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1.
Int J Mol Sci ; 25(5)2024 Feb 23.
Artigo em Inglês | MEDLINE | ID: mdl-38473862

RESUMO

Hereditary spastic paraplegias (HSPs) comprise a family of degenerative diseases mostly hitting descending axons of corticospinal neurons. Depending on the gene and mutation involved, the disease could present as a pure form with limb spasticity, or a complex form associated with cerebellar and/or cortical signs such as ataxia, dysarthria, epilepsy, and intellectual disability. The progressive nature of HSPs invariably leads patients to require walking canes or wheelchairs over time. Despite several attempts to ameliorate the life quality of patients that have been tested, current therapeutical approaches are just symptomatic, as no cure is available. Progress in research in the last two decades has identified a vast number of genes involved in HSP etiology, using cellular and animal models generated on purpose. Although unanimously considered invaluable tools for basic research, those systems are rarely predictive for the establishment of a therapeutic approach. The advent of induced pluripotent stem (iPS) cells allowed instead the direct study of morphological and molecular properties of the patient's affected neurons generated upon in vitro differentiation. In this review, we revisited all the present literature recently published regarding the use of iPS cells to differentiate HSP patient-specific neurons. Most studies have defined patient-derived neurons as a reliable model to faithfully mimic HSP in vitro, discovering original findings through immunological and -omics approaches, and providing a platform to screen novel or repurposed drugs. Thereby, one of the biggest hopes of current HSP research regards the use of patient-derived iPS cells to expand basic knowledge on the disease, while simultaneously establishing new therapeutic treatments for both generalized and personalized approaches in daily medical practice.


Assuntos
Ataxia Cerebelar , Células-Tronco Pluripotentes , Paraplegia Espástica Hereditária , Animais , Humanos , Paraplegia Espástica Hereditária/genética , Neurônios , Axônios , Mutação
2.
Int J Mol Sci ; 25(5)2024 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-38474113

RESUMO

NOTCH1-related leukoencephalopathy is a new diagnostic entity linked to heterozygous gain-of-function variants in NOTCH1 that neuroradiologically show some overlap with the inflammatory microangiopathy Aicardi-Goutières syndrome (AGS). To report a 16-year-old boy harbouring a novel NOTCH1 mutation who presented neuroradiological features suggestive of enhanced type I interferon signalling. We describe five years of follow-up and review the current literature on NOTCH1-related leukoencephalopathy. Clinical evaluation, standardised scales (SPRS, SARA, CBCL, CDI-2:P, WISCH-IV and VABS-2) and neuroradiological studies were performed, as well as blood DNA analysis. For the literature review, a search was performed on Pubmed, Scopus and Web of Science up to December 2023 using the following text word search strategy: (NOTCH1) AND (leukoencephalopathy). Our patient presents clinical features consistent with other reported cases with NOTCH1 mutations but is among the minority of patients with an onset after infancy. During the five-year follow-up, we observed an increase in the severity of spasticity and ataxia. However, at the age of 16 years, our proband is still ambulatory. As for other reported patients, he manifests psychiatric features ranging from hyperactivity during childhood to anxiety and depression during adolescence. The neuroradiological picture remained essentially stable over five years. In addition to the typical findings of leukoencephalopathy with cysts and calcifications already described, we report the presence of T2-hyperintensity and T1-hypotensity of the transverse pontine fibres, enhancement in the periventricular white matter after gadolinium administration and decreased NAA and Cho peaks in the periventricular white matter on MRS. We identified a novel heterozygous variant in NOTCH1 (c.4788_4799dup), a frame insertion located in extracellular negative regulatory region (NRR)-domain as in previously published cases. Blood interferon signalling was not elevated compared to controls. This case provides further data on a new diagnostic entity, i.e., NOTCH1-related leukoencephalopathy. By describing a standardised five-year follow-up in one case and reviewing the other patients described to date, we outline recommendations relating to monitoring in this illness, emphasising the importance of psychiatric and gastroenterological surveillance alongside neurological and neuropsychological management. Studies are needed to better understand the factors influencing disease onset and severity, which are heterogeneous.


Assuntos
Cistos , Leucoencefalopatias , Malformações do Sistema Nervoso , Masculino , Adolescente , Humanos , Encéfalo , Leucoencefalopatias/genética , Malformações do Sistema Nervoso/genética , Mutação , Imageamento por Ressonância Magnética , Receptor Notch1/genética
3.
Int J Mol Sci ; 24(23)2023 Nov 23.
Artigo em Inglês | MEDLINE | ID: mdl-38068960

RESUMO

Genetic defects in the nuclear encoded subunits and assembly factors of cytochrome c oxidase (mitochondrial complex IV) are very rare and are associated with a wide variety of phenotypes. Biallelic pathogenic variants in the COX11 protein were previously identified in two unrelated children with infantile-onset mitochondrial encephalopathies. Through comprehensive clinical, genetic and functional analyses, here we report on a new patient harboring novel heterozygous variants in COX11, presenting with Leigh-like features, and provide additional experimental evidence for a direct correlation between COX11 protein expression and sensitivity to oxidative stress. To sort out the contribution of the single mutations to the phenotype, we employed a multi-faceted approach using Saccharomyces cerevisiae as a genetically manipulable system, and in silico structure-based analysis of human COX11. Our results reveal differential effects of the two novel COX11 mutations on yeast growth, respiration, and cellular redox status, as well as their potential impact on human protein stability and function. Strikingly, the functional deficits observed in patient fibroblasts are recapitulated in yeast models, validating the conservation of COX11's role in mitochondrial integrity across evolutionarily distant organisms. This study not only expands the mutational landscape of COX11-associated mitochondrial disorders but also underscores the continued translational relevance of yeast models in dissecting complex molecular pathways.


Assuntos
Doenças Mitocondriais , Proteínas de Saccharomyces cerevisiae , Criança , Humanos , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismo , Proteínas de Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/metabolismo , Sequência de Aminoácidos , Proteínas de Membrana/metabolismo , Complexo IV da Cadeia de Transporte de Elétrons/genética , Complexo IV da Cadeia de Transporte de Elétrons/metabolismo , Proteínas Mitocondriais/genética , Proteínas Mitocondriais/metabolismo , Mutação , Doenças Mitocondriais/genética , Fibroblastos/metabolismo , Proteínas de Transporte de Cobre/metabolismo , Complexo de Proteínas da Cadeia de Transporte de Elétrons/metabolismo
4.
J Clin Med ; 12(7)2023 Mar 29.
Artigo em Inglês | MEDLINE | ID: mdl-37048663

RESUMO

Cerebral excitability and systemic metabolic balance are closely interconnected. Energy supply to neurons depends critically on glucose, whose fluctuations can promote immediate hyperexcitability resulting in acute symptomatic seizures. On the other hand, chronic disorders of sugar metabolism (e.g., diabetes mellitus) are often associated with long-term epilepsy. In this paper, we aim to review the existing knowledge on the association between acute and chronic glycaemic imbalances (hyper- and hypoglycaemia) with seizures and epilepsy, especially in the developing brain, focusing on clinical and instrumental features in order to optimize the care of children and adolescents and prevent the development of chronic neurological conditions in young patients.

5.
Neuropediatrics ; 54(5): 347-350, 2023 10.
Artigo em Inglês | MEDLINE | ID: mdl-37003255

RESUMO

DEPDC5 is an upstream repressor of the mechanistic target of rapamycin pathway via the GATOR-1 complex. Pathogenic variants causing loss of function typically result in familial focal epilepsy with variable foci. Neuroimaging may either be normal or show brain malformations. Lesional and nonlesional cases may be present within the same family. Here, we describe a parent-child dyad affected by a truncating DEPDC5 pathogenic variant (c.727C > T; p.Arg243*), analyze the epilepsy clinical course, and describe neuroimaging characteristics from a 3T brain magnetic resonance imaging. Despite sharing the same variant, patients diverged both in terms of epilepsy severity and neuroimaging features. Surprisingly, the mother is still suffering from drug-resistant seizures and has normal neuroimaging, while the child has been experiencing prolonged seizure freedom notwithstanding a bottom-of-sulcus focal cortical dysplasia. An increasing gradient of severity has been proposed for families with GATOR1-related epilepsies. We confirm clinical and neuroradiological expressivities are variable and also suggest the prognostication of epilepsy outcome may be particularly difficult. The epilepsy outcome could partially be independent from brain structural abnormalities.


Assuntos
Epilepsia , Síndromes Epilépticas , Humanos , Progressão da Doença , Epilepsia/diagnóstico por imagem , Epilepsia/genética , Proteínas Ativadoras de GTPase/genética , Mutação , Neuroimagem
7.
Seizure ; 104: 32-37, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36476360

RESUMO

BACKGROUND: Cabezas syndrome is a rare X-linked disease caused by mutations in CUL4B and characterized by developmental delay/intellectual disability, somatic dysmorphisms, behavioural disorder, ataxia/tremors. Although seizures have been formerly reported, their clinical semiology, EEG features and long-term outcome are largely unknown. PURPOSE: This study aims to expand knowledge on epilepsy associated with Cabezas syndrome and to understand whether different types of variants in the CUL4B gene or brain MRI abnormalities may influence seizure onset and epilepsy course. METHODS: With this in mind, we characterised the epileptic phenotype of a 17-year-old adolescent harbouring a CUL4B novel variant and performed a systematic literature review of CUL4B-associated seizures, analysing mutation types and neuroimaging features as epilepsy predictors. RESULTS: Our case observation indicates that CUL4B-associated epilepsy may also be drug-resistant and persist beyond infancy. Literature analysis shows that 43% of CUL4B patients develop seizures, with no statistically significant differences in epilepsy development according to mutation type and neuroimaging features. CONCLUSION: Our study extends knowledge of CUL4B-associated epilepsy, offering new insights into disease progression.


Assuntos
Epilepsia , Deficiência Intelectual Ligada ao Cromossomo X , Humanos , Proteínas Culina/genética , Eletroencefalografia , Epilepsia/diagnóstico por imagem , Epilepsia/tratamento farmacológico , Epilepsia/genética , Deficiência Intelectual Ligada ao Cromossomo X/complicações , Mutação/genética , Convulsões/tratamento farmacológico , Convulsões/genética , Convulsões/complicações
8.
Biomedicines ; 10(12)2022 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-36551859

RESUMO

BACKGROUND: Lafora disease (LD) is a neurodegenerative condition characterized by the accumulation of polyglucosan bodies (PBs) throughout the brain. Alongside metabolic and molecular alterations, neuroinflammation has emerged as another key histopathological feature of LD. METHODS: To investigate the role of astrocytes and microglia in LD, we performed a systematic review according to the PRISMA statement. PubMed, Scopus, and Web-of-Science database searches were performed independently by two reviewers. RESULTS: Thirty-five studies analyzing the relationship of astrocytes and microglia with LD and/or the effects of anti-inflammatory treatments in LD animal models were identified and included in the review. Although LD has long been dominated by a neuronocentric view, a growing body of evidence suggests a role of glial cells in the disease, starting with the finding that these cells accumulate PBs. We discuss the potential meaning of glial PB accumulations, the likely factors activating glial cells, and the possible contribution of glial cells to LD neurodegeneration and epilepsy. CONCLUSIONS: Given the evidence for the role of neuroinflammation in LD, future studies should consider glial cells as a potential therapeutic target for modifying/delaying LD progression; however, it should be kept in mind that these cells can potentially assume multiple reactive phenotypes, which could influence the therapeutic response.

9.
J Psychiatr Res ; 156: 679-689, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-36399860

RESUMO

BACKGROUND: Attention-Deficit/Hyperactivity Disorder (ADHD) is a highly heterogeneous diagnostic category, encompassing several endophenotypes and comorbidities, including sleep problems. However, no predictor of clinical long-term trajectories or comorbidity has yet been established. Sleep EEG has been proposed as a potential tool for evaluating the synaptic strength during development, as well as the cortical thickness, which is presumed to be altered in ADHD. We investigated whether the slope of the Slow Waves (SWs), a microstructural parameter of the sleep EEG, was a potential predictive parameter for psychiatric comorbidities and neuropsychological dimensions in ADHD. METHODS: 70 children (58 m; 8.76 ± 2.77 y) with ADHD who underwent psychiatric and neurologic evaluations and a standard EEG recording during naps were investigated. After sleep EEG analysis, we grouped the extracted SWs in bins of equal amplitude and then measured the associations, through generalized linear regression, between their maximum downward slopes (MDS) and the individual scores obtained from clinical rating scales. RESULTS: The presence of Multiple Anxiety Disorders was positively associated with MDS of medium amplitude SWs in temporo-posterior left areas. The Child Behavior Checklist scores showed negative associations in the same areas for small SWs. The presence of autistic traits was positively associated with MDS of high amplitude SWs in bilateral anterior and temporal left areas. The WISC-IV Processing Speed Index showed negative associations with MDS of small-to-medium SWs in anterior and temporal right areas, while positive associations in posterior and temporal left areas. CONCLUSIONS: Consistency of association clusters' localization on the scalp suggests that variations in the local MDS, revealing alterations of local synaptic strength and/or in daytime use of certain cortical circuits, could underlie specific neurodevelopmental trajectories resulting in different ADHD clinical phenotypes.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade , Humanos , Sono
10.
Front Neurol ; 13: 942667, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36071899

RESUMO

Cardiac magnetic resonance imaging (MRI) is an essential tool for the study of hypertrophic cardiomyopathies (HCM) and for differentiating HCM from conditions with increased ventricular wall thickness, such as cardiac storage diseases. Although cardiac MRI is already used for the diagnosis and characterization of some forms of storage diseases involving the myocardium, it has not yet been used to study myocardial involvement in neuronal ceroid lipofuscinosis (NCL). Here, we describe comprehensive cardiac MRI findings in a patient with the CLN3 form of NCL showing basal inferior interventricular septal hypertrophy with maintained indexed LV mass within reference values and low T1-native values. MRI findings support a finding of abnormal storage material within the myocardium in CLN3 disease. We recommend the possible routine use of cardiac MRI for early diagnosis of cardiac involvement in CLN3 disease (also termed juvenile NCL) and to monitor the effects of emerging CLN3 therapies on the myocardium as well.

11.
Int J Mol Sci ; 23(12)2022 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-35743315

RESUMO

Mutations in the EPM2A gene encoding laforin cause Lafora disease (LD), a progressive myoclonic epilepsy characterized by drug-resistant seizures and progressive neurological impairment. To date, rodents are the only available models for studying LD; however, their use for drug screening is limited by regulatory restrictions and high breeding costs. To investigate the role of laforin loss of function in early neurodevelopment, and to screen for possible new compounds for treating the disorder, we developed a zebrafish model of LD. Our results showed the epm2a-/- zebrafish to be a faithful model of LD, exhibiting the main disease features, namely motor impairment and neuronal hyperexcitability with spontaneous seizures. The model also showed increased inflammatory response and apoptotic death, as well as an altered autophagy pathway that occurs early in development and likely contributes to the disease progression. Early administration of trehalose was found to be effective for rescuing motor impairment and neuronal hyperexcitability associated with seizures. Our study adds a new tool for investigating LD and might help to identify new treatment opportunities.


Assuntos
Doença de Lafora , Animais , Doença de Lafora/tratamento farmacológico , Doença de Lafora/genética , Doença de Lafora/metabolismo , Mutação , Proteínas Tirosina Fosfatases não Receptoras/genética , Proteínas Tirosina Fosfatases não Receptoras/metabolismo , Convulsões , Trealose/farmacologia , Ubiquitina-Proteína Ligases/genética , Peixe-Zebra/metabolismo
13.
Cells ; 10(10)2021 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-34685608

RESUMO

A serotonergic dysfunction has been largely postulated as the main cause of depression, mainly due to its effective response to drugs that increase the serotonergic tone, still currently the first therapeutic line in this mood disorder. However, other dysfunctional pathomechanisms are likely involved in the disorder, and this may in part explain why some individuals with depression are resistant to serotonergic therapies. Among these, emerging evidence suggests a role for the astrocytic inward rectifier potassium channel 4.1 (Kir4.1) as an important modulator of neuronal excitability and glutamate metabolism. To discuss the relationship between Kir4.1 dysfunction and depression, a systematic review was performed according to the PRISMA statement. Searches were conducted across PubMed, Scopus, and Web of Science by two independent reviewers. Twelve studies met the inclusion criteria, analyzing Kir4.1 relationships with depression, through in vitro, in vivo, and post-mortem investigations. Increasing, yet not conclusive, evidence suggests a potential pathogenic role for Kir4.1 upregulation in depression. However, the actual contribution in the diverse subtypes of the disorder and in the comorbid conditions, for example, the epilepsy-depression comorbidity, remain elusive. Further studies are needed to better define the clinical phenotype associated with Kir4.1 dysfunction in humans and the molecular mechanisms by which it contributes to depression and implications for future treatments.


Assuntos
Depressão/metabolismo , Depressão/fisiopatologia , Canais de Potássio Corretores do Fluxo de Internalização/metabolismo , Antidepressivos/farmacologia , Antidepressivos/uso terapêutico , Antidepressivos Tricíclicos/farmacologia , Antidepressivos Tricíclicos/uso terapêutico , Astrócitos/efeitos dos fármacos , Astrócitos/metabolismo , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Depressão/tratamento farmacológico , Regulação para Baixo/efeitos dos fármacos , Humanos , Ketamina , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Inibidores Seletivos de Recaptação de Serotonina/uso terapêutico , Regulação para Cima/efeitos dos fármacos
14.
Artigo em Inglês | MEDLINE | ID: mdl-34360193

RESUMO

The lockdown due to the COVID-19 pandemic has had adverse psychological effects on children and parents. While parenting is essential for positive development, increased parental distress has interfered with children's wellbeing. In our study, we aimed to identify the predictors of parental distress in families of children with neuropsychiatric disorders during lockdown. Seventy-seven parents of children with neuropsychiatric disorders were asked to fill three online questionnaires (a socio-demographic questionnaire, the Child Behavior Checklist (CBCL) and Parental-Stress-Index (PSI-4-SF) to explore the relationship between parental distress, emotional/behavioral problems in children and quarantine-related factors through univariate analyses and multiple mediation models. Significant positive associations between CBCL-internalizing-problems and all PSI-4-SF subscales, and between CBCL-externalizing-problems and "Difficult Child" subscales were found. "Parent-Child Dysfunctional Interaction" subscale and teachers-child relationship quality resulted negatively associated, as well as the "Difficult Child" subscale and peers-child relationship quality. The effect of teachers-child relationship quality on "Parent-Child Dysfunctional Interaction" was mediated by children internalizing problems, while the effect of peers-child relationship quality on "Difficult Child" by the child internalizing/externalizing problems. Internalizing problems in children with neuropsychiatric disorders were among the strongest predictors of parental stress during lockdown, mediating the indirect effects of quarantine-related factors, thus suggesting the importance of their detection during and after emergency situations to provide assistance and reduce parenting pressure.


Assuntos
COVID-19 , Criança , Controle de Doenças Transmissíveis , Estudos Transversais , Humanos , Pandemias , Relações Pais-Filho , Poder Familiar , SARS-CoV-2
15.
Children (Basel) ; 8(6)2021 May 26.
Artigo em Inglês | MEDLINE | ID: mdl-34073322

RESUMO

BACKGROUND: Xia-Gibbs syndrome (XGS) is a rare disorder caused by de novo mutations in the AT-Hook DNA binding motif Containing 1 (AHDC1) gene, which is characterised by a wide spectrum of clinical manifestations, including global developmental delay, intellectual disability, structural abnormalities of the brain, global hypotonia, feeding problems, sleep difficulties and apnoea, facial dysmorphisms, and short stature. METHODS: Here, we report on a girl patient who shows a peculiar cognitive and behavioural profile including high-functioning autism spectrum disorder (ASD) without intellectual disability and provide information on her developmental trajectory with the aim of expanding knowledge of the XGS clinical spectrum. On the basis of the current clinical case and the literature review, we also attempt to deepen understanding of behavioural and psychiatric manifestations associated with XGS. RESULTS: In addition to the patient we described, a considerable rate of individuals with XGS display autistic symptoms or have been diagnosed with an autistic spectrum disorder. Moreover, the analysis of the few psychopathological profiles of patients with XGS described in the literature shows a frequent presence of aggressive and self-injurious behaviours that could be either an expression of autistic functioning or an additional symptom of the ASD evolution. A careful investigation of the abovementioned symptoms is therefore required, since they could represent a "red flag" for ASD.

16.
Brain Sci ; 10(12)2020 Nov 27.
Artigo em Inglês | MEDLINE | ID: mdl-33260987

RESUMO

On 11 March 2020, a national lockdown was imposed by the Italian government to contain the spread of COVID19 disease. This is an observational longitudinal study conducted at Fondazione Stella Maris (FSM), Italy to investigate lockdown-related emotional and behavioural changes in paediatric neuropsychiatric population. Families having children (1.5-18 years) with neuropsychiatric disorders referred to FSM have been contacted and proposed to fulfil two online questionnaires (General questionnaire and Child Behaviour Check List (CBCL)) to (i) compare (paired two-sample t-tests) the CBCL scores during lockdown with previous ones, and (ii) investigate the influence (multiple linear regression models) of variables such as age, diagnosis grouping (neurological, neurodevelopmental, emotional, and behavioural disorders) and financial hardship. One hundred and forty-one parents fulfilled the questionnaires. Anxiety and somatic problems increased in 1.5-5 years subpopulation, while obsessive-compulsive, post-traumatic and thought problems increased in 6-18 years subpopulation. In the regression models, younger age in the 1.5-5 years subpopulation resulted as "protective" while financial hardship experienced by families during lockdown was related to psychiatric symptoms increasing in the 6-18 years subpopulation. Some considerations, based on first clinical impressions, are provided in text together with comments in relation to previous and emerging literature on the topic.

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