RESUMEN
Treatment-resistant epilepsy is among the most serious complications of cardiofaciocutaneous syndrome (CFCS), a rare disorder caused by germline variants in the RAS-MAPK signaling pathway. This study analyzed the clinical characteristics of epilepsy and response to anti-seizure medications (ASMs) in a multinational CFCS cohort. A caregiver survey provided data regarding seizure history, use of ASMs and other treatment approaches, adverse effects, caregiver perception of treatment response, and neurological disease burden impact among individuals with CFCS. Results from 138 survey responses were quantitatively analyzed in conjunction with molecular genetic results and neurological records. The disease burden impact of CFCS was higher among individuals with epilepsy (n = 74/138), especially those with more severe seizure presentation. Oxcarbazepine, a sodium-channel blocker, had the best seizure control profile with relatively infrequent adverse effects. The most commonly prescribed ASM, levetiracetam, demonstrated comparatively poor seizure control. ASM efficacy was generally similar for individuals with BRAF and MAP2K1 gene variants. The high proportion of patients with CFCS who experienced poor seizure control despite use of multiple ASMs highlights a substantial unmet treatment need. Prospective study of ASM efficacy and clinical trials of therapies to attenuate RAS-MAPK signaling may improve avenues for clinical management.
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Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Displasia Ectodérmica , Epilepsia , Facies , Insuficiencia de Crecimiento , Cardiopatías Congénitas , Humanos , Estudios Prospectivos , Epilepsia/tratamiento farmacológico , Epilepsia/genética , Levetiracetam , Convulsiones/tratamiento farmacológico , Convulsiones/genética , Anticonvulsivantes/uso terapéuticoRESUMEN
Germline pathogenic variants in the RAS/mitogen-activated protein kinase (MAPK) signaling pathway are the molecular cause of RASopathies, a group of clinically overlapping genetic syndromes. RASopathies constitute a wide clinical spectrum characterized by distinct facial features, short stature, predisposition to cancer, and variable anomalies in nearly all the major body systems. With increasing global recognition of these conditions, the 8th International RASopathies Symposium spotlighted global perspectives on clinical care and research, including strategies for building international collaborations and developing diverse patient cohorts in anticipation of interventional trials. This biannual meeting, organized by RASopathies Network, was held in a hybrid virtual/in-person format. The agenda featured emerging discoveries and case findings as well as progress in preclinical and therapeutic pipelines. Stakeholders including basic scientists, clinician-scientists, practitioners, industry representatives, patients, and family advocates gathered to discuss cutting edge science, recognize current gaps in knowledge, and hear from people with RASopathies about the experience of daily living. Presentations by RASopathy self-advocates and early-stage investigators were featured throughout the program to encourage a sustainable, diverse, long-term research and advocacy partnership focused on improving health and bringing treatments to people with RASopathies.
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Síndrome de Costello , Displasia Ectodérmica , Cardiopatías Congénitas , Neoplasias , Síndrome de Noonan , Humanos , Proteínas ras/genética , Sistema de Señalización de MAP Quinasas/genética , Síndrome de Costello/genética , Neoplasias/genética , Displasia Ectodérmica/genética , Síndrome de Noonan/genética , Cardiopatías Congénitas/genéticaRESUMEN
X-linked adrenoleukodystrophy (ALD) is a rare inherited neurological disorder that poses considerable challenges for clinical management throughout the lifespan. Although males are generally more severely affected than females, the time course and presentation of clinical symptoms are otherwise difficult to predict. Opportunities to improve outcomes for individuals with ALD are rapidly expanding due to the introduction of newborn screening programs for this condition and an evolving treatment landscape. The aim of this comprehensive review is to synthesize current knowledge regarding the neurocognitive and mental health effects of ALD. This review provides investigators and clinicians with context to improve case conceptualization, inform prognostic counseling, and optimize neuropsychological and mental health care for patients and their families. Results highlight key predictive factors and brain-behavior relationships associated with the diverse manifestations of ALD. The review also discusses considerations for endpoints within clinical trials and identifies gaps to address in future research.
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Adrenoleucodistrofia , Masculino , Recién Nacido , Femenino , Humanos , Adrenoleucodistrofia/complicaciones , Tamizaje Neonatal/métodos , Longevidad , Salud Mental , EncéfaloRESUMEN
Gene variants that dysregulate signaling through the RAS-MAPK pathway cause cardiofaciocutaneous syndrome (CFCS), a rare multi-system disorder. Infantile epileptic spasms syndrome (IESS) and other forms of epilepsy are among the most serious complications. To investigate clinical presentation, treatment outcomes, and genotype-phenotype associations in CFCS patients with IESS, molecular genetics and clinical neurological history were reviewed across two large clinical research cohorts (n = 180). IESS presented in 18/180 (10%) cases, including 16 patients with BRAF variants and 2 with MAP2K1 variants. Among IESS patients with BRAF variants, 16/16 (100%) had sequence changes affecting the protein kinase domain (exons 11-16), although only 57% of total BRAF variants occurred in this domain. Clinical onset of spasms occurred at a median age of 5.4 months (range: 1-24 months). Among 13/18 patients whose IESS resolved with anti-seizure medications, 10 were treated with ACTH and/or vigabatrin. A substantial majority of CFCS patients with IESS subsequently developed other epilepsy types (16/18; 89%). In terms of neurodevelopmental outcomes, gross motor function and verbal communication were more limited in patients with a history of IESS compared to those without IESS. These findings can inform clinical neurological care guidelines for CFCS and development of relevant pre-clinical models for severe epilepsy phenotypes.
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Epilepsia , Espasmos Infantiles , Humanos , Espasmos Infantiles/genética , Espasmos Infantiles/complicaciones , Espasmos Infantiles/tratamiento farmacológico , Proteínas Proto-Oncogénicas B-raf/genética , Proteínas Proto-Oncogénicas B-raf/uso terapéutico , Epilepsia/genética , Genotipo , Síndrome , Espasmo/complicacionesRESUMEN
PURPOSE: Dysregulation of RAS or its major effector pathway is the molecular mechanism of RASopathies, a group of multisystemic congenital disorders. Neurologic complications are especially challenging in the management of the rare RASopathy cardiofaciocutaneous (CFC) syndrome. This study evaluated clinical neurologic and neurodevelopmental features and their associations with CFC syndrome gene variants. METHODS: A multinational cohort of 138 individuals with CFC syndrome (BRAF = 90, MAP2K1 = 36, MAP2K2 = 10, KRAS = 2) was recruited. Neurologic presentation was captured via clinician review of medical records and caregiver-completed electronic surveys. Validated measures of seizure severity, adaptive function, and gross motor function were obtained. RESULTS: The overall frequency of intellectual disability and seizures was 82% and 55%, respectively. The frequency and severity of seizures was higher among individuals with BRAF or MAP2K1 variants than in those with MAP2K2 variants. A disproportionate incidence of severe, treatment-resistant seizures was observed in patients with variants in the catalytic protein kinase domain of BRAF and at the common p.Y130 site of MAP2K1. Neurodevelopmental outcomes were associated with genotype as well as seizure severity. CONCLUSION: Molecular genetic testing can aid in prediction of epilepsy and neurodevelopmental phenotypes in CFC syndrome. Study results identified potential CFC syndrome-associated variants in the development of relevant animal models for neurologic, neurocognitive, and motor function impairment.
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Cardiopatías Congénitas , Proteínas Proto-Oncogénicas B-raf , Estudios de Cohortes , Displasia Ectodérmica , Facies , Insuficiencia de Crecimiento , Genotipo , Cardiopatías Congénitas/complicaciones , Cardiopatías Congénitas/genética , Humanos , Proteínas Proto-Oncogénicas B-raf/genética , Convulsiones/genéticaRESUMEN
RASopathies are a group of genetic disorders that are caused by genes that affect the canonical Ras/mitogen-activated protein kinase (MAPK) signaling pathway. Despite tremendous progress in understanding the molecular consequences of these genetic anomalies, little movement has been made in translating these findings to the clinic. This year, the seventh International RASopathies Symposium focused on expanding the research knowledge that we have gained over the years to enhance new discoveries in the field, ones that we hope can lead to effective therapeutic treatments. Indeed, for the first time, research efforts are finally being translated to the clinic, with compassionate use of Ras/MAPK pathway inhibitors for the treatment of RASopathies. This biannual meeting, organized by the RASopathies Network, brought together basic scientists, clinicians, clinician scientists, patients, advocates, and their families, as well as representatives from pharmaceutical companies and the National Institutes of Health. A history of RASopathy gene discovery, identification of new disease genes, and the latest research, both at the bench and in the clinic, were discussed.
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Síndrome de Costello , Síndrome de Noonan , Síndrome de Costello/genética , Humanos , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Síndrome de Noonan/genética , Transducción de Señal , Proteínas ras/genética , Proteínas ras/metabolismoRESUMEN
Cobalamin J disease (CblJ) is an ultra-rare autosomal recessive disorder of intracellular cobalamin metabolism associated with combined methylmalonic acidemia and homocystinuria. It is caused by pathogenic variants in ABCD4, which encodes an ATP-binding cassette (ABC) transporter that affects the lysosomal release of cobalamin (Cbl) into the cytoplasm. Only six cases of CblJ have been reported in the literature. Described clinical features include feeding difficulties, failure to thrive, hypotonia, seizures, developmental delay, and hematological abnormalities. Information on clinical outcomes is extremely limited, and no cases of presymptomatic diagnosis have been reported. We describe a now 17-month-old male with CblJ detected by newborn screening and confirmed by biochemical, molecular, and complementation studies. With early detection and initiation of treatment, this patient has remained asymptomatic with normal growth parameters and neurodevelopmental function. To the best of our knowledge, this report represents the first asymptomatic and neurotypical patient with CblJ.
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Transportadoras de Casetes de Unión a ATP/genética , Errores Innatos del Metabolismo de los Aminoácidos/diagnóstico , Errores Innatos del Metabolismo de los Aminoácidos/genética , Deficiencia de Vitamina B 12/diagnóstico , Vitamina B 12/genética , Errores Innatos del Metabolismo de los Aminoácidos/patología , Femenino , Predisposición Genética a la Enfermedad , Homocistinuria/diagnóstico , Homocistinuria/genética , Homocistinuria/patología , Humanos , Lactante , Recién Nacido , Masculino , Ácido Metilmalónico/metabolismo , Mutación/genética , Tamizaje Neonatal , Vitamina B 12/metabolismo , Deficiencia de Vitamina B 12/genética , Deficiencia de Vitamina B 12/patologíaRESUMEN
In the most common variant of childhood cerebral adrenoleukodystrophy (cALD), demyelinating brain lesions are distributed predominately in parieto-occipital white matter. Less frequently, lesions first develop in frontal white matter. This matched cohort study examined whether outcomes after standard treatment with hematopoietic cell transplantation (HCT) differ in patients with early stage frontal lesions as compared to parieto-occipital lesions. Retrospective chart review identified seven pediatric patients with frontal cALD lesions and MRI severity score < 10 who underwent a single HCT at our center between 1990 and 2019. Concurrent MRI, neurocognitive and psychiatric outcomes at last comprehensive follow-up (mean 1.2 years; range 0.5-2.1 years) were compared with a group of seven boys with the parieto-occipital variant matched on pre-HCT MRI severity score. Both groups showed similar rates of transplant complications and radiographic disease advancement. Neurocognitive outcomes were broadly similar, with more frequent working memory deficits among individuals with frontal lesions. Psychiatric problems (hyperactivity, aggression, and atypical behavior) were considerably more common and severe among patients with frontal lesions. Aligned with the critical role of the frontal lobes in emotional and behavioral regulation, functional disruption of self-regulation skills is widely observed among patients with frontal lesions. Comprehensive care for cALD should address needs for psychiatric care and management.
Asunto(s)
Adrenoleucodistrofia/cirugía , Enfermedades Desmielinizantes/etiología , Lóbulo Frontal/patología , Trasplante de Células Madre Hematopoyéticas , Trastornos Mentales/etiología , Sustancia Blanca/patología , Adolescente , Adrenoleucodistrofia/complicaciones , Adrenoleucodistrofia/diagnóstico por imagen , Niño , Preescolar , Enfermedades Desmielinizantes/diagnóstico por imagen , Emociones , Lóbulo Frontal/diagnóstico por imagen , Humanos , Imagen por Resonancia Magnética , Masculino , Trastornos Mentales/diagnóstico por imagen , Pruebas Neuropsicológicas , Estudios Retrospectivos , Índice de Severidad de la Enfermedad , Resultado del Tratamiento , Sustancia Blanca/diagnóstico por imagenRESUMEN
PURPOSE: Abnormalities in cerebrospinal fluid (CSF) have been reported in Hurler syndrome, a fatal neurodegenerative lysosomal disorder. While no biomarker has predicted neurocognitive response to treatment, one of these abnormalities, glycosaminoglycan nonreducing ends (NREs), holds promise to monitor therapeutic efficacy. A trial of intrathecal enzyme replacement therapy (ERT) added to standard treatment enabled tracking of CSF abnormalities, including NREs. We evaluated safety, biomarker response, and neurocognitive correlates of change. METHODS: In addition to intravenous ERT and hematopoietic cell transplantation, patients (N = 24) received intrathecal ERT at four peritransplant time points; CSF was evaluated at each point. Neurocognitive functioning was quantified at baseline, 1 year, and 2 years posttransplant. Changes in CSF biomarkers and neurocognitive function were evaluated for an association. RESULTS: Over treatment, there were significant decreases in CSF opening pressure, biomarkers of disease activity, and markers of inflammation. Percent decrease in NRE from pretreatment to final intrathecal dose posttransplant was positively associated with percent change in neurocognitive score from pretreatment to 2 years posttransplant. CONCLUSION: Intrathecal ERT was safe and, in combination with standard treatment, was associated with reductions in CSF abnormalities. Critically, we report evidence of a link between a biomarker treatment response and neurocognitive outcome in Hurler syndrome.
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Terapia de Reemplazo Enzimático/métodos , Inyecciones Espinales/métodos , Mucopolisacaridosis I/tratamiento farmacológico , Biomarcadores Farmacológicos/líquido cefalorraquídeo , Preescolar , Femenino , Glicosaminoglicanos/análisis , Glicosaminoglicanos/líquido cefalorraquídeo , Trasplante de Células Madre Hematopoyéticas , Humanos , Lactante , Masculino , Mucopolisacaridosis I/fisiopatología , Resultado del TratamientoRESUMEN
While neurofibromatosis type 1 (NF1) and Noonan syndrome (NS) are clinically distinct genetic syndromes, they have overlapping features because they are caused by pathogenic variants in genes encoding molecules within the Ras-mitogen-activated protein kinase signaling pathway. Increased risk for emotional and behavioral challenges has been reported in both children and adults with these syndromes. The current study examined parent-report and self-report measures of emotional functioning among children with NF1 and NS as compared to their unaffected siblings. Parents and children with NS (n = 39), NF1 (n = 39), and their siblings without a genetic condition (n = 32) completed well-validated clinical symptom rating scales. Results from parent questionnaires indicated greater symptomatology on scales measuring internalizing behaviors and symptoms of attention deficit hyperactivity disorder (ADHD) in both syndrome groups as compared with unaffected children. Frequency and severity of emotional and behavioral symptoms were remarkably similar across the two clinical groups. Symptoms of depression and anxiety were higher in children who were also rated as meeting symptom criteria for ADHD. While self-report ratings by children generally correlated with parent ratings, symptom severity was less pronounced. Among unaffected siblings, parent ratings indicated higher than expected levels of anxiety. Study findings may assist with guiding family-based interventions to address emotional challenges.
Asunto(s)
Emociones , Neurofibromatosis 1/diagnóstico , Síndrome de Noonan/diagnóstico , Adolescente , Factores de Edad , Niño , Conducta Infantil , Femenino , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Humanos , Masculino , Neurofibromatosis 1/genética , Síndrome de Noonan/genética , Padres , Fenotipo , Autoinforme , Hermanos , Encuestas y CuestionariosRESUMEN
Minnesota became the fourth state to begin newborn screening (NBS) for X-linked adrenoleukodystrophy (X-ALD) in 2017. As there is limited retrospective data available on NBS for X-ALD, we analyzed Minnesota's NBS results from the first year of screening. C26:0 lysophosphatidylcholine (C26:0-LPC) screening results of 67,836 infants and confirmatory testing (ABCD1 gene and serum VLCFA analysis) for screen positives were obtained. Fourteen infants (nine males, five females) screened positive for X-ALD and all were subsequently confirmed to have X-ALD, with zero false positives. The birth prevalence of X-ALD in screened infants was 1 in 4,845 and 1 in 3,878 males, more than five times previous reported incidences. Pedigrees of affected infants were analyzed, and 17 male (mean age of 17) and 24 female relatives were subsequently diagnosed with X-ALD. Phenotypes of these family members included self-reported mild neuropathy symptoms in two males and seven females, and childhood cerebral disease (ccALD) and adrenal insufficiency in one male. We observed fewer cases of ccALD and adrenal insufficiency than expected in male family members (5.9% of males for both) compared to previous observations. Together, these findings suggest that the spectrum of X-ALD may be broader than previously described and that milder cases may previously have been underrepresented. Other challenges included a high frequency of variants of uncertain significance in ABCD1 and an inability to predict phenotypic severity. We posit that thoughtful planning to address these novel challenges and coordination by dedicated specialists will be imperative for successful implementation of population-based screening for X-ALD.
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Miembro 1 de la Subfamilia D de Transportador de Casetes de Unión al ATP/genética , Insuficiencia Suprarrenal/diagnóstico , Adrenoleucodistrofia/diagnóstico , Mutación , Tamizaje Neonatal , Miembro 1 de la Subfamilia D de Transportador de Casetes de Unión al ATP/metabolismo , Adolescente , Insuficiencia Suprarrenal/complicaciones , Insuficiencia Suprarrenal/epidemiología , Insuficiencia Suprarrenal/genética , Adrenoleucodistrofia/complicaciones , Adrenoleucodistrofia/epidemiología , Adrenoleucodistrofia/genética , Adulto , Anciano , Niño , Preescolar , Familia , Ácidos Grasos/sangre , Femenino , Expresión Génica , Humanos , Incidencia , Lactante , Recién Nacido , Lisofosfatidilcolinas/sangre , Masculino , Persona de Mediana Edad , Minnesota/epidemiología , Linaje , Fenotipo , Índice de Severidad de la EnfermedadRESUMEN
BACKGROUND: Congenital disorders of glycosylation are rare conditions caused by genetic defects in glycan synthesis, processing or transport. Most congenital disorders of glycosylation involve defects in the formation or transfer of the lipid-linked oligosaccharide precursor of N-linked glycans. SLC35A2-CDG (previously CDG-IIm) is caused by hemizygous or heterozygous mutations in the X-linked gene SLC35A2 that encodes a UDP-galactose transporter. To date there have only been 10 reported patients with SLC35A2 mutations. Importantly, the patient presented here was not identified in infancy by transferrin isoform analysis, the most common testing to identify patients with a congenital disorder of glycosylation. CASE PRESENTATION: A 27 month old girl with developmental delay, central hypotonia, cerebral atrophy, and failure to thrive with growth retardation was identified by whole exome sequencing to have a mosaic missense variant in SLC35A2 (c.991G > A). This particular variant has been previously reported in a male as a mutation. Comparison of all clinical findings and new information on growth pattern, growth hormone testing and neurodevelopmental evaluation are detailed on the patient presented. CONCLUSION: This patient report increases the clinical and scientific knowledge of SLC35A2-CDG, a rare condition. New information on reduced growth, growth hormone sufficiency, lack of seizures, and neurodevelopmental status are presented. This new information will be helpful to clinicians caring for individuals with SLC35A2-CDG. This report also alerts clinicians that transferrin isoform measurements do not identify all patients with congenital disorders of glycosylation.
Asunto(s)
Trastornos Congénitos de Glicosilación/genética , Trastornos Congénitos de Glicosilación/patología , Proteínas de Transporte de Monosacáridos/genética , Mutación Missense , Preescolar , Femenino , Humanos , Mosaicismo , PronósticoRESUMEN
Mutations in MAP2K1, a gene expressed within the RAS-mitogen activated protein kinase (RAS/MAPK) pathway, are generally associated with the clinical phenotype of cardiofaciocutaneous syndrome. Here we describe two male patients (ages 16 and 20 years) with mutations in MAP2K1 and heterogeneous clinical presentations. Both young men had short stature, some facial features suggesting a RASopathy and minimal cardiac involvement. Detailed medical and neuropsychological findings are presented alongside a comprehensive review of features of patients with MAP2K1 mutations reported in the literature. Published studies have indicated that cognitive functioning of individuals with MAP2K1 mutations can range from severe intellectual disability to mildly below average. Neither of the individuals presented here had severe intellectual disability, and one had intellectual functioning within the average range. Neurodevelopmental concerns that were common among our two patients included fine motor difficulties, slow processing speed, reduced attention span, learning disabilities, and diminished energy/alertness. Taken together, our findings demonstrate that mutations in MAP2K1, which are frequently associated with neurological complications and intellectual disability, can be associated with a milder clinical and neurocognitive profile more typical of individuals with Noonan syndrome. Variability of expression may arise from a complex interplay between RAS/MAPK pathway genotype, epigenetics, medical and obstetric factors, and environmental influences. © 2016 Wiley Periodicals, Inc.
Asunto(s)
Estudios de Asociación Genética , MAP Quinasa Quinasa 1/genética , Mutación , Fenotipo , Adaptación Psicológica , Adolescente , Alelos , Sustitución de Aminoácidos , Displasia Ectodérmica/diagnóstico , Displasia Ectodérmica/genética , Emociones , Facies , Insuficiencia de Crecimiento/diagnóstico , Insuficiencia de Crecimiento/genética , Genotipo , Cardiopatías Congénitas/diagnóstico , Cardiopatías Congénitas/genética , Humanos , Masculino , Pruebas Neuropsicológicas , Conducta Social , Adulto JovenRESUMEN
The present study is an investigation of behavioral functioning in children with cardiofaciocutaneous syndrome (CFC). CFC is a rare single-gene disorder associated with cardiac disease, characteristic skin and facial features, intellectual disability, and neurological complications such as seizures and structural brain anomalies. Emotional and behavioral features of CFC have not been systematically investigated. We aimed to identify key variables that contribute to psychopathology during childhood and adolescence, and to examine the impact of challenging behaviors on the caregiving experience. Parents of 34 children and adolescents with CFC completed standardized broadband measures of child emotional and behavioral functioning, as well as measures of sensory modulation, functional communication, and caregiver stress. Results indicate that children with CFC syndrome are at heightened risk for psychopathology, with attention problems, social difficulties, and unusual behaviors (e.g., obsessive thoughts, strange behaviors, repetitive acts) found to be especially prevalent. Behavioral challenges in children with CFC syndrome were significantly associated with a history of obstetric complications and with problems modulating sensory information. With regard to the impact of child neurocognitive and behavioral issues on the caregiving experience, parent self-reported stress was significantly higher among parents of children who engaged in more problem behaviors, and lower among parents whose children could communicate effectively with others. Results of this study suggest avenues to help families cope with CFC-related stressors and enhance overall functioning. In particular, this study highlights the need for educational and treatment interventions aimed at addressing sensory needs, increasing functional communication, and identifying and managing challenging behaviors. © 2016 Wiley Periodicals, Inc.
Asunto(s)
Conducta , Displasia Ectodérmica/diagnóstico , Insuficiencia de Crecimiento/diagnóstico , Cardiopatías Congénitas/diagnóstico , Fenotipo , Adolescente , Cuidadores/psicología , Lista de Verificación , Niño , Conducta Infantil , Trastornos de la Conducta Infantil/diagnóstico , Trastornos de la Conducta Infantil/genética , Comunicación , Displasia Ectodérmica/genética , Facies , Insuficiencia de Crecimiento/genética , Femenino , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Cardiopatías Congénitas/genética , Humanos , Masculino , Responsabilidad Parental , Factores de Riesgo , Estrés PsicológicoAsunto(s)
Genética/historia , Femenino , Historia del Siglo XX , Historia del Siglo XXI , Humanos , Estados UnidosRESUMEN
AIM: Emerging research indicates that gene mutations within the RAS-MAPK signaling cascade, which cause Noonan syndrome and related disorders, affect neurophysiologic activity in brain regions underlying attention and executive functions. The present study examined whether children with Noonan syndrome are at heightened risk for symptoms of attention-deficit-hyperactivity disorder (ADHD) and executive dysfunction relative to an unaffected sibling comparison group, and investigated three key aspects of behavioral attention: auditory attention, sustained attention, and response inhibition. METHOD: Children and adolescents with Noonan syndrome (n=32, 17 males, 15 females, mean age 11y 3mo, SD 3y) and their unaffected siblings (n=16, eight males, eight females, mean age 11y, SD 3y 6mo) were administered standardized tests of intellectual functioning and clinic-based measures of behavioral attention. Parent ratings of ADHD symptoms, executive functioning, and behavior were also obtained. RESULTS: Children with Noonan syndrome demonstrated higher rates of past ADHD diagnosis, as well as reduced performance compared with unaffected siblings on behavioral attention measures. Parent-rated functional impairments in attention, social skills, working memory, and self-monitoring were more prevalent in the Noonan syndrome group. The relationship between attention regulation skills (sustained attention and inhibitory control) and intellectual test performance was significantly stronger in the Noonan syndrome group than the comparison group. INTERPRETATION: Clinical screening/evaluation for ADHD and executive dysfunction in Noonan syndrome is recommended to facilitate appropriate intervention and to address functional impact on daily life activities.
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Trastorno por Déficit de Atención con Hiperactividad/diagnóstico , Función Ejecutiva/fisiología , Inteligencia/fisiología , Síndrome de Noonan/diagnóstico , Hermanos , Adolescente , Atención , Trastorno por Déficit de Atención con Hiperactividad/epidemiología , Niño , Estudios de Cohortes , Comorbilidad , Femenino , Humanos , Masculino , Síndrome de Noonan/epidemiología , Síndrome de Noonan/genéticaRESUMEN
Developmental language disorder (DLD) is a common neurodevelopmental disorder with adverse impacts that continue into adulthood. However, its neural bases remain unclear. Here we address this gap by systematically identifying and quantitatively synthesizing neuroanatomical studies of DLD using co-localization likelihood estimation, a recently developed neuroanatomical meta-analytic technique. Analyses of structural brain data (22 peer-reviewed papers, 577 participants) revealed highly consistent anomalies only in the basal ganglia (100% of participant groups in which this structure was examined, weighted by group sample sizes; 99.8% permutation-based likelihood the anomaly clustering was not due to chance). These anomalies were localized specifically to the anterior neostriatum (again 100% weighted proportion and 99.8% likelihood). As expected given the task dependence of activation, functional neuroimaging data (11 peer-reviewed papers, 414 participants) yielded less consistency, though anomalies again occurred primarily in the basal ganglia (79.0% and 95.1%). Multiple sensitivity analyses indicated that the patterns were robust. The meta-analyses elucidate the neuroanatomical signature of DLD, and implicate the basal ganglia in particular. The findings support the procedural circuit deficit hypothesis of DLD, have basic research and translational implications for the disorder, and advance our understanding of the neuroanatomy of language.
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Ganglios Basales , Trastornos del Desarrollo del Lenguaje , Humanos , Trastornos del Desarrollo del Lenguaje/diagnóstico por imagen , Trastornos del Desarrollo del Lenguaje/fisiopatología , Ganglios Basales/diagnóstico por imagen , Encéfalo/diagnóstico por imagen , Neuroimagen Funcional , Neuroanatomía , Neostriado/diagnóstico por imagen , Neostriado/fisiopatología , Neostriado/patologíaRESUMEN
BACKGROUND AND OBJECTIVES: Childhood cerebral adrenoleukodystrophy (C-ALD) is a severe inflammatory demyelinating disease that must be treated at an early stage to prevent permanent brain injury and neurocognitive decline. In standard clinical practice, C-ALD lesions are detected and characterized by a neuroradiologist reviewing anatomical MRI scans. We aimed to assess whether diffusion tensor imaging (DTI) is sensitive to the presence and severity of C-ALD lesions and to investigate associations with neurocognitive outcomes after hematopoietic cell therapy (HCT). METHODS: In this retrospective cohort study, we analyzed high-resolution anatomical MRI, DTI, and neurocognitive assessments from boys with C-ALD undergoing HCT at the University of Minnesota between 2011 and 2021. Longitudinal DTI data were compared with an age-matched group of boys with ALD and no lesion (NL-ALD). DTI metrics were obtained for atlas-based regions of interest (ROIs) within 3 subdivisions of the corpus callosum (CC), corticospinal tract (CST), and total white matter (WM). Between-group baseline and slope differences in fractional anisotropy (FA) and axial (AD), radial (RD), and mean (MD) diffusivities were compared using analysis of covariance accounting for age, MRI severity (Loes score), and lesion location. RESULTS: Among patients with NL-ALD (n = 14), stable or increasing FA, stable AD, and stable or decreasing RD and MD were generally observed during the 1-year study period across all ROIs. In comparison, patients with mild posterior lesions (Loes 1-2; n = 13) demonstrated lower baseline FA in the CC splenium (C-ALD 0.50 ± 0.08 vs NL-ALD 0.58 ± 0.04; pBH = 0.022 adjusted Benjamini-Hochberg p-value), lower baseline AD across ROIs (e.g., C-ALD 1.34 ± 0.03 ×10-9 m2/s in total WM vs NL-ALD 1.38 ± 0.04 ×10-9 m2/s; pBH = 0.005), lower baseline RD in CC body and CST, and lower baseline MD across ROIs except CC splenium. Longitudinal slopes in CC splenium showed high sensitivity and specificity in differentiating early C-ALD from NL-ALD. Among all patients with C-ALD (n = 38), baseline Loes scores and DTI metrics were associated with post-HCT neurocognitive functions, including processing speed (e.g., FA WM Spearman correlation coefficient R = 0.64) and visual-motor integration (e.g., FA WM R = 0.71). DISCUSSION: DTI was sensitive to lesion presence and severity as well as clinical neurocognitive effects of C-ALD. DTI metrics quantify C-ALD even at an early stage.
Asunto(s)
Adrenoleucodistrofia , Cuerpo Calloso , Imagen de Difusión Tensora , Sustancia Blanca , Humanos , Masculino , Adrenoleucodistrofia/diagnóstico por imagen , Adrenoleucodistrofia/complicaciones , Niño , Estudios Retrospectivos , Sustancia Blanca/diagnóstico por imagen , Sustancia Blanca/patología , Cuerpo Calloso/diagnóstico por imagen , Cuerpo Calloso/patología , Adolescente , Tractos Piramidales/diagnóstico por imagen , Tractos Piramidales/patología , Preescolar , Trasplante de Células Madre Hematopoyéticas , Pruebas Neuropsicológicas , Estudios de Cohortes , Encéfalo/diagnóstico por imagen , Encéfalo/patologíaRESUMEN
Genetic syndromes resulting from molecular alterations of the RAS-MAPK signaling cascade have become the focus of heightened interest among behavioral scientists due to discoveries that proteins within this pathway play an important role in memory formation and consolidation. Individuals with Noonan syndrome (NS), caused by germline mutations in the RAS-MAPK pathway, exhibit wide variability in cognitive and memory skills. The current study aimed to characterize memory deficits that occur in some affected individuals as a key step toward understanding the neurocognitive effects of dysregulated Ras signaling. Learning and memory skills were assessed among 29 children and adolescents with NS using the Wide Range Assessment of Memory and Learning, Second Edition. Performance across subdomains (verbal memory, visual memory and working memory) was compared, as well as the effect of response type (free recall vs. recognition). For immediate memory, children with NS performed significantly better on verbal memory tasks than on visual memory or working memory tasks. For delayed memory, verbal free recall tasks that depend heavily on prefrontal-hippocampal networks were more challenging than recognition tasks that rely on more distributed temporal cortical regions. Additionally, verbal information presented in context was more easily retained than that presented in a rote format. The current study contributes to our knowledge of the effects of dysregulated RAS-MAPK signaling on the brain and behavior. Continued research on neurocognitive skills in NS has the potential to generate a novel conceptualization of how learning disabilities can arise from altered molecular processes within a specific biological pathway.