Abstract
Autosomal dominant adult-onset demyelinating leukodystrophy (ADLD) is a very rare neurological disorder featured with late onset, slowly progressive central nervous system demyelination. Duplication or over expression of the lamin B1 (LMNB1) gene causes ADLD. In this study, we undertook a comprehensive clinical evaluation and genetic detection for a Chinese family with ADLD. The proband is a 52-year old man manifested with autonomic abnormalities, pyramidal tract dysfunction. MRI brain scan identified bilateral symmetric white matter (WM) hyper-intensities in periventricular and semi-oval WM, cerebral peduncles and middle cerebellar peduncles. The proband has a positive autosomal dominant family history with similar clinical manifestations with a trend of genetic anticipation. In order to understand the genetic cause of the disease in this family, target exome capture based next generation sequencing has been done, but no causative variants or possibly pathogenic variants has been identified. However, Multiplex ligand-dependent probe amplification (MLPA) showed whole duplication of LMNB1 gene which is co-segregated with the disease phenotype in this family. This is the first genetically confirmed LMNB1 associated ADLD pedigree from China.
Highlights
Autosomal dominant adult-onset demyelinating leukodystrophy (ADLD) [MIM #169500] is a rare neurological disorder characterized by gradually increasing loss of white matter (WM) within the central nervous system (Coffeen et al, 2000)
We identified a three generation Chinese family with ADLD
Multiplex ligand-dependent probe amplification (MLPA) found that whole genomic duplication for lamin B1 (LMNB1) gene occur in patient and other affected family members of this family
Summary
Autosomal dominant adult-onset demyelinating leukodystrophy (ADLD) [MIM #169500] is a rare neurological disorder characterized by gradually increasing loss of white matter (WM) within the central nervous system (Coffeen et al, 2000). It has previously reported that the familial form of ADLD has associated with chromosome 5q23–31 (Padiath et al, 2006). Padiath et al (2006) first identified that the heterozygous duplications of the lamin B1 gene (LMNB1, chr5q23.2) is associated with ADLD. ADLD is related with the duplication or over expression of LMNB1 gene which leads to produce increased levels of LMNB1 protein. ADLD is one of the rare neurological disorders associated with copy number variation of a candidate gene. It has been reported that over-expression of LMNB1 protein leads to increase the nuclear rigidity in vitro which supports from the nuclei of the skin fibroblast of ADLD patients (Ferrera et al, 2014). We identified the classical whole duplication in LMNB1 gene related ADLD in a Chinese family. We demonstrated the significant usefulness of multiplex ligand-dependent probe amplification (MLPA) in course of clinical diagnosis of genetic disease caused by a copy number variation
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