Ten Novel Mutations in Chinese Patients with Megalencephalic Leukoencephalopathy with Subcortical Cysts and a Long-Term Follow-Up Research

PLoS One. 2016 Jun 20;11(6):e0157258. doi: 10.1371/journal.pone.0157258. eCollection 2016.

Abstract

Objective: Megalencephalic 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.

Methods: Clinical 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.

Results: Out 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).

Significance: It'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.

MeSH terms

  • Asian People
  • Brain / diagnostic imaging*
  • Brain / physiopathology
  • Cell Cycle Proteins
  • Child, Preschool
  • Cognitive Dysfunction / diagnostic imaging
  • Cognitive Dysfunction / genetics
  • Cognitive Dysfunction / physiopathology
  • Cysts / diagnostic imaging*
  • Cysts / genetics*
  • Cysts / physiopathology
  • Female
  • Follow-Up Studies
  • Hereditary Central Nervous System Demyelinating Diseases / diagnostic imaging*
  • Hereditary Central Nervous System Demyelinating Diseases / genetics*
  • Hereditary Central Nervous System Demyelinating Diseases / physiopathology
  • Humans
  • Infant
  • Magnetic Resonance Imaging
  • Male
  • Membrane Proteins / genetics*
  • Motor Disorders / diagnostic imaging
  • Motor Disorders / genetics
  • Motor Disorders / physiopathology
  • Mutation
  • Proteins / genetics*
  • Sequence Deletion

Substances

  • Cell Cycle Proteins
  • HEPACAM protein, human
  • MLC1 protein, human
  • Membrane Proteins
  • Proteins

Supplementary concepts

  • Megalencephalic leukoencephalopathy with subcortical cysts

Grants and funding

This research was supported by grants from National Key Research Project “12-5” (No:2012BAI09B04), National Natural Science Foundation of China (No:30973227), Beijing key laboratory of molecular diagnosis and study on pediatric genetic diseases (No:Z141107004414036).