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Glucose transporter 1 deficiency syndrome (GLUT1DS) is a neurometabolic disorder caused by haploinsufficiency of the GLUT1 glucose transporter (encoded by SLC2A1) leading to defective glucose transport across the blood–brain barrier. This work describes the genetic analysis of 56 patients with clinical or biochemical GLUT1DS hallmarks. 55.4% of these patients had a pathogenic variant of SLC2A1, and 23.2% had a variant in one of 13 different genes. No pathogenic variant was identified for the remaining patients. Expression analysis of SLC2A1 indicated a reduction in SLC2A1 mRNA in patients with pathogenic variants of this gene, as well as in one patient with a pathogenic variant in SLC9A6, and in three for whom no candidate variant was identified. Thus, the clinical and biochemical hallmarks generally associated with GLUT1DS may be caused by defects in genes other than SLC2A1, Carlos III Institute (ISCIII), European Regional Development Funds (PI19/01155); CIBERER (ERTRLE0I1); Consejería de Educacion, Juventud y Deporte, Comunidad de Madrid (B2017/BMD3721); Fundacion Isabel Gemio, the Fundacion La Caixa (LCF/PR/ PR16/11110018)

Background: There is a gap of knowledge regarding cerebrospinal fluid (CSF) ion concentrations in normal and pathological states, particularly during the neonatal period. We aim to compare CSF ion concentrations in newborns with different causes of neonatal-onset epilepsy (NOE) and acute symptomatic seizures (ASS) and controls, to examine their usefulness for diagnostic purposes. Methods: A descriptive retrospective study was conducted from January 2019 to June 2020 in a tertiary hospital. We analyzed CSF K+, Na+, Cl-, and Ca2+ concentrations in frozen samples from patients with neonatal seizures (NS) secondary to NOE and ASS (neonatal arterial ischemic stroke [NAIS] and hypoxicischemic encephalopathy). As the control group, we selected CSF samples from newborns who had undergone CSF analysis as part of the diagnostic workup and in whom central nervous system infections had been ruled out, without signs of dehydration, gastroenteritis, or history of seizures. Results: Sixty-eight newborns were included, 16 with NOE, 13 with ASS, and 39 without NS (control group). In comparison with the control group, [K+]CSF was lower in patients with KCNQ2-related epilepsy (P = 0.007), other causes of NOE (P = 0.010), and NAIS (P = 0.002). Changes in [Na+]CSF, [Cl-]CSF, and [Ca2+]CSF were less consistent among subgroups. Conclusions: Here we report for the first time ionic imbalances in the CSF of neonates with NOE and NAIS. No differences were observed between newborns with different causes of NS. Further studies should be undertaken to investigate the physiopathology behind these changes and their impact on biological function. (C) 2021 Elsevier Inc. All rights reserved.

To study neurotransmitter status in children with early epileptic and developmental and epileptic encephalopathy (DEE) and to explore the clinical response to dopaminergic and serotoninergic therapies in a group of patients.Two hundred and five patients (111 males [54.1.%] and 94 females [45.9%], mean age 10 months at the onset of epilepsy [SD 1 year 1 month], range 0-3 year) with epileptic encephalopathy/DEE were recruited, including those with West syndrome, Ohtahara syndrome, early myoclonic encephalopathy, epilepsy of infancy with migrating focal seizures, myoclonic encephalopathy in non-progressive disorders, infantile spasms, Doose syndrome, Lennox-Gastaut syndrome, Landau-Kleffner syndrome, and those unclassified. Cerebrospinal fluid (CSF) neurotransmitter studies and patients' medical records were reviewed. Additionally, we present clinical data of 10 patients with low CSF neurotransmitter levels who received dopaminergic/serotoninergic treatments.Abnormal neurotransmitter values were identified in 68 (33%) patients. 5-Hydroxyindoleacetic acid (5-HIAA) deficit was the most prevalent alteration (91%). Low CSF 5-HIAA levels were significantly higher in 1- to 3-year-old children. A negative significant correlation was found between 5-HIAA levels and epilepsy duration before CSF study (Spearman's ρ=-0.191, p=0.007). Abnormalities in deep grey matter were associated with low levels of CSF homovanillic acid and 5-HIAA. Ten patients with low CSF neurotransmitter levels received dopamine and/or serotonin therapies. Six of them showed initial decrease of seizure frequency and severity and maintained improvement in some neurodevelopmental skills.A considerable number of patients showed neurotransmitter abnormalities. Age at seizure onset and duration of epilepsy before CSF study were the principal factors related to neurotransmitter depletion. Early monoamine supplementation would seem advisable as a neuroprotective strategy.5-Hydroxyindoleacetic acid homeostasis is especially vulnerable in patients with epileptic encephalopathy/developmental and epileptic encephalopathy. Age of seizure onset and duration of epilepsy are determinants of neurotransmitter depletion.

Tyrosine hydroxylase deficiency (THD) is a rare genetic disorder leading to dopaminergic depletion and early-onset parkinsonism. Affected children present with either a severe form that does not respond to L-Dopa treatment (THD-B), or a milder L-Dopa responsive form (THD-A). We generated induced pluripotent stem cells (iPSCs) from THD patients that were differentiated into dopaminergic neurons (DAn) and compared with control-DAn from healthy individuals and gene-corrected isogenic controls. Consistent with patients, THD iPSC-DAn displayed lower levels of DA metabolites and reduced TH expression, when compared to controls. Moreover, THD iPSC-DAn showed abnormal morphology, including reduced total neurite length and either an abnormal TH proximodistal gradient (THDA), or neurite arborization defects (THDB). Treatment of THD-iPSC-DAn with L-Dopa rescued the neuronal defects and disease phenotype only in THDA-DAn. Interestingly, L-Dopa treatment at the stage of neuronal precursors could prevent the alterations in THDB-iPSC-DAn, thus suggesting the existence of a critical developmental window in THD. Our iPSC-based model recapitulates THD disease phenotypes and response to treatment, representing a promising tool for investigating pathogenic mechanisms, drug screening, and personalized management.

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Thiamine transporter-2 deficiency is caused by mutations in the SLC19A3 gene. As opposed to other causes of Leigh syndrome, early administration of thiamine and biotin has a dramatic and immediate clinical effect. New biochemical markers are needed to aid in early diagnosis and timely therapeutic intervention. Thiamine derivatives were analysed by high performance liquid chromatography in 106 whole blood and 38 cerebrospinal fluid samples from paediatric controls, 16 cerebrospinal fluid samples from patients with Leigh syndrome, six of whom harboured mutations in the SLC19A3 gene, and 49 patients with other neurological disorders. Free-thiamine was remarkably reduced in the cerebrospinal fluid of five SLC19A3 patients before treatment. In contrast, free-thiamine was slightly decreased in 15.2% of patients with other neurological conditions, and above the reference range in one SLC19A3 patient on thiamine supplementation. We also observed a severe deficiency of free-thiamine and low levels of thiamine diphosphate in fibroblasts from SLC19A3 patients. Surprisingly, pyruvate dehydrogenase activity and mitochondrial substrate oxidation rates were within the control range. Thiamine derivatives normalized after the addition of thiamine to the culture medium. In conclusion, we found a profound deficiency of free-thiamine in the CSF and fibroblasts of patients with thiamine transporter-2 deficiency. Thiamine supplementation led to clinical improvement in patients early treated and restored thiamine values in fibroblasts and cerebrospinal fluid.

Basic neuroscience and neurometabolism are providing a rapidly increasing amount of knowledge on paediatric epilepsy and, more specifically, on the mechanisms involved in synaptic communication. There is, however, a mismatch between these advances and a vision that integrates them in a global way, in clinical and therapeutic practice.To offer an integrative view of the different molecular and metabolic mechanisms that are known and postulated in paediatric epilepsy, and to suggest concepts such as 'synaptic metabolism' and 'synaptic phenotypes' as useful tools for developing this approach.We also review the most notable studies that attempt to explain the essential characteristics of synaptic communication in the developing brain by means of different molecules, essentially synaptic proteins, ion channels (chlorine, sodium and potassium co-transporters), and pre- and post-synaptic compartmentalisation, as well as the main players in metabolism (neurotransmitters, energy metabolism, growth factors and lipids). This combination of biological mechanisms has led to examples of 'synaptic phenotypes' being suggested in two specific cases of genetic (SCN1A) and metabolic epilepsy (epilepsy with response to pyridoxine).A holistic perspective, which takes into account the diversity of elements that are related and which take place at certain times in neurodevelopment, can help to define phenotypes, channels for synaptic metabolism and brain connectivity, which facilitate not only the understanding of the pathophysiology, but also new therapeutic approaches in paediatric epilepsy.Comunicacion neuronal y metabolismo sinaptico en epilepsia infantil.Introduccion. Los conocimientos que la neurociencia basica y el neurometabolismo estan aportando en epilepsia pediatrica, y en concreto en mecanismos de comunicacion sinaptica, crecen rapidamente. Existe, no obstante, una desconexion entre estos avances y una vision que los integre de manera global y en la practica clinica y terapeutica. Objetivos. Ofrecer una vision integradora de los diferentes mecanismos moleculares y metabolicos que se conocen y postulan en epilepsia pediatrica, y sugerir conceptos como el de 'metabolismo sinaptico' y 'fenotipos sinapticos' como herramientas utiles para desarrollar este enfoque. Desarrollo. Se revisan los estudios mas destacados que intentan explicar las caracteristicas esenciales de la comunicacion sinaptica en el cerebro en desarrollo, a traves de diferentes moleculas, basicamente proteinas sinapticas, canales ionicos (cotransportadores de cloro, sodio y potasio), la compartimentalizacion pre y postsinaptica, y los principales actores metabolicos (neurotransmisores, metabolismo energetico, factores de crecimiento y lipidos). A partir de esta combinacion de mecanismos biologicos se sugieren ejemplos de 'fenotipos sinapticos' en dos casos concretos de epilepsia genetica (SCN1A) y metabolica (epilepsia con respuesta a la piridoxina). Conclusiones. Una perspectiva holistica, entendiendo la diversidad de elementos relacionados y que suceden en determinados momentos del neurodesarrollo, puede ayudar a delinear fenotipos, vias de metabolismo sinaptico y conectividad cerebral, que faciliten no solo la comprension de la fisiopatologia, sino nuevas aproximaciones terapeuticas en epilepsia pediatrica.

Neurotransmitter disorders are a group of inherited neurometabolic diseases attributable to disturbances of neurotransmitter metabolism. Classical neurotransmitter pathways involve amino acids (such as γ-aminobutyric acid [GABA], glycine, and glutamate), cholinergic transmission, monoamines (dopamine, serotonin, noradrenaline, and adrenaline), and purines. Other molecules such as neuropeptides, ion channels, and diverse neuromodulators are also involved in neurotransmission mechanisms and thus in the pathophysiology of neurological disorders. In this chapter we will focus on biogenic amines, GABA and its cofactors defects, since they are the most common groups of human neurotransmitter diseases. The biogenic amines regulate brain functions such as movement, behavior, emotions, temperature, blood pressure and endocrine secretion. Disorders of monoamines include levodopa-related movement disorders and early complex encephalopathies. GABAergic transmission regulates epileptic mechanisms, cognition, behavior, and arousal level. Clinical presentations include epileptic encephalopathies, intellectual disability, behavioral disturbances, and episodes of lethargy. Most neurotransmitter disorders are treatable and require the study of cerebrospinal fluid metabolites for diagnosis.

Cryopyrin-associated periodic syndrome is a category of autoinflammatory disorders caused by mutations of the NLRP3 gene, with chronic infantile neurologic cutaneous and articular syndrome being the severest clinical phenotype. Various pterins have been reported as mediating immunologic functions in the central nervous system, but to date studies of pterin cerebrospinal fluid (CSF) values and cryopyrin-associated periodic syndrome have been lacking. A 2-year-old child was affected with a severe atypical form of cryopyrin-associated periodic syndrome, suspected based on the analysis of neopterin in CSF. He initially presented isolated neurologic manifestations mimicking a neuroregressive disorder. Blood and CSF analyses did not present any routine inflammatory markers, but CSF neopterin was elevated. Later, the patient developed arthritis and recurrent episodes of fever, and the cryopyrin-associated periodic syndrome diagnosis was confirmed by genetic studies. Neopterin was the most altered indicator over the time. Child neurologists should be on the alert when unexplained neurologic signs appear, giving consideration to the possibility of inflammatory or immune-mediated diseases. The present case demonstrates the clinical utility of measurement of CSF neopterin levels in screening for these immune-mediated diseases, especially when neurologic symptoms are associated with normal results on routine CSF tests.

Cerebellar hemorrhage (CH) is a well-known complication in newborns. Among metabolic patients, it has been classically described but rarely reported. This is the first description of a patient with propionic acidemia in whom magnetic resonance imaging (MRI) allowed diagnosis of asymptomatic CH. Due to the usual silent presentation of CH at early ages, we suggest the possibility of including a brain MRI study as part of the routine neurological evaluation in metabolic patients, especially when neurological signs appear.

Hypotonia is one of the most frequent signs of neurological pathology in newborn infants.To determine, in a 12-year retrospective study, the relative frequency of neurological pathologies that can be accompanied by hypotonia during the neonatal period and to describe the neurological development after two years' follow-up.We conducted a systematic review of the newborn infants with hypotonia due to an identifiable cause who were admitted to the neonatal unit of the Hospital Sant Joan de Deu between January 1996 and December 2008. Information collected referred to family history, data related with the pregnancy and childbirth, clinical features and complementary tests. RESULTS. A total of 73 hypotonic newborn infants were identified, 21 (28.7%) of whom met eligibility criteria. The majority, 81% (n = 17), were classified as central hypotonias and the remaining 19% (n = 4) were graded as peripheral hypotonias. In the first group, 47% (n = 8) presented chromosomal disorders, 29.4% (n = 5) had metabolic diseases and 23.5% (n = 4) displayed malformations of the central nervous system.The central causes of hypotonia continue to be the most prevalent in the neonatal period and, within these, chromosomal disorders are the most frequent. Peripheral causes are less common and have a more severe prognosis. Advances in molecular genetics have allowed many neuromuscular diseases to be diagnosed both genetically and at the molecular level. The diversity and complexity of the pathologies justifies a multidisciplinary approach being taken to treat these newborn infants.

This study describes a cblE type of homocystinuria associated with haemolytic-uremic syndrome (HUS) features. We report on a male infant aged 43 days presenting with failure to thrive, hypotonia, pancytopaenia, HUS symptoms (microangiopathic haemolytic anaemia and thrombocytopaenia with signs of renal involvement) and fatal evolution. An underlying cobalamin disorder was diagnosed after a bone marrow examination revealed megaloblastic changes associated with hyperhomocysteinaemia. An urinary organic acid analysis revealed normal methylmalonic acid excretion. The cblE diagnosis was confirmed with a complementation analysis using skin fibroblasts and genetic studies of the MTRR gene. The patient treatment included parenteral hydroxocobalamin, carnitine, betaine and folinic acid, but there was no response. After the autopsy, the histopathological examination of the kidneys showed marked myointimal proliferation and narrowing of the vascular lumen. The central nervous system showed signs of haemorrhage that affected the putamen and the thalamus; diffuse white matter lesions with spongiosis, necrosis and severe astrogliosis were also observed. Microangiopathy was observed with an increase in vessel wall thickness, a reduction of the arterial inner diameter and capillary oedema. The signs of necrosis and haemorrhage were detected in the cerebellum, the cerebellar peduncles, the tegmentum and the bulbar olives.In conclusion, cblE should be considered when diagnosing patients presenting with HUS signs and symptoms during the newborn period. Despite early diagnosis, however, the specific treatment measures were not effective in this patient.

Background Cerebral folate deficiency may be amenable to therapeutic supplementation. Diverse metabolic pathways and unrelated processes can lead to cerebrospinal fluid 5-methyltetrahydrofolate (5-MTHF) depletion, the hallmark of cerebral folate deficiency. Objective To analyze cerebral folate abundance in a large prospective series of children diagnosed with any neurologic disorder for which a diagnostic lumbar puncture was indicated. Design We studied the spectrum and frequency of disorders associated with cerebral folate deficiency by measuring cerebrospinal fluid 5-MTHF, biogenic amines, and pterins. Direct sequencing of the FOLR1 transporter gene was also performed in some patients. Setting Academic pediatric medical center. Participants We studied 134 individuals free of neurometabolic disease and 584 patients with any of several diseases of the central nervous system. Results Of 584 patients, 71 (12%) exhibited 5-MTHF deficiency. Mild to moderate deficiency (n = 63; range, 19-63 nmol/L) was associated with perinatal asphyxia, central nervous system infection, or diseases of probable genetic origin (inborn errors of metabolism, white matter disorders, Rett syndrome, or epileptic encephalopathies). Severe 5-MTHF depletion (n = 8; range, 0.6-13 nmol/L) was detected in severe MTHF reductase deficiency, Kearns-Sayre syndrome, biotin-responsive striatal necrosis, acute necrotizing encephalitis of Hurst, and FOLR1 defect. A strong correlation was observed between cerebrospinal fluid and plasma folate levels in cerebral folate deficiency. Conclusions Of the 2 main forms of cerebral folate deficiency identified, mild to moderate 5-MTHF deficiency was most commonly associated with disorders bearing no primary relation to folate metabolism, whereas profound 5-MTHF depletion was associated with specific mitochondrial disorders, metabolic and transporter defects, or cerebral degenerations. The results suggest that 5-MTHF can serve either as the hallmark of inborn disorders of folate transport and metabolism or, more frequently, as an indicator of neurologic dysfunction.

Lesch-Nyhan disease (LND) is a hereditary disorder of purine metabolism causing severe neurobehavioral disturbances in which an abnormal central nervous system dopaminergic function has been implied. However, levodopa treatment has rarely been used, and reports describe heterogeneous responses. We report an LND patient with low dopamine metabolite values in cerebrospinal fluid for whom early levodopa/carbidopa therapy was begun with a notable clinical improvement. We propose that very early treatment of LND patients with levodopa may improve their neurological symptoms and may contribute to a better outcome.