Daniela Di Bella1, Stefania Magri1, Chiara Benzoni2, Laura Farina3,4, Carmelo Maccagnano3, Elisa Sarto1, Marco Moscatelli3, Silvia Baratta1, Claudia Ciano5, Sylvie H M J Piacentini6, Lara Draghi6, Elena Mauro2, Davide Pareyson2, Cinzia Gellera1, Franco Taroni1, Ettore Salsano2,7. 1. Unit of Medical Genetics and Neurogenetics, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy. 2. Unit of Rare Neurodegenerative and Neurometabolic Diseases, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy. 3. Unit of Neuroradiology, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy. 4. Neuroimaging Laboratory, IRCCS Fondazione Santa Lucia, Rome, Italy. 5. Unit of Neurophysiology, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy. 6. Unit of Neuropsychology, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy. 7. Neuroscience PhD Program, University of Milano-Bicocca, Monza, Italy.
Abstract
BACKGROUND AND PURPOSE: Little is known about hypomyelinating leukodystrophies (HLDs) in adults. The aim of this study was to investigate HLD occurrence, clinical features, and etiology among undefined leukoencephalopathies in adulthood. METHODS: We recruited the patients with cerebral hypomyelinating magnetic resonance imaging pattern (mild T2 hyperintensity with normal or near-normal T1 signal) from our cohort of 62 adult index cases with undefined leukoencephalopathies, reviewed their clinical features, and used a leukoencephalopathy-targeted next generation sequencing panel. RESULTS: We identified 25/62 patients (~40%) with hypomyelination. Cardinal manifestations were spastic gait and varying degree of cognitive impairment. Etiology was determined in 44% (definite, 10/25; likely, 1/25). Specifically, we found pathogenic variants in the POLR3A (n = 2), POLR1C (n = 1), RARS1 (n = 1), and TUBB4A (n = 1) genes, which are typically associated with severe early-onset HLDs, and in the GJA1 gene (n = 1), which is associated with oculodentodigital dysplasia. Duplication of a large chromosome X region encompassing PLP1 and a pathogenic GJC2 variant were found in two patients, both females, with early-onset HLDs persisting into adulthood. Finally, we found likely pathogenic variants in PEX3 (n = 1) and PEX13 (n = 1) and potentially relevant variants of unknown significance in TBCD (n = 1), which are genes associated with severe, early-onset diseases with central hypomyelination/dysmyelination. CONCLUSIONS: A hypomyelinating pattern characterizes a relevant number of undefined leukoencephalopathies in adulthood. A comprehensive genetic screening allows definite diagnosis in about half of patients, and demonstrates the involvement of many disease-causing genes, including genes associated with severe early-onset HLDs, and genes causing peroxisome biogenesis disorders.
BACKGROUND AND PURPOSE: Little is known about hypomyelinating leukodystrophies (HLDs) in adults. The aim of this study was to investigate HLD occurrence, clinical features, and etiology among undefined leukoencephalopathies in adulthood. METHODS: We recruited the patients with cerebral hypomyelinating magnetic resonance imaging pattern (mild T2 hyperintensity with normal or near-normal T1 signal) from our cohort of 62 adult index cases with undefined leukoencephalopathies, reviewed their clinical features, and used a leukoencephalopathy-targeted next generation sequencing panel. RESULTS: We identified 25/62 patients (~40%) with hypomyelination. Cardinal manifestations were spastic gait and varying degree of cognitive impairment. Etiology was determined in 44% (definite, 10/25; likely, 1/25). Specifically, we found pathogenic variants in the POLR3A (n = 2), POLR1C (n = 1), RARS1 (n = 1), and TUBB4A (n = 1) genes, which are typically associated with severe early-onset HLDs, and in the GJA1 gene (n = 1), which is associated with oculodentodigital dysplasia. Duplication of a large chromosome X region encompassing PLP1 and a pathogenic GJC2 variant were found in two patients, both females, with early-onset HLDs persisting into adulthood. Finally, we found likely pathogenic variants in PEX3 (n = 1) and PEX13 (n = 1) and potentially relevant variants of unknown significance in TBCD (n = 1), which are genes associated with severe, early-onset diseases with central hypomyelination/dysmyelination. CONCLUSIONS: A hypomyelinating pattern characterizes a relevant number of undefined leukoencephalopathies in adulthood. A comprehensive genetic screening allows definite diagnosis in about half of patients, and demonstrates the involvement of many disease-causing genes, including genes associated with severe early-onset HLDs, and genes causing peroxisome biogenesis disorders.
Authors: Edgard Verdura; Agustí Rodríguez-Palmero; Valentina Vélez-Santamaria; Laura Planas-Serra; Irene de la Calle; Miquel Raspall-Chaure; Agathe Roubertie; Mehdi Benkirane; Francesco Saettini; Lisa Pavinato; Giorgia Mandrile; Melanie O'Leary; Emily O'Heir; Estibaliz Barredo; Almudena Chacón; Vincent Michaud; Cyril Goizet; Montserrat Ruiz; Agatha Schlüter; Isabelle Rouvet; Julia Sala-Coromina; Chiara Fossati; Maria Iascone; Francesco Canonico; Anna Marcé-Grau; Precilla de Souza; David R Adams; Carlos Casasnovas; Heidi L Rehm; Heather C Mefford; Luis González Gutierrez-Solana; Alfredo Brusco; Michel Koenig; Alfons Macaya; Aurora Pujol Journal: Brain Date: 2021-10-22 Impact factor: 13.501