Abstract
ObjectiveMegalencephalic leukoencephalopathy with subcortical cysts (MLC, OMIM 604004) is a rare neurological deterioration disease. We aimed to clarify clinical and genetic features of Chinese MLC patients.MethodsClinical information and peripheral venous blood of 20 patients and their families were collected, Sanger-sequencing and Multiple Ligation-dependent Probe Amplification were performed to make genetic analysis. Splicing-site mutation was confirmed with RT-PCR. UPD was detected by haplotype analysis. Follow-up study was performed through telephone for 27 patients.ResultsOut of 20 patients, macrocephaly, classic MRI features, motor development delay and cognitive impairment were detected in 20(100%), 20(100%), 17(85%) and 4(20%) patients, respectively. 20(100%) were clinically diagnosed with MLC. 19(95%) were genetically diagnosed with 10 novel mutations in MLC1, MLC1 and GlialCAM mutations were identified in 15 and 4 patients, respectively. Deletion mutation from exon4 to exon9 and a homozygous point mutation due to maternal UPD of chromosome22 in MLC1 were found firstly. c.598-2A>C in MLC1 leads to the skip of exon8. c.772-1G>C in MLC1 accounting for 15.5%(9/58) alleles in Chinese patients might be a founder or a hot-spot mutation. Out of 27 patients in the follow-up study, head circumference was ranged from 56cm to 61cm in patients older than 5yeas old, with a median of 57cm. Motor development delay and cognitive impairment were detected in 22(81.5%) and 5(18.5%) patients, respectively. Motor and cognitive deterioration was found in 5 (18.5%) and 2 patients (7.4%), respectively. Improvements and MRI recovery were first found in Chinese patients. Rate of seizures (45.5%), transient motor retrogress (45.5%) and unconsciousness (13.6%) after head trauma was much higher than that after fever (18.2%, 9.1%, 0%, respectively).SignificanceIt’s a clinical and genetic analysis and a follow-up study for largest sample of Chinese MLC patients, identifying 10 novel mutations, expanding mutation spectrums and discovering clinical features of Chinese MLC patients.
Highlights
Megalencephalic leukoencephalopathy with subcortical cysts (MLC, OMIM 604004) is a rare autosomal recessive or dominant heterogeneous neurodegenerative disease, which was firstly reported in 1995[1]
Out of 20 patients, macrocephaly, classic Magnetic resonance imaging (MRI) features, motor development delay and cognitive impairment were detected in 20(100%), 20(100%), 17(85%) and 4(20%) patients, respectively. 20(100%) were clinically diagnosed with megalencephalic leukoencephalopathy with subcortical cysts (MLC). 19(95%) were genetically diagnosed with 10 novel mutations in MLC1, MLC1 and GlialCAM mutations were identified in 15 and 4 patients, respectively
Clinical severity varies among Pt24 and Pt25 siblings, Pt17’s families which were often seen in patients with the same mutation or even siblings [27,28], but similar features were detected in Pt9 and Pt10, Pt27 and Pt28 in this research. This clinical and genetic analysis for the patients with MLC has the largest samples in Chinese and it is the first time to make follow-up study with the largest MLC patients. 20 patients were clinically diagnosed, with 17 patients classic phenotype, 2 patients atypical improving phenotype and 1(Pt16 missed) unclassified
Summary
Megalencephalic leukoencephalopathy with subcortical cysts (MLC, OMIM 604004) is a rare autosomal recessive or dominant heterogeneous neurodegenerative disease, which was firstly reported in 1995[1]. MLC1 (OMIM 605908) and GlialCAM (OMIM 611642) are the two disease-causing genes identified in 2001 and 2011, accounting for 75% and 20% patients, respectively[8, 10]. About 16 Chinese patients were clinically diagnosed in which 11 were genetically diagnosed with 15 mutations [7,12, 14,15]. Clinical and genetic features of Chinese MLC patients have not been discovered completely. Clinical and genetic analysis was performed in 20 MLC patients, identifying 10 novel mutations in MLC1 and 4 patients with GlialCAM mutations. A follow-up study was undertaken first for 27 patients including 19 in this research (Pt16 missed) (Pt, Patient) and 8 from our previous reports [7], elucidating clinical and genetic features for patients with MLC in China
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