Abstract
Objective To characterize the genetic and clinical features of patients with autosomal dominant adult-onset demyelinating leukodystrophy (ADLD) carrying duplication and deletion upstream of lamin B1 (LMNB1).
Methods Ninety-three patients with adult-onset leukoencephalopathy of unknown etiology were genetically analyzed for copy numbers of LMNB1 and its upstream genes. We examined LMNB1 expression by reverse transcription-qPCR using total RNA extracted from peripheral leukocytes. Clinical and MRI features of the patients with ADLD were retrospectively analyzed.
Results We identified 4 patients from 3 families with LMNB1 duplication. The duplicated genomic regions were different from those previously reported. The mRNA expression level of LMNB1 in patients with duplication was significantly increased. The clinical features of our patients with LMNB1 duplication were similar to those reported previously, except for the high frequency of cognitive impairment in our patients. We found 2 patients from 1 family carrying a 249-kb genomic deletion upstream of LMNB1. Patients with the deletion exhibited relatively earlier onset, more prominent cognitive impairment, and fewer autonomic symptoms than patients with duplication. The presence of cerebellar symptoms and lesions may be characteristic in our patients with the deletion compared with the previously reported family with the deletion. Magnetic resonance images of patients with the deletion exhibited a widespread distribution of white matter lesions including the anterior temporal region.
Conclusions We identified 4 Japanese families with ADLD carrying duplication or deletion upstream of LMNB1. There are differences in clinical and MRI features between the patients with the duplication and those with the deletion upstream of LMNB1.
Glossary
- ADC=
- apparent diffusion coefficient;
- ADLD=
- adult-onset demyelinating leukodystrophy;
- ALDH7A1=
- aldehyde dehydrogenase 7 family member A1;
- CSF1R=
- colony-stimulating factor 1 receptor;
- CNV=
- copy number variation;
- DWI=
- diffusion-weighted imaging;
- FLAIR=
- fluid-attenuated inversion recovery;
- GRAMD3=
- GRAM domain containing 3;
- LMNB1=
- lamin B1;
- MCP=
- middle cerebellar peduncle;
- PHAX=
- phosphorylated adaptor for RNA export;
- RIN=
- RNA integrity number;
- T1WI=
- T1-weighted imaging;
- VWMD=
- vanishing white matter disease
Footnotes
Funding information and disclosures are provided at the end of the article. Full disclosure form information provided by the authors is available with the full text of this article at Neurology.org/NG.
The Article Processing charge was funded by AMED.
- Received April 10, 2018.
- Accepted in final form September 10, 2018.
- Copyright © 2018 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.
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