, protects cells from ferroptosis. We identified a homozygous point mutation in the GPX4 gene, resulting in an R152H coding mutation, in three patients with Sedaghatian-type spondylometaphyseal dysplasia. Using structure-based analyses and cell models, including patient fibroblasts, of this variant, we found that the missense variant destabilized a critical loop, which disrupted the active site and caused a substantial loss of enzymatic function. We also found that the R152H variant of GPX4 is less susceptible to degradation, revealing the degradation mechanism of the GPX4 protein. Proof-of-concept therapeutic treatments, which overcome the impaired R152H GPX4 activity, including selenium supplementation, selective antioxidants and a deuterated polyunsaturated fatty acid were identified. In addition to revealing a general approach to investigating rare genetic diseases, we demonstrate the biochemical foundations of therapeutic strategies targeting GPX4.


Asunto(s)
Fosfolípido Hidroperóxido Glutatión Peroxidasa/genética , Medicina de Precisión , Humanos , Mutación Puntual , Prueba de Estudio Conceptual
3.
Epilepsia ; 2024 Jul 02.
Artículo en Inglés | MEDLINE | ID: mdl-38953796

RESUMEN

OBJECTIVE: DYNC1H1 variants are involved on a disease spectrum from neuromuscular disorders to neurodevelopmental disorders. DYNC1H1-related epilepsy has been reported in small cohorts. We dissect the electroclinical features of 34 patients harboring de novo DYNC1H1 pathogenic variants, identify subphenotypes on the DYNC1H1-related epilepsy spectrum, and compare the genotype-phenotype correlations observed in our cohort with the literature. METHODS: Patients harboring de novo DYNC1H1 pathogenic variants were recruited through international collaborations. Clinical data were retrospectively collected. Latent class analysis was performed to identify subphenotypes. Multivariable binary logistic regression analysis was applied to investigate the association with DYNC1H1 protein domains. RESULTS: DYNC1H1-related epilepsy presented with infantile epileptic spasms syndrome (IESS) in 17 subjects (50%), and in 25% of these individuals the epileptic phenotype evolved into Lennox-Gastaut syndrome (LGS). In 12 patients (35%), focal onset epilepsy was defined. In two patients, the epileptic phenotype consisted of generalized myoclonic epilepsy, with a progressive phenotype in one individual harboring a frameshift variant. In approximately 60% of our cohort, seizures were drug-resistant. Malformations of cortical development were noticed in 79% of our patients, mostly on the lissencephaly-pachygyria spectrum, particularly with posterior predominance in a half of them. Midline and infratentorial abnormalities were additionally reported in 45% and 27% of subjects. We have identified three main classes of subphenotypes on the DYNC1H1-related epilepsy spectrum. SIGNIFICANCE: We propose a classification in which pathogenic de novo DYNC1H1 variants feature drug-resistant IESS in half of cases with potential evolution to LGS (Class 1), developmental and epileptic encephalopathy other than IESS and LGS (Class 2), or less severe focal or genetic generalized epilepsy including a progressive phenotype (Class 3). We observed an association between stalk domain variants and Class 1 phenotypes. The variants p.Arg309His and p.Arg1962His were common and associated with Class 1 subphenotype in our cohort. These findings may aid genetic counseling of patients with DYNC1H1-related epilepsy.

4.
Brain ; 145(3): 925-938, 2022 04 29.
Artículo en Inglés | MEDLINE | ID: mdl-35355055

RESUMEN

Focal malformations of cortical development including focal cortical dysplasia, hemimegalencephaly and megalencephaly, are a spectrum of neurodevelopmental disorders associated with brain overgrowth, cellular and architectural dysplasia, intractable epilepsy, autism and intellectual disability. Importantly, focal cortical dysplasia is the most common cause of focal intractable paediatric epilepsy. Gain and loss of function variants in the PI3K-AKT-MTOR pathway have been identified in this spectrum, with variable levels of mosaicism and tissue distribution. In this study, we performed deep molecular profiling of common PI3K-AKT-MTOR pathway variants in surgically resected tissues using droplet digital polymerase chain reaction (ddPCR), combined with analysis of key phenotype data. A total of 159 samples, including 124 brain tissue samples, were collected from 58 children with focal malformations of cortical development. We designed an ultra-sensitive and highly targeted molecular diagnostic panel using ddPCR for six mutational hotspots in three PI3K-AKT-MTOR pathway genes, namely PIK3CA (p.E542K, p.E545K, p.H1047R), AKT3 (p.E17K) and MTOR (p.S2215F, p.S2215Y). We quantified the level of mosaicism across all samples and correlated genotypes with key clinical, neuroimaging and histopathological data. Pathogenic variants were identified in 17 individuals, with an overall molecular solve rate of 29.31%. Variant allele fractions ranged from 0.14 to 22.67% across all mutation-positive samples. Our data show that pathogenic MTOR variants are mostly associated with focal cortical dysplasia, whereas pathogenic PIK3CA variants are more frequent in hemimegalencephaly. Further, the presence of one of these hotspot mutations correlated with earlier onset of epilepsy. However, levels of mosaicism did not correlate with the severity of the cortical malformation by neuroimaging or histopathology. Importantly, we could not identify these mutational hotspots in other types of surgically resected epileptic lesions (e.g. polymicrogyria or mesial temporal sclerosis) suggesting that PI3K-AKT-MTOR mutations are specifically causal in the focal cortical dysplasia-hemimegalencephaly spectrum. Finally, our data suggest that ultra-sensitive molecular profiling of the most common PI3K-AKT-MTOR mutations by targeted sequencing droplet digital polymerase chain reaction is an effective molecular approach for these disorders with a good diagnostic yield when paired with neuroimaging and histopathology.


Asunto(s)
Epilepsia Refractaria , Epilepsia , Hemimegalencefalia , Malformaciones del Desarrollo Cortical , Encéfalo/patología , Niño , Fosfatidilinositol 3-Quinasa Clase I/genética , Fosfatidilinositol 3-Quinasa Clase I/metabolismo , Epilepsia Refractaria/metabolismo , Epilepsia/genética , Hemimegalencefalia/genética , Hemimegalencefalia/metabolismo , Hemimegalencefalia/patología , Humanos , Malformaciones del Desarrollo Cortical/diagnóstico por imagen , Malformaciones del Desarrollo Cortical/genética , Mutación , Fosfatidilinositol 3-Quinasas/genética , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/genética , Serina-Treonina Quinasas TOR/genética , Serina-Treonina Quinasas TOR/metabolismo
5.
Mol Genet Metab ; 136(2): 125-131, 2022 06.
Artículo en Inglés | MEDLINE | ID: mdl-35606253

RESUMEN

OBJECTIVE: To harmonize terminology in mitochondrial medicine, we propose revised clinical criteria for primary mitochondrial syndromes. METHODS: The North American Mitochondrial Disease Consortium (NAMDC) established a Diagnostic Criteria Committee comprised of members with diverse expertise. It included clinicians, researchers, diagnostic laboratory directors, statisticians, and data managers. The Committee conducted a comprehensive literature review, an evaluation of current clinical practices and diagnostic modalities, surveys, and teleconferences to reach consensus on syndrome definitions for mitochondrial diseases. The criteria were refined after manual application to patients enrolled in the NAMDC Registry. RESULTS: By building upon published diagnostic criteria and integrating recent advances, NAMDC has generated updated consensus criteria for the clinical definition of classical mitochondrial syndromes. CONCLUSIONS: Mitochondrial diseases are clinically, biochemically, and genetically heterogeneous and therefore challenging to classify and diagnose. To harmonize terminology, we propose revised criteria for the clinical definition of mitochondrial disorders. These criteria are expected to standardize the diagnosis and categorization of mitochondrial diseases, which will facilitate future natural history studies and clinical trials.


Asunto(s)
Enfermedades Mitocondriales , Consenso , Humanos , Enfermedades Mitocondriales/diagnóstico , América del Norte , Sistema de Registros , Síndrome
6.
Epilepsia ; 63(7): 1748-1760, 2022 07.
Artículo en Inglés | MEDLINE | ID: mdl-35441706

RESUMEN

OBJECTIVE: This study was undertaken to evaluate efficacy and long-term safety of triheptanoin in patients >1 year old, not on a ketogenic diet, with drug-resistant seizures associated with glucose transporter 1 deficiency syndrome (Glut1DS). METHODS: UX007G-CL201 was a randomized, double-blind, placebo-controlled trial. Following a 6-week baseline period, eligible patients were randomized 3:1 to triheptanoin or placebo. Dosing was titrated to 35% of total daily calories over 2 weeks. After an 8-week placebo-controlled period, all patients received open-label triheptanoin through Week 52. RESULTS: The study included 36 patients (15 children, 13 adolescents, eight adults). A median 12.6% reduction in overall seizure frequency was observed in the triheptanoin arm relative to baseline, and a 13.5% difference was observed relative to placebo (p = .58). In patients with absence seizures only (n = 9), a median 62.2% reduction in seizure frequency was observed in the triheptanoin arm relative to baseline. Only one patient with absence seizures only was present in the control group, preventing comparison. No statistically significant differences in seizure frequency were observed. Common treatment-emergent adverse events included diarrhea, vomiting, abdominal pain, and nausea, mostly mild or moderate in severity. No serious adverse events were considered to be treatment related. One patient discontinued due to status epilepticus. SIGNIFICANCE: Triheptanoin did not significantly reduce seizure frequency in patients with Glut1DS not on the ketogenic diet. Treatment was associated with mild to moderate gastrointestinal treatment-related events; most resolved following dose reduction or interruption and/or medication for treatment. Triheptanoin was not associated with any long-term safety concerns when administered at dose levels up to 35% of total daily caloric intake for up to 1 year.


Asunto(s)
Epilepsia Refractaria , Epilepsia Tipo Ausencia , Triglicéridos , Adolescente , Adulto , Anticonvulsivantes/uso terapéutico , Errores Innatos del Metabolismo de los Carbohidratos , Niño , Método Doble Ciego , Epilepsia Refractaria/tratamiento farmacológico , Quimioterapia Combinada , Epilepsia Tipo Ausencia/tratamiento farmacológico , Transportador de Glucosa de Tipo 1/genética , Humanos , Proteínas de Transporte de Monosacáridos/deficiencia , Convulsiones/tratamiento farmacológico , Resultado del Tratamiento , Triglicéridos/uso terapéutico
8.
Am J Med Genet A ; 185(9): 2690-2718, 2021 09.
Artículo en Inglés | MEDLINE | ID: mdl-33205886

RESUMEN

Twins have an increased risk for congenital malformations and disruptions, including defects in brain morphogenesis. We analyzed data on brain imaging, zygosity, sex, and fetal demise in 56 proband twins and 7 less affected co-twins with abnormal brain imaging and compared them to population-based data and to a literature series. We separated our series into malformations of cortical development (MCD, N = 39), cerebellar malformations without MCD (N = 13), and brain disruptions (N = 11). The MCD group included 37/39 (95%) with polymicrogyria (PMG), 8/39 (21%) with pia-ependymal clefts (schizencephaly), and 15/39 (38%) with periventricular nodular heterotopia (PNH) including 2 with PNH but not PMG. Cerebellar malformations were found in 19 individuals including 13 with a cerebellar malformation only and another 6 with cerebellar malformation and MCD. The pattern varied from diffuse cerebellar hypoplasia to classic Dandy-Walker malformation. Brain disruptions were seen in 11 individuals with hydranencephaly, porencephaly, or white matter loss without cysts. Our series included an expected statistically significant excess of monozygotic (MZ) twin pairs (22/41 MZ, 54%) compared to population data (482/1448 MZ, 33.3%; p = .0110), and an unexpected statistically significant excess of dizygotic (DZ) twins (19/41, 46%) compared to the literature cohort (1/46 DZ, 2%; p < .0001. Recurrent association with twin-twin transfusion syndrome, intrauterine growth retardation, and other prenatal factors support disruption of vascular perfusion as the most likely unifying cause.


Asunto(s)
Encéfalo/anomalías , Encéfalo/patología , Enfermedades en Gemelos/patología , Gemelos Dicigóticos/genética , Gemelos Monocigóticos/genética , Adulto , Enfermedades en Gemelos/genética , Femenino , Humanos , Recién Nacido , Masculino , Embarazo , Literatura de Revisión como Asunto
9.
Epilepsy Behav ; 124: 108298, 2021 Sep 16.
Artículo en Inglés | MEDLINE | ID: mdl-34537627

RESUMEN

OBJECTIVE: Our purpose was to characterize neuropsychological evaluation (NP) outcome following functional hemispherectomy in a large, representative cohort of pediatric patients. METHODS: We evaluated seizure and NP outcomes and medical variables for all post-hemispherectomy patients from Seattle Children's Hospital epilepsy surgery program between 1996 and 2020. Neuropsychological evaluation outcome tests used were not available on all patients due to the diversity of patient ages and competency that is typical of a representative pediatric cohort; all patients had at least an adaptive functioning or intelligence measure, and a subgroup had memory testing. RESULTS: A total of 71 hemispherectomy patients (37 right; 34 females) yielded 66 with both preoperative (PREOP) plus postoperative (POSTOP) NPs and 5 with POSTOP only. Median surgery age was 5.7 (IQR 2-9.9) years. Engel classification indicated excellent seizure outcomes: 59 (84%) Class I, 6 (8%) Class II, 5 (7%) Class III, and 1 (1%) Class IV. Medical variables - including seizure etiology, surgery age, side, presurgical seizure duration, unilateral or bilateral structural abnormalities, secondarily generalized motor seizures - were not associated with either Engel class or POSTOP NP scores, though considerable heterogeneity was evident. Median PREOP and POSTOP adaptive functioning (PREOP n = 45, POSTOP n = 48) and intelligence (PREOP n = 29, POSTOP n = 36) summary scores were exceptionally low and did not reveal group decline from PREOP to POSTOP. Fifty-five of 66 (85%) cases showed stability or improvement. Specifically, 5 (8%) improved; 50 (76%) showed stability; and 11 (16%) declined. Improve and decline groups showed clinically interesting, but not statistical, differences in seizure control and age. Median memory summary scores were low and also showed considerable heterogeneity. Overall median PREOP to POSTOP memory scores (PREOP n = 16, POSTOP n = 24) did not reveal declines, and verbal memory scores improved. Twenty six percent of intelligence and 33% of memory tests had verbal versus visual-spatial discrepancies; all but one favored verbal, regardless of hemispherectomy side. SIGNIFICANCE: This large, single institution study revealed excellent seizure outcome in 91% of all 71 patients plus stability and/or improvement of intelligence and adaptive functioning in 85% of 66 patients who had PREOP plus POSTOP NPs. Memory was similarly stable overall, and verbal memory improved. Medical variables did not predict group NP outcomes though heterogeneity argues for further research. This study is unique for cohort size, intelligence plus memory testing, and evidence of primacy of verbal over visual-spatial development, despite hemispherectomy side. This study reinforces the role of hemispherectomy in achieving good seizure outcome while preserving functioning.

10.
Mol Genet Metab ; 129(3): 236-242, 2020 03.
Artículo en Inglés | MEDLINE | ID: mdl-31917109

RESUMEN

Disorders of the white matter are genetically very heterogeneous including several genes involved in mitochondrial bioenergetics. Diagnosis of the underlying cause is aided by pattern recognition on neuroimaging and by next-generation sequencing. Recently, genetic changes in the complex I assembly factor NUBPL have been characterized by a consistent recognizable pattern of leukoencephalopathy affecting deep white matter including the corpus callosum and cerebellum. Here, we report twin boys with biallelic variants in NUBPL, an unreported c.351 G > A; p.(Met117Ile) and a previously reported pathological variant c. 693 + 1 G > A. Brain magnetic resonance imaging showed abnormal T2 hyperintense signal involving the periventricular white matter, external capsule, corpus callosum, and, prominently, the bilateral thalami. The neuroimaging pattern evolved over 18 months with marked diffuse white matter signal abnormality, volume loss, and new areas of signal abnormality in the cerebellar folia and vermis. Magnetic resonance spectroscopy showed elevated lactate. Functional studies in cultured fibroblasts confirmed pathogenicity of the genetic variants. Complex I activity of the respiratory chain was deficient spectrophotometrically and on blue native gel with in-gel activity staining. There was absent assembly and loss of proteins of the matrix arm of complex I when traced with an antibody to NDUFS2, and incomplete assembly of the membrane arm when traced with an NDUFB6 antibody. There was decreased NUBPL protein on Western blot in patient fibroblasts compared to controls. Compromised NUBPL activity impairs assembly of the matrix arm of complex I and produces a severe, rapidly-progressive leukoencephalopathy with thalamic involvement on MRI, further expanding the neuroimaging phenotype.


Asunto(s)
Enfermedades en Gemelos/genética , Complejo I de Transporte de Electrón/metabolismo , Leucoencefalopatías/genética , Mitocondrias/metabolismo , Proteínas Mitocondriales/genética , Tálamo/diagnóstico por imagen , Línea Celular , Cuerpo Calloso/diagnóstico por imagen , Cuerpo Calloso/patología , Enfermedades en Gemelos/diagnóstico por imagen , Enfermedades en Gemelos/metabolismo , Enfermedades en Gemelos/fisiopatología , Complejo I de Transporte de Electrón/deficiencia , Complejo I de Transporte de Electrón/genética , Cápsula Externa/diagnóstico por imagen , Cápsula Externa/patología , Ojo/fisiopatología , Fibroblastos/metabolismo , Humanos , Lactante , Ácido Láctico/metabolismo , Leucoencefalopatías/diagnóstico por imagen , Leucoencefalopatías/metabolismo , Leucoencefalopatías/fisiopatología , Imagen por Resonancia Magnética , Espectroscopía de Resonancia Magnética , Masculino , Mitocondrias/genética , Proteínas Mitocondriales/metabolismo , Mutación , NADH Deshidrogenasa/metabolismo , Gemelos Monocigóticos/genética , Sustancia Blanca/diagnóstico por imagen , Sustancia Blanca/patología , Secuenciación del Exoma
11.
Epilepsy Behav ; 97: 44-50, 2019 08.
Artículo en Inglés | MEDLINE | ID: mdl-31181428

RESUMEN

RATIONALE: Early-life epilepsies (ELEs) include some of the most challenging forms of epilepsy to manage. Given recent diagnostic and therapeutic advances, a contemporary assessment of the immediate short-term outcomes can provide a valuable framework for identifying priorities and benchmarks for evaluating quality improvement efforts. METHODS: Children with newly diagnosed epilepsy and onset <3 years were prospectively recruited through 17 US hospitals, from 2012 to 2015 and followed for 1 year after diagnosis. Short-term outcome included mortality, drug resistance, evolution of nonsyndromic epilepsy to infantile spasms (IS) and from IS to other epilepsies, and developmental decline. Multivariable analyses assessed the risk of each outcome. RESULTS: Seven hundred seventy-five children were recruited, including 408 (53%) boys. Median age at onset was 7.5 months (interquartile range (IQR): 4.2-16.5), and 509 (66%) had onset in the first year of life. Of 22 deaths that occurred within one year of epilepsy diagnosis, 21 were children with epilepsy onset in infancy (<12 months). Of 680 children followed ≥6 months, 239 (35%) developed drug-resistant seizures; 34/227 (15%) infants with nonsyndromic epilepsy developed IS, and 48/210 (23%) initially presenting with IS developed additional seizure types. One hundred of 435 (23%) with initially typical development or only mild/equivocal delays at seizure onset, had clear developmental impairment within one year after initial diagnosis. Each outcome had a different set of predictors; however, younger age and impaired development at seizure onset were broadly indicative of poorer outcomes. Type of epilepsy and early identification of underlying cause were not reliable predictors of these outcomes. CONCLUSION: Early-life epilepsies carry a high risk of poor outcome which is evident shortly after epilepsy diagnosis. Onset in infancy and developmental delay is associated with an especially high risk, regardless of epilepsy type. The likelihood of poor outcomes is worrisome regardless of specific clinical profiles.


Asunto(s)
Discapacidades del Desarrollo/etiología , Espasmos Infantiles , Anticonvulsivantes/uso terapéutico , Preescolar , Resistencia a Medicamentos , Femenino , Humanos , Lactante , Masculino , Análisis Multivariante , Pronóstico , Estudios Prospectivos , Convulsiones/complicaciones , Convulsiones/tratamiento farmacológico , Espasmos Infantiles/complicaciones , Espasmos Infantiles/tratamiento farmacológico
12.
Am J Med Genet A ; 176(5): 1232-1237, 2018 05.
Artículo en Inglés | MEDLINE | ID: mdl-29681094

RESUMEN

Animal studies have demonstrated the critical roles of the patatin-like protein family plays in cellular growth, lipid homeostasis, and second messenger signaling the nervous system. Of the nine known calcium-independent phospholipase A2γ, only PNPLA2, PNLPA6, PNPLA9 and most recently a single patient with PNPLA8 are associated with mitochondrial-related neurodegeneration. Using whole exome sequencing, we report two unrelated individuals with variable but similar clinical features of microcephaly, severe global developmental delay, spasticity, lactic acidosis, and progressive cerebellar atrophy with biallelic loss-of-function variants in PNPLA8.


Asunto(s)
Alelos , Mutación con Pérdida de Función , Enfermedades Mitocondriales/diagnóstico , Enfermedades Mitocondriales/genética , Enfermedades Neurodegenerativas/diagnóstico , Enfermedades Neurodegenerativas/genética , Fenotipo , Fosfolipasas A2 Calcio-Independiente/genética , Sustitución de Aminoácidos , Encéfalo/anomalías , Encéfalo/diagnóstico por imagen , Preescolar , Análisis Mutacional de ADN , Femenino , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Genotipo , Humanos , Linaje
13.
Epilepsy Behav ; 88: 235-243, 2018 11.
Artículo en Inglés | MEDLINE | ID: mdl-30316150

RESUMEN

INTRODUCTION: This retrospective descriptive study was undertaken to further define the intelligence profiles of children with mitochondrial disorders, in the context of seizures and age of symptom onset. METHODS: We retrospectively identified forty-nine pediatric patients with definitive mitochondrial disease diagnoses and complete intelligence or adaptive functioning testing data. Patients were 0-216 months at onset of symptoms and 61-250 months of age at testing. Twenty-four of 49 patients had seizures. Twenty-one of the 24 patients with seizures had medically intractable seizures. All patients had Wechsler Intellectual Quotient (IQ) testing, except nine patients with seizures who were unable to engage in IQ testing and were assessed with a structured parent interview measure, the Vineland Adaptive Behavior Scales. We used descriptive and exploratory data analysis methods to characterize test results. RESULTS: Distribution of ages for patients with the Vineland assessment was younger than those given the Wechsler. The median overall score (combining Wechsler and Vineland summary scores) for all patients was 85 (interquartile range [IQR]: 50, 102), with the group without seizures obtaining a higher median Full Scale IQ (FSIQ) of 100 (IQR: 86, 109), compared to the group with seizures with a median FSIQ of 67 (IQR: 49.5, 89), a difference that is both statistically and clinically different (Δ = 33; 95% CI: 9, 52). The adaptive function measure was composed of patients only with intractable epilepsy and yielded the lowest overall median summary score of 43 (IQR: 37, 50). This general trend in differences between the FSIQ scores of the groups with and without seizures was also seen across all subscale measures analyzed-IQ index scores and two subtest scores, Digit Span and Coding-though differences were not always statistically different. Vargha-Delaney's A effect sizes ranged between 0.68 and 0.90, trends that mirrored those of distributional and median differences. Groups without versus with seizures differed most distinctly in Performance IQ (PIQ), with the group without seizures' median PIQ being 100 (IQR 94, 112) versus the group with seizures' median PIQ being 63 (IQR 54, 84), a difference of 37 points (95% CI). DISCUSSION: Results suggest that patients with mitochondrial diseases with seizures and early onset disease represent a worse cognitive phenotype, as compared with those with no seizures, who can have average intelligence. Results are discussed in the context of current literature.


Asunto(s)
Trastornos del Conocimiento/epidemiología , Trastornos del Conocimiento/psicología , Enfermedades Mitocondriales/epidemiología , Enfermedades Mitocondriales/psicología , Convulsiones/epidemiología , Convulsiones/psicología , Adolescente , Niño , Preescolar , Cognición/fisiología , Trastornos del Conocimiento/diagnóstico , Femenino , Humanos , Lactante , Recién Nacido , Inteligencia/fisiología , Pruebas de Inteligencia , Masculino , Enfermedades Mitocondriales/diagnóstico , Estudios Retrospectivos , Convulsiones/diagnóstico , Escalas de Wechsler , Adulto Joven
14.
Genet Med ; 19(12)2017 12.
Artículo en Inglés | MEDLINE | ID: mdl-28749475

RESUMEN

The purpose of this statement is to provide consensus-based recommendations for optimal management and care for patients with primary mitochondrial disease. This statement is intended for physicians who are engaged in the diagnosis and management of these patients. Working group members were appointed by the Mitochondrial Medicine Society. The panel included members with several different areas of expertise. The panel members utilized surveys and the Delphi method to reach consensus. We anticipate that this statement will need to be updated as the field continues to evolve. Consensus-based recommendations are provided for the routine care and management of patients with primary genetic mitochondrial disease.


Asunto(s)
Enfermedades Mitocondriales/diagnóstico , Enfermedades Mitocondriales/terapia , Nivel de Atención , Manejo de la Enfermedad , Humanos
15.
Am J Med Genet A ; 173(12): 3127-3131, 2017 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-29048727

RESUMEN

The clinical diagnosis of malformations of cortical development (MCDs) is often challenging due to the complexity of the brain malformation by neuroimaging, the rarity of individual malformation syndromes, and the rapidly evolving genetic landscape of these disorders facilitated with the use of Next Generation Sequencing (NGS) methods. While the clinical and molecular diagnosis of severe cortical malformations, such as classic lissencephaly, is often straightforward, the diagnosis of more subtle and complex types of cortical malformations, such as pachygyria and polymicrogyria (PMG), can be more challenging due to limited knowledge regarding their genetic etiologies. Here, we report two individuals with the same de novo KIF5C mutation who present with subtle MCDs, early onset epilepsy and significant neurodevelopmental and behavioral issues including absent language. Our data, combined with the limited literature on KIF5C mutations, to date, support that KIF5C mutations are associated with a neurodevelopmental disorder characterized by infantile onset epilepsy, and subtle but recognizable types of brain malformations. We also show that the spectrum of KIF5C mutations is narrow, as five out of the six identified individuals have mutations affecting amino acid Glu237. Therefore, the identification of the clinical and neuroimaging features of this disorder may strongly facilitate rapid and efficient molecular diagnosis.


Asunto(s)
Epilepsia/genética , Discapacidad Intelectual/genética , Cinesinas/genética , Malformaciones del Desarrollo Cortical/genética , Trastornos del Neurodesarrollo/genética , Corteza Cerebral/anomalías , Epilepsia/diagnóstico por imagen , Femenino , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Lactante , Discapacidad Intelectual/diagnóstico por imagen , Lenguaje , Lisencefalia/diagnóstico por imagen , Lisencefalia/genética , Masculino , Malformaciones del Desarrollo Cortical/diagnóstico por imagen , Mutación , Trastornos del Neurodesarrollo/diagnóstico por imagen , Polimicrogiria/diagnóstico por imagen , Polimicrogiria/genética
16.
Epilepsia ; 58(12): 2098-2103, 2017 12.
Artículo en Inglés | MEDLINE | ID: mdl-29105055

RESUMEN

OBJECTIVE: The multicenter National Infantile Spasms Consortium prospective cohort was used to compare outcomes and phenotypic features of patients with infantile spasms with and without hypsarrhythmia. METHODS: Patients aged 2 months to 2 years were enrolled prospectively with new-onset infantile spasms. Treatment choice and categorization of hypsarrhythmia were determined clinically at each site. Response to therapy was defined as resolution of clinical spasms (and hypsarrhythmia if present) without relapse 3 months after initiation. RESULTS: Eighty-two percent of patients had hypsarrhythmia, but this was not associated with gender, mean age, preexisting developmental delay or epilepsy, etiology, or response to first-line therapy. Infants with hypsarrhythmia were more likely to receive standard treatment (adrenocorticotropic hormone, prednisolone, or vigabatrin [odds ratio (OR) 2.6, 95% confidence interval (CI) 1.4-4.7] and preexisting epilepsy reduced the likelihood of standard treatment (OR 3.2, 95% CI 1.9-5.4). Hypsarrhythmia was not a determinant of response to treatment. A logistic regression model demonstrated that later age of onset (OR 1.09 per month, 95% CI 1.03-1.15) and absence of preexisting epilepsy (OR 1.7, 95% CI 1.06-2.81) had a small impact on the likelihood of responding to the first-line treatment. However, receiving standard first-line treatment increased the likelihood of responding dramatically: vigabatrin (OR 5.2 ,95% CI 2-13.7), prednisolone (OR 8, 95% CI 3.1-20.6), and adrenocorticotropic hormone (ACTH; OR 10.2, 95% CI 4.1-25.8) . SIGNIFICANCE: First-line treatment with standard therapy was by far the most important variable in determining likelihood of response to treatment of infantile spasms with or without hypsarrhythmia.


Asunto(s)
Espasmos Infantiles/terapia , Hormona Adrenocorticotrópica/uso terapéutico , Edad de Inicio , Anticonvulsivantes/uso terapéutico , Estudios de Cohortes , Femenino , Humanos , Lactante , Masculino , Prednisolona/uso terapéutico , Cobertura de Afecciones Preexistentes , Estudios Prospectivos , Factores Sexuales , Espasmos Infantiles/fisiopatología , Resultado del Tratamiento , Vigabatrin/uso terapéutico
18.
Epilepsy Behav ; 70(Pt B): 328-333, 2017 05.
Artículo en Inglés | MEDLINE | ID: mdl-28254350

RESUMEN

The widespread patient use of artisanal cannabis preparations has preceded quality validation of cannabis use for epilepsy. Neurologists and cannabinoid specialists are increasingly in a position to monitor and guide the use of herbal cannabis in epilepsy patients. We report the retrospective data on efficacy and adverse effects of artisanal cannabis in Patients with medically refractory epilepsy with mixed etiologies in Washington State, California, and Maine. Clinical considerations, including potential risks and benefits, challenges related to artisanal preparations, and cannabinoid dosing, are discussed. RESULTS: Of 272 combined patients from Washington State and California, 37 (14%) found cannabis ineffective at reducing seizures, 29 (15%) experienced a 1-25% reduction in seizures, 60 (18%) experienced a 26-50% reduction in seizures, 45 (17%) experienced a 51-75% reduction in seizures, 75 (28%) experienced a 76-99% reduction in seizures, and 26 (10%) experienced a complete clinical response. Overall, adverse effects were mild and infrequent, and beneficial side effects such as increased alertness were reported. The majority of patients used cannabidiol (CBD)-enriched artisanal formulas, some with the addition of delta-9-tetrahydrocannabinol (THC) and tetrahydrocannabinolic acid (THCA). Four case reports are included that illustrate clinical responses at doses <0.1mg/kg/day, biphasic dose-response effects, the use of THCA for seizure prevention, the use of THC for seizure rescue, and the synergy of cannabinoids and terpenoids in artisanal preparations. This article is part of a Special Issue entitled "Cannabinoids and Epilepsy".


Asunto(s)
Cannabinoides/uso terapéutico , Cannabis , Epilepsia Refractaria/diagnóstico , Epilepsia Refractaria/tratamiento farmacológico , Marihuana Medicinal/uso terapéutico , Adolescente , California/epidemiología , Niño , Preescolar , Dronabinol/uso terapéutico , Epilepsia Refractaria/epidemiología , Femenino , Humanos , Lactante , Masculino , Estudios Retrospectivos , Resultado del Tratamiento , Estados Unidos/epidemiología , Washingtón/epidemiología
19.
Mol Genet Metab ; 118(3): 178-184, 2016 07.
Artículo en Inglés | MEDLINE | ID: mdl-27312126

RESUMEN

Solid organ transplants are rarely performed in both adult and pediatric patients with primary mitochondrial disease. Poor outcomes have been described in case reports and small case series. It is unclear whether the underlying genetic disease has a significant impact on post-transplant morbidity and mortality. Data were obtained for 35 patients from 17 Mitochondrial Disease Centers across North America, the United Kingdom and Australia. Patient outcomes were noted after liver, kidney or heart transplantation. Excluding patients with POLG-related disease, post-transplant survival approached or met outcomes seen in non-mitochondrial disease transplant patients. The majority of mitochondrial disease patients did not have worsening of their mitochondrial disease within 90-days post-transplant. Post-transplant complications, including organ rejection, were not a common occurrence and were generally treatable. Many patients did not have a mitochondrial disease considered or diagnosed prior to transplantation. In conclusion, patients with mitochondrial disease in this cohort generally tolerated solid-organ transplantation. Such patients may not need to be excluded from transplant solely for their mitochondrial diagnosis; additional caution may be needed for patients with POLG-related disease. Transplant teams should be aware of mitochondrial disease as an etiology for organ-failure and consider appropriate consultation in patients without a known cause of their symptoms.


Asunto(s)
Rechazo de Injerto/epidemiología , Cardiopatías/terapia , Enfermedades Renales/terapia , Hepatopatías/terapia , Enfermedades Mitocondriales/complicaciones , Adolescente , Adulto , Niño , Preescolar , Femenino , Trasplante de Corazón , Humanos , Lactante , Trasplante de Riñón , Trasplante de Hígado , Masculino , Persona de Mediana Edad , Factores de Riesgo , Tasa de Supervivencia , Resultado del Tratamiento , Adulto Joven
20.
Genet Med ; 17(9): 689-701, 2015 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-25503498

RESUMEN

PURPOSE: The purpose of this statement is to review the literature regarding mitochondrial disease and to provide recommendations for optimal diagnosis and treatment. This statement is intended for physicians who are engaged in diagnosing and treating these patients. METHODS: The Writing Group members were appointed by the Mitochondrial Medicine Society. The panel included members with expertise in several different areas. The panel members utilized a comprehensive review of the literature, surveys, and the Delphi method to reach consensus. We anticipate that this statement will need to be updated as the field continues to evolve. RESULTS: Consensus-based recommendations are provided for the diagnosis and treatment of mitochondrial disease. CONCLUSION: The Delphi process enabled the formation of consensus-based recommendations. We hope that these recommendations will help standardize the evaluation, diagnosis, and care of patients with suspected or demonstrated mitochondrial disease.


Asunto(s)
Enfermedades Mitocondriales/diagnóstico , Enfermedades Mitocondriales/terapia , Consenso , Técnica Delphi , Medicina Basada en la Evidencia , Humanos , Resultado del Tratamiento
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