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FBRSL1, together with FBRS and AUTS2 (Activator of Transcription and Developmental Regulator; OMIM 607270), constitutes a tripartite AUTS2 gene family. AUTS2 and FBRSL1 are evolutionarily more closely related to each other than to FBRS (Fibrosin 1; OMIM 608601). Despite its paralogous relation to AUTS2, FBRSL1's precise role remains unclear, though it likely shares functions in neurogenesis and transcriptional regulation. Herein, we report the clinical presentation with therapeutic approaches and the molecular etiology of a patient harboring a de novo truncating variant (c.371dupC) in FBRSL1, leading to a premature stop codon (p.Cys125Leufs*7). Our study extends previous knowledge by highlighting potential interactions and implications of this variant, alongside maternal and paternal duplications, for the patient's phenotype. Using sequence conservation data and in silico analysis of the truncated protein, we generated a predicted domain structure. Furthermore, our in silico analysis was extended by taking into account SNP array results. The extension of in silico analysis was performed due to the possibility that the coexistence of FBRSL1 truncating variant contemporary with maternal and paternal duplication could be a modifier of proband's phenotype and/or influence the novel syndrome clinical characteristics. FBRSL1 protein may be involved in neurodevelopment due to its homology with AUTS2, together with distinctive neuronal expression profiles, and thus should be considered as a potential modulation of clinical characteristics in a novel syndrome. Finally, considering that FBRSL1 is apparently involved in neurogenesis and in transcriptional regulatory networks that orchestrate gene expression, together with the observation that different genetic syndromes are associated with distinct genomic DNA methylation patterns, the specific episignature has been explored.
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Proteínas del Citoesqueleto , Discapacidad Intelectual , Factores de Transcripción , Humanos , Discapacidad Intelectual/genética , Discapacidad Intelectual/patología , Factores de Transcripción/genética , Proteínas del Citoesqueleto/genética , Masculino , Femenino , Síndrome , Fenotipo , Codón sin Sentido/genéticaRESUMEN
The cognitive functioning of individuals with spinal muscular atrophy (SMA) is not well understood, prompting a call for more research to better grasp cognitive involvement in SMA. This study aims to explore recent findings regarding cognitive outcomes in SMA patients, including correlations between clinical features and cognitive abilities. The investigation seeks to identify commonly used measures for assessing cognitive function in this patient population. A scoping review following the Joanna Briggs Institute methodology examined literature until December 2023. Two databases were searched along with relevant article references using specific terms such as "spinal muscular atrophy," "SMA," "cognitive," "abilities," "functions," "intellective," or "intellectual." Screening focused on titles and abstracts from English language peer-reviewed journals. After the initial research, 1452 articles were identified. Subsequent screening and selection led to the inclusion of 13 articles in the review. Among these studies, four indicated a cognitive trend within the normal range for SMA patients. In four other studies, the majority of patients fell within the normal range. However, smaller proportions were observed to be either above or below the norm compared to the controls. Three studies reported noted cognitive performance below the average, while two showed above-average scores. The scoping review suggests that most SMA patients have cognitive abilities similar to the general population, with types II and III showing even lesser impact. However, certain cognitive domains may be affected in type I patients, highlighting the need for further research to fully understand cognitive involvement in SMA.
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Atrofia Muscular Espinal , Humanos , Atrofia Muscular Espinal/psicología , Atrofia Muscular Espinal/complicaciones , Atrofia Muscular Espinal/fisiopatología , Atrofia Muscular Espinal/diagnóstico , Cognición/fisiología , Disfunción Cognitiva/etiología , Disfunción Cognitiva/diagnóstico , Disfunción Cognitiva/fisiopatologíaRESUMEN
BACKGROUND: The present study analysed data on children and adolescents with a diagnosis of attention-deficit/hyperactivity disorder (ADHD) who were referred to the ADHD reference centre of Scientific Institute IRCCS E. Medea (Brindisi, Italy) for ADHD pharmacotherapy initiation and monitoring overtime. The main aim of the study was to examine differences in pharmacological treatment status (i.e., treatment continuation vs discontinuation) between patients. METHODS: Seventy-seven children and adolescents (mean age at pharmacotherapy initiation = 9.5, standard deviation = 2.6) with ADHD received drugs treatment for ADHD at the reference center between January, 2013 and May, 2022. Demographic and clinical data were obtained from the Italian Registry for ADHD and medical records. Child Behavior Checklist (CBCL) available data were used. RESULTS: Pharmacological treatment status was examined for patients (n = 63) with at least 12 months of follow-up after the first pharmacological treatment for ADHD. After starting pharmacotherapy treatment, 77.8% (n = 49) patients were still on treatment whereas 22.2% (n = 14) discontinued it. No between group difference were observed in demographic and clinical data except for the intelligence quotient/intellectual disability and rule-breaking behavior (n = 40). CONCLUSIONS: This study stressed the need of periodical assessments, monitoring difficulties with treatment and/or reasons for poor treatment compliance to provide individualized care.
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Trastorno por Déficit de Atención con Hiperactividad , Adolescente , Niño , Humanos , Trastorno por Déficit de Atención con Hiperactividad/tratamiento farmacológico , Italia , Estudios Retrospectivos , Cumplimiento y Adherencia al Tratamiento , PsicofarmacologíaAsunto(s)
Parálisis Cerebral , Epilepsia , Relajantes Musculares Centrales , Niño , Humanos , Parálisis Cerebral/complicaciones , Parálisis Cerebral/tratamiento farmacológico , Baclofeno/efectos adversos , Espasticidad Muscular/tratamiento farmacológico , Espasticidad Muscular/etiología , Relajantes Musculares Centrales/efectos adversos , Epilepsia/complicaciones , Epilepsia/tratamiento farmacológico , Inyecciones Espinales/efectos adversosRESUMEN
Pathogenic variants in genes are involved in histone acetylation and deacetylation resulting in congenital anomalies, with most patients displaying a neurodevelopmental disorder and dysmorphism. Arboleda-Tham syndrome caused by pathogenic variants in KAT6A (Lysine Acetyltransferase 6A; OMIM 601408) has been recently described as a new neurodevelopmental disorder. Herein, we describe a patient characterized by complex phenotype subsequently diagnosed using the clinical exome sequencing (CES) with Arboleda-Tham syndrome (ARTHS; OMIM 616268). The analysis revealed the presence of de novo pathogenic variant in KAT6A gene, a nucleotide c.3385C>T substitution that introduces a premature termination codon (p.Arg1129*). The need for straight multidisciplinary collaboration and accurate clinical description findings (bowel obstruction/megacolon/intestinal malrotation) was emphasized, together with the utility of CES in establishing an etiological basis in clinical and genetical heterogeneous conditions. Therefore, considering the phenotypic characteristics, the condition's rarity and the reviewed literature, we propose additional diagnostic criteria that could help in the development of future clinical diagnostic guidelines. This was possible thanks to objective examinations performed during the long follow-up period, which permitted scrupulous registration of phenotypic changes over time to further assess this rare disorder. Finally, given that different genetic syndromes are associated with distinct genomic DNA methylation patterns used for diagnostic testing and/or as biomarker of disease, a specific episignature for ARTHS has been identified.
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Histona Acetiltransferasas , Trastornos del Neurodesarrollo , Humanos , Codón sin Sentido , Pruebas Genéticas , Histona Acetiltransferasas/genética , Trastornos del Neurodesarrollo/genética , FenotipoRESUMEN
Spinal muscular atrophy is a progressive and severe hereditary (autosomal recessive) neuromuscular disease characterized by lower motor neuron degeneration in the spinal cord and brainstem causing a clinical picture of progressive muscle atrophy and weakness of skeletal and respiratory muscles. There is an ongoing discussion on the extent to which other tissues might be affected in patients with SMA. Several animal models and some case reports or small case series report involvement of other organ systems, such as peripheral nerve, brain, muscle, heart, vascular system, and pancreas. Recent literature reviews identified a number of cases with vascular abnormalities. We present two consecutive cases of patients diagnosed with SMA who developed peripheral circulation disturbances and combine the findings with a thorough review the literature.
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Atrofia Muscular Espinal , Animales , Humanos , Atrofia Muscular Espinal/diagnóstico , Atrofia Muscular Espinal/genéticaRESUMEN
Objective: Standards of care and new genetic and molecular therapies have contributed to increasing life expectancy of patients with neuromuscular diseases (NMDs). This review presents the clinical evidence for an adequate transition from pediatric to adult care in patients with NMDs considering both physical and psychosocial aspects and attempts at identifying a general pattern of transition in the literature that can be used for all patients with NMDs. Method: A search was performed on PubMed, Embase and Scopus using generic terms that could be referred to the transition construct specifically related to NMDs. A narrative approach was used to summarise the available literature. Results: Our review shows that few or no studies explored the transition process from pediatric to adult care in neuromuscular diseases and tried to identify a general pattern of transition applicable to all NMDs. Conclusions: A transition process taking into consideration physical, psychological, social needs of patient and caregiver could produce positive outcomes. However, there is still no unanimous agreement in the literature on what it consists of and how to achieve an optimal and effective transition.
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Enfermedades Neuromusculares , Transición a la Atención de Adultos , Humanos , Niño , Adulto , Enfermedades Neuromusculares/terapiaRESUMEN
Background: Purified cannabidiol (CBD) was administered to highly refractory patients with Dravet (DS) or Lennox-Gastaut (LGS) syndromes in an ongoing expanded access program (EAP). Herein, we report interim results on CBD safety and seizure outcomes in patients treated for a 12-month period. Material and Methods: Thirty centers were enrolled from December 2018 to December 2019 within the open-label prospective EAP up to a maximum of 25 mg/kg per day. Adverse effects and liver function tests were assessed after 2 weeks; 1, 3, and 6 months of treatment; and periodically thereafter. Seizure endpoints were the percentage of patients with ≥50 and 100% reduction in seizures compared to baseline. Results: A total of 93 patients were enrolled and included in the safety analysis. Eighty-two patients [27 (32.9%) DS, 55 (67.1%) LGS] with at least 3 months of treatment have been included in the effectiveness analysis; median previously failed antiseizure medications was eight. Pediatric and adult patients were uniformly represented in the cohort. At 3-month follow-up, compared to the 28-day baseline period, the percentage of patients with at least a 50% reduction in seizure frequency was 40.2% (plus 1.2% seizure-free). Retention rate was similar according to diagnosis, while we found an increased number of patients remaining under treatment in the adult group. CBD was mostly coadministered with valproic acid (62.2%) and clobazam (41.5%). In the safety dataset, 29 (31.2%) dropped out: reasons were lack of efficacy [16 (17.2%)] and adverse events (AEs) [12 (12.9%)], and one met withdrawal criteria (1.1%). Most reported AEs were somnolence (22.6%) and diarrhea (11.9%), followed by transaminase elevation and loss of appetite. Conclusions: CBD is associated with improved seizure control also in a considerable proportion of highly refractory patients with DS and LGS independently from clobazam use. Overall, CBD safety and effectiveness are not dose-related in this cohort.
RESUMEN
In the present study, we describe two novel cases of SCA5 with early onset. The first one, carrying a novel heterozygous de novo missense mutation in SPTBN2 gene, showed a striking very severe cerebellar atrophy and reduction of volume of the pons at a very young age (16 months). The latter, carrying the first de novo intragenic deletion so far reported in SPTBN2 gene, showed a mild cerebellar atrophy involving the hemispheres and a later onset. In both cases, for the first time, a hyperintense signal of the dentate nuclei was observed.
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Espectrina/genética , Ataxias Espinocerebelosas/genética , Ataxias Espinocerebelosas/patología , Edad de Inicio , Preescolar , Femenino , Eliminación de Gen , Humanos , Lactante , Imagen por Resonancia Magnética , Masculino , LinajeRESUMEN
BACKGROUND: Mutations in the elongation factor 1 alpha 2 (EEF1A2) gene have been recently shown to cause epileptic encephalopathy (MIM # 616409 EIEE33) associated with neurodevelopmental disorders such as intellectual disability, autistic spectrum disorder, hypotonia and dysmorphic facial features. EEF1A2 protein is involved in protein synthesis, suppression of apoptosis, regulation of actin function and cytoskeletal structure. To date, only sixteen patients with EEF1A2 mutations have been reported. CASE REPORT: We described a new case, a boy with severe intellectual disability with absent speech, autistic spectrum disorder, mild dysmorphic facial features, failure to thrive and epilepsy associated to a de novo heterozygous missense mutation in EEF1A2 (c.364G>A; p.Glu122Lys) identified by next generation sequencing; it was already reported in other studies. Most clinical features are shared by all individuals with EEF1A2 mutation, but unlike others reports our patient showed a mild epileptic phenotype: epilepsy developed in late infancy and was well-controlled with antiepileptic drugs. Moreover, at the onset of epilepsy, interictal wake/sleep electroencephalograms showed typical pattern that disappeared with age. CONCLUSION: This report focused that EEF1A2 mutations should be considered not only in patients with epileptic encephalopathy, but also in those with less severe epilepsy. A typical EEG pattern may be a biomarker for EEF1A2 mutation, but further investigations and longitudinal clinical observations are required.
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Epilepsias Mioclónicas/genética , Factor 1 de Elongación Peptídica/genética , Anomalías Múltiples/genética , Niño , Preescolar , Humanos , Lactante , Discapacidad Intelectual/genética , Masculino , Mutación Missense , FenotipoRESUMEN
BACKGROUND: Parents' attitudes and psychological adjustment during their child's hospitalization in a pediatric neurorehabilitation care unit are key aspects for the child's adherence to care and the impact of the disease. AIM: The aim of this study was to examine the relationship between parenting stress, coping style, and negative psychological outcomes in families of children admitted for the first time to a pediatric neurorehabilitation care unit. DESIGN: This is an observational study. SETTING: Pediatric neurorehabilitation care unit. POPULATION: One hundred twenty-four parents of children diagnosed with neurodevelopmental or neurological conditions. METHODS: Parents completed standardized questionnaires assessing parenting stress, coping style, anxiety and depressive symptoms. RESULTS: We found that parents of children with neurodevelopmental conditions showed more emotion-focused coping strategies (P=0.016) and depressive symptoms (P=0.01) compared with parents of children with neurological conditions. Hierarchical regression analyses showed that emotion- and avoidance-oriented coping style and socioeconomic status are crucial factors in the adjustment process of parents of children with neurodevelopmental conditions. By contrast, parenting stress and child difficulties were the most significant predictors of negative psychological outcomes in parents with neurological conditions. CONCLUSIONS: This study sought to develop more understanding of the relationship among parenting stress, coping, and anxiety or depressive symptoms in parent of children hospitalized in a pediatric neurorehabilitation care unit. We suggest that examining parents may increase our understanding of the interplay between child and parent functioning in families with children admitted for the first time to a pediatric neurorehabilitation care unit. CLINICAL REHABILITATION IMPACT: Identify these predictors might help professionals to develop screening procedures to identify parent at high risk for anxiety or depression, and to conduct early interventions to reduce uncertainty and maladaptive coping strategies that may influences rehabilitation process.
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Adaptación Psicológica , Ansiedad/psicología , Depresión/psicología , Niños con Discapacidad/rehabilitación , Padres/psicología , Estrés Psicológico/psicología , Adulto , Niño , Niño Hospitalizado , Preescolar , Femenino , Humanos , Masculino , Rehabilitación Neurológica , Encuestas y CuestionariosAsunto(s)
Epilepsia Refractaria/terapia , Estimulación del Nervio Vago/métodos , Epilepsia Refractaria/complicaciones , Epilepsia Refractaria/genética , Electroencefalografía , Femenino , Humanos , Mutación/genética , Cuadriplejía/complicaciones , Cuadriplejía/genética , Cuadriplejía/terapia , Receptores Acoplados a Proteínas G/genética , Adulto JovenRESUMEN
This study aimed to investigate a possible correlation between the gross motor function classification system-expanded and revised (GMFCS-E&R), the manual abilities classification system (MACS) and the communication function classification system (CFCS) functional levels in children with cerebral palsy (CP) by CP subtype. It was also geared to verify whether there is a correlation between these classification systems and intellectual functioning (IF) and parental socio-economic status (SES). A total of 87 children (47 males and 40 females, age range 4-18 years, mean age 8.9±4.2) were included in the study. A strong correlation was found between the three classifications: Level V of the GMFCS-E&R corresponds to Level V of the MACS (rs=0.67, p=0.001); the same relationship was found for the CFCS and the MACS (rs=0.73, p<0.001) and for the GMFCS-E&R and the CFCS (rs=0.61, p=0.001). The correlations between the IQ and the global functional disability profile were strong or moderate (GMFCS and IQ: rs=0.66, p=0.001; MACS and IQ: rs=0.58, p=0.001; CFCS and MACS: rs=0.65, p=0.001). The Kruskal-Wallis test was used to determine if there were differences between the GMFCS-E&R, the CFCS and the MACS by CP type. CP types showed different scores for the IQ level (Chi-square=8.59, df=2, p=0.014), the GMFCS-E&R (Chi-square=36.46, df=2, p<0.001), the CFCS (Chi-square=12.87, df=2, p=0.002), and the MACS Level (Chi-square=13.96, df=2, p<0.001) but no significant differences emerged for the SES (Chi-square=1.19, df=2, p=0.554). This study shows how the three functional classifications (GMFCS-E&R, CFCS and MACS) complement each other to provide a better description of the functional profile of CP. The systematic evaluation of the IQ can provide useful information about a possible future outcome for every functional level. The SES does not appear to affect functional profiles.
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Parálisis Cerebral/fisiopatología , Comunicación , Inteligencia , Limitación de la Movilidad , Destreza Motora/fisiología , Adolescente , Parálisis Cerebral/clasificación , Niño , Preescolar , Femenino , Humanos , Pruebas de Inteligencia , Masculino , Índice de Severidad de la EnfermedadRESUMEN
The diagnosis of Moebius syndrome, a rare congenital disorder, is primarily based on congenital facial and abducent nerve palsy. Involvement of other cranial nerves is also common. Occasionally the V, X, XI, and XII cranial nerves are involved, resulting in a difficulty to chew, swallow, and cough, which often leads to respiratory complications. Mental retardation and autism have been reported in some cases. Moebius syndrome can be associated with orofacial anomalies and limb malformations. The authors describe a patient with a confirmed diagnosis of Moebius syndrome associated with hydrosyringomyelia. No case of Moebius syndrome involving primarily the spinal cord has been reported so far. This patient did not present with other factors directly linked to syringomyelia.
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Síndrome de Mobius/diagnóstico , Siringomielia/diagnóstico , Nervio Abducens/anomalías , Nervio Abducens/patología , Encéfalo/patología , Vértebras Cervicales/patología , Preescolar , Diagnóstico Diferencial , Nervio Facial/anomalías , Nervio Facial/patología , Femenino , Humanos , Cariotipificación , Imagen por Resonancia Magnética , Síndrome de Mobius/genética , Examen Neurológico , Médula Espinal/patología , Siringomielia/genética , Vértebras Torácicas/patologíaRESUMEN
Sjögren-Larsson syndrome (SLS) is a rare autosomal recessively inherited neurocutaneous disorder caused by mutations in the ALDH3A2 gene that encodes fatty aldehyde dehydrogenase, an enzyme that catalyzes the oxidation of fatty aldehyde to fatty acid. It is characterized by an unusual combination of cutaneous and neurologic signs and symptoms. The authors describe two brothers of consanguineous parents with SLS, one of whom was born from a dizygotic twin pregnancy (with an apparently normal sister), and they focus on the variability of the clinical findings of the syndrome even among siblings and twins.
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Síndromes Neurocutáneos/complicaciones , Síndromes Neurocutáneos/genética , Fenotipo , Síndrome de Sjögren-Larsson/etiología , Adolescente , Aldehído Oxidorreductasas/genética , Humanos , Masculino , Gemelos DicigóticosRESUMEN
Septo-optic dysplasia (SOD), also called De Morsier's syndrome, is a highly heterogeneous condition comprising a spectrum of central nervous system malformations that involves in various degrees the optic nerves, the hypothalamic-pituitary axis, and other midline structures such as the septum pellucidum and the corpus callosum. In a discrete number of cases, schizencephaly, agenesis of the corpus callosum or other cortical malformations are associated (SOD-plus). The authors present a 6-year-old boy with dyskinetic cerebral palsy (athetoid-dystonic subtype) associated with SOD-plus. Cranial magnetic resonance imaging (cMRI) revealed the total absence of septum pellucidum, optic nerve hypoplasia, hypoplasia of the corpus callosum and right occipital cortical dysplasia. The patient was diagnosed with septo-optic dysplasia-plus syndrome based on the cMRI findings. To the best of our knowledge, this is the first reported case in which defects of midline brain structures, like in SOD-plus, are associated with a significant hyperkinetic movement disorder such as dyskinesia.
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Parálisis Cerebral/diagnóstico , Displasia Septo-Óptica/diagnóstico , Parálisis Cerebral/complicaciones , Parálisis Cerebral/patología , Niño , Humanos , Masculino , Displasia Septo-Óptica/complicaciones , Displasia Septo-Óptica/patología , Tabique Pelúcido/anomalías , Tabique Pelúcido/patologíaRESUMEN
The authors describe a 12-year-old boy with dyskinetic (athetoid-dystonic subtype) cerebral palsy and os odontoideum. Dystonic and choreoathetotic components in cerebral palsy are movement disorders that are difficult to treat and cause major disability. Dystonic posturing causes excessive flexion, extension, and rotation of the neck. Repetitive abnormal movements in patients with this type of cerebral palsy give rise to a higher incidence of pathologic conditions affecting the craniovertebral junction. Os odontoideum is one of these pathologies, and it represents a rare anomaly of the odontoid process. There are only a few reports describing os odontoideum in children with dyskinetic cerebral palsy. This clinical and neuroradiologic study focuses on the problem of atlantoaxial instability and os odontoideum in these forms of cerebral palsy, which is too often underestimated.
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Articulación Atlantoaxoidea/diagnóstico por imagen , Parálisis Cerebral/complicaciones , Imagen por Resonancia Magnética , Apófisis Odontoides/diagnóstico por imagen , Articulación Atlantoaxoidea/patología , Parálisis Cerebral/diagnóstico por imagen , Parálisis Cerebral/patología , Niño , Humanos , Masculino , Apófisis Odontoides/patología , RadiografíaAsunto(s)
Anticonvulsivantes/farmacocinética , Antagonistas Muscarínicos/farmacología , Trihexifenidilo/farmacología , Ácido Valproico/farmacocinética , Anticonvulsivantes/administración & dosificación , Anticonvulsivantes/uso terapéutico , Parálisis Cerebral/tratamiento farmacológico , Preescolar , Relación Dosis-Respuesta a Droga , Interacciones Farmacológicas , Epilepsia/tratamiento farmacológico , Femenino , Humanos , Antagonistas Muscarínicos/uso terapéutico , Trihexifenidilo/uso terapéutico , Ácido Valproico/administración & dosificación , Ácido Valproico/uso terapéuticoRESUMEN
The authors describe a 5-year-old girl with a neurological phenotype of 22q13 deletion syndrome (neonatal and persisting hypotonia, developmental delay, absence of language, decreased perception of pain) and minor dysmorphisms. Subtelomeric fluorescent in situ hybridization tests revealed de novo 22q13 monosomy and 2pter duplication. Numerous genetic and neurologic disorders of childhood are characterized by congenital hypotonia. This muscle tone disorder is often one of the symptoms that a neurologist is asked to evaluate. Recent advances in genetic testing can help provide a specific diagnosis for children with this symptom. Subtelomeric deletions are a category of disorders of which hypotonia can be a prominent feature. Deletions of chromosome 22q13 are some of the most commonly observed terminal deletions in humans, whereas duplications of chromosome 2p25.2 are very rare, and little is known about the phenotypic effect of these duplications. To the best of the authors' knowledge, this association has never been described before.