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1.
Neurobiol Dis ; 190: 106386, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-38110041

RESUMO

Succinic semialdehyde dehydrogenase deficiency (SSADHD) is a neurometabolic disorder caused by ALDH5A1 mutations presenting with autism and epilepsy. SSADHD leads to impaired GABA metabolism and results in accumulation of GABA and γ-hydroxybutyrate (GHB), which alter neurotransmission and are thought to lead to neurobehavioral symptoms. However, why increased inhibitory neurotransmitters lead to seizures remains unclear. We used induced pluripotent stem cells from SSADHD patients (one female and two male) and differentiated them into GABAergic and glutamatergic neurons. SSADHD iGABA neurons show altered GABA metabolism and concomitant changes in expression of genes associated with inhibitory neurotransmission. In contrast, glutamatergic neurons display increased spontaneous activity and upregulation of mitochondrial genes. CRISPR correction of the pathogenic variants or SSADHD mRNA expression rescue various metabolic and functional abnormalities in human neurons. Our findings uncover a previously unknown role for SSADHD in excitatory human neurons and provide unique insights into the cellular and molecular basis of SSADHD and potential therapeutic interventions.


Assuntos
Erros Inatos do Metabolismo dos Aminoácidos , Células-Tronco Pluripotentes Induzidas , Humanos , Masculino , Feminino , Células-Tronco Pluripotentes Induzidas/metabolismo , Erros Inatos do Metabolismo dos Aminoácidos/tratamento farmacológico , Erros Inatos do Metabolismo dos Aminoácidos/genética , Erros Inatos do Metabolismo dos Aminoácidos/metabolismo , Neurônios/metabolismo , Ácido gama-Aminobutírico/metabolismo , Succinato-Semialdeído Desidrogenase/genética
2.
Mol Genet Metab ; 142(1): 108363, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38452608

RESUMO

Succinic semialdehyde dehydrogenase deficiency (SSADHD) (OMIM #271980) is a rare autosomal recessive metabolic disorder caused by pathogenic variants of ALDH5A1. Deficiency of SSADH results in accumulation of γ-aminobutyric acid (GABA) and other GABA-related metabolites. The clinical phenotype of SSADHD includes a broad spectrum of non-pathognomonic symptoms such as cognitive disabilities, communication and language deficits, movement disorders, epilepsy, sleep disturbances, attention problems, anxiety, and obsessive-compulsive traits. Current treatment options for SSADHD remain supportive, but there are ongoing attempts to develop targeted genetic therapies. This study aimed to create consensus guidelines for the diagnosis and management of SSADHD. Thirty relevant statements were initially addressed by a systematic literature review, resulting in different evidence levels of strength according to the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) criteria. The highest level of evidence (level A), based on randomized controlled trials, was unavailable for any of the statements. Based on cohort studies, Level B evidence was available for 12 (40%) of the statements. Thereupon, through a process following the Delphi Method and directed by the Appraisal of Guidelines for Research and Evaluation (AGREE II) criteria, expert opinion was sought, and members of an SSADHD Consensus Group evaluated all the statements. The group consisted of neurologists, epileptologists, neuropsychologists, neurophysiologists, metabolic disease specialists, clinical and biochemical geneticists, and laboratory scientists affiliated with 19 institutions from 11 countries who have clinical experience with SSADHD patients and have studied the disorder. Representatives from parent groups were also included in the Consensus Group. An analysis of the survey's results yielded 25 (83%) strong and 5 (17%) weak agreement strengths. These first-of-their-kind consensus guidelines intend to consolidate and unify the optimal care that can be provided to individuals with SSADHD.


Assuntos
Erros Inatos do Metabolismo dos Aminoácidos , Deficiências do Desenvolvimento , Succinato-Semialdeído Desidrogenase , Succinato-Semialdeído Desidrogenase/deficiência , Humanos , Succinato-Semialdeído Desidrogenase/genética , Erros Inatos do Metabolismo dos Aminoácidos/diagnóstico , Erros Inatos do Metabolismo dos Aminoácidos/terapia , Erros Inatos do Metabolismo dos Aminoácidos/genética , Consenso , Ácido gama-Aminobutírico/metabolismo , Guias de Prática Clínica como Assunto
3.
J Sleep Res ; 33(4): e14105, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38148273

RESUMO

Succinic semialdehyde dehydrogenase deficiency (SSADHD) is an inherited metabolic disorder of γ-aminobutyrate (GABA) catabolism. Cerebral waste clearance along glymphatic perivascular spaces depends on aquaporin 4 (AQP4) water channels, the function of which was shown to be influenced by GABA. Sleep disturbances are associated independently with SSADHD and glymphatic dysfunction. This study aimed to determine whether indices of the hyperGABAergic state characteristic of SSADHD coincide with glymphatic dysfunction and sleep disturbances and to explicate the modulatory effect that GABA may have on the glymphatic system. The study included 42 individuals (21 with SSADHD; 21 healthy controls) who underwent brain MRIs and magnetic resonance spectroscopy (MRS) for assessment of glymphatic dysfunction and cortical GABA, plasma GABA measurements, and circadian clock gene expression. The SSADHD subjects responded to an additional Children's Sleep Habits Questionnaire (CSHQ). Compared with the control group, SSADHD subjects did not differ in sex and age but had a higher severity of enlarged perivascular spaces in the centrum semiovale (p < 0.001), basal ganglia (p = 0.01), and midbrain (p = 0.001), as well as a higher MRS-derived GABA/NAA peak (p < 0.001). Within the SSADHD group, the severity of glymphatic dysfunction was specific for a lower MRS-derived GABA/NAA (p = 0.04) and lower plasma GABA (p = 0.004). Additionally, the degree of their glymphatic dysfunction correlated with the CSHQ-estimated sleep disturbances scores (R = 5.18, p = 0.03). In the control group, EPVS burden did not correlate with age or cerebral and plasma GABA values. The modulatory effect that GABA may exert on the glymphatic system has therapeutic implications for sleep-related disorders and neurodegenerative conditions associated with glymphatic dysfunction.


Assuntos
Erros Inatos do Metabolismo dos Aminoácidos , Sistema Glinfático , Imageamento por Ressonância Magnética , Transtornos do Sono-Vigília , Succinato-Semialdeído Desidrogenase , Ácido gama-Aminobutírico , Humanos , Masculino , Feminino , Ácido gama-Aminobutírico/metabolismo , Erros Inatos do Metabolismo dos Aminoácidos/fisiopatologia , Erros Inatos do Metabolismo dos Aminoácidos/complicações , Transtornos do Sono-Vigília/fisiopatologia , Sistema Glinfático/fisiopatologia , Criança , Succinato-Semialdeído Desidrogenase/deficiência , Espectroscopia de Ressonância Magnética , Adolescente , Encéfalo/diagnóstico por imagem , Encéfalo/fisiopatologia , Encéfalo/metabolismo , Aquaporina 4 , Laringoestenose/fisiopatologia , Pré-Escolar , Deficiências do Desenvolvimento
4.
Hum Genet ; 142(12): 1755-1776, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-37962671

RESUMO

To investigate the genotype-to-protein-to-phenotype correlations of succinic semialdehyde dehydrogenase deficiency (SSADHD), an inherited metabolic disorder of γ-aminobutyric acid catabolism. Bioinformatics and in silico mutagenesis analyses of ALDH5A1 variants were performed to evaluate their impact on protein stability, active site and co-factor binding domains, splicing, and homotetramer formation. Protein abnormalities were then correlated with a validated disease-specific clinical severity score and neurological, neuropsychological, biochemical, neuroimaging, and neurophysiological metrics. A total of 58 individuals (1:1 male/female ratio) were affected by 32 ALDH5A1 pathogenic variants, eight of which were novel. Compared to individuals with single homotetrameric or multiple homo and heterotetrameric proteins, those predicted not to synthesize any functional enzyme protein had significantly lower expression of ALDH5A1 (p = 0.001), worse overall clinical outcomes (p = 0.008) and specifically more severe cognitive deficits (p = 0.01), epilepsy (p = 0.04) and psychiatric morbidity (p = 0.04). Compared to individuals with predictions of having no protein or a protein impaired in catalytic functions, subjects whose proteins were predicted to be impaired in stability, folding, or oligomerization had a better overall clinical outcome (p = 0.02) and adaptive skills (p = 0.04). The quantity and type of enzyme proteins (no protein, single homotetramers, or multiple homo and heterotetramers), as well as their structural and functional impairments (catalytic or stability, folding, or oligomerization), contribute to phenotype severity in SSADHD. These findings are valuable for assessment of disease prognosis and management, including patient selection for gene replacement therapy. Furthermore, they provide a roadmap to determine genotype-to-protein-to-phenotype relationships in other autosomal recessive disorders.


Assuntos
Erros Inatos do Metabolismo dos Aminoácidos , Criança , Humanos , Masculino , Feminino , Erros Inatos do Metabolismo dos Aminoácidos/genética , Erros Inatos do Metabolismo dos Aminoácidos/metabolismo , Erros Inatos do Metabolismo dos Aminoácidos/patologia , Deficiências do Desenvolvimento/genética , Fenótipo , Succinato-Semialdeído Desidrogenase/genética , Succinato-Semialdeído Desidrogenase/metabolismo
5.
Epilepsia ; 64(11): 2982-2992, 2023 11.
Artigo em Inglês | MEDLINE | ID: mdl-37611929

RESUMO

OBJECTIVES: To assess the occurrence rate, characteristics, and impact of eating disorders (EDs) in adolescents with epilepsy. METHODS: In this observational study, adolescents with epilepsy seen in a single center between 2013 and 2022 who had comorbid EDs were compared to two control groups of adolescents with only epilepsy and only EDs. Patients with intellectual disability or autism spectrum disorder were excluded. Data retrieved included demographic and anthropometric details and clinical variables relating to seizure types, EDs, and psychiatric disorders and behaviors. RESULTS: A total of 376 subjects were included in the study: 84 adolescents with both epilepsy and eating disorders, 135 with only epilepsy, and 157 with only EDs. The rate of EDs in adolescents with epilepsy was 7.0% (95% confidence interval [CI] 5.6%-8.5%) overall, 11.3% (95% CI 8.8%-14.3%) in females, and 3.1% (95% CI 1.9%-4.8%) in males. The median (interquartile range [IQR]) time difference between the onset of epilepsy to an ED was 1.6 (.5-3.6) years. Among adolescents with epilepsy, those with an ED were more likely to be female (p = .001) and have a lower body mass index z-score (zBMI) percentile (p < .001). Epilepsy type, seizure frequency, or seizure duration were not specific for having or not having EDs. Among adolescents with EDs, those with epilepsy had a younger onset of their EDs (p < .001), included relatively more males (p = .007), and consisted of more cases of anorexia-nervosa-restrictive type (p < .001), and fewer cases of bulimia nervosa (p = .04) and binge eating disorder (p = .003). Adolescents with epilepsy and a comorbid ED were more likely to have psychiatric comorbidities such as depression, anxiety, and suicidality than adolescents with only epilepsy or EDs. SIGNIFICANCE: EDs should be suspected and screened for in intellectually intact female and male adolescents with epilepsy, irrespective of their epilepsy type. If disturbed eating behaviors or EDs are identified, further evaluation should be directed at detecting other psychopathologies, including suicidality.


Assuntos
Transtorno do Espectro Autista , Epilepsia , Transtornos da Alimentação e da Ingestão de Alimentos , Suicídio , Humanos , Masculino , Feminino , Adolescente , Suicídio/psicologia , Transtornos da Alimentação e da Ingestão de Alimentos/epidemiologia , Convulsões , Epilepsia/epidemiologia
6.
Epilepsia ; 64(6): 1516-1526, 2023 06.
Artigo em Inglês | MEDLINE | ID: mdl-36961285

RESUMO

OBJECTIVE: Succinic semialdehyde dehydrogenase deficiency (SSADHD) is a rare inherited metabolic disorder caused by a defect of γ-aminobutyrate (GABA) catabolism. Despite the resultant hyper-GABAergic environment facilitated by the metabolic defect, individuals with this disorder have a paradoxically high prevalence of epilepsy. We aimed to study the characteristics of epilepsy in SSADHD and its concordance with GABA-related metabolites and neurophysiologic markers of cortical excitation. METHODS: Subjects in an international natural history study of SSADHD underwent clinical assessments, electroencephalography, transcranial magnetic stimulation (TMS), magnetic resonance spectroscopy for GABA/N-acetyl aspartate quantification, and plasma GABA-related metabolite measurements. RESULTS: A total of 61 subjects with SSADHD and 42 healthy controls were included in the study. Epilepsy was present in 49% of the SSADHD cohort. Over time, there was an increase in severity in 33% of the subjects with seizures. The presence of seizures was associated with increasing age (p = .001) and lower levels of GABA (p = .002), γ-hydroxybutyrate (GHB; p = .004), and γ-guanidinobutyrate (GBA; p = .003). Seizure severity was associated with increasing age and lower levels of GABA-related metabolites as well as lower TMS-derived resting motor thresholds (p = .04). The cutoff values with the highest discriminative ability to predict seizures were age > 9.2 years (p = .001), GABA < 2.57 µmol·L-1 (p = .002), GHB < 143.6 µmol·L-1 (p = .004), and GBA < .075 µmol·L-1 (p = .007). A prediction model for seizures in SSADHD was comprised of the additive effect of older age and lower plasma GABA, GHB, and GBA (area under the receiver operating characteristic curve of .798, p = .008). SIGNIFICANCE: Epilepsy is highly prevalent in SSADHD, and its onset and severity correlate with an age-related decline in GABA and GABA-related metabolite levels as well as TMS markers of reduced cortical inhibition. The reduction of GABAergic activity in this otherwise hyper-GABAergic disorder demonstrates a concordance between epileptogenesis and compensatory responses. These findings may furthermore inform the timing of molecular interventions for SSADHD.


Assuntos
Erros Inatos do Metabolismo dos Aminoácidos , Epilepsia , Oxibato de Sódio , Humanos , Criança , Erros Inatos do Metabolismo dos Aminoácidos/complicações , Erros Inatos do Metabolismo dos Aminoácidos/metabolismo , Deficiências do Desenvolvimento , Epilepsia/metabolismo , Ácido gama-Aminobutírico/metabolismo , Aminobutiratos , Convulsões
7.
J Inherit Metab Dis ; 46(5): 992-1003, 2023 09.
Artigo em Inglês | MEDLINE | ID: mdl-37219411

RESUMO

Succinic semialdehyde dehydrogenase deficiency (SSADHD) is an inherited metabolic disorder with a variable phenotype and rate of progression. We aimed to develop and validate a clinical severity scoring (CSS) system applicable to the clinical setting and composed of five domains reflecting the principal manifestations of this disorder: cognitive, communication, motor, epilepsy, and psychiatry. A prospectively characterized cohort of 27 SSADHD subjects (55% females, median [IQR] age 9.2 [4.6-16.2] years) who enrolled in the SSADHD Natural History Study were included. The CSS was validated by comparison to an objective severity scoring (OSS) system based on comprehensive neuropsychologic and neurophysiologic assessments, which mirror and complement the domains of the CSS. The total CSS was sex and age-independent, and 80% of its domains lacked interdependence. With increasing age, there was a significant improvement in communication abilities (p = 0.05) and a worsening of epilepsy and psychiatric manifestations (p = 0.004 and p = 0.02, respectively). There was a significant correlation between all the CSS and OSS domain scores, as well as between the total CSS and OSS (R = 0.855, p < 0.001). Additionally, there were no significant demographic or clinical differences in the ratio of individuals in the upper quartile to the lower three quartiles of the CSS and OSS. The SSADHD CSS is validated using objective measures and offers a reliable condition-specific instrument universally applicable in clinical settings. This severity score may be utilized for family and patient counseling, genotype-phenotype correlations, biomarker development, clinical trials, and objective descriptions of the natural history of SSADHD.


Assuntos
Erros Inatos do Metabolismo dos Aminoácidos , Epilepsia , Feminino , Masculino , Humanos , Erros Inatos do Metabolismo dos Aminoácidos/genética , Deficiências do Desenvolvimento/genética , Succinato-Semialdeído Desidrogenase , Epilepsia/diagnóstico , Epilepsia/genética
8.
Epilepsy Behav ; 142: 109181, 2023 05.
Artigo em Inglês | MEDLINE | ID: mdl-37001467

RESUMO

The rarity and heterogeneity of neurometabolic diseases make it challenging to reach evidence-based principles for their specific treatments. Indeed, current treatments for many of these diseases remain symptomatic and supportive. However, an ongoing scientific and medical revolution has led to dramatic breakthroughs in molecular sciences and genetics, revealing precise pathophysiologic mechanisms. Accordingly, this has led to significant progress in the development of novel therapeutic approaches aimed at treating epilepsy resulting from these conditions, as well as their other manifestations. We overview recent notable treatment advancements, from vitamins, trace minerals, and diets to unique medications targeting the elemental pathophysiology at a molecular or cellular level, including enzyme replacement therapy, enzyme enhancing therapy, antisense oligonucleotide therapy, stem cell transplantation, and gene therapy.


Assuntos
Epilepsia , Humanos , Epilepsia/terapia , Epilepsia/genética , Dieta
9.
Dev Med Child Neurol ; 65(12): 1596-1606, 2023 12.
Artigo em Inglês | MEDLINE | ID: mdl-37246331

RESUMO

AIM: To elucidate the etiological aspects of autism spectrum disorder (ASD) in succinic semialdehyde dehydrogenase deficiency (SSADHD), related to dysregulation of γ-aminobutyric acid (GABA) and the imbalance of excitatory and inhibitory neurotransmission. METHOD: In this prospective, international study, individuals with SSADHD underwent neuropsychological assessments, as well as biochemical, neurophysiological, and neuroimaging evaluations. RESULTS: Of the 29 individuals (17 females) enrolled (median age [IQR] 10 years 5 months [5 years 11 months-18 years 1 month]), 16 were diagnosed with ASD. ASD severity significantly increased with age (r = 0.67, p < 0.001) but was inversely correlated with plasma GABA (r = -0.67, p < 0.001) and γ-hydroxybutyrate levels (r = -0.538, p = 0.004), and resting motor threshold as measured by transcranial magnetic stimulation (r = -0.44, p = 0.03). A discriminative analysis indicated that an age older than 7 years 2 months (p = 0.004) and plasma GABA levels less than 2.47 µM (p = 0.01) are the threshold values beyond which the likelihood of ASD presenting in individuals with SSADHD is increased. INTERPRETATION: ASD is prevalent but not universal in SSADHD, and it can be predicted by lower levels of plasma GABA and GABA-related metabolites. ASD severity in SSADHD increases with age and the loss of cortical inhibition. These findings add insight into the pathophysiology of ASD and may facilitate its early diagnosis and intervention in individuals with SSADHD.


Assuntos
Transtorno do Espectro Autista , Feminino , Humanos , Criança , Lactente , Estudos Prospectivos , Deficiências do Desenvolvimento , Ácido gama-Aminobutírico/metabolismo
10.
Muscle Nerve ; 66(6): 762-766, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-36214191

RESUMO

INTRODUCTION/AIMS: There is limited information on the potential effects of repeated intrathecal antisense oligonucleotide drug delivery on cerebrospinal fluid (CSF) biochemical and blood cell profiles. This study aimed to examine longitudinal changes in the biochemical components (glucose, protein) and blood cell counts in the CSF of spinal muscular atrophy (SMA) patients treated with intrathecal nusinersen. METHODS: We collected and analyzed clinical and CSF parameters (cell count, protein, glucose, culture) of 50 individuals with SMA during nusinersen treatment (22 type 1, 17 type 2, and 11 type 3). RESULTS: The median protein concentration at baseline and during treatment was within the normal range but rose during treatment and was significantly above baseline at the time of the ninth intrathecal injection (p = 0.02, two-tailed Wilcoxon matched-pairs test, and p = 0.0015, Friedman test for repeated measures). Further analysis showed that the increase in CSF protein concentration was evident for SMA types 2 and 3 patients, but not for type 1. This observation was also demonstrated by a significant correlation between the SMN2 gene copy number and the increase in CSF protein concentration (Spearman rank correlation test). DISCUSSION: Our results demonstrate that a delayed increase in CSF protein concentration is expected during nusinersen treatment for SMA types 2 and 3. This might reflect the medication's effect and a possible therapeutic biochemical marker.


Assuntos
Atrofia Muscular Espinal , Atrofias Musculares Espinais da Infância , Humanos , Atrofia Muscular Espinal/genética , Oligonucleotídeos/uso terapêutico , Atrofias Musculares Espinais da Infância/tratamento farmacológico , Injeções Espinhais , Glucose
11.
Eur J Neurol ; 29(8): 2420-2430, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35510740

RESUMO

BACKGROUND AND PURPOSE: The antisense oligonucleotide nusinersen (Spinraza) regulates splicing of the survival motor neuron 2 (SMN2) messenger RNA to increase SMN protein expression. Nusinersen has improved ventilator-free survival and motor function outcomes in infantile onset forms of spinal muscular atrophy (SMA), treated early in the course of the disease. However, the response in later onset forms of SMA is highly variable and dependent on symptom severity and disease duration at treatment initiation. Therefore, we aimed to identify novel noninvasive biomarkers that could predict the response to nusinersen in type II and III SMA patients. METHODS: Thirty-four SMA patients were included. We applied next generation sequencing to identify microRNAs in the cerebrospinal fluid (CSF) as candidate biomarkers predicting response to nusinersen. Hammersmith Functional Motor Scale Expanded (HFMSE) was conducted at baseline and 6 months after initiation of nusinersen therapy to assess motor function. Patients changing by ≥3 or ≤0 points in the HFMSE total score were considered to be responders or nonresponders, respectively. RESULTS: Lower baseline levels of two muscle microRNAs (miR-206 and miR-133a-3p), alone or in combination, predicted the clinical response to nusinersen after 6 months of therapy. Moreover, miR-206 levels were inversely correlated with the HFMSE score. CONCLUSIONS: Lower miR-206 and miR-133a-3p in the CSF predict more robust clinical response to nusinersen treatment in later onset SMA patients. These novel findings have high clinical relevance for identifying early treatment response to nusinersen in later onset SMA patients and call for testing the ability of miRNAs to predict more sustained long-term benefit.


Assuntos
Biomarcadores Farmacológicos , MicroRNAs , Oligonucleotídeos , Atrofias Musculares Espinais da Infância , Biomarcadores Farmacológicos/líquido cefalorraquidiano , Humanos , MicroRNAs/líquido cefalorraquidiano , Músculos , Oligonucleotídeos/uso terapêutico , Atrofias Musculares Espinais da Infância/líquido cefalorraquidiano , Atrofias Musculares Espinais da Infância/terapia
12.
Neuropediatrics ; 52(6): 475-479, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-33578445

RESUMO

Pompe's disease occurs due to an autosomal recessive trait resulting from numerous distinctive mutations in the GAA gene. It manifests as a broad spectrum of clinical phenotypes with progressive weakness that impairs motor and respiratory functions being common for all its forms. Cardiac hypertrophy is a prominent feature of its classic infantile form. To date, the pathogenic variant c.2015G > A (p.Arg672Gln) in exon 14 of the GAA gene has been described in 10 children of different ethnic groups, with variable phenotypic presentations. This work describes three children from two unrelated families of Arab ethnicity who presented with infantile-onset Pompe's disease as a result of a c.2015G > A (p.Arg672Gln) mutation. The clinical course of the children we report was more severe than previous reports. This further emphasizes the lack of a strict genotype-phenotype correlation in regard to the unique c.2015G > A (p.R672Q) mutation that causes Pompe's disease. This information contributes to the knowledge of the phenotypic expression of the specific mutation c.2015G > A (p.Arg672Gln) that causes Pompe's disease.


Assuntos
Doença de Depósito de Glicogênio Tipo II , alfa-Glucosidases , Progressão da Doença , Estudos de Associação Genética , Doença de Depósito de Glicogênio Tipo II/genética , Doença de Depósito de Glicogênio Tipo II/metabolismo , Humanos , Mutação , alfa-Glucosidases/genética , alfa-Glucosidases/metabolismo
13.
Childs Nerv Syst ; 37(4): 1295-1300, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33404719

RESUMO

PURPOSE: The existing data on the neurodevelopmental outcome of children born with an isolated atretic cephalocele (IAC) are scant. We aimed to expand upon these data by describing our experience with affected children, as well as assist parents and clinicians in deciding how to proceed when an IAC is diagnosed prenatally. METHODS: A follow-up study was conducted on nine children who were born with an IAC. Evaluations were performed by pediatric neurologists and child development specialists. Developmental outcomes were based on a global development evaluation that assessed gross and fine motor skills, receptive and expressive language levels, activities of daily living, communication skills, and social domains. Adaptive skills were estimated by the Adaptive Behavior Assessment System, Second Edition. RESULTS: None of the nine children (median age 4 years and 6 months) had abnormal findings on neurological examination. Six children had age-appropriate developmental milestones, two had a mild motor delay, and one had mild expressive language delay (catchup was achieved by all of the latter three by ~ 3.5 years of age). The mean general adaptive composite score was 105 ± 11.7 (normal = 100). None of the children had behavioral, social, or communication problems. CONCLUSIONS: Children diagnosed with an IAC with/without a falcine sinus and devoid of coexisting intracranial abnormalities seem to have a normal neurodevelopmental outcome. Continuation of pregnancy may be recommended when an IAC is detected prenatally, and reassurance if detected postnatally.


Assuntos
Atividades Cotidianas , Encefalocele , Criança , Desenvolvimento Infantil , Pré-Escolar , Feminino , Seguimentos , Humanos , Exame Neurológico , Gravidez
14.
J Card Surg ; 36(10): 3567-3576, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34350997

RESUMO

OBJECTIVE: The Klotho protein family plays important roles in several metabolic pathways. Soluble Klotho has been recently put forward as an antiaging protein, demonstrating renal and cardiovascular protective traits. Cardiopulmonary bypass (CPB) support during cardiac surgery has been implicated in several adverse outcomes in pediatric and adult patients. Our goal was to assess whether serum Klotho levels can be used to predict outcomes in children undergoing cardiac surgery with CPB due to congenital heart defects (CHDs). METHODS: This prospective study was conducted on pediatric patients admitted to two Pediatric Cardiac Intensive Care Units, between 2012 and 2018. All patients were born with CHD and underwent corrective surgery with CPB. Sequential blood samples were analyzed by enzyme-linked immunosorbent assay for soluble Klotho levels at baseline, 2, 6, and 24 h after surgery. The association between Klotho levels and several demographic, intraoperative, and postoperative clinical and laboratory parameters was studied. RESULTS: Twenty-nine children undergoing cardiac surgery with CPB support were included. Serum Klotho levels were shown to significantly decrease 2 h after surgery and increase to baseline levels after 6 h (p < .001 and p < .05, respectively). Patients with low Klotho levels 2 h after surgery were at a 32-fold higher risk for developing postoperative complications (p = .015, odds ratio < 0.03). Moreover, Klotho levels at each of the four time points were lower in patients who developed postoperative complications. CONCLUSIONS: Cardiac surgery with CPB results in a significant decrease of serum Klotho levels 2 h after surgery in pediatric patients with CHDs, which can be used to predict development of postoperative complications in this patient population.


Assuntos
Procedimentos Cirúrgicos Cardíacos , Cardiopatias Congênitas , Ponte Cardiopulmonar , Criança , Glucuronidase , Cardiopatias Congênitas/cirurgia , Humanos , Proteínas Klotho , Projetos Piloto , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/prevenção & controle , Estudos Prospectivos
15.
Acta Paediatr ; 109(3): 581-586, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31562776

RESUMO

AIM: To examine the prevalence of attention-deficit/hyperactivity disorder (ADHD) and related post-surgical weight loss in adolescents with severe obesity seeking bariatric surgery. METHODS: The study population included 84 adolescents (age 13-19 years; 44 males, 40 females) with severe obesity who sought bariatric surgery at the Sheba Medical Centre in Israel during the years 2011-2017. Anthropometric and clinical data were collected from medical records. A subgroup of 20 participants filled questionnaires that evaluated ADHD-like symptoms, eating behaviours and quality of life. Data on adolescents that ultimately underwent surgery (n = 45) were also obtained. RESULTS: The prevalence of ADHD was 28.6% in adolescents seeking bariatric surgery, much higher than that of the general adolescent population of Israel (17.1%, P < .001). There were no significant differences in reductions of weight, body mass index, body mass index standard deviation scores and body fat percent between participants with or without ADHD. In the subgroup that filled questionnaires, higher scores on ADHD-Rating Scale at baseline were associated with greater excess weight loss. CONCLUSION: The prevalence of ADHD in adolescents seeking bariatric surgery was very high. Diagnosed ADHD was not related to post-surgical weight loss, whereas baseline ADHD-related behaviour was associated with higher post-surgical weight loss.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade , Cirurgia Bariátrica , Obesidade Mórbida , Adolescente , Adulto , Transtorno do Deficit de Atenção com Hiperatividade/epidemiologia , Feminino , Humanos , Israel/epidemiologia , Masculino , Obesidade Mórbida/epidemiologia , Obesidade Mórbida/cirurgia , Prevalência , Qualidade de Vida , Inquéritos e Questionários , Adulto Jovem
16.
Eat Weight Disord ; 25(2): 365-371, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30368766

RESUMO

PURPOSE: Celiac disease (CD) is a chronic immune-mediated systemic disease characterized by inflammation and villous atrophy of the small intestine. A strict, lifelong gluten-free diet (GFD) is the only treatment for CD. Disordered eating behaviors (DEBs) prevail in adolescence and young adulthood, and confer a risk of developing into full-blown eating disorders. The aims of the current study were to assess the incidence and risk factors for DEBs among individuals with CD, and to examine an association between adherence to GFD and DEBs. METHODS: A cohort of 136 individuals with CD responded to a web-mediated survey that assessed DEBs and adherence to a GFD. The survey included demographic data (gender, age, weight, disease duration) and two self-rating questionnaires: the Eating Attitudes Test-26 and the gluten-free diet questionnaire. RESULTS: DEBs were found in 19% of female and 7% of male responders. These individuals were characterized by being overweight (p = 0.02), of an older age (p = 0.04) and female sex (p = 0.06). Strict adherence to a GFD was reported by 32% of the responders and was not correlated with age, disease duration, age at diagnosis of CD and with being overweight. CONCLUSIONS: Caregivers should be aware of the increased occurrence of DEBs in adolescents with CD, especially those who are overweight, older and of a female gender. LEVEL OF EVIDENCE: Level V, cross-sectional descriptive study.


Assuntos
Doença Celíaca/dietoterapia , Dieta Livre de Glúten , Comportamento Alimentar , Transtornos da Alimentação e da Ingestão de Alimentos/epidemiologia , Obesidade Infantil/epidemiologia , Adolescente , Fatores Etários , Criança , Feminino , Humanos , Israel/epidemiologia , Masculino , Cooperação do Paciente/estatística & dados numéricos , Fatores Sexuais , Inquéritos e Questionários
17.
Pediatr Crit Care Med ; 20(5): e231-e239, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31058792

RESUMO

OBJECTIVES: Stenotrophomonas maltophilia is a gram-negative opportunistic bacterium that may cause a myriad of clinical diseases in immunocompromised individuals. We aimed to describe the clinical characteristics, risk factors, mortality, and treatment of S. maltophilia bacteremia in critically ill children, a topic on which data are sparse. DESIGN: A multicenter observational retrospective study in which medical charts of critically ill children with S. maltophilia bacteremia were reviewed between 2012 and 2017. SETTING: Data were collected from each of the four largest PICUs nationwide, allocated in tertiary medical centers to which children with complex conditions are referred regularly. PATIENTS: A total of 68 suitable cases of S. maltophilia bacteremia were retrieved and reviewed. MEASUREMENTS AND MAIN RESULTS: The total occurrence rate of S. maltophilia isolation had increased significantly during the study period (r = 0.65; p = 0.02). The crude mortality was 42%, and the attributed mortality was 18%. Significant risk factors for mortality were a longer length of hospital stay prior to infection (33 d in nonsurvivors vs 28 in survivors; p = 0.03), a nosocomial source of infection (p = 0.02), presentation with septic shock (p < 0.001), and treatment with chemotherapy (p = 0.007) or carbapenem antibiotics (p = 0.05) prior to culture retrieval. On multivariate analysis, septic shock (odds ratio, 14.6; 95% CI, 1.45-147.05; p = 0.023) and being treated with chemotherapy prior to infection (odds ratio, 5.2; 95% CI, 1.59-17.19; p = 0.006)] were associated with mortality. The combination of ciprofloxacin, trimethoprim-sulfamethoxazole, and minocycline resulted in the longest survival time (p < 0.01). CONCLUSIONS: The significant attributed mortality associated with S. maltophilia bacteremia in critically ill children calls for an aggressive therapeutic approach. The findings of this investigation favor a combination of trimethoprim-sulfamethoxazole, ciprofloxacin, and minocycline.


Assuntos
Antibacterianos/administração & dosagem , Ciprofloxacina/administração & dosagem , Infecções por Bactérias Gram-Negativas , Minociclina/administração & dosagem , Stenotrophomonas maltophilia/imunologia , Sulfadoxina/administração & dosagem , Trimetoprima/administração & dosagem , Criança , Pré-Escolar , Comorbidade , Estado Terminal , Combinação de Medicamentos , Feminino , Infecções por Bactérias Gram-Negativas/tratamento farmacológico , Infecções por Bactérias Gram-Negativas/mortalidade , Humanos , Hospedeiro Imunocomprometido , Lactente , Unidades de Terapia Intensiva Pediátrica/estatística & dados numéricos , Masculino , Estudos Retrospectivos , Fatores de Risco
18.
Pediatr Diabetes ; 19(4): 749-755, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29493097

RESUMO

BACKGROUND: Disordered eating behaviors (DEBs) may lead to full blown eating disorders. Both type 1 diabetes mellitus (T1DM) and celiac disease (CD) have been linked to DEBs. OBJECTIVE: To compare the presence of DEBs between adolescents and young adults with a dual diagnosis of T1DM and CD, and individuals with only one of the diagnoses. METHODS: Individuals with a dual diagnosis of T1DM and CD ("T1DM + CD group" n = 39), with a diagnosis of T1DM only ("T1DM group" n = 97) and with a diagnosis of CD only ("CD group" n = 267) filled the Eating Attitude Test-26 (EAT-26) questionnaire. Those with T1DM completed in addition to the Diabetes Eating Problem Survey-Revised (DEPS-R). RESULTS: The study population comprised of 403 individuals, of whom 65% were females. There were no statistically significant differences among the groups in distribution of sex, age, hemoglobin A1c (HbA1c) levels, age of disease diagnosis and duration. The prevalence of DEBs in the T1DM + CD group was 3-fold higher (26.0%) than in the T1DM (8.2%) and CD (8.2%) groups (P = .003). This trend was observed for both females and males. Multivariate analysis demonstrated that the T1DM + CD group had an increased risk for DEBs (odds ratio, OR: 4.7, 95% confidence interval, CI: 1.9-11.2, P = .001) after adjustment for age, sex, and body mass index. Additionally, being female, older and overweight increased the risk for DEBs. HbA1c values were not associated with an increased DEBs rate. CONCLUSIONS: Individuals with the dual diagnoses of T1DM and CD have an increased likelihood to develop DEBs compared to those with only one of these diagnoses.


Assuntos
Doença Celíaca/complicações , Doença Celíaca/epidemiologia , Diabetes Mellitus Tipo 1/complicações , Diabetes Mellitus Tipo 1/epidemiologia , Transtornos da Alimentação e da Ingestão de Alimentos/complicações , Transtornos da Alimentação e da Ingestão de Alimentos/epidemiologia , Adolescente , Adulto , Doença Celíaca/diagnóstico , Criança , Pré-Escolar , Diabetes Mellitus Tipo 1/diagnóstico , Comportamento Alimentar/fisiologia , Transtornos da Alimentação e da Ingestão de Alimentos/diagnóstico , Feminino , Humanos , Masculino , Prevalência , Inquéritos e Questionários , Adulto Jovem
19.
J Neurodev Disord ; 16(1): 21, 2024 Apr 24.
Artigo em Inglês | MEDLINE | ID: mdl-38658850

RESUMO

BACKGROUND: Succinic semialdehyde dehydrogenase deficiency (SSADHD) represents a model neurometabolic disease at the fulcrum of translational research within the Boston Children's Hospital Intellectual and Developmental Disabilities Research Centers (IDDRC), including the NIH-sponsored natural history study of clinical, neurophysiological, neuroimaging, and molecular markers, patient-derived induced pluripotent stem cells (iPSC) characterization, and development of a murine model for tightly regulated, cell-specific gene therapy. METHODS: SSADHD subjects underwent clinical evaluations, neuropsychological assessments, biochemical quantification of γ-aminobutyrate (GABA) and related metabolites, electroencephalography (standard and high density), magnetoencephalography, transcranial magnetic stimulation, magnetic resonance imaging and spectroscopy, and genetic tests. This was parallel to laboratory molecular investigations of in vitro GABAergic neurons derived from induced human pluripotent stem cells (hiPSCs) of SSADHD subjects and biochemical analyses performed on a versatile murine model that uses an inducible and reversible rescue strategy allowing on-demand and cell-specific gene therapy. RESULTS: The 62 SSADHD subjects [53% females, median (IQR) age of 9.6 (5.4-14.5) years] included in the study had a reported symptom onset at ∼ 6 months and were diagnosed at a median age of 4 years. Language developmental delays were more prominent than motor. Autism, epilepsy, movement disorders, sleep disturbances, and various psychiatric behaviors constituted the core of the disorder's clinical phenotype. Lower clinical severity scores, indicating worst severity, coincided with older age (R= -0.302, p = 0.03), as well as age-adjusted lower values of plasma γ-aminobutyrate (GABA) (R = 0.337, p = 0.02) and γ-hydroxybutyrate (GHB) (R = 0.360, p = 0.05). While epilepsy and psychiatric behaviors increase in severity with age, communication abilities and motor function tend to improve. iPSCs, which were differentiated into GABAergic neurons, represent the first in vitro neuronal model of SSADHD and express the neuronal marker microtubule-associated protein 2 (MAP2), as well as GABA. GABA-metabolism in induced GABAergic neurons could be reversed using CRISPR correction of the pathogenic variants or mRNA transfection and SSADHD iPSCs were associated with excessive glutamatergic activity and related synaptic excitation. CONCLUSIONS: Findings from the SSADHD Natural History Study converge with iPSC and animal model work focused on a common disorder within our IDDRC, deepening our knowledge of the pathophysiology and longitudinal clinical course of a complex neurodevelopmental disorder. This further enables the identification of biomarkers and changes throughout development that will be essential for upcoming targeted trials of enzyme replacement and gene therapy.


Assuntos
Erros Inatos do Metabolismo dos Aminoácidos , Deficiências do Desenvolvimento , Células-Tronco Pluripotentes Induzidas , Succinato-Semialdeído Desidrogenase , Adolescente , Animais , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Camundongos , Erros Inatos do Metabolismo dos Aminoácidos/terapia , Erros Inatos do Metabolismo dos Aminoácidos/fisiopatologia , Erros Inatos do Metabolismo dos Aminoácidos/genética , Erros Inatos do Metabolismo dos Aminoácidos/complicações , Erros Inatos do Metabolismo dos Aminoácidos/metabolismo , Encéfalo/metabolismo , Encéfalo/fisiopatologia , Modelos Animais de Doenças , Neurônios GABAérgicos/metabolismo , Ácido gama-Aminobutírico/metabolismo , Células-Tronco Pluripotentes Induzidas/metabolismo , Transtornos do Neurodesenvolvimento/metabolismo , Transtornos do Neurodesenvolvimento/etiologia , Transtornos do Neurodesenvolvimento/genética , Succinato-Semialdeído Desidrogenase/deficiência , Succinato-Semialdeído Desidrogenase/metabolismo , Succinato-Semialdeído Desidrogenase/genética
20.
Neurology ; 101(3): 124-133, 2023 07 18.
Artigo em Inglês | MEDLINE | ID: mdl-36878704

RESUMO

Treatment options for inherited metabolic epilepsies are rapidly expanding with advances in molecular biology and the genomic revolution. Traditional dietary and nutrient modification and inhibitors or enhancers of protein and enzyme function, the mainstays of therapy, are undergoing continuous revisions to increase biological activity and reduce toxicity. Enzyme replacement and gene replacement and editing hold promise for genetically targeted treatment and cures. Molecular, imaging, and neurophysiologic biomarkers are emerging as key indicators of disease pathophysiology, severity, and response to therapy.


Assuntos
Epilepsia , Humanos , Criança , Epilepsia/genética , Epilepsia/terapia
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