Publications by authors named "Àngels García-Cazorla"

120 Publications

U-IMD: the first Unified European registry for inherited metabolic diseases.

Orphanet J Rare Dis 2021 Feb 18;16(1):95. Epub 2021 Feb 18.

Division of Neuropediatrics and Metabolic Medicine, Department of General Pediatrics, Centre for Child and Adolescent Medicine, Im Neuenheimer Feld 430, 69120, Heidelberg, Germany.

Background: Following the broad application of new analytical methods, more and more pathophysiological processes in previously unknown diseases have been elucidated. The spectrum of clinical presentation of rare inherited metabolic diseases (IMDs) is broad and ranges from single organ involvement to multisystemic diseases. With the aim of overcoming the limited knowledge about the natural course, current diagnostic and therapeutic approaches, the project has established the first unified patient registry for IMDs that fully meets the requirements of the European Infrastructure for Rare Diseases (ERDRI).

Results: In collaboration with the European Reference Network for Rare Hereditary Metabolic Disorders (MetabERN), the Unified European registry for Inherited Metabolic Diseases (U-IMD) was established to collect patient data as an observational, non-interventional natural history study. Following the recommendations of the ERDRI the U-IMD registry uses common data elements to define the IMDs, report the clinical phenotype, describe the biochemical markers and to capture the drug treatment. Until today, more than 1100 IMD patients have been registered.

Conclusion: The U-IMD registry is the first observational, non-interventional patient registry that encompasses all known IMDs. Full semantic interoperability for other registries has been achieved, as demonstrated by the use of a minimum common core data set for equivalent description of metabolic patients in U-IMD and in the patient registry of the European Rare Kidney Disease Reference Network (ERKNet). In conclusion, the U-IMD registry will contribute to a better understanding of the long-term course of IMDs and improved patients care by understanding the natural disease course and by enabling an optimization of diagnostic and therapeutic strategies.
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http://dx.doi.org/10.1186/s13023-021-01726-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7893973PMC
February 2021

Unraveling Molecular Pathways Altered in MeCP2-Related Syndromes, in the Search for New Potential Avenues for Therapy.

Biomedicines 2021 Feb 3;9(2). Epub 2021 Feb 3.

Neural Development Lab, Departament de Patologia i Terapèutica Experimental, Institut de Neurociències, Universitat de Barcelona, l'Hospitalet de Llobregat, 08907 Barcelona, Spain.

Methyl-CpG-binding protein 2 (MeCP2) is an X-linked epigenetic modulator whose dosage is critical for neural development and function. Loss-of-function mutations in cause Rett Syndrome (RTT, OMIM #312750) while duplications in the Xq28 locus containing and Interleukin-1 receptor-associated kinase 1 () cause duplication syndrome (MDS, OMIM #300260). Both are rare neurodevelopmental disorders that share clinical symptoms, including intellectual disability, loss of speech, hand stereotypies, vasomotor deficits and seizures. The main objective of this exploratory study is to identify novel signaling pathways and potential quantitative biomarkers that could aid early diagnosis and/or the monitoring of disease progression in clinical trials. We analyzed by RT-PCR gene expression in whole blood and microRNA (miRNA) expression in plasma, in a cohort of 20 females with Rett syndrome, 2 males with duplication syndrome and 28 healthy controls, and correlated RNA expression with disease and clinical parameters. We have identified a set of potential biomarker panels for RTT diagnostic and disease stratification of patients with microcephaly and vasomotor deficits. Our study sets the basis for larger studies leading to the identification of specific miRNA signatures for early RTT detection, stratification, disease progression and segregation from other neurodevelopmental disorders. Nevertheless, these data will require verification and validation in further studies with larger sample size including a whole range of ages.
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http://dx.doi.org/10.3390/biomedicines9020148DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7913493PMC
February 2021

GRIN database: A unified and manually curated repertoire of GRIN variants.

Hum Mutat 2021 Jan 30;42(1):8-18. Epub 2020 Nov 30.

School of International Studies, ESCI-UPF, Barcelona, Spain.

Glutamatergic neurotransmission is crucial for brain development, wiring neuronal function, and synaptic plasticity mechanisms. Recent genetic studies showed the existence of autosomal dominant de novo GRIN gene variants associated with GRIN-related disorders (GRDs), a rare pediatric neurological disorder caused by N-methyl- d-aspartate receptor (NMDAR) dysfunction. Notwithstanding, GRIN variants identification is exponentially growing and their clinical, genetic, and functional annotations remain highly fragmented, representing a bottleneck in GRD patient's stratification. To shorten the gap between GRIN variant identification and patient stratification, we present the GRIN database (GRINdb), a publicly available, nonredundant, updated, and curated database gathering all available genetic, functional, and clinical data from more than 4000 GRIN variants. The manually curated GRINdb outputs on a web server, allowing query and retrieval of reported GRIN variants, and thus representing a fast and reliable bioinformatics resource for molecular clinical advice. Furthermore, the comprehensive mapping of GRIN variants' genetic and clinical information along NMDAR structure revealed important differences in GRIN variants' pathogenicity and clinical phenotypes, shedding light on GRIN-specific fingerprints. Overall, the GRINdb and web server is a resource for molecular stratification of GRIN variants, delivering clinical and investigational insights into GRDs. GRINdb is accessible at http://lmc.uab.es/grindb.
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http://dx.doi.org/10.1002/humu.24141DOI Listing
January 2021

Novel Protein Biomarkers of Monoamine Metabolism Defects Correlate with Disease Severity.

Mov Disord 2021 03 5;36(3):690-703. Epub 2020 Nov 5.

Synaptic Metabolism Laboratory, Sant Joan de Déu Foundation, Research Pediatric Institute (IPR), Sant Joan de Déu Hospital, Barcelona, Spain.

Background: Genetic defects of monoamine neurotransmitters are rare neurological diseases amenable to treatment with variable response. They are major causes of early parkinsonism and other spectrum of movement disorders including dopa-responsive dystonia.

Objectives: The objective of this study was to conduct proteomic studies in cerebrospinal fluid (CSF) samples of patients with monoamine defects to detect biomarkers involved in pathophysiology, clinical phenotypes, and treatment response.

Methods: A total of 90 patients from diverse centers of the International Working Group on Neurotransmitter Related Disorders were included in the study (37 untreated before CSF collection, 48 treated and 5 unknown at the collection time). Clinical and molecular metadata were related to the protein abundances in the CSF.

Results: Concentrations of 4 proteins were significantly altered, detected by mass spectrometry, and confirmed by immunoassays. First, decreased levels of apolipoprotein D were found in severe cases of aromatic L-amino acid decarboxylase deficiency. Second, low levels of apolipoprotein H were observed in patients with the severe phenotype of tyrosine hydroxylase deficiency, whereas increased concentrations of oligodendrocyte myelin glycoprotein were found in the same subset of patients with tyrosine hydroxylase deficiency. Third, decreased levels of collagen6A3 were observed in treated patients with tetrahydrobiopterin deficiency.

Conclusion: This study with the largest cohort of patients with monoamine defects studied so far reports the proteomic characterization of CSF and identifies 4 novel biomarkers that bring new insights into the consequences of early dopaminergic deprivation in the developing brain. They open new possibilities to understand their role in the pathophysiology of these disorders, and they may serve as potential predictors of disease severity and therapies. © 2020 International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.28362DOI Listing
March 2021

Laboratory Diagnosis of a Case with Coenzyme Q10 Deficiency.

Clin Chem 2020 Nov;66(11):1465-1467

Institut de Recerca Sant Joan de Déu, Clinical Biochemistry, Paediatric Neurology and Genetics Departments, Barcelona, Spain.

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http://dx.doi.org/10.1093/clinchem/hvaa202DOI Listing
November 2020

Cerebrospinal fluid neopterin as a biomarker of neuroinflammatory diseases.

Sci Rep 2020 10 26;10(1):18291. Epub 2020 Oct 26.

Institut de Recerca Sant Joan de Déu, Barcelona, Spain.

The elevation of neopterin in cerebrospinal fluid (CSF) has been reported in several neuroinflammatory disorders. However, it is not expected that neopterin alone can discriminate among different neuroinflammatory etiologies. We conducted an observational retrospective and case-control study to analyze the CSF biomarkers neopterin, total proteins, and leukocytes in a large cohort of pediatric patients with neuroinflammatory disorders. CSF samples from 277 subjects were included and classified into four groups: Viral meningoencephalitis, bacterial meningitis, acquired immune-mediated disorders, and patients with no-immune diseases (control group). CSF neopterin was analyzed with high-performance liquid chromatography. Microbiological diagnosis included bacterial CSF cultures and several specific real-time polymerase chain reactions. Molecular testing for multiple respiratory pathogens was also included. Antibodies against neuronal and glial proteins were tested. Canonical discriminant analysis of the three biomarkers was conducted to establish the best discriminant functions for the classification of the different clinical groups. Model validation was done by biomarker analyses in a new cohort of 95 pediatric patients. CSF neopterin displayed the highest values in the viral and bacterial infection groups. By applying canonical discriminant analysis, it was possible to classify the patients into the different groups. Validation analyses displayed good results for neuropediatric patients with no-immune diseases and for viral meningitis patients, followed by the other groups. This study provides initial evidence of a more efficient approach to promote the timely classification of patients with viral and bacterial infections and acquired autoimmune disorders. Through canonical equations, we have validated a new tool that aids in the early and differential diagnosis of these neuroinflammatory conditions.
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http://dx.doi.org/10.1038/s41598-020-75500-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7588460PMC
October 2020

Disease-associated GRIN protein truncating variants trigger NMDA receptor loss-of-function.

Hum Mol Genet 2021 Feb;29(24):3859-3871

Neuroscience Program, Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, 08908 Barcelona, Spain.

De novo GRIN variants, encoding for the ionotropic glutamate NMDA receptor subunits, have been recently associated with GRIN-related disorders, a group of rare paediatric encephalopathies. Current investigational and clinical efforts are focused to functionally stratify GRIN variants, towards precision therapies of this primary disturbance of glutamatergic transmission that affects neuronal function and brain. In the present study, we aimed to comprehensively delineate the functional outcomes and clinical phenotypes of GRIN protein truncating variants (PTVs)-accounting for ~20% of disease-associated GRIN variants-hypothetically provoking NMDAR hypofunctionality. To tackle this question, we created a comprehensive GRIN PTVs variants database compiling a cohort of nine individuals harbouring GRIN PTVs, together with previously identified variants, to build-up an extensive GRIN PTVs repertoire composed of 293 unique variants. Genotype-phenotype correlation studies were conducted, followed by cell-based assays of selected paradigmatic GRIN PTVs and their functional annotation. Genetic and clinical phenotypes meta-analysis revealed that heterozygous GRIN1, GRIN2C, GRIN2D, GRIN3A and GRIN3B PTVs are non-pathogenic. In contrast, heterozygous GRIN2A and GRIN2B PTVs are associated with specific neurological clinical phenotypes in a subunit- and domain-dependent manner. Mechanistically, cell-based assays showed that paradigmatic pathogenic GRIN2A and GRIN2B PTVs result on a decrease of NMDAR surface expression and NMDAR-mediated currents, ultimately leading to NMDAR functional haploinsufficiency. Overall, these findings contribute to delineate GRIN PTVs genotype-phenotype association and GRIN variants stratification. Functional studies showed that GRIN2A and GRIN2B pathogenic PTVs trigger NMDAR hypofunctionality, and thus accelerate therapeutic decisions for this neurodevelopmental condition.
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http://dx.doi.org/10.1093/hmg/ddaa220DOI Listing
February 2021

Cataract in You-Hoover-Fong syndrome: TELO2 deficiency.

Ophthalmic Genet 2020 12 17;41(6):656-658. Epub 2020 Sep 17.

Ophthalmology Department, Sant Joan de deu Hospital , Barcelona, Spain.

Introduction: Recently, You, Hoover-Fong, and colleagues described a disease caused by a deficiency of the telomere maintenance 2 gene () function. The clinical spectrum includes early-onset global delay, dysmorphic facial features, auditory disorder, and reduced vision.

Materials And Methods: We report two siblings, diagnosed with You-Hoover-Fong syndrome at the age of 28 and 14 months. Both were genetically studied to find the cause of their developmental delay and microcephaly.

Results: The identical compound heterozygous missense mutations in the gene were found in each. Ophthalmologically, both siblings were diagnosed with progressive congenital bilateral nuclear-lamellar cataracts.

Conclusions: We report nuclear-lamellar cataracts in two siblings diagnosed with You-Hoover-Fong syndrome.
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http://dx.doi.org/10.1080/13816810.2020.1821382DOI Listing
December 2020

Impairment of adenosinergic system in Rett syndrome: Novel therapeutic target to boost BDNF signalling.

Neurobiol Dis 2020 11 14;145:105043. Epub 2020 Aug 14.

Instituto de Farmacologia e Neurociências, Faculdade de Medicina e Instituto de Medicina Molecular - João Lobo Antunes, Universidade de Lisboa, Lisboa, Portugal. Electronic address:

Rett syndrome (RTT; OMIM#312750) is mainly caused by mutations in the X-linked MECP2 gene (methyl-CpG-binding protein 2 gene; OMIM*300005), which leads to impairments in the brain-derived neurotrophic factor (BDNF) signalling. The boost of BDNF mediated effects would be a significant breakthrough but it has been hampered by the difficulty to administer BDNF to the central nervous system. Adenosine, an endogenous neuromodulator, may accomplish that role since through AR it potentiates BDNF synaptic actions in healthy animals. We thus characterized several hallmarks of the adenosinergic and BDNF signalling in RTT and explored whether AR activation could boost BDNF actions. For this study, the RTT animal model, the Mecp2 knockout (Mecp2) (B6.129P2 (C)-Mecp2tm1.1Bird/J) mouse was used. Whenever possible, parallel data was also obtained from post-mortem brain samples from one RTT patient. Ex vivo extracellular recordings of field excitatory post-synaptic potentials in CA1 hippocampal area were performed to evaluate synaptic transmission and long-term potentiation (LTP). RT-PCR was used to assess mRNA levels and Western Blot or radioligand binding assays were performed to evaluate protein levels. Changes in cortical and hippocampal adenosine content were assessed by liquid chromatography with diode array detection (LC/DAD). Hippocampal ex vivo experiments revealed that the facilitatory actions of BDNF upon LTP is absent in Mecp2 mice and that TrkB full-length (TrkB-FL) receptor levels are significantly decreased. Extracts of the hippocampus and cortex of Mecp2 mice revealed less adenosine amount as well as less AR protein levels when compared to WT littermates, which may partially explain the deficits in adenosinergic tonus in these animals. Remarkably, the lack of BDNF effect on hippocampal LTP in Mecp2 mice was overcome by selective activation of AR with CGS21680. Overall, in Mecp2 mice there is an impairment on adenosinergic system and BDNF signalling. These findings set the stage for adenosine-based pharmacological therapeutic strategies for RTT, highlighting AR as a therapeutic target in this devastating pathology.
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http://dx.doi.org/10.1016/j.nbd.2020.105043DOI Listing
November 2020

Severe Pulmonary Hypertension as the Debut of Metabolic Disease.

Arch Bronconeumol 2020 12 10;56(12):820-821. Epub 2020 Aug 10.

Unidad de Cuidados Intensivos Pediátricos (UCIP), Hospital Sant Joan de Déu. Institut de Recerca H. Sant Joan de Déu, Barcelona, España.

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http://dx.doi.org/10.1016/j.arbres.2020.06.020DOI Listing
December 2020

DNAJC6 Mutations Disrupt Dopamine Homeostasis in Juvenile Parkinsonism-Dystonia.

Mov Disord 2020 08 30;35(8):1357-1368. Epub 2020 May 30.

Molecular Neurosciences, Developmental Neurosciences Programme, UCL Great Ormond Street Institute of Child Health, London, United Kingdom.

Background: Juvenile forms of parkinsonism are rare conditions with onset of bradykinesia, tremor and rigidity before the age of 21 years. These atypical presentations commonly have a genetic aetiology, highlighting important insights into underlying pathophysiology. Genetic defects may affect key proteins of the endocytic pathway and clathrin-mediated endocytosis (CME), as in DNAJC6-related juvenile parkinsonism.

Objective: To report on a new patient cohort with juvenile-onset DNAJC6 parkinsonism-dystonia and determine the functional consequences on auxilin and dopamine homeostasis.

Methods: Twenty-five children with juvenile parkinsonism were identified from a research cohort of patients with undiagnosed pediatric movement disorders. Molecular genetic investigations included autozygosity mapping studies and whole-exome sequencing. Patient fibroblasts and CSF were analyzed for auxilin, cyclin G-associated kinase and synaptic proteins.

Results: We identified 6 patients harboring previously unreported, homozygous nonsense DNAJC6 mutations. All presented with neurodevelopmental delay in infancy, progressive parkinsonism, and neurological regression in childhood. I-FP-CIT SPECT (DaTScan) was performed in 3 patients and demonstrated reduced or absent tracer uptake in the basal ganglia. CSF neurotransmitter analysis revealed an isolated reduction of homovanillic acid. Auxilin levels were significantly reduced in both patient fibroblasts and CSF. Cyclin G-associated kinase levels in CSF were significantly increased, whereas a number of presynaptic dopaminergic proteins were reduced.

Conclusions: DNAJC6 is an emerging cause of recessive juvenile parkinsonism-dystonia. DNAJC6 encodes the cochaperone protein auxilin, involved in CME of synaptic vesicles. The observed dopamine dyshomeostasis in patients is likely to be multifactorial, secondary to auxilin deficiency and/or neurodegeneration. Increased patient CSF cyclin G-associated kinase, in tandem with reduced auxilin levels, suggests a possible compensatory role of cyclin G-associated kinase, as observed in the auxilin knockout mouse. DNAJC6 parkinsonism-dystonia should be considered as a differential diagnosis for pediatric neurotransmitter disorders associated with low homovanillic acid levels. Future research in elucidating disease pathogenesis will aid the development of better treatments for this pharmacoresistant disorder. © 2020 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.28063DOI Listing
August 2020

Molecular Characterization of New FBXL4 Mutations in Patients With mtDNA Depletion Syndrome.

Front Genet 2019 8;10:1300. Epub 2020 Jan 8.

Departamento de Bioquímica, Biología Molecular y Celular, Universidad de Zaragoza, Zaragoza, Spain.

Encephalomyopathic mitochondrial DNA (mtDNA) depletion syndrome 13 (MTDPS13) is a rare genetic disorder caused by defects in F-box leucine-rich repeat protein 4 (FBXL4). Although FBXL4 is essential for the bioenergetic homeostasis of the cell, the precise role of the protein remains unknown. In this study, we report two cases of unrelated patients presenting in the neonatal period with hyperlactacidemia and generalized hypotonia. Severe mtDNA depletion was detected in muscle biopsy in both patients. Genetic analysis showed one patient as having in compound heterozygosis a splice site variant c.858+5G>C and a missense variant c.1510T>C (p.Cys504Arg) in . The second patient harbored a frameshift novel variant c.851delC (p.Pro284LeufsTer7) in homozygosis. To validate the pathogenicity of these variants, molecular and biochemical analyses were performed using skin-derived fibroblasts. We observed that the mtDNA depletion was less severe in fibroblasts than in muscle. Interestingly, the cells harboring a nonsense variant in homozygosis showed normal mtDNA copy number. Both patient fibroblasts, however, demonstrated reduced mitochondrial transcript quantity leading to diminished steady state levels of respiratory complex subunits, decreased respiratory complex IV (CIV) activity, and finally, low mitochondrial ATP levels. Both patients also revealed citrate synthase deficiency. Genetic complementation assays established that the deficient phenotype was rescued by the canonical version of , confirming the pathological nature of the variants. Further analysis of fibroblasts allowed to establish that increased mitochondrial mass, mitochondrial fragmentation, and augmented autophagy are associated with FBXL4 deficiency in cells, but are probably secondary to a primary metabolic defect affecting oxidative phosphorylation.
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http://dx.doi.org/10.3389/fgene.2019.01300DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6960396PMC
January 2020

Comprehensive Analysis of GABA-A1R Developmental Alterations in Rett Syndrome: Setting the Focus for Therapeutic Targets in the Time Frame of the Disease.

Int J Mol Sci 2020 01 14;21(2). Epub 2020 Jan 14.

Synaptic Metabolism Lab, Neurology Department, Institut Pediàtric de Recerca, Hospital Sant Joan de Déu and CIBERER, 08950 Barcelona, Spain.

Rett syndrome, a serious neurodevelopmental disorder, has been associated with an altered expression of different synaptic-related proteins and aberrant glutamatergic and γ-aminobutyric acid (GABA)ergic neurotransmission. Despite its severity, it lacks a therapeutic option. Through this work we aimed to define the relationship between MeCP2 and GABAA.-A1 receptor expression, emphasizing the time dependence of such relationship. For this, we analyzed the expression of the ionotropic receptor subunit in different MeCP2 gene-dosage and developmental conditions, in cells lines, and in primary cultured neurons, as well as in different developmental stages of a Rett mouse model. Further, RNAseq and systems biology analysis was performed from post-mortem brain biopsies of Rett patients. We observed that the modulation of the MeCP2 expression in cellular models (both Neuro2a (N2A) cells and primary neuronal cultures) revealed a MeCP2 positive effect on the GABAA.-A1 receptor subunit expression, which did not occur in other proteins such as KCC2 (Potassium-chloride channel, member 5). In the Mecp2+/- mouse brain, both the KCC2 and GABA subunits expression were developmentally regulated, with a decreased expression during the pre-symptomatic stage, while the expression was variable in the adult symptomatic mice. Finally, the expression of the gamma-aminobutyric acid (GABA) receptor-related synaptic proteins from the postmortem brain biopsies of two Rett patients was evaluated, specifically revealing the GABA A1R subunit overexpression. The identification of the molecular changes along with the Rett syndrome prodromic stages strongly endorses the importance of time frame when addressing this disease, supporting the need for a neurotransmission-targeted early therapeutic intervention.
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http://dx.doi.org/10.3390/ijms21020518DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7014188PMC
January 2020

Targeted cerebrospinal fluid analysis for inborn errors of metabolism on an LC-MS/MS analysis platform.

J Inherit Metab Dis 2020 07 23;43(4):712-725. Epub 2020 Jan 23.

Department of General Pediatrics, Division of Neuropediatrics and Metabolic Medicine, Centre for Pediatric and Adolescent Medicine, University Hospital Heidelberg, Heidelberg, Germany.

Background: Laboratory investigations of cerebrospinal fluid (CSF) are essential when suspecting an inborn error of metabolism (IEM) involving neurological features. Available tests are currently performed on different analytical platforms, requiring a large sample volume and long turnaround time, which often delays timely diagnosis. Therefore, it would be preferable to have an "one-instrument" targeted multi-metabolite approach.

Method: A liquid chromatography-tandem mass spectrometry (LC-MS/MS) platform, based on two different methods for analysing 38 metabolites using positive and negative electrospray ionisation modes, was established. To allow for platform extension, both methods were designed to use the same CSF sample preparation procedure and to be run on the same separation column (ACE C18-PFP).

Results: Assessment of the LC-MS/MS platform methods was first made by analytical validation, followed by the establishment of literature-based CSF cut-off values and reference ranges, and by the measurement of available samples obtained from patients with confirmed diagnoses of aromatic l-amino acid decarboxylase deficiency, guanidinoacetate methyltransferase deficiency, ornithine aminotransferase deficiency, cerebral folate deficiency and methylenetetrahydrofolate reductase deficiency.

Conclusion: An extendable targeted LC-MS/MS platform was developed for the analysis of multiple metabolites in CSF, thereby distinguishing samples from patients with IEM from non-IEM samples. Reference concentrations for several biomarkers in CSF are provided for the first time. By measurement on a single analytical platform, less sample volume is required (200 μL), diagnostic results are obtained faster, and preanalytical issues are reduced.

Synopsis: LC-MS/MS platform for CSF analysis consisting of two differentially designed methods.
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http://dx.doi.org/10.1002/jimd.12213DOI Listing
July 2020

Effect of blood contamination of cerebrospinal fluid on amino acids, biogenic amines, pterins and vitamins.

Fluids Barriers CNS 2019 Nov 14;16(1):34. Epub 2019 Nov 14.

Clinical Biochemistry Department, Hospital Sant Joan de Déu, Barcelona, Spain.

Background: Cerebrospinal fluid (CSF) metabolomic investigations are a powerful tool for studying neurometabolic diseases. We aimed to assess the effect of CSF contamination with blood on the concentrations of selected biomarkers.

Methods: CSF samples were spiked in duplicate with increasing volumes of whole blood under two conditions: (A) pooled CSF spiked with fresh whole blood and frozen to cause red blood cell (RBC) lysis; (B) pooled CSF spiked with fresh blood and centrifuged (the supernatant with no RBCs was frozen until the moment of analysis). CSF concentrations of amino acids, biogenic amines, pterins, and vitamins were analysed by HPLC coupled with tandem mass spectrometry, electrochemical and fluorescence detection.

Results: Aspartate, glutamate, taurine, ornithine, glycine, citrulline, pyridoxal 5´-phosphate, 5-methyltetrahydrofolate, and thiamine showed higher values when RBCs were lysed when compared with those of CSF with no RBC, while arginine, 5-hydroxyindoleacetic and homovanillic acids showed lower values. When RBCs were removed from CSF, only some amino acids, thiamine and pyridoxal 5´-phosphate showed moderately higher values when compared with the non-spiked CSF sample.

Conclusions: CSF-targeted metabolomic analysis is feasible even when substantial RBC contamination of CSF has occurred since CSF centrifugation to remove RBC prior to freezing eliminated most of the interferences observed.
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http://dx.doi.org/10.1186/s12987-019-0154-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6857153PMC
November 2019

Infectious stress triggers a POLG-related mitochondrial disease.

Neurogenetics 2020 01 26;21(1):19-27. Epub 2019 Oct 26.

Departamento de Bioquímica, Biología Molecular y Celular, Universidad de Zaragoza-Instituto de Investigación Sanitaria de Aragón (IIS-Aragón), C/Pedro Cerbuna, 12, 50009, Zaragoza, Spain.

A 3-year-old girl presented with severe epilepsy in the context of Borrelia infection. After ceftriaxone/lidocaine administration, she showed secondarily generalized focal crises that led to neurological and motor sequelae. Genetic studies identified in the patient two heterozygous POLG mutations (c.2591A>G; p.Asn864Ser and c.3649G>C; p.Ala1217Pro). Through analysis of POLG activity in cultured fibroblasts, we confirmed that the mutations altered the mtDNA turnover. Moreover, patient fibroblasts were more sensitive than controls in the presence of a mitochondrial replication-affecting drug, the antiretroviral azidothymidine. To test if ceftriaxone treatment could worsen the deleterious effect of the patient mutations, toxicity assays were performed. Cell toxicity, without direct effect on mitochondrial respiratory function, was detected at different antibiotic concentrations. The clinical outcome, together with the different in vitro sensitivity to ceftriaxone among patient and control cells, suggested that the mitochondrial disease symptoms were hastened by the infection and were possibly worsened by the pharmacological treatment. This study underscores the benefit of early genetic diagnosis of the patients with mitochondrial diseases, since they may be a target group of patients especially vulnerable to environmental factors.
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http://dx.doi.org/10.1007/s10048-019-00593-2DOI Listing
January 2020

Clinical presentation and proteomic signature of patients with TANGO2 mutations.

J Inherit Metab Dis 2020 03 13;43(2):297-308. Epub 2019 Aug 13.

Wellcome Centre for Mitochondrial Research, Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, UK.

Transport And Golgi Organization protein 2 (TANGO2) deficiency has recently been identified as a rare metabolic disorder with a distinct clinical and biochemical phenotype of recurrent metabolic crises, hypoglycemia, lactic acidosis, rhabdomyolysis, arrhythmias, and encephalopathy with cognitive decline. We report nine subjects from seven independent families, and we studied muscle histology, respiratory chain enzyme activities in skeletal muscle and proteomic signature of fibroblasts. All nine subjects carried autosomal recessive TANGO2 mutations. Two carried the reported deletion of exons 3 to 9, one homozygous, one heterozygous with a 22q11.21 microdeletion inherited in trans. The other subjects carried three novel homozygous (c.262C>T/p.Arg88*; c.220A>C/p.Thr74Pro; c.380+1G>A), and two further novel heterozygous (c.6_9del/p.Phe6del); c.11-13delTCT/p.Phe5del mutations. Immunoblot analysis detected a significant decrease of TANGO2 protein. Muscle histology showed mild variation of fiber diameter, no ragged-red/cytochrome c oxidase-negative fibers and a defect of multiple respiratory chain enzymes and coenzyme Q (CoQ ) in two cases, suggesting a possible secondary defect of oxidative phosphorylation. Proteomic analysis in fibroblasts revealed significant changes in components of the mitochondrial fatty acid oxidation, plasma membrane, endoplasmic reticulum-Golgi network and secretory pathways. Clinical presentation of TANGO2 mutations is homogeneous and clinically recognizable. The hemizygous mutations in two patients suggest that some mutations leading to allele loss are difficult to detect. A combined defect of the respiratory chain enzymes and CoQ with altered levels of several membrane proteins provides molecular insights into the underlying pathophysiology and may guide rational new therapeutic interventions.
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http://dx.doi.org/10.1002/jimd.12156DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7078914PMC
March 2020

Discovery of Biomarker Panels for Neural Dysfunction in Inborn Errors of Amino Acid Metabolism.

Sci Rep 2019 06 24;9(1):9128. Epub 2019 Jun 24.

Metabolic Unit, Departments of Neurology, Nutrition Biochemistry and Genetics, Institut Pediàtric de Recerca Sant Joan de Déu, CIBERER, ISCIII and metabERN, Hospital San Joan de Déu, Barcelona, Spain.

Patients with inborn errors of amino acid metabolism frequently show neuropsychiatric symptoms despite accurate metabolic control. This study aimed to gain insight into the underlying mechanisms of neural dysfunction. Here we analyzed the expression of brain-derived neurotrophic factor (BDNF) and 10 genes required for correct brain functioning in plasma and blood of patients with Urea Cycle Disorders (UCD), Maple Syrup Urine Disease (MSUD) and controls. Receiver-operating characteristic (ROC) analysis was used to evaluate sensitivity and specificity of potential biomarkers. CACNA2D2 (α2δ2 subunit of voltage-gated calcium channels) and MECP2 (methyl-CpG binding protein 2) mRNA and protein showed an excellent neural function biomarker signature (AUC ≥ 0,925) for recognition of MSUD. THBS3 (thrombospondin 3) mRNA and AABA gave a very good biomarker signature (AUC 0,911) for executive-attention deficits. THBS3, LIN28A mRNA, and alanine showed a perfect biomarker signature (AUC 1) for behavioral and mood disorders. Finally, a panel of BDNF protein and at least two large neural AAs showed a perfect biomarker signature (AUC 1) for recognition of psychomotor delay, pointing to excessive protein restriction as central causative of psychomotor delay. To conclude, our study has identified promising biomarker panels for neural function evaluation, providing a base for future studies with larger samples.
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http://dx.doi.org/10.1038/s41598-019-45674-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6591213PMC
June 2019

L-Serine dietary supplementation is associated with clinical improvement of loss-of-function -related pediatric encephalopathy.

Sci Signal 2019 06 18;12(586). Epub 2019 Jun 18.

Bellvitge Biomedical Research Institute (IDIBELL)-Unit of Neuropharmacology and Pain, University of Barcelona, Barcelona 08908, Spain.

Autosomal dominant mutations in are associated with severe encephalopathy, but little is known about the pathophysiological outcomes and any potential therapeutic interventions. Genetic studies have described the association between de novo mutations of genes encoding the subunits of the -methyl-d-aspartate receptor (NMDAR) and severe neurological conditions. Here, we evaluated a missense mutation in , causing a proline-to-threonine switch (P553T) in the GluN2B subunit of NMDAR, which was found in a 5-year-old patient with Rett-like syndrome with severe encephalopathy. Structural molecular modeling predicted a reduced pore size of the mutant GluN2B-containing NMDARs. Electrophysiological recordings in a HEK-293T cell line expressing the mutated subunit confirmed this prediction and showed an associated reduced glutamate affinity. Moreover, GluN2B(P553T)-expressing primary murine hippocampal neurons showed decreased spine density, concomitant with reduced NMDA-evoked currents and impaired NMDAR-dependent insertion of the AMPA receptor subunit GluA1 at stimulated synapses. Furthermore, the naturally occurring coagonist d-serine restored function to GluN2B(P553T)-containing NMDARs. l-Serine dietary supplementation of the patient was hence initiated, resulting in the increased abundance of d-serine in the plasma and brain. The patient has shown notable improvements in motor and cognitive performance and communication after 11 and 17 months of l-serine dietary supplementation. Our data suggest that l-serine supplementation might ameliorate -related severe encephalopathy and other neurological conditions caused by glutamatergic signaling deficiency.
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http://dx.doi.org/10.1126/scisignal.aaw0936DOI Listing
June 2019

Celia's encephalopathy and c.974dupG in BSCL2 gene: a hidden change in a known variant.

Neurogenetics 2019 05 23;20(2):73-82. Epub 2019 Mar 23.

Thyroid and Metabolic Diseases Unit, Biomedical Research Institute (CIMUS)-IDIS, School of Medicine, Universidade de Santiago de Compostela, Santiago, Spain.

Celia's encephalopathy (progressive encephalopathy with/without lipodystrophy (PELD)) is a childhood neurodegenerative disorder with a fatal prognosis before the age of 10, due to the variant c.985C>T in the BSCL2 gene that causes a cryptic splicing site leading to skipping of exon 7. For years, different authors have reported cases of congenital generalized lipodystrophy due to the variant c.974dupG in BSCL2 associated with neurological manifestations of variable severity, although some of them clearly superimposable to PELD. To identify the molecular mechanisms responsible for these neurological alterations in two patients with c.974dupG. Clinical characterization, biochemistry, and neuroimaging studies of two girls carrying this variant. In silico analysis, PCR amplification, and BSCL2 cDNA sequencing. BSCL2-201 transcript expression, which lacks exon 7, by qPCR in fibroblasts from the index case, from a healthy child as a control and from two patients with PELD, and in leukocytes from the index case and her parents. One with a severe encephalopathy including a picture of intellectual deficiency, severe language impairment, myoclonic epilepsy, and lipodystrophy as described in PELD, dying at 9 years and 9 months of age. The other 2-year-old patient showed incipient signs of neurological involvement. In silico and cDNA sequencing studies showed that variant c.974dupG gives rise to skipping of exon 7. The expression of BSCL2-201 in fibroblasts was significantly higher in the index case than in the healthy child, although less than in the case with homozygous PELD due to c.985C>T variant. The expression of this transcript was approximately half in the healthy carrier parents of this patient. The c.974dupG variant leads to the skipping of exon 7 of the BSCL2 gene and is responsible for a variant of Celia's encephalopathy, with variable phenotypic expression.
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http://dx.doi.org/10.1007/s10048-019-00574-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7288395PMC
May 2019

Betaine anhydrous in homocystinuria: results from the RoCH registry.

Orphanet J Rare Dis 2019 03 14;14(1):66. Epub 2019 Mar 14.

CHRU de Tours, Service de Médecine Interne, Université François Rabelais, Tours, France.

Background: The Registry of Adult and Paediatric Patients Treated with Cystadane® - Homocystinuria (RoCH) is a non-interventional, observational, multi-centre, post-authorization safety study that aimed to identify safety of betaine anhydrous (Cystadane®) in the treatment of patients with inborn errors of homocysteine metabolism (homocystinuria) in order to minimise the treatment associated risks and establish better knowledge on its clinical use. The registry included patients of all ages with homocystinuria who were treated with betaine anhydrous in conjunction with other therapies. Clinical data were collected retrospectively from 2007 to 2013, then prospectively up to February 2014. All adverse events (AEs) reported during the study were recorded. The clinical and biological status of patients was monitored at least once a year.

Results: A total of 125 patients with homocystinuria (adults [> 18 years]: 50; paediatric [≤18 years]: 75) were enrolled at 29 centres in France and Spain. Patients were treated with betaine anhydrous for a mean duration of 7.4 ± 4.3 years. The median total daily dose of betaine anhydrous at the first and last study visits was 6 g/day for cystathionine β-synthase (CBS)-deficient vitamin B6 responders and 9 g/day for methylenetetrahydrofolate reductase-deficient patients, while the median daily dose increased in CBS-deficient B6 non-responders (from 6 to 9 g/day) and cobalamin metabolism-defective patients (from 3 to 6 g/day) between the first and last visits. Treatment caused a mean overall reduction of 29% in plasma homocysteine levels in the study population. A total of 277 AEs were reported during the study, of which two non-serious AEs (bad taste and headache) and one serious AE (interstitial lung disease) were considered to be drug related. Overall, betaine anhydrous was well tolerated with no major safety concerns.

Conclusions: Data from the RoCH registry provided real-world evidence on the clinical safety and efficacy of betaine anhydrous in the management of homocystinuria in paediatric and adult patients.
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http://dx.doi.org/10.1186/s13023-019-1036-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6419445PMC
March 2019

Plasma coenzyme Q status is impaired in selected genetic conditions.

Sci Rep 2019 01 28;9(1):793. Epub 2019 Jan 28.

Inborn errors of metabolism Unit, Institut de Recerca Sant Joan de Déu, Barcelona, Spain.

Identifying diseases displaying chronic low plasma Coenzyme Q (CoQ) values may be important to prevent possible cardiovascular dysfunction. The aim of this study was to retrospectively evaluate plasma CoQ concentrations in a large cohort of pediatric and young adult patients. We evaluated plasma CoQ values in 597 individuals (age range 1 month to 43 years, average 11 years), studied during the period 2005-2016. Patients were classified into 6 different groups: control group of healthy participants, phenylketonuric patients (PKU), patients with mucopolysaccharidoses (MPS), patients with other inborn errors of metabolism (IEM), patients with neurogenetic diseases, and individuals with neurological diseases with no genetic diagnosis. Plasma total CoQ was measured by reverse-phase high-performance liquid chromatography with electrochemical detection and ultraviolet detection at 275 nm. ANOVA with Bonferroni correction showed that plasma CoQ values were significantly lower in the PKU and MPS groups than in controls and neurological patients. The IEM group showed intermediate values that were not significantly different from those of the controls. In PKU patients, the Chi-Square test showed a significant association between having low plasma CoQ values and being classic PKU patients. The percentage of neurogenetic and other neurological patients with low CoQ values was low (below 8%). In conclusión, plasma CoQ monitoring in selected groups of patients with different IEM (especially in PKU and MPS patients, but also in IEM under protein-restricted diets) seems advisable to prevent the possibility of a chronic blood CoQ suboptimal status in such groups of patients.
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http://dx.doi.org/10.1038/s41598-018-37542-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6349877PMC
January 2019

Muscle Involvement in a Large Cohort of Pediatric Patients with Genetic Diagnosis of Mitochondrial Disease.

J Clin Med 2019 Jan 10;8(1). Epub 2019 Jan 10.

Clinical Biochemistry, Pathology, Paediatric Neurology and Molecular Medicine Departments and Biobank, Institut de Recerca Sant Joan de Déu and CIBERER-ISCIII, 08950 Esplugues, Spain.

Mitochondrial diseases (MD) are a group of genetic and acquired disorders which present significant diagnostic challenges. Here we report the disease characteristics of a large cohort of pediatric MD patients ( = 95) with a definitive genetic diagnosis, giving special emphasis on clinical muscle involvement, biochemical and histopathological features. Of the whole cohort, 51 patients harbored mutations in nuclear DNA (nDNA) genes and 44 patients had mutations in mitochondrial DNA (mtDNA) genes. The nDNA patients were more likely to have a reduction in muscle fiber succinate dehydrogenase (SDH) stains and in SDH-positive blood vessels, while a higher frequency of mtDNA patients had ragged red (RRF) and blue fibers. The presence of positive histopathological features was associated with ophthalmoplegia, myopathic facies, weakness and exercise intolerance. In 17 patients younger than two years of age, RRF and blue fibers were observed only in one case, six cases presented cytochrome c oxidase (COX) reduction/COX-fibers, SDH reduction was observed in five and all except one presented SDH-positive blood vessels. In conclusion, muscle involvement was a frequent finding in our series of MD patients, especially in those harboring mutations in mtDNA genes.
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http://dx.doi.org/10.3390/jcm8010068DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6352184PMC
January 2019

Synaptic metabolism and brain circuitries in inborn errors of metabolism.

J Inherit Metab Dis 2018 11;41(6):909-910

Molecular Physiology of the Synapse Laboratory, Biomedical Research Institute Sant Pau (IIB Sant Pau), Barcelona, Spain.

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http://dx.doi.org/10.1007/s10545-018-00252-yDOI Listing
November 2018

Reply.

Liver Transpl 2019 01;25(1):178-179

HPB Surgery and Transplants Department, Hospital Universiatri Vall d'Hebron, Barcelona, Spain.

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http://dx.doi.org/10.1002/lt.25389DOI Listing
January 2019

Presynaptic disorders: a clinical and pathophysiological approach focused on the synaptic vesicle.

J Inherit Metab Dis 2018 11 18;41(6):1131-1145. Epub 2018 Jul 18.

Department of Neurology, Neurometabolic Unit and Synaptic Metabolism Laboratory, Institut Pediàtric de Recerca and CIBERER, ISCIII, Hospital Sant Joan de Déu, Passeig Sant Joan de Déu, 2, 08950, Esplugues, Barcelona, Spain.

The aim of this report is to present a tentative clinical and pathophysiological approach to diseases affecting the neuronal presynaptic terminal, with a major focus on synaptic vesicles (SVs). Diseases are classified depending on which step of the neurobiology of the SV is predominantly affected: (1) biogenesis of vesicle precursors in the neuronal soma; (2) transport along the axon; (3) vesicle cycle at the presynaptic terminal (exocytosis-endocytosis cycle, with the main purpose of neurotransmitter release). Given that SVs have been defined as individual organelles, we highlight the link between the biological processes disturbed by genetic mutations and the clinical presentation of these disorders. The great majority of diseases may present as epileptic encephalopathies, intellectual disability (syndromic or nonsyndromic) with/without autism spectrum disorder (and other neuropsychiatric symptoms), and movement disorders. These symptoms may overlap and present in patients as a combination of clinical signs that results in the spectrum of the synaptopathies. A small number of diseases may also exhibit neuromuscular signs. In general, SV disorders tend to be severe, early encephalopathies that interfere with neurodevelopment. As a consequence, developmental delay and intellectual disability are constant in almost all the defects described. Considering that some of these diseases might mimic other neurometabolic conditions (and in particular treatable disorders), an initial extensive metabolic workup should always be considered. Further knowledge into pathophysiological mechanisms and biomarkers, as well as descriptions of new presynaptic disorders, will probably take place in the near future.
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http://dx.doi.org/10.1007/s10545-018-0230-zDOI Listing
November 2018

Synaptic metabolism: a new approach to inborn errors of neurotransmission.

J Inherit Metab Dis 2018 11 16;41(6):1065-1075. Epub 2018 Jul 16.

Synaptic Metabolism Laboratory, Department of Neurology, Fundació Sant Joan de Déu, Institut Pediàtric de Recerca, Barcelona, Spain.

To date, inborn errors of neurotransmitters have been defined based on the classic concept of inborn error of metabolism (IEM), and they include defects in synthesis, catabolism, and transport pathways. However, the omics era is bringing insights into new diseases and is leading to an extended definition of IEM including new categories and mechanisms. Neurotransmission takes place at the synapse, the most specialized tight junction in the brain. The concept of "synaptic metabolism" would point to the specific chemical composition and metabolic functions of the synapse. Based on these specialized functions, we aim to provide a tentative overview about the major categories of IEM susceptible to affect neurotransmission. Small molecule defects (biogenic amines and amino acids) and energy defects are amongst the most prevalent diseases reported to disturb the concentration of CSF neurotransmitters. In these IEM, the neurological phenotypes have been largely described. Disorders of complex molecules are not typically considered as diseases affecting neurotransmission. However, most of them have been recently discovered and are involved in intracellular vesiculation, trafficking, processing, and quality control mechanisms. In this large group, neurotransmission is affected in disorders of chaperones and autophagy, disorders of the synaptic vesicle, and diseases affecting pre-synaptic membranes (synthesis and remodeling of complex lipids, defects of glycosylation). Disorders of the vesicle pools, receptor trafficking, and the chronobiology of neurotransmission are potentially emerging new categories. Finally, although not considered as IEM, channelopathies are a large group of diseases disturbing neurotransmitter homeostasis. New CSF biomarkers will probably contribute to improve the diagnosis of these disorders and find new therapeutic targets.
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http://dx.doi.org/10.1007/s10545-018-0235-7DOI Listing
November 2018

Cellular neurometabolism: a tentative to connect cell biology and metabolism in neurology.

J Inherit Metab Dis 2018 11 16;41(6):1043-1054. Epub 2018 Jul 16.

Department of Neurology, Neurometabolic Unit, Hopital Pitié Salpétrière, 47-83 Boulevard de l'Hopital, 75651, Paris Cedex 13, France.

It has become increasingly evident that inborn errors of metabolism (IEMs) are particularly prevalent as diseases of the nervous system and that a broader, more inclusive definition of IEM is necessary. In fact, as long as biochemistry is involved, any kind of monogenic disease can become an IEM. This new, extended definition includes new categories and mechanisms, and as a general trend will go beyond a single biochemical pathway and/or organelle, and will appear as a connection of multiple crossroads in a system biology approach.From one side, a simplified and updated classification of IEM is presented that mixes elements from the diagnostic approach with pathophysiological considerations into three large categories based on the size of molecules ("small and simple" or "large and complex") and their implication in energy metabolism. But from another side, whatever their size, metabolites involved in IEM may behave in the brain as signalling molecules, structural components and fuels, and many metabolites have more than one role. Neurometabolism is becoming more relevant, not only in relation to these new categories of diseases but also as a necessary way to explain the mechanisms of brain damage in classically defined categories of IEM. Brain metabolism, which has been largely disregarded in the traditional approach to investigating and treating neurological diseases, is a major clue and probably the next imminent "revolution" in neurology and neuroscience. Biochemistry (metabolism) and cell neurobiology need to meet. Additionally, the brain should be studied as a system (connecting different levels of complexity).
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http://dx.doi.org/10.1007/s10545-018-0226-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6326994PMC
November 2018

Cerebrospinal fluid monoamines, pterins, and folate in patients with mitochondrial diseases: systematic review and hospital experience.

J Inherit Metab Dis 2018 11 4;41(6):1147-1158. Epub 2018 Jul 4.

Clinical Biochemistry, Institut de Recerca Sant Joan de Déu, Barcelona, Spain.

Mitochondrial diseases are a group of genetic disorders leading to the dysfunction of mitochondrial energy metabolism pathways. We aimed to assess the clinical phenotype and the biochemical cerebrospinal fluid (CSF) biogenic amine profiles of patients with different diagnoses of genetic mitochondrial diseases. We recruited 29 patients with genetically confirmed mitochondrial diseases harboring mutations in either nuclear or mitochondrial DNA (mtDNA) genes. Signs and symptoms of impaired neurotransmission and neuroradiological data were recorded. CSF monoamines, pterins, and 5-methyltetrahydrofolate (5MTHF) concentrations were analyzed using high-performance liquid chromatography with electrochemical and fluorescence detection procedures. The mtDNA mutations were studied by Sanger sequencing, Southern blot, and real-time PCR, and nuclear DNA was assessed either by Sanger or next-generation sequencing. Five out of 29 cases showed predominant dopaminergic signs not attributable to basal ganglia involvement, harboring mutations in different nuclear genes. A chi-square test showed a statistically significant association between high homovanillic acid (HVA) values and low CSF 5-MTHF values (chi-square = 10.916; p = 0.001). Seven out of the eight patients with high CSF HVA values showed cerebral folate deficiency. Five of them harbored mtDNA deletions associated with Kearns-Sayre syndrome (KSS), one had a mitochondrial point mutation at the mtDNA ATPase6 gene, and one had a POLG mutation. In conclusion, dopamine deficiency clinical signs were present in some patients with mitochondrial diseases with different genetic backgrounds. High CSF HVA values, together with a severe cerebral folate deficiency, were observed in KSS patients and in other mtDNA mutation syndromes.
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http://dx.doi.org/10.1007/s10545-018-0224-xDOI Listing
November 2018