Alice Kuster1, Jean-Baptiste Arnoux2, Magalie Barth3, Delphine Lamireau4, Nada Houcinat4, Cyril Goizet4, Bérénice Doray5, Stéphanie Gobin6, Manuel Schiff7, Aline Cano8, Daniel Amsallem9, Christine Barnerias10, Boris Chaumette11, Marion Plaze11, Abdelhamid Slama12, Christine Ioos13, Isabelle Desguerre10, Anne-Sophie Lebre14, Pascale de Lonlay2, Laurence Christa15. 1. Neurometabolism department, Nantes Hospital and University, Nantes, France. 2. Reference center for inherited metabolic diseases, Necker Enfants-Malades Hospital, Assistance Publique Hôpitaux de Paris, Imagine Institute, Paris Descartes University, Paris, France. 3. Neurometabolism department, Angers Hospital and University, Angers, France. 4. Neuropediatric and Neurogenetic department, MRGM laboratory, National institute for health and medical research U1211, Pellegrin Hospital and University, Bordeaux, France. 5. Genetic department, Félix Guyon Hospital and University, Saint-Denis de la Réunion, France. 6. Genetic department, Necker-Enfants Malades Hospital, Assistance Publique Hôpitaux de Paris, Paris, France. 7. Neurometabolism and Biochemical department, Robert Debré Hospital and University, Paris, France. 8. Reference center for inherited metabolic diseases, la Timone-Marseille Hospital and University, Marseille, France. 9. Neuropediatric department, Jean Minjoz Hospital, Besançon, France. 10. Neurology department, Necker Enfants Malades Hospital and Paris Descartes University, Paris, France. 11. Sainte Anne Hospital, University Hospital Department (SHU), Paris Descartes University and Institut National de la Santé et de la Recherche Médicale INSERM U894, CNRS GDR, 3557, Paris, France. 12. Biochemical department, Bicêtre Hospital, Assistance Publique Hôpitaux de Paris, Le Kremlin Bicêtre, France. 13. Neuropediatric department, Raymond Poincaré Hospital, Garches, France. 14. Genetic and Biological department, Reims University, Maison Blanche Hospital, F-51092, Reims, France. 15. Metabolomic and proteomic Biochemical department, Necker Enfants-Malades Hospital, Paris Descartes University, Paris, France. christablr@aol.com.
Abstract
BACKGROUND AND AIM: To improve the diagnostic work-up of patients with diverse neurological diseases, we have elaborated specific clinical and CSF neurotransmitter patterns. METHODS: Neurotransmitter determinations in CSF from 1200 patients revealed abnormal values in 228 (19%) cases. In 54/228 (24%) patients, a final diagnosis was identified. RESULTS: We have reported primary (30/54, 56%) and secondary (24/54, 44%) monoamine neurotransmitter disorders. For primary deficiencies, the most frequently mutated gene was DDC (n = 9), and the others included PAH with neuropsychiatric features (n = 4), PTS (n = 5), QDPR (n = 3), SR (n = 1), and TH (n = 1). We have also identified mutations in SLC6A3, FOXG1 (n = 1 of each), MTHFR (n = 3), FOLR1, and MTHFD (n = 1 of each), for dopamine transporter, neuronal development, and folate metabolism disorders, respectively. For secondary deficiencies, we have identified POLG (n = 3), ACSF3 (n = 1), NFU1, and SDHD (n = 1 of each), playing a role in mitochondrial function. Other mutated genes included: ADAR, RNASEH2B, RNASET2, SLC7A2-IT1 A/B lncRNA, and EXOSC3 involved in nuclear and cytoplasmic metabolism; RanBP2 and CASK implicated in post-traductional and scaffolding modifications; SLC6A19 regulating amino acid transport; MTM1, KCNQ2 (n = 2), and ATP1A3 playing a role in nerve cell electrophysiological state. Chromosome abnormalities, del(8)(p23)/dup(12) (p23) (n = 1), del(6)(q21) (n = 1), dup(17)(p13.3) (n = 1), and non-genetic etiologies (n = 3) were also identified. CONCLUSION: We have classified the final 54 diagnoses in 11 distinctive biochemical profiles and described them through 20 clinical features. To identify the specific molecular cause of abnormal NT profiles, (targeted) genomics might be used, to improve diagnosis and allow early treatment of complex and rare neurological genetic diseases.
BACKGROUND AND AIM: To improve the diagnostic work-up of patients with diverse neurological diseases, we have elaborated specific clinical and CSF neurotransmitter patterns. METHODS: Neurotransmitter determinations in CSF from 1200 patients revealed abnormal values in 228 (19%) cases. In 54/228 (24%) patients, a final diagnosis was identified. RESULTS: We have reported primary (30/54, 56%) and secondary (24/54, 44%) monoamine neurotransmitter disorders. For primary deficiencies, the most frequently mutated gene was DDC (n = 9), and the others included PAH with neuropsychiatric features (n = 4), PTS (n = 5), QDPR (n = 3), SR (n = 1), and TH (n = 1). We have also identified mutations in SLC6A3, FOXG1 (n = 1 of each), MTHFR (n = 3), FOLR1, and MTHFD (n = 1 of each), for dopamine transporter, neuronal development, and folatemetabolism disorders, respectively. For secondary deficiencies, we have identified POLG (n = 3), ACSF3 (n = 1), NFU1, and SDHD (n = 1 of each), playing a role in mitochondrial function. Other mutated genes included: ADAR, RNASEH2B, RNASET2, SLC7A2-IT1 A/B lncRNA, and EXOSC3 involved in nuclear and cytoplasmic metabolism; RanBP2 and CASK implicated in post-traductional and scaffolding modifications; SLC6A19 regulating amino acid transport; MTM1, KCNQ2 (n = 2), and ATP1A3 playing a role in nerve cell electrophysiological state. Chromosome abnormalities, del(8)(p23)/dup(12) (p23) (n = 1), del(6)(q21) (n = 1), dup(17)(p13.3) (n = 1), and non-genetic etiologies (n = 3) were also identified. CONCLUSION: We have classified the final 54 diagnoses in 11 distinctive biochemical profiles and described them through 20 clinical features. To identify the specific molecular cause of abnormal NT profiles, (targeted) genomics might be used, to improve diagnosis and allow early treatment of complex and rare neurological genetic diseases.
Entities:
Keywords:
Neurotransmitter disorders; Primary and secondary diagnoses
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