Clinical Characteristics, Developmental Trajectory, and Caregiver Burden of Patients With Creatine Transporter Deficiency (SLC6A8)

被引:5
作者
Curie, Aurore [1 ,2 ,3 ,4 ]
Lion-Francois, Laurence [1 ,2 ]
Valayannopoulos, Vassili [5 ]
Perreton, Nathalie [6 ]
Gavanon, Marie [1 ,2 ,3 ]
Touil, Nathalie [6 ]
Brun-Laurisse, Amandine [1 ,2 ,3 ]
Gheurbi, Fahra [1 ,2 ,3 ]
Buchy, Marion [1 ,2 ,3 ]
Halep, Hulya [6 ]
Cheillan, David [7 ]
Mercier, Catherine [8 ]
Brassier, Anais [5 ]
Desnous, Beatrice [9 ]
Kassai, Behrouz [6 ]
De Lonlay, Pascale [5 ]
Des Portes, Vincent [1 ,2 ,3 ,4 ]
机构
[1] Lyon Univ Hosp, Child Neurol Dept, Hosp Civils Lyon, Lyon, France
[2] Lyon Univ Hosp, Reference Ctr Rare Dis Intellectual Disabil, Hosp Civils Lyon, Lyon, France
[3] Lyon Neurosci Res Ctr, CNRS UMR5292, INSERM U1028, Lyon, France
[4] Lyon Univ, Lyon, France
[5] Univ Paris 05, Paris Univ Hosp, Necker Enfants Malad Hosp, Imagine Inst,Reference Ctr Inherited Metab Dis, Paris, France
[6] Clin Invest Ctr 1407 INSERM Hosp Civils Lyon, Bron, France
[7] Lyon Univ Hosp, Biochem & Mol Biol Dept, Inborn Errors Metab Unit, Lyon, France
[8] Lyon Univ Hosp, Dept Biostat, Lyon, France
[9] Marseille Univ Hosp, Reference Ctr Inherited Metab Dis, Dept Child Neurol, Marseille, France
关键词
MENTAL-RETARDATION; DEFECT; SPECTROSCOPY; MALES;
D O I
10.1212/WNL.0000000000209243
中图分类号
R74 [神经病学与精神病学];
学科分类号
摘要
Background and ObjectivesCreatine transporter deficiency (CTD) is a rare X-linked genetic disorder characterized by intellectual disability (ID). We evaluated the clinical characteristics and trajectory of patients with CTD and the impact of the disease on caregivers to identify relevant endpoints for future therapeutic trials. MethodsAs part of a French National Research Program, patients with CTD were included based on (1) a pathogenic SLC6A8 variant and (2) ID and/or autism spectrum disorder. Families and patients were referred by the physician who ordered the genetic analysis through Reference Centers of ID from rare causes and inherited metabolic diseases. After we informed the patients and their parents/guardians about the study, all of them gave written consent and were included. A control group of age-matched and sex-matched patients with Fragile X syndrome was also included. Physical examination, neuropsychological assessments, and caregiver impact were assessed. All data were analyzed using R software. ResultsThirty-one patients (27 male, 4 female) were included (25/31 aged 18 years or younger). Most of the patients (71%) had symptoms at <24 months of age. The mean age at diagnosis was 6.5 years. Epilepsy occurred in 45% (mean age at onset: 8 years). Early-onset behavioral disorder occurred in 82%. Developmental trajectory was consistently delayed (fine and gross motor skills, language, and communication/sociability). Half of the patients with CTD had axial hypotonia during the first year of life. All patients were able to walk without help, but 7/31 had ataxia and only 14/31 could walk tandem gait. Most of them had abnormal fine motor skills (27/31), and most of them had language impairment (30/31), but 12/23 male patients (52.2%) completed the Peabody Picture Vocabulary Test. Approximately half (14/31) had slender build. Most of them needed nursing care (20/31), generally 1-4 h/d. Adaptive assessment (Vineland) confirmed that male patients with CTD had moderate-to-severe ID. Most caregivers (79%) were at risk of burnout, as shown by Caregiver Burden Inventory (CBI) > 36 (significantly higher than for patients with Fragile X syndrome) with a high burden of time dependence. DiscussionIn addition to clinical endpoints, such as the assessment of epilepsy and the developmental trajectory of the patient, the Vineland scale, PPVT5, and CBI are of particular interest as outcome measures for future trials. Trial Registration InformationANSM Registration Number 2010-A00327-32.
引用
收藏
页数:13
相关论文
共 31 条
[1]  
AMAN MG, 1985, AM J MENT DEF, V89, P485
[2]  
Aman MG., 1999, Grille D'valuation Comportementale Pour Enfant Nisonger (French Translation of the Nisonger Child Behavior Rating Form)
[3]   Creatine transporter deficiency:: Prevalence among patients with mental retardation and pitfalls in metabolite screening [J].
Arias, Angela ;
Corbella, Marc ;
Fons, Carmen ;
Sempere, Angela ;
Garcia-Villoria, Judit ;
Ormazabal, Aida ;
Poo, Pilar ;
Pineda, Merce ;
Vilaseca, Maria Antonia ;
Campistol, Jaume ;
Briones, Paz ;
Pampols, Teresa ;
Salomons, Gajja S. ;
Ribes, Antonia ;
Artuch, Rafael .
CLINICAL BIOCHEMISTRY, 2007, 40 (16-17) :1328-1331
[4]   Drug development for neurodevelopmental disorders: lessons learned from fragile X syndrome [J].
Berry-Kravis, Elizabeth M. ;
Lindemann, Lothar ;
Jonch, Aia E. ;
Apostol, George ;
Bear, Mark F. ;
Carpenter, Randall L. ;
Crawley, Jacqueline N. ;
Curie, Aurore ;
Des Portes, Vincent ;
Hossain, Farah ;
Gasparini, Fabrizio ;
Gomez-Mancilla, Baltazar ;
Hessl, David ;
Loth, Eva ;
Scharf, Sebastian H. ;
Wang, Paul P. ;
Von Raison, Florian ;
Hagerman, Randi ;
Spooren, Will ;
Jacquemont, Sebastien .
NATURE REVIEWS DRUG DISCOVERY, 2018, 17 (04) :280-298
[5]   AGAT, GAMT and SLC6A8 distribution in the central nervous system, in relation to creatine deficiency syndromes: A review [J].
Braissant, O. ;
Henry, H. .
JOURNAL OF INHERITED METABOLIC DISEASE, 2008, 31 (02) :230-239
[6]   Treatment outcome of creatine transporter deficiency: international retrospective cohort study [J].
Bruun, Theodora U. J. ;
Sidky, Sarah ;
Bandeira, Anabela O. ;
Debray, Francoise-Guillaume ;
Ficicioglu, Can ;
Goldstein, Jennifer ;
Joost, Kairit ;
Koeberl, Dwight D. ;
Luisa, Diogo ;
Nassogne, Marie-Cecile ;
O'Sullivan, Siobhan ;
Ounap, Katrin ;
Schulze, Andreas ;
van Maldergem, Lionel ;
Salomons, Gajja S. ;
Mercimek-Andrews, Saadet .
METABOLIC BRAIN DISEASE, 2018, 33 (03) :875-884
[7]   Cyclocreatine treatment ameliorates the cognitive, autistic and epileptic phenotype in a mouse model of Creatine Transporter Deficiency [J].
Cacciante, Francesco ;
Gennaro, Mariangela ;
Sagona, Giulia ;
Mazziotti, Raffaele ;
Lupori, Leonardo ;
Cerri, Elisa ;
Putignano, Elena ;
Butt, Mark ;
Do, Minh-Ha T. ;
McKew, John C. ;
Alessandri, Maria Grazia ;
Battini, Roberta ;
Cioni, Giovanni ;
Pizzorusso, Tommaso ;
Baroncelli, Laura .
SCIENTIFIC REPORTS, 2020, 10 (01)
[8]   Exploring the caregiver burden inventory (CBI): Further evidence for a multidimensional view of burden [J].
Caserta, MS ;
Lund, DA ;
Wright, SD .
INTERNATIONAL JOURNAL OF AGING & HUMAN DEVELOPMENT, 1996, 43 (01) :21-34
[9]   Screening for primary creatine deficiencies in French patients with unexplained neurological symptoms [J].
Cheillan, David ;
Curt, Marie Joncquel-Chevalier ;
Briand, Gilbert ;
Salomons, Gajja S. ;
Mention-Mulliez, Karine ;
Dobbelaere, Dries ;
Cuisset, Jean-Marie ;
Lion-Francois, Laurence ;
Portes, Vincent Des ;
Chabli, Allel ;
Valayannopoulos, Vassili ;
Benoist, Jean-Francois ;
Pinard, Jean-Marc ;
Simard, Gilles ;
Douay, Olivier ;
Deiva, Kumaran ;
Afenjar, Alexandra ;
Heron, Delphine ;
Rivier, Francois ;
Chabrol, Brigitte ;
Prieur, Fabienne ;
Cartault, Francois ;
Pitelet, Gaelle ;
Goldenberg, Alice ;
Bekri, Soumeya ;
Gerard, Marion ;
Delorme, Richard ;
Tardieu, Marc ;
Porchet, Nicole ;
Vianey-Saban, Christine ;
Vamecq, Joseph .
ORPHANET JOURNAL OF RARE DISEASES, 2012, 7
[10]   A Novel Analog Reasoning Paradigm: New Insights in Intellectually Disabled Patients [J].
Curie, Aurore ;
Brun, Amandine ;
Cheylus, Anne ;
Reboul, Anne ;
Nazir, Tatjana ;
Bussy, Gerald ;
Delange, Karine ;
Paulignan, Yves ;
Mercier, Sandra ;
David, Albert ;
Marignier, Stephanie ;
Merle, Lydie ;
de Freminville, Benedicte ;
Prieur, Fabienne ;
Till, Michel ;
Mortemousque, Isabelle ;
Toutain, Annick ;
Bieth, Eric ;
Touraine, Renaud ;
Sanlaville, Damien ;
Chelly, Jamel ;
Kong, Jian ;
Ott, Daniel ;
Kassai, Behrouz ;
Hadjikhani, Nouchine ;
Gollub, Randy L. ;
des Portes, Vincent .
PLOS ONE, 2016, 11 (02)