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

Journal

Neurology
ISSN: 1526-632X
Titre abrégé: Neurology
Pays: United States
ID NLM: 0401060

Informations de publication

Date de publication:
23 Apr 2024
Historique:
medline: 26 3 2024
pubmed: 26 3 2024
entrez: 26 3 2024
Statut: ppublish

Résumé

Creatine 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. As part of a French National Research Program, patients with CTD were included based on (1) a pathogenic Thirty-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. In 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. ANSM Registration Number 2010-A00327-32.

Sections du résumé

BACKGROUND AND OBJECTIVES OBJECTIVE
Creatine 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.
METHODS METHODS
As part of a French National Research Program, patients with CTD were included based on (1) a pathogenic
RESULTS RESULTS
Thirty-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.
DISCUSSION CONCLUSIONS
In 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 INFORMATION UNASSIGNED
ANSM Registration Number 2010-A00327-32.

Identifiants

DOI: 10.1212/WNL.0000000000209243 PMID: 38531017
pubmed: 38531017
doi: 10.1212/WNL.0000000000209243
doi:

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Pagination

e209243

Auteurs

Aurore Curie (A)

From the Child Neurology Department and Reference Centre of Rare Disease with Intellectual Disability (A.C., L.L.-F., M.G., A.B.-L., F.G., M.B., V.D.P.), Hospices Civils de Lyon, Lyon University Hospital; Lyon Neuroscience Research Centre (A.C., M.G., A.B.-L., F.G., M.B., V.D.P.), CNRS UMR5292, INSERM U1028; Lyon University (A.C., V.D.P.); Reference Centre for Inherited Metabolic Diseases (V.V., A.B., P.D.L.), Imagine Institute, Necker Enfants-Malades Hospital, Paris University Hospital, University of Paris Descartes; Clinical Investigation Center 1407/INSERM-Hospices Civils de Lyon (N.P., N.T., H.H., B.K.), Bron; Inborn Errors of Metabolism Unit (D.C.), Biochemistry and Molecular Biology Department; Department of Biostatistics (C.M.), Lyon University Hospital; and Reference Centre for Inherited Metabolic Diseases (B.D.), Department of Child Neurology, Marseille University Hospital, France.
ORCID: 0000-0001-7823-290X

Laurence Lion-François (L)

From the Child Neurology Department and Reference Centre of Rare Disease with Intellectual Disability (A.C., L.L.-F., M.G., A.B.-L., F.G., M.B., V.D.P.), Hospices Civils de Lyon, Lyon University Hospital; Lyon Neuroscience Research Centre (A.C., M.G., A.B.-L., F.G., M.B., V.D.P.), CNRS UMR5292, INSERM U1028; Lyon University (A.C., V.D.P.); Reference Centre for Inherited Metabolic Diseases (V.V., A.B., P.D.L.), Imagine Institute, Necker Enfants-Malades Hospital, Paris University Hospital, University of Paris Descartes; Clinical Investigation Center 1407/INSERM-Hospices Civils de Lyon (N.P., N.T., H.H., B.K.), Bron; Inborn Errors of Metabolism Unit (D.C.), Biochemistry and Molecular Biology Department; Department of Biostatistics (C.M.), Lyon University Hospital; and Reference Centre for Inherited Metabolic Diseases (B.D.), Department of Child Neurology, Marseille University Hospital, France.

Vassili Valayannopoulos (V)

From the Child Neurology Department and Reference Centre of Rare Disease with Intellectual Disability (A.C., L.L.-F., M.G., A.B.-L., F.G., M.B., V.D.P.), Hospices Civils de Lyon, Lyon University Hospital; Lyon Neuroscience Research Centre (A.C., M.G., A.B.-L., F.G., M.B., V.D.P.), CNRS UMR5292, INSERM U1028; Lyon University (A.C., V.D.P.); Reference Centre for Inherited Metabolic Diseases (V.V., A.B., P.D.L.), Imagine Institute, Necker Enfants-Malades Hospital, Paris University Hospital, University of Paris Descartes; Clinical Investigation Center 1407/INSERM-Hospices Civils de Lyon (N.P., N.T., H.H., B.K.), Bron; Inborn Errors of Metabolism Unit (D.C.), Biochemistry and Molecular Biology Department; Department of Biostatistics (C.M.), Lyon University Hospital; and Reference Centre for Inherited Metabolic Diseases (B.D.), Department of Child Neurology, Marseille University Hospital, France.

Nathalie Perreton (N)

From the Child Neurology Department and Reference Centre of Rare Disease with Intellectual Disability (A.C., L.L.-F., M.G., A.B.-L., F.G., M.B., V.D.P.), Hospices Civils de Lyon, Lyon University Hospital; Lyon Neuroscience Research Centre (A.C., M.G., A.B.-L., F.G., M.B., V.D.P.), CNRS UMR5292, INSERM U1028; Lyon University (A.C., V.D.P.); Reference Centre for Inherited Metabolic Diseases (V.V., A.B., P.D.L.), Imagine Institute, Necker Enfants-Malades Hospital, Paris University Hospital, University of Paris Descartes; Clinical Investigation Center 1407/INSERM-Hospices Civils de Lyon (N.P., N.T., H.H., B.K.), Bron; Inborn Errors of Metabolism Unit (D.C.), Biochemistry and Molecular Biology Department; Department of Biostatistics (C.M.), Lyon University Hospital; and Reference Centre for Inherited Metabolic Diseases (B.D.), Department of Child Neurology, Marseille University Hospital, France.

Marie Gavanon (M)

From the Child Neurology Department and Reference Centre of Rare Disease with Intellectual Disability (A.C., L.L.-F., M.G., A.B.-L., F.G., M.B., V.D.P.), Hospices Civils de Lyon, Lyon University Hospital; Lyon Neuroscience Research Centre (A.C., M.G., A.B.-L., F.G., M.B., V.D.P.), CNRS UMR5292, INSERM U1028; Lyon University (A.C., V.D.P.); Reference Centre for Inherited Metabolic Diseases (V.V., A.B., P.D.L.), Imagine Institute, Necker Enfants-Malades Hospital, Paris University Hospital, University of Paris Descartes; Clinical Investigation Center 1407/INSERM-Hospices Civils de Lyon (N.P., N.T., H.H., B.K.), Bron; Inborn Errors of Metabolism Unit (D.C.), Biochemistry and Molecular Biology Department; Department of Biostatistics (C.M.), Lyon University Hospital; and Reference Centre for Inherited Metabolic Diseases (B.D.), Department of Child Neurology, Marseille University Hospital, France.

Nathalie Touil (N)

From the Child Neurology Department and Reference Centre of Rare Disease with Intellectual Disability (A.C., L.L.-F., M.G., A.B.-L., F.G., M.B., V.D.P.), Hospices Civils de Lyon, Lyon University Hospital; Lyon Neuroscience Research Centre (A.C., M.G., A.B.-L., F.G., M.B., V.D.P.), CNRS UMR5292, INSERM U1028; Lyon University (A.C., V.D.P.); Reference Centre for Inherited Metabolic Diseases (V.V., A.B., P.D.L.), Imagine Institute, Necker Enfants-Malades Hospital, Paris University Hospital, University of Paris Descartes; Clinical Investigation Center 1407/INSERM-Hospices Civils de Lyon (N.P., N.T., H.H., B.K.), Bron; Inborn Errors of Metabolism Unit (D.C.), Biochemistry and Molecular Biology Department; Department of Biostatistics (C.M.), Lyon University Hospital; and Reference Centre for Inherited Metabolic Diseases (B.D.), Department of Child Neurology, Marseille University Hospital, France.

Amandine Brun-Laurisse (A)

From the Child Neurology Department and Reference Centre of Rare Disease with Intellectual Disability (A.C., L.L.-F., M.G., A.B.-L., F.G., M.B., V.D.P.), Hospices Civils de Lyon, Lyon University Hospital; Lyon Neuroscience Research Centre (A.C., M.G., A.B.-L., F.G., M.B., V.D.P.), CNRS UMR5292, INSERM U1028; Lyon University (A.C., V.D.P.); Reference Centre for Inherited Metabolic Diseases (V.V., A.B., P.D.L.), Imagine Institute, Necker Enfants-Malades Hospital, Paris University Hospital, University of Paris Descartes; Clinical Investigation Center 1407/INSERM-Hospices Civils de Lyon (N.P., N.T., H.H., B.K.), Bron; Inborn Errors of Metabolism Unit (D.C.), Biochemistry and Molecular Biology Department; Department of Biostatistics (C.M.), Lyon University Hospital; and Reference Centre for Inherited Metabolic Diseases (B.D.), Department of Child Neurology, Marseille University Hospital, France.

Fahra Gheurbi (F)

From the Child Neurology Department and Reference Centre of Rare Disease with Intellectual Disability (A.C., L.L.-F., M.G., A.B.-L., F.G., M.B., V.D.P.), Hospices Civils de Lyon, Lyon University Hospital; Lyon Neuroscience Research Centre (A.C., M.G., A.B.-L., F.G., M.B., V.D.P.), CNRS UMR5292, INSERM U1028; Lyon University (A.C., V.D.P.); Reference Centre for Inherited Metabolic Diseases (V.V., A.B., P.D.L.), Imagine Institute, Necker Enfants-Malades Hospital, Paris University Hospital, University of Paris Descartes; Clinical Investigation Center 1407/INSERM-Hospices Civils de Lyon (N.P., N.T., H.H., B.K.), Bron; Inborn Errors of Metabolism Unit (D.C.), Biochemistry and Molecular Biology Department; Department of Biostatistics (C.M.), Lyon University Hospital; and Reference Centre for Inherited Metabolic Diseases (B.D.), Department of Child Neurology, Marseille University Hospital, France.

Marion Buchy (M)

From the Child Neurology Department and Reference Centre of Rare Disease with Intellectual Disability (A.C., L.L.-F., M.G., A.B.-L., F.G., M.B., V.D.P.), Hospices Civils de Lyon, Lyon University Hospital; Lyon Neuroscience Research Centre (A.C., M.G., A.B.-L., F.G., M.B., V.D.P.), CNRS UMR5292, INSERM U1028; Lyon University (A.C., V.D.P.); Reference Centre for Inherited Metabolic Diseases (V.V., A.B., P.D.L.), Imagine Institute, Necker Enfants-Malades Hospital, Paris University Hospital, University of Paris Descartes; Clinical Investigation Center 1407/INSERM-Hospices Civils de Lyon (N.P., N.T., H.H., B.K.), Bron; Inborn Errors of Metabolism Unit (D.C.), Biochemistry and Molecular Biology Department; Department of Biostatistics (C.M.), Lyon University Hospital; and Reference Centre for Inherited Metabolic Diseases (B.D.), Department of Child Neurology, Marseille University Hospital, France.

Hulya Halep (H)

From the Child Neurology Department and Reference Centre of Rare Disease with Intellectual Disability (A.C., L.L.-F., M.G., A.B.-L., F.G., M.B., V.D.P.), Hospices Civils de Lyon, Lyon University Hospital; Lyon Neuroscience Research Centre (A.C., M.G., A.B.-L., F.G., M.B., V.D.P.), CNRS UMR5292, INSERM U1028; Lyon University (A.C., V.D.P.); Reference Centre for Inherited Metabolic Diseases (V.V., A.B., P.D.L.), Imagine Institute, Necker Enfants-Malades Hospital, Paris University Hospital, University of Paris Descartes; Clinical Investigation Center 1407/INSERM-Hospices Civils de Lyon (N.P., N.T., H.H., B.K.), Bron; Inborn Errors of Metabolism Unit (D.C.), Biochemistry and Molecular Biology Department; Department of Biostatistics (C.M.), Lyon University Hospital; and Reference Centre for Inherited Metabolic Diseases (B.D.), Department of Child Neurology, Marseille University Hospital, France.

David Cheillan (D)

From the Child Neurology Department and Reference Centre of Rare Disease with Intellectual Disability (A.C., L.L.-F., M.G., A.B.-L., F.G., M.B., V.D.P.), Hospices Civils de Lyon, Lyon University Hospital; Lyon Neuroscience Research Centre (A.C., M.G., A.B.-L., F.G., M.B., V.D.P.), CNRS UMR5292, INSERM U1028; Lyon University (A.C., V.D.P.); Reference Centre for Inherited Metabolic Diseases (V.V., A.B., P.D.L.), Imagine Institute, Necker Enfants-Malades Hospital, Paris University Hospital, University of Paris Descartes; Clinical Investigation Center 1407/INSERM-Hospices Civils de Lyon (N.P., N.T., H.H., B.K.), Bron; Inborn Errors of Metabolism Unit (D.C.), Biochemistry and Molecular Biology Department; Department of Biostatistics (C.M.), Lyon University Hospital; and Reference Centre for Inherited Metabolic Diseases (B.D.), Department of Child Neurology, Marseille University Hospital, France.

Catherine Mercier (C)

From the Child Neurology Department and Reference Centre of Rare Disease with Intellectual Disability (A.C., L.L.-F., M.G., A.B.-L., F.G., M.B., V.D.P.), Hospices Civils de Lyon, Lyon University Hospital; Lyon Neuroscience Research Centre (A.C., M.G., A.B.-L., F.G., M.B., V.D.P.), CNRS UMR5292, INSERM U1028; Lyon University (A.C., V.D.P.); Reference Centre for Inherited Metabolic Diseases (V.V., A.B., P.D.L.), Imagine Institute, Necker Enfants-Malades Hospital, Paris University Hospital, University of Paris Descartes; Clinical Investigation Center 1407/INSERM-Hospices Civils de Lyon (N.P., N.T., H.H., B.K.), Bron; Inborn Errors of Metabolism Unit (D.C.), Biochemistry and Molecular Biology Department; Department of Biostatistics (C.M.), Lyon University Hospital; and Reference Centre for Inherited Metabolic Diseases (B.D.), Department of Child Neurology, Marseille University Hospital, France.

Anaïs Brassier (A)

From the Child Neurology Department and Reference Centre of Rare Disease with Intellectual Disability (A.C., L.L.-F., M.G., A.B.-L., F.G., M.B., V.D.P.), Hospices Civils de Lyon, Lyon University Hospital; Lyon Neuroscience Research Centre (A.C., M.G., A.B.-L., F.G., M.B., V.D.P.), CNRS UMR5292, INSERM U1028; Lyon University (A.C., V.D.P.); Reference Centre for Inherited Metabolic Diseases (V.V., A.B., P.D.L.), Imagine Institute, Necker Enfants-Malades Hospital, Paris University Hospital, University of Paris Descartes; Clinical Investigation Center 1407/INSERM-Hospices Civils de Lyon (N.P., N.T., H.H., B.K.), Bron; Inborn Errors of Metabolism Unit (D.C.), Biochemistry and Molecular Biology Department; Department of Biostatistics (C.M.), Lyon University Hospital; and Reference Centre for Inherited Metabolic Diseases (B.D.), Department of Child Neurology, Marseille University Hospital, France.

Béatrice Desnous (B)

From the Child Neurology Department and Reference Centre of Rare Disease with Intellectual Disability (A.C., L.L.-F., M.G., A.B.-L., F.G., M.B., V.D.P.), Hospices Civils de Lyon, Lyon University Hospital; Lyon Neuroscience Research Centre (A.C., M.G., A.B.-L., F.G., M.B., V.D.P.), CNRS UMR5292, INSERM U1028; Lyon University (A.C., V.D.P.); Reference Centre for Inherited Metabolic Diseases (V.V., A.B., P.D.L.), Imagine Institute, Necker Enfants-Malades Hospital, Paris University Hospital, University of Paris Descartes; Clinical Investigation Center 1407/INSERM-Hospices Civils de Lyon (N.P., N.T., H.H., B.K.), Bron; Inborn Errors of Metabolism Unit (D.C.), Biochemistry and Molecular Biology Department; Department of Biostatistics (C.M.), Lyon University Hospital; and Reference Centre for Inherited Metabolic Diseases (B.D.), Department of Child Neurology, Marseille University Hospital, France.

Behrouz Kassai (B)

From the Child Neurology Department and Reference Centre of Rare Disease with Intellectual Disability (A.C., L.L.-F., M.G., A.B.-L., F.G., M.B., V.D.P.), Hospices Civils de Lyon, Lyon University Hospital; Lyon Neuroscience Research Centre (A.C., M.G., A.B.-L., F.G., M.B., V.D.P.), CNRS UMR5292, INSERM U1028; Lyon University (A.C., V.D.P.); Reference Centre for Inherited Metabolic Diseases (V.V., A.B., P.D.L.), Imagine Institute, Necker Enfants-Malades Hospital, Paris University Hospital, University of Paris Descartes; Clinical Investigation Center 1407/INSERM-Hospices Civils de Lyon (N.P., N.T., H.H., B.K.), Bron; Inborn Errors of Metabolism Unit (D.C.), Biochemistry and Molecular Biology Department; Department of Biostatistics (C.M.), Lyon University Hospital; and Reference Centre for Inherited Metabolic Diseases (B.D.), Department of Child Neurology, Marseille University Hospital, France.

Pascale De Lonlay (P)

From the Child Neurology Department and Reference Centre of Rare Disease with Intellectual Disability (A.C., L.L.-F., M.G., A.B.-L., F.G., M.B., V.D.P.), Hospices Civils de Lyon, Lyon University Hospital; Lyon Neuroscience Research Centre (A.C., M.G., A.B.-L., F.G., M.B., V.D.P.), CNRS UMR5292, INSERM U1028; Lyon University (A.C., V.D.P.); Reference Centre for Inherited Metabolic Diseases (V.V., A.B., P.D.L.), Imagine Institute, Necker Enfants-Malades Hospital, Paris University Hospital, University of Paris Descartes; Clinical Investigation Center 1407/INSERM-Hospices Civils de Lyon (N.P., N.T., H.H., B.K.), Bron; Inborn Errors of Metabolism Unit (D.C.), Biochemistry and Molecular Biology Department; Department of Biostatistics (C.M.), Lyon University Hospital; and Reference Centre for Inherited Metabolic Diseases (B.D.), Department of Child Neurology, Marseille University Hospital, France.
ORCID: 0000-0001-7107-1250

Vincent Des Portes (V)

From the Child Neurology Department and Reference Centre of Rare Disease with Intellectual Disability (A.C., L.L.-F., M.G., A.B.-L., F.G., M.B., V.D.P.), Hospices Civils de Lyon, Lyon University Hospital; Lyon Neuroscience Research Centre (A.C., M.G., A.B.-L., F.G., M.B., V.D.P.), CNRS UMR5292, INSERM U1028; Lyon University (A.C., V.D.P.); Reference Centre for Inherited Metabolic Diseases (V.V., A.B., P.D.L.), Imagine Institute, Necker Enfants-Malades Hospital, Paris University Hospital, University of Paris Descartes; Clinical Investigation Center 1407/INSERM-Hospices Civils de Lyon (N.P., N.T., H.H., B.K.), Bron; Inborn Errors of Metabolism Unit (D.C.), Biochemistry and Molecular Biology Department; Department of Biostatistics (C.M.), Lyon University Hospital; and Reference Centre for Inherited Metabolic Diseases (B.D.), Department of Child Neurology, Marseille University Hospital, France.

Classifications MeSH