RESUMO
Activity-dependent neuroprotective protein (ADNP) syndrome is a rare neurodevelopmental disorder resulting in intellectual disability, developmental delay and autism spectrum disorder (ASD) and is due to mutations in the ADNP gene. Ketamine treatment has emerged as a promising therapeutic option for ADNP syndrome, showing safety and apparent behavioral improvements in a first open label study. However, the molecular perturbations induced by ketamine remain poorly understood. Here, we investigated the longitudinal effect of ketamine on the blood transcriptome of 10 individuals with ADNP syndrome. Transcriptomic profiling was performed before and at multiple time points after a single low-dose intravenous ketamine infusion (0.5 mg/kg). We show that ketamine triggers immediate and profound gene expression alterations, with specific enrichment of monocyte-related expression patterns. These acute alterations encompass diverse signaling pathways and co-expression networks, implicating upregulation of immune and inflammatory-related processes and down-regulation of RNA processing mechanisms and metabolism. Notably, these changes exhibit a transient nature, returning to baseline levels 24 hours to 1 week after treatment. These findings enhance our understanding of ketamine's molecular effects and lay the groundwork for further research elucidating its specific cellular and molecular targets. Moreover, they contribute to the development of therapeutic strategies for ADNP syndrome and potentially, ASD more broadly.
Assuntos
Transtorno do Espectro Autista , Ketamina , Transcriptoma , Ketamina/farmacologia , Ketamina/administração & dosagem , Ketamina/uso terapêutico , Humanos , Masculino , Transcriptoma/efeitos dos fármacos , Criança , Feminino , Transtorno do Espectro Autista/tratamento farmacológico , Transtorno do Espectro Autista/genética , Transtorno do Espectro Autista/sangue , Pré-Escolar , Proteínas do Tecido Nervoso/genética , Deficiência Intelectual/tratamento farmacológico , Deficiência Intelectual/genética , Deficiências do Desenvolvimento/genética , Deficiências do Desenvolvimento/tratamento farmacológico , Perfilação da Expressão Gênica , Adolescente , Proteínas de HomeodomínioRESUMO
BACKGROUND: Compared with the general population, adults with an intellectual developmental disorder (IDD) are more likely to develop mental health problems and to receive high levels of psychotropic medication, particularly antipsychotics. The emotional development (ED) approach may help to better understand the nature of challenging behaviour (CB) and tailor treatment and support accordingly. The aim of this retrospective study was to investigate the impact of the ED approach on the prescription of psychotropic medication during inpatient psychiatric treatment. METHODS: The clinical data of 1758 patients were analysed within a retrospective study design over a period of 12 years. ED level was assessed (1) for the first time (INITIAL-SEO), (2) during a previous hospital stay (PAST-SEO) or (3) not at all (NO-SEO). The effects of the ED assessment and the respective intervention during the current admission on the number of psychotropics and the number and dosage of antipsychotics were analysed for the total sample, including those with CB, autism spectrum disorders and psychosis. Group differences were analysed by a chi-square test and a one-factorial analysis of variance. For analysing the impact of the application of the ED approach on psychotropic medication, a covariance model was applied. Changes between the subsamples were analysed by t-tests for dependent samples. RESULTS: The ED approach had a significant impact on reducing the overall amount of psychotropic medication and the dosage of antipsychotics in all patients with IDD. These effects were mainly attributable to those showing CB. In patients with autism spectrum disorders, the developmental approach reduced the number of antipsychotics. No effects could be observed in patients with psychosis; in this subsample, both the number and dosage of antipsychotics increased. CONCLUSIONS: The application of the ED approach in the current hospital stay reduced the number of psychotropic drugs and the number and dosage of antipsychotics, especially in those patients with IDD and CB, but also in those with autism spectrum disorders.
Assuntos
Deficiência Intelectual , Psicotrópicos , Humanos , Adulto , Estudos Retrospectivos , Deficiência Intelectual/tratamento farmacológico , Masculino , Feminino , Pessoa de Meia-Idade , Psicotrópicos/uso terapêutico , Adulto Jovem , Deficiências do Desenvolvimento/tratamento farmacológico , Antipsicóticos/uso terapêutico , Adolescente , Transtorno do Espectro Autista/tratamento farmacológico , Comportamento ProblemaRESUMO
BACKGROUND/AIMS/METHODS: Medication information is available from many sources. This short report provides a simple description of where caregivers of people with intellectual/developmental disability (IDD) obtain medication information, and compares these sources between family caregivers and direct support professionals (DSP). PROCEDURES/OUTCOMES: Cross-sectional study design using an internet-based survey of caregivers, aged 18 years or older, who provided support to adults with IDD. The primary outcome is the source of medication information reported by caregivers. RESULTS/CONCLUSIONS: Eighty-nine caregivers responded. Health care professionals were the primary source (87.6 %) of medication information, followed by the internet (77.5 %). There was no difference between caregiver groups for these two sources. The prescription label/information sheet was the next most common source (56.2 %), with significantly more family (76.2 %) versus DSP (38.3 %), p < 0.001. A medication reference was also common (43.8 %), with 28.6 % of family and 57.4 % of DSP, p = 0.006. House manager/nurse was next, with 16.9 %, and television/radio as a source (10.1 %), no difference between groups. Lastly, friends or coworkers were 7.9 %, with no DSP endorsing this option, p = 0.006. IMPLICATIONS: Caregivers obtain medication information from a variety of sources, with health care professionals being the primary source. The internet was also very common, which may be worrisome, due to the wide range of level of quality of information available. Educational interventions should be developed to provide caregivers with tools to be able identify and use legitimate medication information.
Assuntos
Cuidadores , Deficiência Intelectual , Adulto , Criança , Humanos , Deficiências do Desenvolvimento/tratamento farmacológico , Estudos Transversais , Pessoal de Saúde , Deficiência Intelectual/tratamento farmacológicoRESUMO
OBJECTIVE: Patients with developmental disabilities (DD) are frequently excluded from acute ischemic stroke (AIS) randomized control trials. We sought to evaluate the impact of having DD on this patient cohort. METHODS: The National Inpatient Sample was analyzed to explore the impact of AIS and treatment on discharge dispositions in patients with DD. Clinical characteristics, treatments, and outcomes were compared to fully-abled patients with AIS. RESULTS: 1,605,723 patients with AIS were identified from 2010-2019, of whom 4094 (0.30%) had a DD. AIS patients with DD were younger (60.31 vs 70.93 years, p < 0.01), less likely to be Caucasian (66.37%vs 68.09%, p = 0.01), and had higher AIS severity (0.63 vs 0.58, p < 0.01). Tissue plasminogen activator (tPA) was administered in 99,739 (6.2%) fully-abled patients and 196 (4.79%) of patients with DD (p < 0.01). Endovascular thrombectomy (EVT) was performed in 21,066 (1.31%) of fully-abled patients and 35 (0.85%) of patients with DD (p < 0.01). The presence of developmental disabilities were predictive of lower rates of tPA (OR:0.71,CI:0.56-0.87,p < 0.01) and EVT (OR:0.24,CI:0.16-0.36,p < 0.01). In a propensity score-matched cohort of all AIS patients who underwent EVT, there was no difference in functional outcome (p = 0.41), in-hospital mortality (0.10), and LOS (p = 0.79). CONCLUSION: AIS patients with DD were less likely to receive tPA and EVT compared to fully-abled patients. Individuals with DD had higher mortality and worse discharge disposition. There was no significant difference in post-EVT outcomes between fully-abled patients and patients with developmental disabilities. In the absence of prospective clinical trials, population based cross-sectional analyses such as the present study provide valuable clinical insight.
Assuntos
Isquemia Encefálica , Procedimentos Endovasculares , AVC Isquêmico , Acidente Vascular Cerebral , Humanos , Criança , Ativador de Plasminogênio Tecidual/uso terapêutico , Acidente Vascular Cerebral/terapia , Estudos Transversais , AVC Isquêmico/etiologia , Terapia Trombolítica/métodos , Estudos Prospectivos , Deficiências do Desenvolvimento/induzido quimicamente , Deficiências do Desenvolvimento/tratamento farmacológico , Resultado do Tratamento , Trombectomia/métodos , Isquemia Encefálica/cirurgia , Procedimentos Endovasculares/métodosRESUMO
BACKGROUND/AIMS: Persons with intellectual or developmental disabilities and who exhibit challenging behaviors are often prescribed medication to control behavior. Little is known about the environmental factors that may be associated with taking these medications. METHODS AND OUTCOMES: This study examined the association between individual and intermediate or environmental factors and the documented use of medication for clients with intellectual or developmental disabilities (IDD) who exhibit challenging behavior, using the 2014-15 National Core Indicators Adult Consumer Survey dataset. RESULTS AND CONCLUSIONS: Individual-level variables associated with a higher likelihood of taking medication for persons with IDD exhibiting challenging behaviors included being of younger age, male gender, having moderate or severe intellectual disability, being ambulatory, communicating verbally, having a behavioral plan, requiring support for behavioral challenges, and having a history of mental illness. Environment-level variables included infrequently eating out and having less everyday choice. This study found that restrictions in opportunities to make choices in their life was associated with a greater likelihood of being on a medication for persons with IDD who exhibit challenging behavior. Living in group home settings also increased the likelihood of medication use. A limitation of the study is a lack of information on why medications were prescribed and whether they were intended to treat the challenging behavior. IMPLICATIONS: This work has important implications for health providers, as addressing malleable social factors may provide an avenue for reducing challenging behaviors without the need for medication.
Assuntos
Deficiências do Desenvolvimento , Deficiência Intelectual , Adulto , Criança , Deficiências do Desenvolvimento/tratamento farmacológico , Humanos , Deficiência Intelectual/tratamento farmacológico , MasculinoRESUMO
OBJECTIVE: Adults with intellectual and developmental disabilities (IDD) are living longer, yet research about the medical and psychiatric needs of older adults still lags behind that of younger individuals with IDD. The aim of this study was to assess age-related differences in the mental health presentations of adults with IDD. METHODS: Fully deidentified data for adults 30 years and older were extracted from the START (Systemic, Therapeutic, Assessment, Resources, and Treatment) Information Reporting System, a deidentified database housed at the Center for START Services. Caregivers and START team documents reported psychiatric diagnoses, service use, recent stressors, and challenging behaviors. t Tests, Mann Whitney U tests, χ2 tests, and multinominal logistic regression models were used to compare the two age groups, 30-49 years (n = 1,188) versus 50 years and older (n = 464). RESULTS: Older adults had more medical conditions, fewer reported psychiatric conditions, and were more likely to be taking more psychiatric medications compared to younger adults, after adjusting for demographic variables, disability level, and number of recent stressors. CONCLUSION: Although older individuals reported fewer psychiatric diagnoses, they were more likely to take higher numbers of psychiatric medications and have more medical conditions. Clinicians and researchers ought to devote more attention to the healthcare needs of older adults with IDD, a vulnerable group exposed to polypharmacy and at risk of adverse events.
Assuntos
Deficiências do Desenvolvimento , Deficiência Intelectual , Idoso , Cuidadores , Criança , Deficiências do Desenvolvimento/tratamento farmacológico , Deficiências do Desenvolvimento/epidemiologia , Humanos , Deficiência Intelectual/tratamento farmacológico , Deficiência Intelectual/epidemiologia , PolimedicaçãoRESUMO
Adults with intellectual or developmental disabilities often have hypertension and mental illness, and are prescribed medications for treatment. This study examined psychotropic medication adherence as a mediator between the association of residence type and antihypertensive medication adherence for adults with intellectual or developmental disabilities. We used Medicaid data of adults with intellectual or developmental disabilities who had hypertension and prescribed antihypertensive medication (N = 1,201) to measure the direct effect, indirect effect, and total effect of residence type (home vs. supervised setting) and antihypertensive medication adherence, with a mediator of psychotropic medication adherence. The indirect effect of psychotropic medication adherence on antihypertensive medication adherence was 1.26 (OR = 1.26, CI: 1.08-1.52), holding residency constant. The direct effect of residential type on antihypertensive medication adherence was 3.75 (OR = 3.75, CI: 1.61-8.75). This association may be due to some features of having a mental illness or maybe the result of being prescribed more than one medication.
Assuntos
Hipertensão , Deficiência Intelectual , Adulto , Anti-Hipertensivos/uso terapêutico , Criança , Deficiências do Desenvolvimento/tratamento farmacológico , Humanos , Hipertensão/tratamento farmacológico , Deficiência Intelectual/tratamento farmacológico , Adesão à Medicação , Psicotrópicos/uso terapêutico , Estados UnidosRESUMO
Tyrosine hydroxylase (TH) deficiency is an autosomal recessive condition first described as a progressive, early-onset hypokinetic-rigid and dystonic syndrome that was responsive to levodopa. Here we present a child with developmental regression, proximal tremor, and encephalopathy found to have tyrosine hydroxylase deficiency in whom treatment resulted in acquisition of developmental milestones.
Assuntos
Encefalopatias/tratamento farmacológico , Deficiências do Desenvolvimento/tratamento farmacológico , Distúrbios Distônicos/congênito , Tremor/tratamento farmacológico , Encefalopatias/congênito , Deficiências do Desenvolvimento/genética , Distúrbios Distônicos/complicações , Distúrbios Distônicos/tratamento farmacológico , Humanos , Lactente , Levodopa/uso terapêutico , Masculino , Resultado do Tratamento , Tremor/congênitoRESUMO
Developmental and epileptic encephalopathies (DEE) constitute an expanding group of severely disabling and, most frequently, drug-resistant disorders starting in the first year of life. Among them, there is DEE43, caused by dominant mutations in the GABRB3 gene. We present first neuropathological findings in a novel, molecularly confirmed case with the fatal course. The neuropathological analysis revealed co-existing developmental anomalies and retardation of myelination resulting from disturbed early brain growth as well as lesions caused by epileptic hypoxic-ischemic episodes. Developmental anomalies included misplaced neurons in the cerebellar white matter, heterotopic neurons in the cortical molecular layer and in the molecular layer of the hippocampal dentate gyrus, dysmorphic cerebellar dentate nuclei and inferior olivary nuclei in the medulla oblongata. The migrational and maturational disorders leading to the neuronal network dysfunction could be the cause of both the lack of development and the ineffectiveness of antiepileptic treatment in children affected by DEE. Giving the presented neuropathological description and based on the literature, we discuss the pathomechanism of the disease, to improve current understanding of both the lack of development and the ineffectiveness of treatment of affected children.
Assuntos
Encefalopatias , Eletroencefalografia , Anticonvulsivantes/uso terapêutico , Encéfalo/diagnóstico por imagem , Encefalopatias/tratamento farmacológico , Criança , Deficiências do Desenvolvimento/tratamento farmacológico , HumanosRESUMO
Bachmann-Bupp syndrome (BABS) is a rare syndrome caused by gain-of-function variants in the C-terminus of ornithine decarboxylase (ODC coded by the ODC1 gene). BABS is characterized by developmental delay, macrocephaly, macrosomia, and an unusual pattern of non-congenital alopecia. Recent diagnosis of four more BABS patients provides further characterization of the phenotype of this syndrome including late-onset seizures in the oldest reported patient at 23 years of age, representing the first report for this phenotype in BABS. Neuroimaging abnormalities continue to be an inconsistent feature of the syndrome. This may be related to the yet unknown impact of ODC/polyamine dysregulation on the developing brain in this syndrome. Variants continue to cluster, providing support to a universal biochemical mechanism related to elevated ODC protein, enzyme activity, and abnormalities in polyamine levels. Recommendations for medical management can now be suggested as well as the potential for targeted molecular or metabolic testing when encountering this unique phenotype. The natural history of this syndrome will evolve with difluoromethylornithine (DFMO) therapy and raise new questions for further study and understanding.
Assuntos
Alopecia/genética , Deficiências do Desenvolvimento/genética , Transportadores de Ácidos Dicarboxílicos/genética , Megalencefalia/genética , Proteínas de Transporte da Membrana Mitocondrial/genética , Adolescente , Adulto , Alopecia/diagnóstico , Alopecia/tratamento farmacológico , Alopecia/patologia , Encéfalo/anormalidades , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Criança , Pré-Escolar , Deficiências do Desenvolvimento/diagnóstico , Deficiências do Desenvolvimento/diagnóstico por imagem , Deficiências do Desenvolvimento/tratamento farmacológico , Eflornitina/uso terapêutico , Feminino , Predisposição Genética para Doença , Humanos , Lactente , Recém-Nascido , Masculino , Megalencefalia/diagnóstico por imagem , Megalencefalia/tratamento farmacológico , Megalencefalia/patologia , Neuroimagem , Fenótipo , Poliaminas/metabolismo , Convulsões/diagnóstico , Convulsões/tratamento farmacológico , Convulsões/genética , Convulsões/patologia , Adulto JovemRESUMO
AIM: To compare the effect of bilateral submandibular duct ligation and botulinum neurotoxin A (BoNT-A) on drooling severity and its impact on daily life and care in children and adolescents with moderate-to-severe drooling. METHOD: This was a randomized, interventional, controlled trial in which 53 children and adolescents (31 males, 22 females, mean age 11y, range 8-22y, SD 2y 10mo) with cerebral palsy (58.5%) or other non-progressive developmental disorders (41.5%) were randomized to BoNT-A (n=26) or bilateral submandibular duct ligation (n=27). A parent questionnaire on the severity of drooling in specific positions and daily activities and the impact of drooling on daily life and care was filled out at baseline and 8 and 32 weeks posttreatment. RESULTS: Both BoNT-A and bilateral submandibular duct ligation had a positive effect on daily care, damage to electronic equipment and/or furniture, social interactions, and self-esteem. However, bilateral submandibular duct ligation had a significant greater and longer-lasting short- (8wks) and medium-term (32wks) effect on daily care, reducing damage to electronic devices, and improving social interactions and satisfaction with life in general. INTERPRETATION: This randomized controlled trial confirms reduced drooling by both BoNT-A and bilateral submandibular duct ligation, but provides new evidence on improved well-being through a reduction in drooling. Even though there is a greater risk of complications and morbidity after bilateral submandibular duct ligation, compared to BoNT-A there was a significantly greater and longer-lasting positive effect on most outcomes. What this paper adds Bilateral botulinum neurotoxin A (BoNT-A) and submandibular duct ligation had a positive effect on the well-being of individuals with moderate-to-severe drooling. Bilateral submandibular duct ligation had a greater effect on the impact of drooling during daily care than BoNT-A. Bilateral submandibular duct ligation reduced damage to electronic devices and improved social interactions and satisfaction with life.
Assuntos
Toxinas Botulínicas Tipo A/uso terapêutico , Deficiências do Desenvolvimento/terapia , Qualidade de Vida , Ductos Salivares/cirurgia , Sialorreia/terapia , Adolescente , Criança , Deficiências do Desenvolvimento/tratamento farmacológico , Deficiências do Desenvolvimento/cirurgia , Feminino , Humanos , Masculino , Sialorreia/tratamento farmacológico , Sialorreia/cirurgia , Resultado do Tratamento , Adulto JovemRESUMO
Schaaf-Yang syndrome is a genetic disorder caused by mutations in the paternal allele of the MAGEL2 gene. Developmental delay, feeding difficulties, joint contractures and a high prevalence of autism spectrum disorders are characteristic of the syndrome. Endocrine abnormalities include mostly various pituitary hormonal deficiencies, presenting as hypoglycemia in 48% of reported cases. Persistent hyperinsulinism was only described in two siblings and responded to diazoxide treatment. We describe a unique case of an infant with Schaaf-Yang syndrome that presented with persistent hyperinsulinism unresponsive to diazoxide. Furthermore, we conducted a literature review of the endocrine abnormalities described in MAGEL2 related disorders. The case presented expands the clinical phenotype of Schaaf-Yang syndrome and emphasizes the importance of endocrine follow-up in these patients. Further investigation into the role of MAGEL2 in the regulation of pancreatic beta-cell insulin secretion, will improve our understanding of the abnormalities in glucose regulation in this syndrome.
Assuntos
Deficiências do Desenvolvimento/genética , Hiperinsulinismo/genética , Fenótipo , Proteínas/genética , Deficiências do Desenvolvimento/tratamento farmacológico , Deficiências do Desenvolvimento/patologia , Diazóxido/uso terapêutico , Feminino , Humanos , Hiperinsulinismo/tratamento farmacológico , Hiperinsulinismo/patologia , Lactente , Insulina/sangue , Mutação , SíndromeRESUMO
The use of psychotropic medication in children is increasing worldwide. Children with developmental disabilities seem to be prescribed these medications at a higher rate compared to their non-disabled peers. Little is known about prescribing in non-Western, middle-income studies. In Iran, the file records of 1133 children, aged 2 to 17 years, assessed as having autism spectrum disorder (ASD) or an intellectual disability (ID) in Tehran City and Province from 2005 to 2019 were collated, and information from parental reports of medications was extracted. Upwards of 80% of children with ASD and 56% of those with ID were prescribed a psychotropic medication with around one quarter in each group taking two or more medications. The rates were higher among male children showing difficult-to-manage behaviors such as hyperactivity, but less so for children of fathers with higher levels of education. The lack of alternative management strategies may be a significant driver for the use of psychotropic medications in Iran and other Low and Middle Income countries, despite their known side effects, and their failure to address the developmental needs of the children. Rather, multi-disciplinary, behavioral, therapeutic, and educational interventions are required, but these are not available widely in Iran, although a start has been made.
Assuntos
Transtorno do Espectro Autista , Deficiência Intelectual , Adolescente , Transtorno do Espectro Autista/tratamento farmacológico , Transtorno do Espectro Autista/epidemiologia , Criança , Pré-Escolar , Deficiências do Desenvolvimento/tratamento farmacológico , Deficiências do Desenvolvimento/epidemiologia , Humanos , Deficiência Intelectual/tratamento farmacológico , Deficiência Intelectual/epidemiologia , Irã (Geográfico)/epidemiologia , Masculino , Psicotrópicos/uso terapêuticoRESUMO
OBJECTIVE: The authors examined the prevalence and correlates of psychotropic medication prescribing among outpatient youths with intellectual and developmental disabilities. METHODS: The authors reviewed cross-sectional data on medications for 1,333 youths (ages 5-21 years) with intellectual and developmental disabilities who were referred to a community-based mental health crisis service. Descriptive statistics and regression analysis were used to describe the study group and to identify correlates of psychotropic polypharmacy, antipsychotic use, and anticonvulsant use in the absence of a seizure disorder. RESULTS: Most youths were taking psychotropic medications (N=1,139, 86%), often three or more medications (N=733, 55%) from two or more drug classes (N=919, 69%). Most youths received antipsychotics (N=863, 65%), and a third (N=432, 32%) were taking anticonvulsants in the absence of a seizure disorder. Greater severity (number of psychiatric diagnoses and recent psychiatric hospitalization), older age, and living in a group home were significantly correlated with these practices. CONCLUSIONS: Polypharmacy, antipsychotic use, and anticonvulsant use in the absence of seizure disorders were common among youths with intellectual and developmental disabilities referred to the crisis service. Older age, number of psychiatric diagnoses, living in a group home, and psychiatric hospitalization correlate with these prescribing practices. These elevated prescribing rates in a very vulnerable population warrant further study.
Assuntos
Deficiências do Desenvolvimento , Deficiência Intelectual , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Estudos Transversais , Deficiências do Desenvolvimento/tratamento farmacológico , Deficiências do Desenvolvimento/epidemiologia , Humanos , Deficiência Intelectual/tratamento farmacológico , Deficiência Intelectual/epidemiologia , Polimedicação , Psicotrópicos/uso terapêutico , Adulto JovemRESUMO
BACKGROUND: Creatine transporter deficiency is an inborn error of metabolism caused by a deficiency in the creatine transporter protein encoded by the SLC6A8 gene. Previous treatment with creatine supplementation, either alone or in combination with creatine precursors (arginine or glycine), has been attempted; the efficacy of therapy, however, remains controversial. METHODS AND RESULTS: To analyze the treatment efficacy of high-dose creatine supplementation on creatine transporter deficiency, we reported a child diagnosed with creatine transporter deficiency, who was treated with a conventional dose of creatine (400 mg/kg/d) for 1 month, then twice the dose (800 mg/kg/d) for 2 months, and finally 3 times the dose (1200 mg/kg/d) for 3 months. The patient tolerated the treatment well and showed improvements in muscle mass and strength when the creatine dose was gradually increased to 1200 mg/kg/d. However, when assessed by proton magnetic resonance spectroscopy (H-MRS), the brain creatine concentration did not increase, and there was no improvement in speech and neurodevelopmental symptoms. CONCLUSION: We conclude that high-dose creatine supplementation (1200 mg/kg/d) alone improved muscular symptoms, but did not improve cognitive symptoms and brain creatine concentration assessed using H-MRS. Therefore, new treatment strategies are required for the management of creatine transporter deficiency.
Assuntos
Creatina/uso terapêutico , Deficiências do Desenvolvimento/tratamento farmacológico , Erros Inatos do Metabolismo/tratamento farmacológico , Proteínas do Tecido Nervoso/genética , Proteínas da Membrana Plasmática de Transporte de Neurotransmissores/genética , Criança , Cognição , Creatina/administração & dosagem , Creatina/efeitos adversos , Deficiências do Desenvolvimento/genética , Deficiências do Desenvolvimento/patologia , Suplementos Nutricionais , Tolerância a Medicamentos , Humanos , Desenvolvimento da Linguagem , Masculino , Erros Inatos do Metabolismo/genética , Erros Inatos do Metabolismo/patologia , Força Muscular , Proteínas do Tecido Nervoso/deficiência , Proteínas da Membrana Plasmática de Transporte de Neurotransmissores/deficiênciaRESUMO
Succinic semialdehyde dehydrogenase deficiency (SSADHD) is a rare inborn metabolic disorder caused by the functional impairment of SSADH (encoded by the ALDH5A1 gene), an enzyme essential for metabolism of the inhibitory neurotransmitter γ-aminobutyric acid (GABA). In SSADHD, pathologic accumulation of GABA and its metabolite γ-hydroxybutyrate (GHB) results in broad spectrum encephalopathy including developmental delay, ataxia, seizures, and a heightened risk of sudden unexpected death in epilepsy (SUDEP). Proof-of-concept systemic SSADH restoration via enzyme replacement therapy increased survival of SSADH knockout mice, suggesting that SSADH restoration might be a viable intervention for SSADHD. However, before testing enzyme replacement therapy or gene therapy in patients, we must consider its safety and feasibility in the context of early brain development and unique SSADHD pathophysiology. Specifically, a profound use-dependent downregulation of GABAA receptors in SSADHD indicates a risk that any sudden SSADH restoration might diminish GABAergic tone and provoke seizures. In addition, the tight developmental regulation of GABA circuit plasticity might limit the age window when SSADH restoration is accomplished safely. Moreover, given SSADH expressions are cell type-specific, targeted instead of global restoration might be necessary. We therefore describe 3 key parameters for the clinical readiness of SSADH restoration: (1) rate, (2) timing, and (3) cell type specificity. Our work focuses on the construction of a novel SSADHD mouse model that allows "on-demand" SSADH restoration for the systematic investigation of these key parameters. We aim to understand the impacts of specific SSADH restoration protocols on brain physiology, accelerating bench-to-bedside development of enzyme replacement therapy or gene therapy for SSADHD patients.
Assuntos
Erros Inatos do Metabolismo dos Aminoácidos/tratamento farmacológico , Erros Inatos do Metabolismo dos Aminoácidos/metabolismo , Deficiências do Desenvolvimento/tratamento farmacológico , Deficiências do Desenvolvimento/metabolismo , Terapia de Reposição de Enzimas/métodos , Succinato-Semialdeído Desidrogenase/deficiência , Ácido gama-Aminobutírico/efeitos dos fármacos , Ácido gama-Aminobutírico/metabolismo , Animais , Modelos Animais de Doenças , Camundongos , Camundongos Endogâmicos C57BL , Succinato-Semialdeído Desidrogenase/metabolismoAssuntos
Deficiências do Desenvolvimento/tratamento farmacológico , Deficiências do Desenvolvimento/genética , Dopaminérgicos/uso terapêutico , Distúrbios Distônicos/congênito , Levodopa/uso terapêutico , Distúrbios Distônicos/tratamento farmacológico , Distúrbios Distônicos/genética , Exoma/genética , Ácido Homovanílico/líquido cefalorraquidiano , Humanos , Ácido Hidroxi-Indolacético/líquido cefalorraquidiano , Lactente , Masculino , Mutação/genética , Resultado do TratamentoRESUMO
PSTPIP1-associated myeloid-related proteinemia inflammatory (PAMI) syndrome is a rare early-onset autoinflammatory disease associated with various hematologic findings, including chronic neutropenia and pancytopenia. We report a unique case of PAMI syndrome in a toddler with transfusion-dependent hemolytic anemia, hepatosplenomegaly, failure to thrive, developmental delay, and multiple malformations. Because of acute inflammatory-driven decompensation, anakinra was started with dramatic improvement of both the hematologic and neurologic involvement. A customized next-generation sequencing panel later identified a de novo pathogenic variant in the PSTPIP1 gene, confirming the diagnosis. Our case illustrates the broad spectrum of phenotypes associated with PAMI syndrome, which should be considered in any case of unexplained cytopenias associated with autoinflammatory stigmata. It is also one of the few reports of neurologic involvement in PSTPIP1-associated inflammatory diseases. Increased awareness of this rare disease and early performance of genetic testing can correctly diagnose PAMI syndrome and prevent disease complications.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas do Citoesqueleto/genética , Hemólise , Proteína Antagonista do Receptor de Interleucina 1/uso terapêutico , Doenças Raras/genética , Anormalidades Múltiplas , Anemia Hemolítica Congênita/sangue , Anemia Hemolítica Congênita/tratamento farmacológico , Atrofia/diagnóstico por imagem , Atrofia/tratamento farmacológico , Transfusão de Sangue , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Proteína C-Reativa/análise , Doença Crônica , Deficiências do Desenvolvimento/tratamento farmacológico , Fácies , Insuficiência de Crescimento/tratamento farmacológico , Febre/urina , Hemólise/efeitos dos fármacos , Hepatomegalia/diagnóstico por imagem , Hepatomegalia/tratamento farmacológico , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Lactente , Linfadenopatia/tratamento farmacológico , Masculino , Pancitopenia , Fenótipo , Doenças Raras/sangue , Doenças Raras/tratamento farmacológico , Contagem de Reticulócitos , Esplenomegalia/diagnóstico por imagem , Esplenomegalia/tratamento farmacológico , SíndromeRESUMO
We report two siblings with intractable epilepsy, developmental regression, and progressive cerebellar atrophy due to biallelic variants in the gene CAD. For the affected girl, uridine started at age 5 resulted in dramatic improvements in seizure control and development, cessation of cerebellar atrophy, and resolution of hematological abnormalities. Her older brother had a more severe course and only modest response to uridine started at 14 years old. Treatment of this progressive condition via uridine supplementation provides an example of precision diagnosis and treatment using clear outcome measures and biomarkers to monitor efficacy.