Revista de Medicina de Laboratorio 00150 / http://dx.doi.org/10.20960/revmedlab.00150
Resumen| PDF

Revisiones - Metaanálisis

Utilidad de la espectrometría de masas para el análisis de metabolitos en líquido cefalorraquídeo de pacientes con errores congénitos del metabolismo


Maria Antònia Caro-Miró, Blai Morales-Romero, Judit García-Villoria

Prepublicado: 2022-12-13
Publicado: 2023-01-05

Logo Descargas   Número de descargas: 5202      Logo Visitas   Número de visitas: 2095      Citas   Citas: 0

Compártelo:


Los errores congénitos del metabolismo de los neurotransmisores son enfermedades poco prevalentes que cursan con síntomas en el sistema nervioso central y, en algunos casos, afectan también a nivel periférico. En general, estos pacientes tienen que pasar por largos procesos hasta conocer su diagnóstico definitivo. El análisis de los metabolitos en el líquido cefalorraquídeo por espectrometría de masas en tándem presenta una buena sensibilidad y especificidad, agiliza el diagnóstico bioquímico y optimiza el uso de la muestra. En los últimos años, se tiende al estudio de paneles de metabolitos para facilitar el diagnóstico.

Palabras Clave: Enfermedades genéticas congénitas. Agentes neurotransmisores. Aminas biógenas. Líquido cefalorraquídeo. Espectrometría de masas.



Prasad C, Galbraith PA. Sir Archibald Garrod and alkaptonuria-'Story of metabolic genetics'. Clin Genet 2005;68(3):199-203.
DOI: 10.1111/j.1399-0004.2005.00487.x
Mussap M, Zaffanello M, Fanos V. Metabolomics: a challenge for detecting and monitoring inborn errors of metabolism. Ann Transl Med 2018;6(17):338.
DOI: 10.21037/atm.2018.09.18
Klinke G, Richter S, Monostori P, Schmidt-Mader B, García-Cazorla A, Artuch R, et al. Targeted cerebrospinal fluid analysis for inborn errors of metabolism on an LC-MS/MS analysis platform. J Inherit Metab Dis 2020;43(4):712-25.
DOI: 10.1002/jimd.12213
Coene KLM, Kluijtmans LAJ, van der Heeft E, Engelke UFH, de Boer S, Hoegen B, et al. Next-generation metabolic screening: targeted and untargeted metabolomics for the diagnosis of inborn errors of metabolism in individual patients. J Inherit Metab Dis 2018;41(3):337-53.
DOI: 10.1007/s10545-017-0131-6
Wishart DS, Guo AC, Oler E, Wang F, Anjum A, Peters H, et al. HMDB 5.0: The Human Metabolome Database for 2022. Nucleic Acids Res 2022;50(D1):D622-31.
DOI: 10.1093/nar/gkab1062
Saudubray JM, García-Cazorla À. An overview of inborn errors of metabolism affecting the brain: from neurodevelopment to neurodegenerative disorders. Dialogues Clin Neurosci 2018;20(4):301-25.
DOI: 10.31887/DCNS.2018.20.4/jmsaudubray
Pearl PL, Capp PK, Novotny EJ, Gibson KM. Inherited disorders of neurotransmitters in children and adults. Clin Biochem 2005;38(12):1051-8.
DOI: 10.1016/j.clinbiochem.2005.09.012
Opladen T, Cortès-Saladelafont E, Mastrangelo M, Horvath G, Pons R, López-Laso E, et al. The International Working Group on Neurotransmitter related Disorders (iNTD): A worldwide research project focused on primary and secondary neurotransmitter disorders. Mol Genet Metab Reports 2016;9:61-6.
DOI: 10.1016/j.ymgmr.2016.09.006
Szymańska K, Kuśmierska K, Demkow U. Inherited disorders of brain neurotransmitters: Pathogenesis and diagnostic approach. Adv Exp Med Biol 2015;837:1-8.
Guibal P, Lo A, Maitre P, Moussa F. Pterin determination in cerebrospinal fluid: State of the art. Pteridines 2017;28(2):83-9.
DOI: 10.1515/pterid-2017-0001
Brennenstuhl H, Jung-Klawitter S, Assmann B, Opladen T. Inherited Disorders of Neurotransmitters: Classification and Practical Approaches for Diagnosis and Treatment. Neuropediatrics 2019;50(1):2-14.
DOI: 10.1055/s-0038-1673630
Couce ML, Aldámiz-Echevarría L, García-Jiménez MC, González-Lamuño D. Diagnóstico y tratamiento de las enfermedades metabólicas hereditarias; 2022.
Ruiz A, García-Villoria J, Ormazábal A, Zschocke J, Fiol M, Navarro-Sastre A, et al. A new fatal case of pyridox(am)ine 5′-phosphate oxidase (PNPO) deficiency. Mol Genet Metab 2008;93(2):216-8.
DOI: 10.1016/j.ymgme.2007.10.003
Wassenberg T, Geurtz BPH, Monnens L, Wevers RA, Willemsen MA, Verbeek MM. Blood, urine and cerebrospinal fluid analysis in TH and AADC deficiency and the effect of treatment. Mol Genet Metab Reports 2021;27:100762.
DOI: 10.1016/j.ymgmr.2021.100762
Opladen T, López-Laso E, Cortès-Saladelafont E, Pearson TS, Sivri HS, Yildiz Y, et al. Consensus guideline for the diagnosis and treatment of tetrahydrobiopterin (BH4) deficiencies. Orphanet J Rare Dis 2020;15(1):126.
DOI: 10.1186/s13023-020-01379-8
Longo N. Disorders of biopterin metabolsim. J Inherit Metab Dis 2009;32(3):333-42.
DOI: 10.1007/s10545-009-1067-2
Kurian MA, Gissen P, Smith M, Heales SJR, Clayton PT. The monoamine neurotransmitter disorders: An expanding range of neurological syndromes. Lancet Neurol 2011;10(8):721-33.
DOI: 10.1016/S1474-4422(11)70141-7
Ng J, Papandreou A, Heales SJ, Kurian MA. Monoamine neurotransmitter disorders - Clinical advances and future perspectives. Nat Rev Neurol 2015;11(10):567-84.
DOI: 10.1038/nrneurol.2015.172
Opladen T, Hoffmann GF, Blau N. An international survey of patients with tetrahydrobiopterin deficiencies presenting with hyperphenylalaninaemia. J Inherit Metab Dis 2012;35(6):963-73.
DOI: 10.1007/s10545-012-9506-x
Steinberg D, Blau N, Goriuonov D, Bitsch J, Zuker M, Humel S, et al. Heterozygous mutation in 5’-untranslated region of sepiapterin reductase gene (SPR) in a patient with dopa-responsive dystonia. Neurogenetics 2004;5:187-90.
DOI: 10.1007/s10048-004-0182-3
Mena MA, Aguado EG, de Yebenes JG. Monoamine metabolites in human cerebrospinal fluid. HPLC/ED method. Acta Neurol Scand 1984;69(4):218-25.
DOI: 10.1111/j.1600-0404.1984.tb07804.x
Ormazábal A, García-Cazorla A, Fernández Y, Fernández-Álvarez E, Campistol J, Artuch R. HPLC with electrochemical and fluorescence detection procedures for the diagnosis of inborn errors of biogenic amines and pterins. J Neurosci Methods 2005;142(1):153-8.
DOI: 10.1016/j.jneumeth.2004.08.007
Cox JM, Butler JP, Lutzke BS, Jones BA, Buckholz JE, Biondolillo R, et al. A validated LC-MS/MS method for neurotransmitter metabolite analysis in human cerebrospinal fluid using benzoyl chloride derivatization. Bioanalysis 2015;7(19):2461-75.
DOI: 10.4155/bio.15.170
Tufi S, Lamoree M, de Boer J, Leonards P. Simultaneous analysis of multiple neurotransmitters by hydrophilic interaction liquid chromatography coupled to tandem mass spectrometry. J Chromatogr A 2015;1395:79-87.
DOI: 10.1016/j.chroma.2015.03.056
Galla Z, Rajda C, Rácz G, Grecsó N, Baráth Á, Vécsei L, et al. Simultaneous determination of 30 neurologically and metabolically important molecules: A sensitive and selective way to measure tyrosine and tryptophan pathway metabolites and other biomarkers in human serum and cerebrospinal fluid. J Chromatogr A 2021;1635:461775.
DOI: 10.1016/j.chroma.2020.461775
Marcos J, Renau N, Valverde O, Aznar-Laín G, Gracia-Rubio I, González-Sepúlveda M, et al. Targeting tryptophan and tyrosine metabolism by liquid chromatography tandem mass spectrometry. J Chromatogr A 2016;1434:91-101.
DOI: 10.1016/j.chroma.2016.01.023
Fuertig R, Ceci A, Camus SM, Bezard E, Luippold AH, Hengerer B. LC-MS/MS-based quantification of kynurenine metabolites, tryptophan, monoamines and neopterin in plasma, cerebrospinal fluid and brain. Bioanalysis 2016;8(18):1903-17.
DOI: 10.4155/bio-2016-0111
Fukushima T, Nixon JC. Analysis of reduced forms of biopterin in biological tissues and fluids. Anal Biochem 1980;102(1):176-88.
DOI: 10.1016/0003-2697(80)90336-X
Hyland K. Estimation of tetrahydro, dihydro and fully oxidised pterins by high-performance liquid chromatography using sequential electrochemical and fluorometric detection. J Chromatogr B Biomed Sci Appl 1985;343(1):35-41.
DOI: 10.1016/S0378-4347(00)84565-X
Arning E, Bottiglieri T. LC-MS/MS Analysis of Cerebrospinal Fluid Metabolites in the Pterin Biosyntetic Pathway. JIMD Rep 2016;29:1-9.
Parviz M, Vogel K, Gibson K, Pearl P. Disorders of GABA metabolism: SSADH and GABA-transaminase deficiencies. J Pediatr Epilepsy 2014;3(4):217-27.
DOI: 10.3233/PEP-14097
Kennedy AD, Pappan KL, Donti T, Delgado MR, Shinawi M, Pearson TS, et al. 2-Pyrrolidinone and succinimide as clinical screening biomarkers for gaba-transaminase deficiency: Anti-seizure medications impact accurate diagnosis. Front Neurosci 2019;13:394.
DOI: 10.3389/fnins.2019.00394
Jaeken J, Casaer P, de Cock P, Corbeel L, Eeckels R, Eggermont E. Gamma-aminobutyric acid-transaminase deficiency: a newly recognized inborn error of neurotransmitter metabolism. Neuropediatrics 1984;15(3):165-9.
DOI: 10.1055/s-2008-1052362
Pearl PL, Shukla L, Theodore WH, Jakobs C, Gibson KM. Epilepsy in succinic semialdehyde dehydrogenase deficiency, a disorder of GABA metabolism. Brain Dev 2011;33(9):796-805.
DOI: 10.1016/j.braindev.2011.04.013
Goldsmith RF, Earl JW, Cunningham AM. Determination of gamma-aminobutyric acid and other amino acids in cerebrospinal fluid of pediatric patients by reversed-phase liquid chromatography. Clin Chem 1987;33(10):1736-40.
DOI: 10.1093/clinchem/33.10.1736
Naini AB, Vontzalidou E, Côté LJ. lsocratic HPLC Assay with Electrochemical Detection of Free gamma-aminobutyric Acid in Cerebrospinal Fluid. Clin Chem 1993;39(2):247-50.
DOI: 10.1093/clinchem/39.2.247
Arning E, Bottiglieri T. Quantification of γ-aminobutyric acid in cerebrospinal fluid using liquid chromatography-electrospray tandem mass spectrometry. Methods Mol Biol 2016;1378:109-18.
DOI: 10.1007/978-1-4939-3182-8_13
Dunnett M, Harris RC. High-performance liquid chromatographic determination of imidazole dipeptides, histidine, 1-methylhistidine and 3-methylhistidine in equine and camel muscle and individual muscle fibres. J Chromatogr B Biomed Appl 1997;688(1):47-55.
DOI: 10.1016/S0378-4347(97)88054-1
Yokoyama Y, Horikoshi S, Takahashi T, Sato H. Low-capacity cation-exchange chromatography of ultraviolet-absorbing urinary basic metabolites using a reversed-phase column coated with hexadecylsulfonate. J Chromatogr A 2000;886(1-2):297-302.
DOI: 10.1016/S0021-9673(00)00520-3
Jansen EEW, Gibson KM, Shigematsu Y, Jakobs C, Verhoeven NM. A novel, quantitative assay for homocarnosine in cerebrospinal fluid using stable-isotope dilution liquid chromatography-tandem mass spectrometry. J Chromatogr B Anal Technol Biomed Life Sci 2006;830(2):196-200.
DOI: 10.1016/j.jchromb.2005.10.053
Ramaekers VT, Paediatric D. Cerebral folate deficiency. Neurology 2004;46(12):843-51.
Chládek J, Šišpera L, Martínková J. High-performance liquid chromatographic assay for the determination of 5-methyltetrahydrofolate in human plasma. J Chromatogr B Biomed Sci Appl 2000;744(2):307-13.
DOI: 10.1016/S0378-4347(00)00257-7
Arning E, Bottiglieri T. Quantitation of 5-methyltetrahydrofolate in cerebrospinal fluid using liquid chromatography-electrospray tandem mass spectrometry. Methods Mol Biol 2016;1378:175-82.
DOI: 10.1007/978-1-4939-3182-8_19
Ormazábal A, García-Cazorla A, Pérez-Dueñas B, González V, Fernández-Álvarez E, Pineda M, et al. Determination of 5-methyltetrahydrofolate in cerebrospinal fluid of paediatric patients: Reference values for a paediatric population. Clin Chim Acta 2006;371(1-2):159-62.
DOI: 10.1016/j.cca.2006.03.004
Akiyama T, Tada H, Shiokawa T, Kobayashi K, Yoshinaga H. Total folate and 5-methyltetrahydrofolate in the cerebrospinal fluid of children: correlation and reference values. Clin Chem Lab Med 2015;53(12):2009-14.
DOI: 10.1515/cclm-2015-0208
Albersen M, Bosma M, Jans JJM, Hofstede FC, van Hasselt PM, de Sain-van der Velden MGM, et al. Vitamin B6 in plasma and cerebrospinal fluid of children. PLoS One. 2015;10(3):e0120972.
DOI: 10.1371/journal.pone.0120972
Wilson MP, Plecko B, Mills PB, Clayton PT. Disorders affecting vitamin B6 metabolism. J Inherit Metab Dis 2019;42(4):629-46.
DOI: 10.1002/jimd.12060
Clayton PT. B6-responsive disorders: A model of vitamin dependency. J Inherit Metab Dis 2006;29(2-3):317-26.
DOI: 10.1007/s10545-005-0243-2
Mills PB, Surtees RAH, Champion MP, Beesley CE, Dalton N, Scamber PJ, et al. Neonatal epileptic encephalopathy caused by mutations in the PNPO gene encoding pyridox(am)ine 5′-phosphate oxidase. Hum Mol Genet 2005;14(8):1077-86.
DOI: 10.1093/hmg/ddi120
Rahman S, Footitt EJ, Varadkar S, Clayton PT. Inborn errors of metabolism causing epilepsy. Dev Med Child Neurol 2013;55(1):23-36.
DOI: 10.1111/j.1469-8749.2012.04406.x
Mills PB, Struys E, Jakobs C, Plecko B, Baxter P, Baumgartner M, et al. Mutations in antiquitin in individuals with pyridoxine-dependent seizures. Nat Med 2006;12(3):307-9.
DOI: 10.1038/nm1366
Sharma S, Prasad AN. Inborn errors of metabolism and epilepsy: Current understanding, diagnosis, and treatment approaches. Int J Mol Sci 2017;18(7):1384.
DOI: 10.3390/ijms18071384
Bates CJ, Pentieva KD, Matthews N, Macdonald A. A simple, sensitive and reproducible assay for pyridoxal 5’-phosphate and 4-pyridoxic acid in human plasma. Clin Chim Acta 1999;280(1-2):101-11.
DOI: 10.1016/S0009-8981(98)00173-9
Ormazábal A, Oppenheim M, Serrano M, García-Cazorla A, Campistol J, Ribes A, et al. Pyridoxal 5′-phosphate values in cerebrospinal fluid: Reference values and diagnosis of PNPO deficiency in paediatric patients. Mol Genet Metab 2008;94(2):173-7.
DOI: 10.1016/j.ymgme.2008.01.004
Van der Ham M, Albersen M, de Koning TJ, Visser G, Middendorp A, Bosma M, et al. Quantification of vitamin B6 vitamers in human cerebrospinal fluid by ultra performance liquid chromatography-tandem mass spectrometry. Anal Chim Acta 2012;712:108-14.
DOI: 10.1016/j.aca.2011.11.018
Hyland K, Surtees RAH, Heales SJR, Bowron A, Howells DW, Smith I. Cerebrospinal fluid concentrations of pterins and metabolites of serotonin and dopamine in a pediatric reference population. Pediatr Res 1993;34(1):10-4.
DOI: 10.1203/00006450-199307000-00003
57. Assmann B, Surtees R, Hoffmann GF. Approach to the diagnosis of neurotransmitter diseases exemplified by the differential diagnosis of childhood-onset dystonia. Ann Neurol 2003;54(Suppl.6):S18-24.
DOI: 10.1002/ana.10628
Yan J, Han V, Heng B, Guillemin G, Bandodkar S, Dale R. Development of a translational inflammation panel for the quantification of cerebrospinal fluid Pterin, Tryptophan-Kynurenine and Nitric oxide pathway metabolites. eBioMedicine 2022;77:103917.
DOI: 10.1016/j.ebiom.2022.103917

Imagen - Infografías: Carcinomatosis meníngea: hallazgo de células malignas en el líquido cefalorraquídeo

María Gloria García Arévalo , Juan Manuel Adell Ruiz de León , Julia Maroto García

Revisiones - Metaanálisis: Biomarcadores diagnósticos de la enfermedad de Creutzfeld-Jakob

Beatriz Nafría Jiménez , Adolfo Garrido Chércoles

Originales: Utilidad clínica de la proteína tau total y la ratio con su fracción fosforilada en el diagnóstico de enfermedad de Creutzfeldt-Jakob

Beatriz Nafría Jiménez , Adolfo Garrido Chércoles , Fermín Moreno Izco

Artículos más populares

Casos Clínicos: Neonato ingresado en UCI con crisis convulsivas

Publicado: 2023-03-17

Casos Clínicos: Strongyloides stercolaris en esperma

Publicado: 2023-03-11

Casos Clínicos: Producción ectópica de ACTH-SIADH

Publicado: 2023-03-13

Una cookie o galleta informática es un pequeño archivo de información que se guarda en su navegador cada vez que visita nuestra página web. La utilidad de las cookies es guardar el historial de su actividad en nuestra página web, de manera que, cuando la visite nuevamente, ésta pueda identificarle y configurar el contenido de la misma en base a sus hábitos de navegación, identidad y preferencias. Las cookies pueden ser aceptadas, rechazadas, bloqueadas y borradas, según desee. Ello podrá hacerlo mediante las opciones disponibles en la presente ventana o a través de la configuración de su navegador, según el caso. En caso de que rechace las cookies no podremos asegurarle el correcto funcionamiento de las distintas funcionalidades de nuestra página web. Más información en el apartado “POLÍTICA DE COOKIES” de nuestra página web.