Clinical And Genetic Study On Patients With Megalencephalic Leukoencephalopathy With Subcortical Cysts (MLC)

ObjectiveMegalencephalic leukoencephalopathy with subcortical cysts (MLC, OMIM 604004) is a rarevacuolating myelinopathy, which was first described in 1995 by Van der Knaap et al. MLC isan autosomal recessively inherited disease caused by mutations in the MLC1 gene. The diseaseis characterized by early-onset macrocephaly presenting at birth or during the first year of life,often accompanied by the occurrence of motor dysfunction provoking severe walking disability,onset of seizure and usually late onset of mild mental deterioration. The pathogenesis of MLCis still far from well understood. Our aim was to collect clinical features and MLC1 mutationscreening, analyze the characteristics of genotype and phenotype of patients with MLC, and toidentify Chinese MLC patients spectrum of MLC1 mutations .MethodsThe clinical features and imaging features of 13 patients (8 boys and 5 girls) and familymembers were collected. Clinical diagnosis was mainly based on the criteria proposed by vander Knaap et al. Clinically diagnosed cases were screened for mutations in the entire codingregion, including the exon-intron boundaries of the MLC1 gene, to determine their genotype.Results(1) Clinical outcomes:The initial presentation of all individuals was macrocephaly, whichbegan to appear between birth and 1 year of age. Independent sitting and walking wereachieved in all but three cases, delayed from mildly to moderately. Their cognitive functionswere relatively better preserved except for patients 3 and 5, with mild and moderate mentalretardation, respectively. Among the 13 patients, three patients had occasional seizures during the course. Physical examination mainly showed large head circumference, low muscle toneand symmetric pyramidal tract signs. The cranial MRI showed diffuse long T1 and T2abnormal signal changes in cerebral white matter, with water-like subcortical cysts in anteriortemporalregions in all cases.(2) Genetic results: 10 MLC1 mutations were identified in 13 MLC diagnosis clinically.Seven novel mutations were found: five missense mutations (c.65G>A, p.R22Q; c.95C>T,p.A32V; c.218G>A, p.G73E; c.823G>A, p.A275T; c.832T>C, p.Y278H), one splicingmutation (c.772-1G>C in IVS9-1), and one small deletion (c.907₉30del,p.V303_L310del).Three known mutations: c.593delCTCA, p.Y198X, c.206C>T, p.S69L andc.353C>T, p.T118M.ConclusionAll 13 enrolled subjects in this study were met criteria of MLC and diagnoses as MLCclinically. 10 MLC1 mutations were detected in 13 MLC patients. 10 MLC1 mutationsincluding 7 novel mutations were found from 13 MLC patients, which expended the MLC1mutation spectrum. Out of 13 MLC patients, 11 were measured MLC1 mutations. Thosefamilies with probands genetic diagnosis are able to perform exact genetic counseling andprenatal diagnosis. This study should be the first report about MLC1 gene mutations in Chinesepatients with MLC.