Diagnostic approach to neurotransmitter monoamine disorders: experience from clinical, biochemical, and genetic profiles.

Alice Kuster, , Jean-Baptiste Arnoux, Magalie Barth, Delphine Lamireau, Nada Houcinat, Cyril Goizet, Bérénice Doray, Stéphanie Gobin, Manuel Schiff, Aline Cano, Daniel Amsallem, Christine Barnerias, Boris Chaumette, Marion Plaze, Abdelhamid Slama, Christine Ioos, Isabelle Desguerre, Anne-Sophie Lebre, Pascale de Lonlay, Laurence Christa
J Inherit Metab Dis. 2017-09-18; 41(1): 129-139
DOI: 10.1007/s10545-017-0079-6

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1. J Inherit Metab Dis. 2018 Jan;41(1):129-139. doi: 10.1007/s10545-017-0079-6. Epub
2017 Sep 18.

Diagnostic approach to neurotransmitter monoamine disorders: experience from
clinical, biochemical, and genetic profiles.

Kuster A(1), Arnoux JB(2), Barth M(3), Lamireau D(4), Houcinat N(4), Goizet C(4),
Doray B(5), Gobin S(6), Schiff M(7), Cano A(8), Amsallem D(9), Barnerias C(10),
Chaumette B(11), Plaze M(11), Slama A(12), Ioos C(13), Desguerre I(10), Lebre
AS(14), de Lonlay P(2), Christa L(15); Individual contributors who contributed to
this work.

Collaborators: Pedespan JM, Henrion-Caude A, Damaj L, Odent S, Clot F, Corne C,
de Pontual L, Bahi-Buisson N, Martinez G, Gaillard R, Krebs MO, Benoist JF.

Author information:
(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. .

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.

DOI: 10.1007/s10545-017-0079-6
PMID: 28924877 [Indexed for MEDLINE]

Auteurs Bordeaux Neurocampus