Session Information
Date: Saturday, October 6, 2018
Session Title: Pediatric Movement Disorders
Session Time: 1:45pm-3:15pm
Location: Hall 3FG
Objective: To characterize genotype–phenotype correlations in basal ganglia degeneration (BGD) in childhood.
Background: BGD in childhood causes movement disorders, neurodevelopmental dysfunction and long-lasting severe disability. Clinical, radiological and biochemical analysis allow classification in clinical categories, but massive parallel sequencing stablishes a firm molecular diagnosis.
Methods: Observational clinical study and experimental genetic analysis combined with biomarkers in a prospective cohort of 40 patients with BGD.
Results: Mean age at onset was 26.6(0-132) months. 25 patients had an acute onset with encephalopathy related to infection/fever. Most patients developed spasticity(33), dystonia(31), parkinsonism(10), chorea(3), ataxia(5), abnormal ocular movements(11) and severe disability (IV-V GMFCS, 34). Patients were classified in three groups: Striatal Necrosis (SN)(31), calcification(8) and metal deposition (MD)(1). We achieved genetic diagnosis in 22 (17 probands, 5 affected siblings) using target multigene panel: 10/27, 37% and WES: 7/13, 53.8%. We identified 12 recessive variants, 4 de novo mutations, and one X linked. 8/21 were novel variants in previously known genes. We identified genetic defects in: 1)SN: NDUFS4 and NDUFAF6 (complex I subunits/assembly factors), PDHA1 (piruvate deshydrogenase), SLC25A19 and MECR (mitochondrial cofactors thiamine and lipoic acid), ECHS1 and HIBCH (valine metabolism), and non-mitochondrial genes (TUBB4A, GNAO1); 2)Calcification: IFIH1, ADAR, RNASEH2B (Aicardi Goutières syndrome) and RNF213 (Moyamoya disease); 3)MD: SLC39A14 (manganese transporter deficiency). Biomarker analysis (hypermanganesemia in SLC39A14, interferon signature in ADAR) and muscle functional assays (NDUFAF6 and NDUFS4 genes) allowed us to validate novel variants.
Conclusions: BGD leads to severe disability and complex movement disorders in early childhood. Exome sequencing allows genetic confirmation in half of the patients, suggesting novel candidate genes remain to be identified. Patients with SN were affected by heterogeneous conditions undistinguishable from a clinical and biochemical perspective. These include primary mitochondrial defects, inborn errors of metabolism causing toxicity and secondary mitochondrial dysfunction, and non-mitochondrial genes. In some patients, cofactor supplementation and special diets improved clinical outcome after genetic confirmation.
To cite this abstract in AMA style:
H. Baide-Mairena, L. Martí-Sánchez, J. Muchart, M. Rebollo, E. Turón, JC. Cabrera López, Y. Tong-Hong, M. Madruga-Garrido, O. Alonso-Luengo, P. Quijada-Fraile, M.T. García-Silva, A. Cerisola, R. Velazquez-Fragua, E. Schuler, E. López-Laso, L. Gutiérrez-Solana, C. Cáceres-Marzal, I. Marti, O. García-Campos, M. Tomas-Vila, A. Macaya, H. Ben-Pazi, G.I. Rice, Y. Crow, R. Pons, J.D. Ortigoza-Escobar, B. Pérez Dueñas. Genetic defects causing complex movement disorders and basal ganglia degeneration in childhood [abstract]. Mov Disord. 2018; 33 (suppl 2). https://www.mdsabstracts.org/abstract/genetic-defects-causing-complex-movement-disorders-and-basal-ganglia-degeneration-in-childhood/. Accessed November 24, 2024.« Back to 2018 International Congress
MDS Abstracts - https://www.mdsabstracts.org/abstract/genetic-defects-causing-complex-movement-disorders-and-basal-ganglia-degeneration-in-childhood/