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Sialorrhea, uncontrolled, excessive drooling, accompanies different, mostly neurological disorders from childhood to adulthood. With incobotulinumtoxinA (Xeomin, IncoBoNT/A, Merz Pharmaceuticals GmbH), an approved medication for the treatment of sialorrhea has been available since 2019. Patient selection, possible therapy goals, treatment and the management of specific treatment situations build the focus of this interdisciplinary expert consensus recommendations with the intent to facilitate access to treatment and to contribute to qualified botulinum toxin therapy.
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Toxinas Botulínicas Tipo A , Doenças do Sistema Nervoso , Sialorreia , Adolescente , Adulto , Toxinas Botulínicas Tipo A/uso terapêutico , Criança , Consenso , Humanos , Sialorreia/tratamento farmacológico , Resultado do Tratamento , Adulto JovemRESUMO
The endoplasmic reticulum enzyme fatty acid 2-hydroxylase (FA2H) plays a major role in the formation of 2-hydroxy glycosphingolipids, main components of myelin. FA2H deficiency in mice leads to severe central demyelination and axon loss. In humans it has been associated with phenotypes from the neurodegeneration with brain iron accumulation (fatty acid hydroxylase-associated neurodegeneration, FAHN), hereditary spastic paraplegia (HSP type SPG35) and leukodystrophy (leukodystrophy with spasticity and dystonia) spectrum. We performed an in-depth clinical and retrospective neurophysiological and imaging study in a cohort of 19 cases with biallelic FA2H mutations. FAHN/SPG35 manifests with early childhood onset predominantly lower limb spastic tetraparesis and truncal instability, dysarthria, dysphagia, cerebellar ataxia, and cognitive deficits, often accompanied by exotropia and movement disorders. The disease is rapidly progressive with loss of ambulation after a median of 7 years after disease onset and demonstrates little interindividual variability. The hair of FAHN/SPG35 patients shows a bristle-like appearance; scanning electron microscopy of patient hair shafts reveals deformities (longitudinal grooves) as well as plaque-like adhesions to the hair, likely caused by an abnormal sebum composition also described in a mouse model of FA2H deficiency. Characteristic imaging features of FAHN/SPG35 can be summarized by the 'WHAT' acronym: white matter changes, hypointensity of the globus pallidus, ponto-cerebellar atrophy, and thin corpus callosum. At least three of four imaging features are present in 85% of FA2H mutation carriers. Here, we report the first systematic, large cohort study in FAHN/SPG35 and determine the phenotypic spectrum, define the disease course and identify clinical and imaging biomarkers.
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Transtornos Heredodegenerativos do Sistema Nervoso/genética , Fenótipo , Paraplegia Espástica Hereditária/genética , Criança , Estudos de Coortes , Doenças Desmielinizantes/genética , Feminino , Humanos , Masculino , Oxigenases de Função Mista/genética , Mutação/genética , Linhagem , Estudos Retrospectivos , Paraplegia Espástica Hereditária/classificaçãoRESUMO
OBJECTIVE: This study aimed to provide information on the burden of illness and health-related quality of life (HRQoL) in children with epilepsy who experience prolonged acute convulsive seizures (PACS) in the community setting, and to investigate factors that may predict poor HRQoL in this population. METHODS: Noninstitutionalized children (aged 3-16â¯years) who had experienced at least one PACS within the past year and had currently prescribed PACS rescue medication were enrolled in a cross-sectional study in Germany, Italy, Spain, and the United Kingdom (Practices in Emergency and Rescue medication For Epilepsy managed with Community-administered Therapy 3 [PERFECT-3]). Clinicians, parents/guardians, and patients completed web-based questionnaires regarding clinical characteristics, PACS frequency, and day-to-day impairment. Patients' HRQoL was rated by clinicians, parents/guardians, and patients themselves using the 5-dimension EuroQol questionnaire (EQ-5D) and summarized as a utility score. Potential predictors of poor HRQoL were tested in individual univariate generalized linear models and a global multivariable model. RESULTS: Enrolled children (Nâ¯=â¯286) had experienced 1-400 PACS (median: 4) in the past year. Clinicians reported that 216/281 patients (76.9%) had learning disabilities of varying severity. Mean EQ-5D utility scores rated by clinicians (nâ¯=â¯279), parents (nâ¯=â¯277), and patients (nâ¯=â¯85) were 0.52 (standard deviation: 0.41), 0.51 (0.39), and 0.74 (0.29), respectively. Increasing PACS frequency, increasing severity of learning disability, and specialist school attendance were significantly associated with decreasing EQ-5D utility score. In the multivariable model, having learning disabilities was the best predictor of poor HRQoL. SIGNIFICANCE: Health-related quality of life was very poor in many children with epilepsy whose PACS were managed with rescue medication in the community, with learning disability being the most powerful predictor of patients' HRQoL. Mean EQ-5D utility scores were lower (worse) than published values for many other chronic disorders, indicating that optimal treatment should involve helping children and their families to manage learning disabilities and day-to-day impairments, in addition to preventing seizures.
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Serviços de Saúde Comunitária/tendências , Efeitos Psicossociais da Doença , Serviços Médicos de Emergência/tendências , Epilepsia/psicologia , Qualidade de Vida/psicologia , Convulsões/psicologia , Adolescente , Anticonvulsivantes/administração & dosagem , Criança , Pré-Escolar , Serviços de Saúde Comunitária/métodos , Estudos Transversais , Serviços Médicos de Emergência/métodos , Epilepsia/tratamento farmacológico , Epilepsia/epidemiologia , Feminino , Alemanha/epidemiologia , Humanos , Itália/epidemiologia , Masculino , Pais/psicologia , Convulsões/tratamento farmacológico , Convulsões/epidemiologia , Espanha/epidemiologia , Inquéritos e Questionários , Fatores de Tempo , Reino Unido/epidemiologiaRESUMO
INTRODUCTION: Familial hemiplegic migraine (FHM) is a rare subtype of migraine with transient hemiplegic aura. PATIENTS AND METHODS: We describe three unrelated families with familial hemiplegic migraine type II (FHM2). Retrospectively, information on 47 family members could be obtained, 15 by personal examination and 32 by indirect anamnesis from relatives. Genetic analyses were performed in 13 patients. RESULTS: One family had a novel missense mutation in the ATP1A2 gene (c.659C>T, p.Ser220Leu) that segregated with the phenotype in three generations. Two further unrelated families with different ethnic backgrounds (one from Germany and one from Russia) had a missense mutation that has not been described as yet in FHM, but occurred in only a single patient with sporadic hemiplegic migraine (c.2723G>A, p.Arg908Gln). Clinically the patients had severe attacks lasting up to several weeks as well as epileptic seizures. Three patients with a proven mutation in the ATP1A2 gene clinically presented without hemiparesis. Furthermore, there was a possible relation of FHM2 to mental retardation in another two patients. CONCLUSION: Clinical symptoms may last for several weeks in some patients. Patients with FHM2 may also present without hemiplegia. Therefore, the full family history has to be taken into account to establish the diagnosis of FHM.
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Predisposição Genética para Doença/genética , Enxaqueca com Aura/diagnóstico , Enxaqueca com Aura/genética , Polimorfismo de Nucleotídeo Único/genética , ATPase Trocadora de Sódio-Potássio/genética , Adulto , Idoso , Sequência de Bases , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Dados de Sequência Molecular , Mutação/genética , LinhagemRESUMO
In recent years, intrathecal baclofen (ITB) has attained an important role in the treatment of severe spasticity and dystonia in children. There are principal differences between the use of ITB in children and its use in neurology and oncology in adults. Here, we present a consensus report on best practice for the treatment of severe spastic and dystonic movement disorders with ITB. Using a problem-orientated approach to integrate theories and methods, the consensus was developed by an interdisciplinary group of experienced ITB users and experts in the field of movement disorders involving 14 German centers. On the basis of the data pooled from more than 400 patients, the authors have summarized their experience and supporting evidence in tabular form to provide a concise, but still a comprehensive information base that represents our current understanding regarding ITB treatment options in children and adolescents.
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Baclofeno/uso terapêutico , Distúrbios Distônicos/tratamento farmacológico , Relaxantes Musculares Centrais/uso terapêutico , Espasticidade Muscular/tratamento farmacológico , Índice de Gravidade de Doença , Adolescente , Criança , Consenso , Feminino , Seguimentos , Humanos , Injeções Espinhais , MasculinoRESUMO
An increasing number of patients with 3p proximal deletions were reported in the previous decade, but the region responsible for the main features such as intellectual disability (ID) and developmental delay is not yet characterized. Here we report on two monozygotic twin brothers of 2 10/12 years and an 18-year-old man, all three of them displaying severe ID, psychomotoric delay, autistic features, and only mild facial dysmorphisms. Array CGH (aCGH), revealed a 6.55 Mb de novo interstitial deletion of 3p14.1p14.3 in the twin brothers and a 4.76 Mb interstitial deletion of 3p14.1p14.2 in the 18-year-old patient, respectively. We compared the malformation spectrum with previous molecularly well-defined patients in the literature and in the DECIPHER database (Database of Chromosomal Imbalance and Phenotype in Humans using Ensembl Resources; http://decipher.sanger.ac.uk/). In conclusion, the deletion of a region containing 3p14.2 seems to be associated with a relative concise phenotype including ID and developmental delay. Thus, we hypothesize that 3p14.2 is the potential core region in 3p proximal deletions. The knowledge of this potential core region could be helpful in the genetic counselling of patients with 3p proximal deletions, especially concerning their phenotype.
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Deleção Cromossômica , Cromossomos Humanos Par 3 , Gêmeos Monozigóticos/genética , Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/genética , Adolescente , Pré-Escolar , Mapeamento Cromossômico , Hibridização Genômica Comparativa , Fácies , Humanos , Masculino , FenótipoRESUMO
PURPOSE: Rasmussen encephalitis (RE) leads to progressive tissue and function loss of one brain hemisphere and often intractable epilepsy. This is the first randomized prospective treatment trial in RE. METHODS: Germany-wide, patients with suspected recent-onset RE were recruited and if eligible randomized to tacrolimus or intravenous immunoglobulins (IVIGs). A loss of motor function or hemispheric volume by ≥ 15% (in patients >12 years at disease onset: ≥ 8%) led to study exit. Untreated patients served as a historical control group. KEY FINDINGS: Over 6.3 years, 21 patients with recent-onset RE were identified. Sixteen were randomized to tacrolimus (n = 9) or IVIG (n = 7). Immunotreated patients had a longer "survival" than the historical controls. Neither treatment was more efficacious than the other. Two tacrolimus patients experienced serious adverse events. No immunotreated but several untreated patients developed intractable epilepsy. No patient with refractory epilepsy became treatment-responsive under immunotherapy. SIGNIFICANCE: The countrywide incidence rate of diagnosed RE is estimated as 2.4 cases/107 people ≤ age 18/year. Treatment with tacrolimus or IVIG may slow down tissue and function loss and prevent development of intractable epilepsy. However, immunotherapy may "arrest" patients in a dilemma state of pharmacoresistant epilepsy but too good function to be offered functional hemispherectomy. These compounds may therefore contribute to the therapeutic armamentarium for RE patients without difficult-to-treat epilepsies.
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Encefalite/tratamento farmacológico , Encefalite/epidemiologia , Imunoglobulinas Intravenosas/administração & dosagem , Imunossupressores/administração & dosagem , Tacrolimo/administração & dosagem , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Seguimentos , Humanos , Incidência , Estudos Longitudinais , Masculino , Estudos Prospectivos , Estudos Retrospectivos , Adulto JovemRESUMO
Spinal muscular atrophy (SMA) is a rare genetic disorder, with the most common form being 5q SMA. Survival of children with severe SMA is poor, yet major advances have been made in recent years in pharmaceutical treatment, such as gene-therapy, which has improved patient survival. Therefore, clinical problems, such as the development of spinal deformities in these genetically treated SMA children represent an unknown challenge in clinical work. In a retrospective case series, the development of spinal deformities was analyzed in 16 SMA children (9 male, 7 female) treated with onasemnogene abeparvovec in two institutions during the years 2020 to 2022. Ten out of sixteen patients had a significant kyphosis, and nine out of sixteen patients had significant scoliosis, with the mean curvature angles of 24 ± 27° for scoliosis, and 69 ± 15° for kyphosis. Based on these preliminary data, it can be assumed that early-onset kyphosis presents a clinical challenge in gene-therapy-treated SMA children. Larger datasets with longer follow-up times need to be collected in order to verify these preliminary observations.
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BACKGROUND: Infants with Rett syndrome (RTT) may have subtle anomalies in their prelinguistic vocalisations but the detection of these is difficult, since their conspicuous vocalisations are often interspersed with inconspicuous ones. AIMS AND METHODS: Extending a previous study with predominantly non-parents, the present study sampled parents of children with RTT and aimed to examine their gestalt perception of prelinguistic vocalisations. METHODS AND PROCEDURE: Parents (n = 76) of female children with RTT listened to vocalisation recordings from RTT and typically developing (TD) infants, including an inconspicuous vocalisation from a RTT girl. For each recording, parents indicated if the vocalisation was produced by a RTT or a TD child. RESULTS: Overall correct to incorrect identification rate was 2:1, which was comparable to that of the previous study. Intriguingly, parents of RTT children seemed to be sensitive to features characterising the vocalisations of RTT infants, which has especially influenced their perception of the inconspicuous vocalisation from a RTT girl. CONCLUSIONS AND IMPLICATIONS: These results invite further research on the potential characterising differences between vocalisations from TD infants and infants with divergent neurodevelopment.
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Percepção Auditiva , Síndrome de Rett , Criança , Lactente , Humanos , Feminino , Aprendizagem , Síndrome de Rett/diagnóstico , PaisRESUMO
Sialorrhea is defined as a chronic excessive flow of saliva from the mouth, often with adverse consequences for health and quality of life of patients. In addition to currently used non-drug treatment and systemic drugs, intraglandular Botulinum Neurotoxin A (BoNT/A) injections have been examined in case studies, controlled trials and clinical practice. Two pivotal Phase III trials recently led to market approval in the USA and EU for IncobotulinumtoxinA [Xeomin®, IncoBoNT/A, Clostridium botulinum neurotoxin type A (150 kD), free from complexing proteins, Merz Pharmaceuticals GmbH] for treatment of chronic sialorrhea in adults and pediatric patients. This review provides a multidisciplinary approach to discuss the current state of sialorrhea therapy as well as benefits and current limitations of BoNT/A injections. A consensus regarding treatment recommendations made available to physicians in Germany in 2022 has now been updated here for presentation to an international audience. This review provides a framework including a flow chart for patient selection, recommendations for dosing and the injection process, as well as a discussion of therapeutic goals, long-term benefits and safety aspects. This review is aimed at supporting physicians in developing multidisciplinary and individualized treatment approaches to achieve optimal benefits for patients.
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OBJECTIVE: Cannabidiol (CBD) is approved for treatment of Dravet syndrome (DS), Lennox-Gastaut syndrome (LGS), and tuberous sclerosis complex (TSC). Several studies suggest antiseizure effects also beyond these three epilepsy syndromes. METHODS: In a retrospective multicenter study, we analyzed the efficacy and tolerability of CBD in patients with epilepsy at 16 epilepsy centers. RESULTS: The study cohort comprised 311 patients with epilepsy with a median age of 11.3 (0-72) years (235 children and adolescents, 76 adults). Therapy with CBD was off-label in 91.3% of cases due to age, epilepsy subtype, lack of adjunct therapy with clobazam, and/or higher dose applied. CBD titration regimens were slower than recommended, with good tolerability of higher doses particularly in children. Of all patients, 36.9% experienced a reduction in seizure frequency of >50%, independent of their epilepsy subtype or clobazam co-medication. The median observation period was 15.8 months. About one third of all patients discontinued therapy within the observation period due to adverse effects or lack of efficacy. Adverse effects were reported frequently (46.9%). SIGNIFICANCE: Our study highlights that CBD has an antiseizure effect comparable to other antiseizure medications with a positive safety profile independent of the epilepsy subtype. Comedication with clobazam was not associated with a better outcome. Higher doses to achieve seizure frequency reduction were safe, particularly in children. These findings call for further trials for an extended approval of CBD for other epilepsy subtypes and for children <2 years of age.
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Canabidiol , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Epilepsia , Criança , Adulto , Adolescente , Humanos , Adulto Jovem , Pessoa de Meia-Idade , Idoso , Canabidiol/uso terapêutico , Anticonvulsivantes , Estudos Retrospectivos , Epilepsia/tratamento farmacológico , Convulsões/tratamento farmacológico , Clobazam/uso terapêutico , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/tratamento farmacológicoRESUMO
PURPOSE: To apply myelin-sensitive quantitative magnetic resonance imaging (MRI) techniques in defined hypomyelinating conditions and to identify spatial patterns of myelination as criteria for characterization of undefined disorders. MATERIALS AND METHODS: Seven patients were included, based on the diagnosis of mitochondrial cytopathy, Pelizaeus-Merzbacher disease, GJA12/GJC2-related Pelizaeus-Merzbacher-like disease, hypomyelination with atrophy of the basal ganglia and cerebellum, and leukoencephalopathy with ataxia, delayed dentition, and hypomyelination. The control group comprised 23 children and adolescents (age range 2.6-22.4 years). The 3T MRI protocol consisted of high-resolution T1- and T2-weighted 3D MRI, diffusion tensor (DTI), and magnetization transfer (MT) imaging. Parameter maps of mean diffusivity, fractional anisotropy, and MT saturation were displayed as pseudocolor overlays and assessed by region-of-interest and histogram analysis. RESULTS: Structural MRI revealed widespread signal alterations in white matter, but were hampered by signal heterogeneity. Quantitative DTI and MT reflected the degree of hypomyelination and discriminative patterns of myelination emerged on MT saturation maps. CONCLUSION: The quantitative parameters in the defined hypomyelination conditions provide additional criteria to further classify undefined white matter disorders.
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Encéfalo/patologia , Doenças Desmielinizantes/patologia , Imagem de Tensor de Difusão/métodos , Interpretação de Imagem Assistida por Computador/métodos , Imageamento Tridimensional/métodos , Fibras Nervosas Mielinizadas/patologia , Reconhecimento Automatizado de Padrão/métodos , Adolescente , Algoritmos , Criança , Pré-Escolar , Feminino , Humanos , Aumento da Imagem/métodos , Lactente , Masculino , Reprodutibilidade dos Testes , Sensibilidade e EspecificidadeRESUMO
We report a 2.5-year-old boy who was presented with acute lower gastrointestinal bleeding. Emergency endoscopy showed two active mucosal bleeding sites that were successfully clipped. Initially, multiple intestinal angiodysplasias were considered, ruled out by a second control endoscopy. Here, multiple superficial lesions were observed that bled upon contact by the endoscope, suggestive of connective tissue disorder. However, the patient showed no clinical dysmorphias, only hypermobility of the toes but no other symptoms typical for such disorders. Gene testing for Ehlers-Danlos-syndrome (EDS) revealed a pathogenic mutation in the COL3A1 causing loss-of-function of type 3-collagen. Thus, diagnosis of EDS type IV was established. Overall, EDS is a rare cause for intestinal bleeding in children, even in children with no other clinical symptoms. This case is the earliest presentation of EDS type IV with intestinal complications.
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Fatty acid hydroxylase-associated neurodegeneration (FAHN) is a rare disease that exhibits brain modifications and motor dysfunctions in early childhood. The condition is caused by a homozygous or compound heterozygous mutation in fatty acid 2 hydroxylase (FA2H), whose encoded protein synthesizes 2-hydroxysphingolipids and 2-hydroxyglycosphingolipids and is therefore involved in sphingolipid metabolism. A few FAHN model organisms have already been established and give the first insight into symptomatic effects. However, they fail to establish the underlying cellular mechanism of FAHN so far. Drosophila is an excellent model for many neurodegenerative disorders; hence, here, we have characterized and validated the first FAHN Drosophila model. The investigation of loss of dfa2h lines revealed behavioral abnormalities, including motor impairment and flying disability, in addition to a shortened lifespan. Furthermore, alterations in mitochondrial dynamics, and autophagy were identified. Analyses of patient-derived fibroblasts, and rescue experiments with human FA2H, indicated that these defects are evolutionarily conserved. We thus present a FAHN Drosophila model organism that provides new insights into the cellular mechanism of FAHN.
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The TuberOus SClerosis registry to increase disease Awareness (TOSCA) Post-Authorization Safety Study (PASS) was a non-interventional, multicenter, safety substudy that assessed the long-term safety of everolimus in patients with tuberous sclerosis complex (TSC) receiving everolimus for its licensed indications in the European Union (EU). This substudy also aimed to address TSC-associated neuropsychiatric disorders (TAND), sexual development, and male infertility. Eligible patients were enrolled from 39 sites across 11 countries in the EU. Outcomes of interest included the incidence of adverse events (AEs), serious adverse events (SAEs), treatment-related AEs (TRAEs), AEs leading to everolimus discontinuation, AEs of special interest (AESIs), the observed relationship between everolimus blood levels and incidence of AESIs, TAND, and reproductive clinical features. Herein, we present the final analysis results from this substudy (data cutoff date: 22 January 2020). At data cutoff, 179 patients were enrolled (female, 59.2%; age ≥18 years, 65.9%), of which the majority completed the study (76%). Overall, 121 patients (67.6%) had AEs regardless of causality. The most frequent TRAEs (≥5%) were stomatitis (7.8%), aphthous ulcer (6.7%), and hypercholesterolemia (6.1%). The most common treatment-related SAEs (>1%) were pneumonia (3.4%), influenza, pyelonephritis, aphthous ulcer, stomatitis, dyslipidemia, and hypercholesterolemia (1.1% each). Ten patients (5.6%) reported AEs leading to everolimus discontinuation. The common psychiatric disorders (N = 179) were autism spectrum disorder (21.8%), anxiety disorder (12.8%), "other" psychiatric disorders (8.9%), attention-deficit hyperactivity disorder, and depressive disorder (7.8% each). Of 179 patients, 88 (49.2%) had ≥1 behavioral problem. Of these (n = 88), the most common (>20%) were sleep difficulties (47.7%), anxiety (43.2%), mood swings (37.5%), depression mood (35.2%), impulsivity (30.7%), severe aggression (23.9%), and overactivity (22.7%). Of 179 patients, four (2.2%) reported abnormal puberty onset, and three (1.7%) reported other reproductive disorders. Of 106 females, 23 (21.7%) reported menstrual cycle disorders and 10 (9.4%) reported amenorrhea. Available data did not show delays in sexual maturation or an association between sexual development and infertility. The results demonstrate that everolimus has a manageable long-term safety profile in the TSC treatment setting. No new safety signals emerged. This substudy also contributed to the mapping of TAND and reproductive clinical features in patients with TSC.
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Variants in transcription factor p63 have been linked to several autosomal dominantly inherited malformation syndromes. These disorders show overlapping phenotypic characteristics with various combinations of the following features: ectodermal dysplasia, split-hand/foot malformation/syndactyly, lacrimal duct obstruction, hypoplastic breasts and/or nipples, ankyloblepharon filiforme adnatum, hypospadias and cleft lip/palate. We describe a family with six individuals presenting with a striking novel phenotype characterized by a furrowed or cleft tongue, a narrow face, reddish hair, freckles and various foot deformities. Whole-exome sequencing (WES) identified a novel heterozygous variant, c.3G>T, in TP63 affecting the translation initiation codon (p.1Met?). Sanger sequencing confirmed dominant inheritance of this unique variant in all six affected family members. In summary, our findings indicate that heterozygous variants in TP63 affecting the first translation initiation codon result in a novel phenotype dominated by a cleft tongue, expanding the complex genotypic and phenotypic spectrum of TP63-associated disorders.
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Fenda Labial , Fissura Palatina , Displasia Ectodérmica , Fenda Labial/genética , Fissura Palatina/genética , Códon de Iniciação , Displasia Ectodérmica/genética , Humanos , Masculino , Língua , Fatores de Transcrição/genética , Proteínas Supressoras de Tumor/genéticaRESUMO
Rett syndrome (RTT) is defined as a rare disease caused by mutations of the methyl-CpG binding protein 2 (MECP2). It is one of the most common causes of genetic mental retardation in girls, characterized by normal early psychomotor development, followed by severe neurologic regression. Hitherto, RTT lacks a specific biomarker, but altered lipid homeostasis has been found in RTT model mice as well as in RTT patients. We performed LC-MS/MS lipidomics analysis to investigate the cerebrospinal fluid (CSF) and plasma composition of patients with RTT for biochemical variations compared to healthy controls. In all seven RTT patients, we found decreased CSF cholesterol levels compared to age-matched controls (n = 13), whereas plasma cholesterol levels were within the normal range in all 13 RTT patients compared to 18 controls. Levels of phospholipid (PL) and sphingomyelin (SM) species were decreased in CSF of RTT patients, whereas the lipidomics profile of plasma samples was unaltered in RTT patients compared to healthy controls. This study shows that the CSF lipidomics profile is altered in RTT, which is the basis for future (functional) studies to validate selected lipid species as CSF biomarkers for RTT.
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STAG2 is a component of the large, evolutionarily highly conserved cohesin complex, which has been linked to various cellular processes like genome organization, DNA replication, gene expression, heterochromatin formation, sister chromatid cohesion, and DNA repair. A wide spectrum of germline variants in genes encoding subunits or regulators of the cohesin complex have previously been identified to cause distinct but phenotypically overlapping multisystem developmental disorders belonging to the group of cohesinopathies. Pathogenic variants in STAG2 have rarely been implicated in an X-linked cohesinopathy associated with undergrowth, developmental delay, and dysmorphic features. Here, we describe for the first time a mosaic STAG2 variant in an individual with developmental delay, microcephaly, and hemihypotrophy of the right side. We characterized the grade of mosaicism by deep sequencing analysis on DNA extracted from EDTA blood, urine and buccal swabs. Furthermore, we report an additional female with a novel de novo splice variant in STAG2. Interestingly, both individuals show supernumerary nipples, a feature that has not been reported associated to STAG2 before. Remarkably, additional analysis of STAG2 transcripts in both individuals showed only wildtype transcripts, even after blockage of nonsense-mediated decay using puromycin in blood lymphocytes. As the phenotype of STAG2-associated cohesinopathies is dominated by global developmental delay, severe microcephaly, and brain abnormalities, we investigated the expression of STAG2 and other related components of the cohesin complex during Bioengineered Neuronal Organoids (BENOs) generation by RNA sequencing. Interestingly, we observed a prominent expression of STAG2, especially between culture days 0 and 15, indicating an essential function of STAG2 in early brain development. In summary, we expand the genotypic and phenotypic spectrum of STAG2-associated cohesinopathies and show that BENOs represent a promising model to gain further insights into the critical role of STAG2 in the complex process of nervous system development.