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GLUT1 DEFICIENCY SYNDROME 30 YEARS LATER: NOVEL PERSPECTIVES INTO GLUT1DS PHENOTYPIC SPECTRUM
No full textCandidate: Costanza Varesio
Title: GLUT1 DEFICIENCY SYNDROME 30 YEARS LATER: NOVEL PERSPECTIVES INTO GLUT1DS PHENOTYPIC SPECTRUM
Tutor: Prof.ssa De Giorgis Valentina
Track: neuroscience
36° cicle
La sindrome da deficit di GLUT1 (GLUT1DS) è una malattia rara e scoperta relativamente di recente. Sebbene negli ultimi anni la ricerca scientifica si sia dedicata ad approfondire le conoscenze su questa patologia, appare evidente che molti aspetti, tra cui quelli fenotipici, genetici e terapeutici, devono ancora essere completamente delucidati e descritti al fine di meglio chiarire la storia naturale della malattia e l’ outcome a lungo termine.
L'obiettivo principale di questa tesi, svolta durante il programma di dottorato, è quello di approfondire la conoscenza dello spettro fenotipico della GLUT1DS.
Il capitolo 1 fornisce una narrative review dello stato dell'arte delle conoscenze sulla sindrome e una sintesi delle questioni aperte che devono ancora essere chiarite.
Il capitolo 2 illustra gli aspetti metodologici alla base dell'implementazione del registro italiano GLUT1DS e della coorte di pazienti GLUT1DS della Fondazione IRCCS Mondino (uno dei centri di riferimento italiani per la malattia).
Il capitolo 3 si propone di approfondire la conoscenza degli aspetti neuropsicologici e, in particolare, degli aspetti comunicativi, linguistici e oromotori, nonché degli aspetti emotivi e comportamentali. Il capitolo si conclude con la proposta di un protocollo per la valutazione e il follow-up degli aspetti neuropsicologici nelle diverse età della vita.
Il capitolo 4 fornisce nuovi dati sul fenotipo motorio, con particolare interesse per i disturbi della coordinazione motoria e dell'andatura, proponendo un protocollo innovativo per la valutazione dell'analisi cinematica del cammino mediante sensori inerziali.
Il Capitolo 5 rappresenta la conclusione di questo lavoro di tesi e raccoglie gli unmet needs dei pazienti con GLUT1DS e dei loro caregiver nella pratica clinica quotidiana e nella ricerca scientifica.Abstract
Candidate: Costanza Varesio
Title: GLUT1 DEFICIENCY SYNDROME 30 YEARS LATER: NOVEL PERSPECTIVES INTO GLUT1DS PHENOTYPIC SPECTRUM
Tutor: Prof.ssa De Giorgis Valentina
Track: neuroscience
36° cicle
GLUT1 Deficiency Syndrome (GLUT1DS) is a rare and relatively recently discovered disease. Although in recent years a growing body of literature has been devoted to deepen knowledge on this pathology, it appears evident that many aspects, including phenotypic, genetic and therapeutic aspects still need to be detected and described in order to shed further lights on the disease natural history and long term outcome.
The main goal of this thesis carried out during the PhD program, is to deepen the knowledge of the phenotypic spectrum of GLUT1DS.
Chapter 1 provides a comprehensive narrative review of the state of the art of knowledge on the syndrome and a summary of the open questions that still need to be elucidated.
Chapter 2 encompasses the methodological aspects underpinning the implementation of the Italian GLUT1DS registry and the IRCCS Mondino Foundation’s (one of the Italian Reference Centre for the disease) GLUT1DS patients cohort.
Chapter 3 aims to deepen our knowledge of neuropsychological aspects and, in particular, communicative, linguistic and oromotor aspects, as well as emotional and behavioral aspects. This chapter concludes with the proposal of a protocol for the assessment and follow-up of neuropsychological aspects at different ages of life.
Chapter 4 provides novel insights into the motor phenotype with particular interest on motor coordination disorder and on gait disturbances, proposing an innovative protocol for a kinematic gait analysis evaluation using inertial sensors.
Chapter 5 represents the conclusion of this thesis work and brings together the unmet needs of GLUT1DS patients and their caregivers in daily clinical practice and scientific research
Dietary Treatments and New Therapeutic Perspective in GLUT1 Deficiency Syndrome
No full textGLUT1 deficiency syndrome (GLUT1DS) results from impaired glucose transport into the brain: awareness of its wide phenotypic spectrum is a prerequisite in order to ensure an early diagnosis, treating the patients is the subsequent challenge to allow prompt compensation for the brain’s lack of fuel. The ketogenic diet (KD) plays a primary role in the treatment of GLUT1DS because it provides ketone bodies as an alternative source to meet the demands of energy of the brain. Therefore, we recommend early initiation of the KD based on the assumption that early diagnosis and treatment improves the long term neurological outcome: the classic KD (4:1 or 3:1) at the present time is the most proven and effective in GLUT1DS. A KD should be continued at least until adolescence, although there are reports of good tolerability even in adulthood, possibly with a less rigorous ratio; in our experience seizure and movement disorder control can be achieved by a 2:1 ketogenic ratio but the relationship between ketosis and neurodevelopmental outcome remains undetermined. Other types of KDs can, therefore, be considered. The Modified Atkins diet, for example, is also well tolerated and provides effective symptom control; furthermore, this diet has the advantage of being easy to prepare and more palatable, which are important requirements for good compliance. Nevertheless, about 20 % of these patients have compliance trouble or the same diet loses its effectiveness over time; for these reasons, new therapeutic strategies are currently under investigation but further studies on pathophysiological mechanisms and potential effects of novel “diets” or “therapies” are needed for this new pathology
One Month of Classic Therapeutic Ketogenic Diet Decreases Short Chain Fatty Acids Production in Epileptic Patients
No full textKetogenic diet (KD), a high fat and very low carbohydrates diet, is used worldwide for the treatment of drug resistant epilepsy but, due to its composition, it might exert an impact on gut health. Even though data of KD effects on intestinal microbiota changes are recently emerging, its influence on the gut environment has been scarcely addressed so far. The aim of this study was to investigate whether 1 month of KD affects the gut environment in epileptic patients, by analyzing short chain fatty acids (SCFA) production and fecal water toxicity. A total of seven patients were enrolled. Stool samples were collected before (T0) and after 1 month of KD (4:1 ketogenic ratio) (T1). SCFA were determined by GC-FID and fecal water toxicity in Caco-2 cell culture by comet assay. Concentrations of SCFA significantly decreased after KD (p < 0.05): in particular, we found a 55% reduction of total SCFA level, a 64% reduction of acetate, 33% of propionate, and 20% of butyrate (p < 0.05). Cytotoxicity of fecal water extracted from stool samples was not significantly altered by diet, while genotoxicity was slightly decreased after KD (p < 0.05). Genotoxicity values were consistent with data previously obtained from a healthy Italian population. The present study suggests that 1 month of KD significantly reduce SCFA production. Since SCFA produced by gut microbiota exert many health promoting effects on either the gut environment or human metabolism, these results open a new branch of investigation into KD effects
GLUT1 deficiency syndrome 2013: Current state of the art
No full textAbstractGlucose transporter type 1 deficiency syndrome (GLUT1DS) is the result of impaired glucose transport into the brain. The “classic” GLUT1DS patient presents with infantile seizures (resistant to traditional seizure medications), developmental delay, acquired microcephaly, hypotonia, spasticity, and a complex movement disorder consisting of ataxia and dystonia. However, over the years, other clinical manifestations have been described, such as paroxysmal exertion-induced dystonia with or without seizures, choreoathetosis, alternating hemiplegia, and other paroxysmal events, such as intermittent ataxia, dystonia, and migraine.At the current state of the art in understanding of GLUT1DS, classifying the disease phenotype as “classical” or “non-classical” seems to be of limited clinical utility. It seems more appropriate to think in terms of a broad clinical spectrum in which we can observe intellectual impairment, acquired microcephaly, epilepsy, and movement disorders characterized by different clinical manifestations and degrees of severity.Lumbar puncture, a simple investigation, should be considered the first diagnostic step that, moreover, is feasible worldwide. Thereafter, mutational analysis of the solute carrier family 2 (facilitated glucose transporter) member 1 (SLC2A1) gene should be performed in patients with highly suggestive clinical findings and low cerebrospinal fluid glucose (<50mg/dl or ratio <0.60).Early diagnosis is critical because it allows prompt initiation of treatment with a ketogenic diet (KD). Childhood is the critical period for treatment of GLUT1DS: early diagnosis is crucial for an effective etiological therapy. KD treatment can be useful in adulthood too. Compliance has been found to be much better in GLUT1DS than in the other conditions for which KD treatment is indicated
ANDAMENTO DELL’INDICE GLUCO-CHETONICO IN CORSO DI TRATTAMENTO DIEPILESSIA REFRATTARIA CON DIETA CHETOGENICA
No full textThe changing face of dietary therapy for epilepsy
No full textKetogenic diet is an established and effective non-pharmacologic treatment for drug-resistant epilepsy. Ketogenic diet represents the treatment of choice for GLUT-1 deficiency syndrome and pyruvate dehydrogenase complex deficiency. Infantile spasms, Dravet syndrome and myoclonic-astatic epilepsy are epilepsy syndromes for which ketogenic diet should be considered early in the therapeutic pathway. Recently, clinical indications for ketogenic diet have been increasing, as there is emerging evidence regarding safety and effectiveness. Specifically, ketogenic diet response has been investigated in refractory status epilepticus and encephalopathy with status epilepticus during sleep. New targets in neuropharmacology, such as mitochondrial permeability transition, are being studied and might lead to using it effectively in other neurological diseases. But, inefficient connectivity and impaired ketogenic diet proposal limit ideal availability of this therapeutic option. Ketogenic diet in Italy is not yet considered as standard of care, not even as a therapeutic option for many child neurologists and epileptologists.
CONCLUSIONS:
The aim of this review is to revisit ketogenic diet effectiveness and safety in order to highlight its importance in drug-resistant epilepsy and other neurological disorders.
WHAT IS KNOWN:
• Ketogenic diet efficacy is now described in large case series, with adequate diet compliance and side effects control. • Ketogenic diet is far from being attempted as a first line therapy. Its availability varies worldwide. What is New: • New pharmacological targets such as mitochondrial permeability transition and new epileptic syndromes and etiologies responding to the diet such as refractory status epilepticus are being pointed out. • Ketogenic diet can function at its best when used as a tailor-made therapy. Fine tuning is crucial
The effects of ketogenic dietary therapies on sleep: A scoping review
No full textSleep problems are common in neurological conditions for which ketogenic dietary therapies (KDTs) are recognised as an effective intervention (drug-resistant epilepsy, autism spectrum disorder, and migraine). Given the composite framework of action of ketogenic dietary therapies, the prevalence of sleep disturbance, and the importance of sleep regulation, the present scoping review aimed at identifying and mapping available evidence of the effects of ketogenic dietary therapies on sleep. A comprehensive web-based literature search was performed retrieving publications published to June 2023 using PubMed and Scopus, yielding to 277 records. Twenty papers were finally selected and included in the review. Data were abstracted by independent coders. High variability was identified in study design and sleep outcome evaluation among the selected studies. Several changes in sleep quality and sleep structure under ketogenic dietary therapies were found, namely an improvement of overall sleep quality, improvement in the difficulty falling asleep and nighttime awakenings, improvement in daytime sleepiness and an increase of REM sleep. The relevance and possible physiological explanations of these changes, clinical recommendations, and future directions in the field are discussed
Intravenous methylprednisolone pulse therapy for children with epileptic encephalopathy
No full textThe aim of this retrospective study of children affected by epileptic encephalopathy was to evaluate seizure frequency, electroencephalographic pattern and neuropsychological status, before and after intravenous methylprednisolone therapy. Eleven children with epileptic encephalopathy were administered one cycle of intravenous methylprednisolone (15-30 mg/kg/day for three consecutive days, once a month for four months) in addition to constant dosages of their regular antiepileptic drugs. The treatment resulted in statistically significant reductions of generalized slow spike-and-wave discharges (p<0.0028) and seizure frequency (p<0.013), which persisted even after methylprednisolone pulse therapy was stopped. A globally positive outcome was noted in 9/11 patients (81.8%). This methylprednisolone treatment regimen did not cause significant or persistent adverse effects. We suggest that children with epileptic encephalopathy without an underlying structural lesion could be the best candidates for intravenous methylprednisolone pulse therapy
How to Manage Electrical Status Epilepticus in Sleep
No full textElectrical status epilepticus in sleep is an age-dependent syndrome with the characteristic pattern of continuous spike and waves during non-rapid eye movement sleep. Most children can present developmental deterioration. The demonstration of the EEG pattern has to rely on all night long EEG recordings. A comprehensive neuropsychologic evaluation with periodic reassessment should be performed. For the idiopathic forms of electrical status epilepticus in sleep, clobazam could be considered as the firstline therapy; in the other cases, corticosteroids, in particular intravenous methylprednisolone pulse therapy, remain the most effective and should be considered the therapy of choice
Case report: KETOLAND the psychoeducation program for ketogenic diet
No full textGlucose transporter type 1 deficiency syndrome (GLUT1DS) is a rare neurological disorder characterized by a wide spectrum of symptoms: epilepsy, movement disorders and neurocognitive impairment. The gold standard treatment for GLUT1DS are ketogenic dietary therapies (KDTs), specifically classical ketogenic diet (CKD). Despite the benefits, CKD often represents a challenge for patients and their families since meal preparation is extremely demanding and deviates a lot from normal diet. To assure an optimal compliance to CKD a psychological support for parents and patients with GLUT1DS is highly recommended. Specifically, a psychoeducational intervention that ameliorates the knowledge about the illness and its therapy improves treatment' s adherence and efficacy. The aim of this case report is to investigate the effectiveness of a psychoeducational program, partially implemented through telepsychology, based on the theoretical model of Cognitive Behavioral Play Therapy (CBPT) to support KDT knowledge and adherence in a patient with GLUT1DS who presented a worsening of her clinical picture due to a sparse knowledge of KDTs principles which determined a low adherence. Thus, with this case report we propose a model of intervention with psychoeducation in a patient with a complex chronic disease
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