Carbon Monoxide and Nitric Oxide as Examples of the Youngest Class of Transmitters.

The year 2021 is the 100th anniversary of the confirmation of the neurotransmission phenomenon by Otto Loewi. Over the course of the hundred years, about 100 neurotransmitters belonging to many chemical groups have been discovered. In order to celebrate the 100th anniversary of the confirmation of neurotransmitters, we present an overview of the first two endogenous gaseous transmitters i.e., nitric oxide, and carbon monoxide, which are often termed as gasotransmitters.

Modernized Classification of Cardiac Antiarrhythmic Drugs.

BACKGROUND: Among his major cardiac electrophysiological contributions, Miles Vaughan Williams (1918-2016) provided a classification of antiarrhythmic drugs that remains central to their clinical use. METHODS: We survey implications of subsequent discoveries concerning sarcolemmal, sarcoplasmic reticular, and cytosolic biomolecules, developing an expanded but pragmatic classification that encompasses approved and potential antiarrhythmic drugs on this centenary of his birth. RESULTS: We first consider the range of pharmacological targets, tracking these through to cellular electrophysiological effects. We retain the original Vaughan Williams Classes I through IV but subcategorize these divisions in light of more recent developments, including the existence of Na+ current components (for Class I), advances in autonomic (often G protein-mediated) signaling (for Class II), K+ channel subspecies (for Class III), and novel molecular targets related to Ca2+ homeostasis (for Class IV). We introduce new classes based on additional targets, including channels involved in automaticity, mechanically sensitive ion channels, connexins controlling electrotonic cell coupling, and molecules underlying longer-term signaling processes affecting structural remodeling. Inclusion of this widened range of targets and their physiological sequelae provides a framework for a modernized classification of established antiarrhythmic drugs based on their pharmacological targets. The revised classification allows for the existence of multiple drug targets/actions and for adverse, sometimes actually proarrhythmic, effects. The new scheme also aids classification of novel drugs under investigation. CONCLUSIONS: We emerge with a modernized classification preserving the simplicity of the original Vaughan Williams framework while aiding our understanding and clinical management of cardiac arrhythmic events and facilitating future developments in this area.

Neurotransmission systems in Parkinson's disease.

Parkinson's disease (PD) is histologically characterized by the accumulation of α-synuclein particles, known as Lewy bodies. The second most common neurodegenerative disorder, PD is widely known because of the typical motor manifestations of active tremor, rigidity, and postural instability, while several prodromal non-motor symptoms including REM sleep behavior disorders, depression, autonomic disturbances, and cognitive decline are being more extensively recognized. Motor symptoms most commonly arise from synucleinopathy of nigrostriatal pathway. Glutamatergic, γ-aminobutyric acid (GABA)ergic, cholinergic, serotoninergic, and endocannabinoid neurotransmission systems are not spared from the global cerebral neurodegenerative assault. Wide intrabasal and extrabasal of the basal ganglia provide enough justification to evaluate network circuits disturbance of these neurotransmission systems in PD. In this comprehensive review, English literature in PubMed, Science direct, EMBASE, and Web of Science databases were perused. Characteristics of dopaminergic and non-dopaminergic systems, disturbance of these neurotransmitter systems in the pathophysiology of PD, and their treatment applications are discussed.

[Developmental changes of neurotransmitter properties in sympathetic neurons].

Sympathetic ganglia consist of neurochemically and functionally distinct populations of neurons, characterized by a specific projection pattern and a set of neutransmitters including classical mediators (catecholamines and acetylcholine), neuropeptides and small molecules such as NO, H2S, CO. The majority of the principal ganglionic sympathetic neurons is noradrenergic and expresses tyrosine hydroxylase (TH), i.e., a key enzyme in catecholamine synthesis. In mammals, two third of catecholaminergic neurons also co-localizes neuropeptide Y. A small number of ganglionic sympathetic neurons contains enzyme of acetylcholine synthesis and some neuropeptides, such as somatostatin, vasoactive intestinal (poly)peptide (VIP), calcitonin gene-related peptide (CGRP). Acetylcholine-containing sympathetic neurons in most cases colocalize VIP and/or CGRP. Phenotype of autonomic neurons is regulated by both target-independent and target-dependent mechanisms. The most of transmitters are expressed during embryogenesis. TH appears during embryonic development and the percentage of TH-positive neurons remains virtually identical during ontogenesis. After birth, cholinergic neurons exhibit a noradrenergic phenotype. Expression of different neuropeptides changes in pre- and postnatal development. Neurotransmitter expression in sympathetic neurons is influenced by growth factor signaling via innervated target tissues. Multiple growth factors including bone morphogenetic proteins, neurotrophins, glial cell line-derived neurotrophic factor family ligands and neuropoietic cytokines play instructive role at different stages of neurotransmitter development.

Neurotransmitter measures in the cerebrospinal fluid of patients with Alzheimer's disease: a review.

BACKGROUND: Alzheimer's disease (AD) is a severe neurodegenerative disorder characterized by progressive cognitive and functional decline, as well as by a variety of neuropsychiatric and psychological symptoms and behavioral dysfunctions. Various studies proposed the role of different neurotransmitter systems not only in AD-related cognitive, but also psychotic symptoms and behavioral and emotional deficits. Due to the close proximity, pathological neurochemical changes in brain occurring in AD are likely to be reflected in the cerebrospinal fluid (CSF). The purpose of this review is to provide a summary of the CSF neurotransmitter correlates of AD in order to get further insights into the potential role of altered neurotransmitters in the pathophysiology of AD and to offer novel AD biomarkers. METHODS: PubMed and MEDLINE data bases were searched for English-language articles by using "Alzheimer's disease", "CSF" and "neurotransmitter" as primary terms. No time or article type constraints were applied. Moreover, the lists of references were searched manually for additional articles. RESULTS: Changes in various correlates of cholinergic, monoaminergic and amino acid neurotransmitter systems, as well as neuropeptides, have been observed in CSF of AD patients. However, as the results of these studies have been controversial, the importance of CSF neurotransmitter parameters as potential biomarkers in AD remains quite unclear. The observed discrepancies could be bypassed by implementation of new sensitive methods, such as novel proteomics approaches that include protein separation techniques, mass spectroscopy and targeted multiplex panels of specific analytes. CONCLUSION: Although no individual CSF neurotransmitter correlate was demonstrated as suitable biomarker of AD, a combined profile of several CSF neurochemical parameters might show enhanced sensitivity and specificity and thus contribute to earlier and more accurate diagnosis of AD, crucial for application of effective treatments.

A targeted review of the neurobiology and genetics of behavioural addictions: an emerging area of research.

This review summarizes neurobiological and genetic findings in behavioural addictions, draws parallels with findings pertaining to substance use disorders, and offers suggestions for future research. Articles concerning brain function, neurotransmitter activity, and family history and (or) genetic findings for behavioural addictions involving gambling, Internet use, video game playing, shopping, kleptomania, and sexual activity were reviewed. Behavioural addictions involve dysfunction in several brain regions, particularly the frontal cortex and striatum. Findings from imaging studies incorporating cognitive tasks have arguably been more consistent than cue-induction studies. Early results suggest white and grey matter differences. Neurochemical findings suggest roles for dopaminergic and serotonergic systems, but results from clinical trials seem more equivocal. While limited, family history and genetic data support heritability for pathological gambling and that people with behavioural addictions are more likely to have a close family member with some form of psychopathology. Parallels exist between neurobiological and genetic and family history findings in substance and nonsubstance addictions, suggesting that compulsive engagement in these behaviours may constitute addictions. To date, findings are limited, particularly for shopping, kleptomania, and sexual behaviour. Genetic understandings are at an early stage. Future research directions are offered.

Cette revue résume les résultats neurobiologiques et génétiques des dépendances comportementales, établit des parallèles avec les résultats relatifs aux troubles d'utilisation d'une substance, et offre des suggestions à la future recherche. Les articles concernant la fonction cérébrale, l'activité des neurotransmetteurs, et les antécédents familiaux et (ou) les résultats génétiques pour les dépendances comportementales que sont le jeu de hasard, l'utilisation d'Internet, les jeux vidéo, le magasinage, la cleptomanie, et l'activité sexuelle ont été examinés. Les dépendances comportementales présentent une dysfonction de plusieurs régions du cerveau, en particulier le cortex frontal et le striatum. Il est permis de croire que les résultats des études d'imagerie comportant des tâches cognitives étaient plus cohérents que ceux des études par induction de signaux. Les résultats préliminaires suggèrent des différences de matière blanche et grise. Les résultats neurochimiques suggèrent des rôles pour les systèmes dopaminergique et sérotoninergique, mais les résultats des essais cliniques semblent plus équivoques. Bien que limités, les antécédents familiaux et les données génétiques soutiennent l'héritabilité du jeu pathologique et le fait que les personnes ayant des dépendances comportementales sont plus susceptibles d'avoir un membre de la famille proche qui souffre d'une forme quelconque de psychopathologie. Il existe des parallèles entre les résultats neurobiologiques, génétiques et d'antécédents familiaux dans les dépendances à une substance et à une non-substance, ce qui suggère que l'exercice compulsif de ces comportements peut constituer des dépendances. Jusqu'ici, les résultats sont limités, particulièrement en ce qui concerne le magasinage, la cleptomanie, et le comportement sexuel. Les explications génétiques sont encore au premier stade. Des orientations sont offertes pour la future recherche.

Review and recommendations for the prevention, management, and treatment of postoperative and postdischarge nausea and vomiting.

Patients have rated severe nausea to be worse than postoperative pain. The overall incidence of postoperative nausea and vomiting (PONV) is 25%-30% and can lead to delayed discharge and unanticipated hospital admission. After outpatient surgery, the overall incidence of postdischarge nausea has been reported to be 17% and of vomiting 8%, higher than nausea and vomiting reported during the procedure or recovery. Patients who experienced postdischarge nausea and vomiting (PDNV) were unable to resume normal daily activities as quickly. This paper addresses the frequency, pathophysiology and patient perception of PONV and PDNV and reviews antiemetics and adjunctive medications used for the prevention, management, and treatment of PONV and PDNV. For each, the indication, mechanism of action, adverse effects, drug interactions, and implications for oral surgery and outpatient sedation are provided. Because many antiemetics are available for prevention, management, and treatment of PONV and PDNV, optimal medication choices are important for each procedure and patient.

[Age-dependent changes of neurochemical properties of sensory neurons].

Sensory neurons represent various groups of neurons differ on their morphological, immunohistochemical and receptor characteristics. The most of large neurons with myelinated Adelta fibers contain neurofilament 200 kD (NF200), some small afferent neurons can bind the isolectin B4 (IB4). Also, sensory neurons may include different types of tyrosine kinases (trkA, B and C) and neurotransmitters. Neuropeptides are generally located in small and medium-sized neurons. The proportion of neurons which contain trkA decreases and the percentage of NF200-, IB4-,substance P- and CGRP-positive neurons increases during the early development. Development of different types of sensory neurons fulfill under control of neurotrophins.

Emerging opportunities for serotypes of botulinum neurotoxins.

BACKGROUND: Two decades ago, botulinum neurotoxin (BoNT) type A was introduced to the commercial market. Subsequently, the toxin was approved by the FDA to address several neurological syndromes, involving muscle, nerve, and gland hyperactivity. These syndromes have typically been associated with abnormalities in cholinergic transmission. Despite the multiplicity of botulinal serotypes (designated as types A through G), therapeutic preparations are currently only available for BoNT types A and B. However, other BoNT serotypes are under study for possible clinical use and new clinical indications; OBJECTIVE: To review the current research on botulinum neurotoxin serotypes A-G, and to analyze potential applications within basic science and clinical settings; CONCLUSIONS: The increasing understanding of botulinal neurotoxin pathophysiology, including the neurotoxin's effects on specific neuronal populations, will help us in tailoring treatments for specific diagnoses, symptoms and patients. Scientists and clinicians should be aware of the full range of available data involving neurotoxin subtypes A-G.

[Dynamic hierarchy of regulatory peptides. Structure of the induction relations of regulators as the target for therapeutic agents].

Based on the database information (literature period 1970-2010 gg.) on the effects of regulatory peptides (RP) and non-peptide neurotransmitters (dopamine, serotonin, norepi-nephrine, acetylcholine) it was analyzed of possible cascade processes of endogenous regulators. It was found that the entire continuum of RP and mediators is a chaotic soup of the ordered three-level compartments. Such a dynamic functional hierarchy of endogenous regulators allows to create start-up and corrective tasks for a variety of physiological functions. Some examples of static and dynamic patterns of induction processes of RP and mediators (that regulate the states of anxiety, depression, learning and memory, feeding behavior, reproductive processes, etc.) are considered.

Neurotransmitter segregation: functional and plastic implications.

Synaptic cotransmission is the ability of neurons to use more than one transmitter to convey synaptic signals. Cotransmission was originally described as the presence of a classic transmitter, which conveys main signal, along one or more cotransmitters that modulate transmission, later on, it was found cotransmission of classic transmitters. It has been generally accepted that neurons store and release the same set of transmitters in all their synaptic processes. However, some findings that show axon endings of individual neurons storing and releasing different sets of transmitters, are not in accordance with this assumption, and give support to the hypothesis that neurons can segregate transmitters to different synapses. Here, we review the studies showing segregation of transmitters in invertebrate and mammalian central nervous system neurons, and correlate them with our results obtained in sympathetic neurons. Our data show that these neurons segregate even classic transmitters to separated axons. Based on our data we suggest that segregation is a plastic phenomenon and responds to functional synaptic requirements, and to 'environmental' cues such as neurotrophins. We propose that neurons have the machinery to guide the different molecules required in synaptic transmission through axons and sort them to different axon endings. We believe that transmitter segregation improves neuron interactions during cotransmission and gives them selective and better control of synaptic plasticity.

The role of neuromodulators in selective attention.

Several classes of neurotransmitters exert modulatory effects on a broad and diverse population of neurons throughout the brain. Some of these neuromodulators, especially acetylcholine and dopamine, have long been implicated in the neural control of selective attention. We review recent evidence and evolving ideas about the importance of these neuromodulatory systems in attention, particularly visual selective attention. We conclude that, although our understanding of their role in the neural circuitry of selective attention remains rudimentary, recent research has begun to suggest unique contributions of neuromodulators to different forms of attention, such as bottom-up and top-down attention.

Neurotransmitter phenotype differentiation and synapse formation of neural precursors engrafting in amyloid-ß(1-40) injured rat hippocampus.

Alzheimer's disease (AD) is characterized by the dysfunction or loss of a vulnerable group of neurons. At present, only a few options exist for treating neurodegenerative diseases effectively. Advances in stem cell research have raised the hope and possibility for therapy in neurodegenerative diseases. In AD transgenic animal models, stem cell transplantation has been demonstrated to reverse behavioral deficits. Our recent study demonstrates that neural precursor cells, derived from embryonic stem (ES) cells, improve memory dysfunction in rats caused by injections of amyloid-ß peptide (1-40) (Aß1₋40) in the dorsal hippocampus. However, the underlying mechanisms remain unknown. The present study tests a murine ES cell-based transplantation approach in rats subjected to Aß1₋40 injection into the hippocampus dentate gyrus. Efficacy of cell therapy with regard to graft survival, neuronal yield and diversity, synapse formation of the grafted cells, and the behavioral improvements was determined after transplanting ES cell-derived neural precursors into the hippocampus of adult rats. Here, we show that grafted cells can survive, and differentiate with high yield into immunohistochemically mature glial cells and neurons of diverse neurotransmitter-subtypes. More importantly, transplanted cells demonstrate characteristics of proper synapse formation between host and grafted neural cells. Thus, our observations show that an ES cell-based transplantation approach may be promising in the treatment of AD.

Pleiotropic effects of neurotransmission during development: modulators of modularity.

The formation and function of the mammalian cerebral cortex relies on the complex interplay of a variety of genetic and environmental factors through protracted periods of gestational and postnatal development. Biogenic amine systems are important neuromodulators, both in the adult nervous system, and during critical epochs of brain development. Abnormalities in developmental programming likely contribute to developmental delays and multiple neurological and psychiatric disorders, often with symptom onset much later than the actual induction of pathology. We review several genetic and pharmacological models of dopamine, norepinephrine and serotonin modulation during development, each of which produces permanent changes in cerebral cortical structure and function. These models clearly illustrate the ability of these neurotransmitters to function beyond their classic roles and show their involvement in the development and modulation of fine brain circuitry that is sensitive to numerous effectors. Furthermore, these studies demonstrate the need to consider not only gene by environment interactions, but also gene by environment by developmental time interactions.

Chemokines and neuromodulation.

Chemokines are not only mediators of the immune system and expressed in inflammatory situations. They are also constitutively expressed in the brain in both glial cells and neurons. Several recent evidence suggest that they can have a neurotransmitter/neuromodulatory role on brain functions similar to several neuropeptides reported so far. The aim of this short review is to illustrate that point using two chemokine systems, SDF-1/CXCL12 and its receptor CXCR4 and MCP-1/CCL2 and its receptor CCR2.

Monoaminergic agents modulate antidepressant-like effect caused by diphenyl diselenide in rats.

In this study, the antidepressant-like effect caused by diphenyl diselenide on rat forced swimming test (FST) was investigated. The involvement of the monoaminergic system in the antidepressant-like effect was also evaluated. Diphenyl diselenide (0.1-30 mg/kg), given by oral route (p.o.), 30 min earlier, reduced the immobility time in the FST, without accompanying changes in ambulation when assessed in an open field. The anti-immobility effect of diphenyl diselenide (1 mg/kg, p.o.) on the FST was prevented by pretreatment of rats with p-chlorophenylalanine methyl ester (PCPA; 100 mg/kg, i.p., an inhibitor of serotonin synthesis, given once a day, for 3 consecutive days), WAY100635 (0.1 mg/kg, s.c., a selective 5-HT(1A) receptor antagonist), ketanserin (1 mg/kg, i.p., a 5-HT(2A)/(2C) receptor antagonist), ondasentron (1 mg/kg, i.p., a 5-HT(3) receptor antagonist), haloperidol (1 mg/kg, i.p., a D(1), D(2) and D(3) receptor antagonist), SCH233390 (0.05 mg/kg, s.c., a D(1) receptor antagonist), sulpiride (50 mg/kg, i.p., a D(2) receptor antagonist), prazosin (1 mg/kg, i.p., an alpha(1)-adrenoceptor antagonist), yohimbine (1 mg/kg, i.p., an alpha(2)-adrenoceptor antagonist). However, the anti-immobility effect caused by diphenyl diselenide (1 mg/kg, p.o.) on the FST was not affected by pretreatment with propanolol (2 mg/kg, i.p., a beta-adrenoceptor antagonist). Furthermore, monoamine oxidase (MAO) activity was inhibited (39%) in the animals treated with diphenyl diselenide (30 mg/kg, p.o.) when compared to the control group. Taken together these data demonstrated that the antidepressant-like effect caused by diphenyl diselenide seems to be mediated by involvement of the central monoaminergic system.

Lack of localization of 5-HT6 receptors on cholinergic neurons: implication of multiple neurotransmitter systems in 5-HT6 receptor-mediated acetylcholine release.

The involvement of the cholinergic system in learning and memory together with the cognitive enhancing properties of 5-HT6 receptor antagonists led us to study the relationship between 5-HT6 receptors and cholinergic neurotransmission. A selective cholinergic lesion, induced by injection of the immunotoxin 192-IgG-Saporin into the nucleus basalis magnocellularis, failed to alter the density of 5-HT6 receptor mRNA or protein expression in the deafferentated frontal cortex, suggesting that 5-HT6 receptors are not located on cholinergic neurons. The 5-HT6 receptor antagonist SB-357134 (0.001-1 microM) induced a concentration-dependant K+-evoked [3H]acetylcholine (ACh) release in vitro in rat cortical and striatal slices, which was blocked by tetrodotoxin. SB-357134, up to 1 microM, stimulated glutamate release in cortical and striatal slices. In the cortex, riluzole (1 microM) blocked the SB-357134-induced K+-stimulated [3H]ACh release, and simultaneous administration of MK-801 (1 microM) and SB-357134 (0.05 microM) elicited an increase in K+-evoked ACh release. In the striatum, SB-357134, 1 microM, decreased dopamine release, and the increase in K+-evoked [3H]ACh release induced by 5-HT6 receptor blockade was reversed by the D1 receptor antagonist, SCH23390 (1 microM). In both the frontal cortex and striatum, bicuculline, 1 microM, showed no effect on SB-357134-evoked [3H]ACh. These results are discussed in terms of neurochemical mechanisms involved in 5-HT6 receptor functions.

Interstitial cells of Cajal in the urethra.

The smooth muscle layer of the urethra generates spontaneous myogenic tone that is thought to make a major contribution to urinary continence. The mechanisms underlying generation of tone remain unclear, however recent studies from our laboratory highlighted a role for a specialised population of pacemaker cells which we originally referred to as interstitial cells (IC) and now term ICC. Urethra ICC possess an electrical pacemaker mechanism characterised by rhythmic activation of Ca(2+)-activated Cl(-) channels leading to spontaneous transient inward currents (STICs) under voltage clamp and spontaneous transient depolarisations (STDs) under current clamp conditions. Both STICS and STDs are now known to be associated with spontaneous Ca(2+) oscillations that result from a complex interplay between release of Ca(2+) from intracellular stores and Ca(2+) influx across the plasma membrane. In this review we will consider some of the precise mechanisms involved in the generation of pacemaker activity and discuss how these are modulated by excitatory and inhibitory neurotransmitters.

Membrane phospholipid composition, alterations in neurotransmitter systems and schizophrenia.

This review addresses the relationship between modifications in membrane phospholipid composition (MPC) and alterations in dopaminergic, serotonergic and cholinergic neurotransmitter systems in schizophrenia. The main evidence in support of the MPC hypothesis of schizophrenia comes from post-mortem and platelet studies, which show that in schizophrenia, certain omega-3 and omega-6 polyunsaturated fatty acid (PUFA) levels are reduced. Furthermore, examination of several biochemical markers suggests abnormal fatty acid metabolism may be present in schizophrenia. Dietary manipulation of MPC with polyunsaturated fatty acid diets has been shown to affect densities of dopamine, serotonin and muscarinic receptors in rats. Also, supplementation with omega-3 fatty acids has been shown to improve mental health rating scores, and there is evidence that the mechanism behind this involves the serotonin receptor complex. This suggests that a tight relationship exists between essential fatty acid status and normal neurotransmission, and that altered PUFA levels may contribute to the abnormalities in neurotransmission seen in schizophrenia.

Errores congénitos de los neurotransmisores en Neuropediatría / Inborn errors of neurotransmitters in neuropaediatrics

Objetivo. Describir las características clínicas, bioquímicasy genéticas de las enfermedades de los neurotransmisoresen la edad pediátrica, así como las posibilidades terapéuticas.Determinar la metodología diagnóstica de estos trastornos (recogiday análisis de muestras). Desarrollo. Estas enfermedades comprendenbásicamente déficit de las aminas biógenas y alteracionesdel metabolismo del GABA (ácido ã-aminobutírico). Los trastornosde la neurotransmisión de las aminas biógenas se presentangeneralmente en forma de hipocinesia, hipotonía troncal con aumentodel tono en las extremidades, crisis oculogíricas, ptosis,desregulaciones de la temperatura o movimientos anormales. Losdefectos del metabolismo del GABA producen encefalopatías epilépticasy retraso mental inespecífico, asociado en ocasiones asignos de disfunción cerebelosa, convulsiones y alteraciones en laneuroimagen. La incidencia global de estas enfermedades es baja,pero sin duda se infradiagnostican, dado que no pueden detectarsemediante estudios convencionales en plasma y orina, y se requierede la extracción y análisis dirigido del líquido cefalorraquídeo(LCR) para su detección. El estudio del LCR debe realizarse,además, en unas determinadas condiciones estandarizadas. Laenfermedad de Segawa o distonía dopasensible presenta una respuestaexcelente al tratamiento, mientras que el resto de las entidades responden de manera variable a las diferentes alternativasterapéuticas. Conclusiones. Es importante que el neuropediatraconozca estas entidades como un grupo de enfermedades neurometabólicastratables. Su detección, además, permitiría la realizaciónde un diagnóstico prenatal en la gran mayoría de los casos

Aims. The aim of this work is to describe the clinical, biochemical and genetic characteristics of neurotransmitterdiseases at the paediatric age, together with possible forms of treatment. We also sought to determine the diagnosticmethodology of these disorders (collection and analysis of samples). Development. These diseases essentially consist of adeficit of biogenic amines and alterations in GABA metabolism ( ã-aminobutyric acid). Disorders affecting the neurotransmissionof biogenic amines often present in the form of hypokinesia, trunk hypotonia with increased limb tone, oculogyriccrises, ptosis, faulty temperature regulation or abnormal movements. Defects in GABA metabolism give rise to epilepticencephalopathies and unspecific mental retardation, sometimes associated to signs of cerebellar dysfunction, convulsions andalterations in neuroimaging studies. Overall incidence of these diseases is low but they are unquestionably under-diagnosed,since they cannot be detected by conventional studies in plasma and urine, and require extraction and directed analysis ofcerebrospinal fluid (CSF) for their detection. Additionally, the CSF study must be carried out in specific standardisedconditions. Segawa’s disease, or dopa-responsive dystonia, responds extremely well to therapy, whereas the other entitiesrespond in varying ways to the different therapeutic alternatives. Conclusions. It is important for the paediatrician to knowabout these entities as a group of treatable neurometabolic diseases. Moreover, their detection would allow prenatal diagnosisin the vast majority of cases