Novel compound heterozygous mutations in LMAN2L cause early childhood refractory epilepsy
Teng Wang1, Yan Gao1, Yuhan Yan1
1Department of Pediatrics, Qilu Hospital of Shandong University, Jinan, China.
Background:
Autosomal recessive mental retardation-52(MRT52) is a subtype of mental retardation whose clinical features include global developmental delay, severe intellectual disability with poor speech, and mild seizures in early childhood. Mutations in the LMAN2L gene resulting in mental retardation and seizures have been previously reported in 3 families. Here we describe 2 children in 1 family who presented with severe intellectual disability and drug-refractory epilepsy( DRE) at 2 months of age.
Methods:
Two individuals from 1 family admitted to the pediatric department of Qilu Hospital were included in the study. Whole exome sequencing (WES) was used to detect LMAN2L gene variants. The clinical manifestations, electroencephalography, neuroimaging characteristics and treatment of epilepsy were retrospectively analyzed.
Result:
We identified two new LMAN2L compound heterozygous variants, c.476A > G, p.D159G, c.1060_1061del, p.S354Pfs*29, which appeared in two children from the same family. Both cases showed severe postnatal psychomotor developmental lag and developed seizures at 2 months of age, which manifested themselves in a variety of ways and were not relieved by the administration of multiple antiepileptic drugs.
Conclusion:
Complex heterozygous mutations at the newly identified locus of LMAN2L cause refractory epilepsy, with epileptic symptoms beginning at 2 months of age and manifesting as multiple seizure types and developmental delays. This is the first report to link LMAN2L to the phenotype of epileptic encephalopathy and refractory epilepsy, suggesting that the heterozygous p.D159G, p.S354Pfs*29 LMAN2L variants are likely pathogenic. These 2 newly identified pathogenic variants enrich the spectrum of pathogenic variants in the LMAN2L gene.
Insights
New LMAN2L gene variants cause severe intellectual disability and drug-refractory epilepsy in infants. This study identifies two novel compound heterozygous variants linked to early-onset seizures and developmental delays, expanding the known LMAN2L mutation spectrum.
Area of Science:
- Genetics
- Neurology
- Pediatrics
Background:
- Autosomal recessive mental retardation-52 (MRT52) is characterized by global developmental delay, severe intellectual disability, and early childhood seizures.
- Previous studies linked LMAN2L gene mutations to mental retardation and seizures in three families.
- This study focuses on two children with severe intellectual disability and drug-refractory epilepsy (DRE) starting at two months of age.
Purpose of the Study:
- To investigate the genetic basis of severe intellectual disability and drug-refractory epilepsy in two pediatric patients.
- To identify novel variants in the LMAN2L gene associated with these neurological conditions.
Main Methods:
- Whole exome sequencing (WES) was performed on two affected individuals from a single family.
- Clinical data, including seizure characteristics, electroencephalography, neuroimaging, and treatment responses, were retrospectively analyzed.
- Identification and analysis of LMAN2L gene variants.
Main Results:
- Two novel compound heterozygous variants in the LMAN2L gene (c.476A>G, p.D159G and c.1060_1061del, p.S354Pfs*29) were identified in both children.
- Both patients exhibited severe postnatal psychomotor developmental lag and early-onset seizures (at 2 months of age).
- The epilepsy was characterized by diverse seizure types and proved refractory to multiple antiepileptic drugs.
Conclusions:
- Compound heterozygous mutations in LMAN2L are associated with refractory epilepsy presenting in early infancy with developmental delays.
- This is the first report linking LMAN2L to epileptic encephalopathy and drug-refractory epilepsy phenotypes.
- The identified LMAN2L variants (p.D159G and p.S354Pfs*29) are considered likely pathogenic, expanding the known spectrum of LMAN2L-associated disorders.
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