Abstract Details

Title Atypical Presentation of a LMNB1 Duplication Involving the Silencer Region: Beyond Classical Autosomal Dominant Leukodystrophy

Topic General Neurology

Presentation(s) P2 - Poster Session 2 (8:00 AM-9:00 AM)

Poster/Presentation
Number 2-002

Objective

To characterise the clinical, genetic and radiological presentation of a patient with LMNB1 gene duplication, including the duplication of the silencer element.

Background LMNB1-related autosomal dominant leukodystrophy (ADLD) is a fatal neurodegenerative disorder marked by progressive loss of white matter in the central nervous system. Symptoms typically emerge in the fourth or fifth decade of life, presenting with dysautonomia like constipation and bladder dysfunction, followed by pyramidal signs and cerebellar involvement.

Design/Methods

A 69-year-old male with no significant family history presented with a one-year history of right shoulder stiffness and constipation. Initial neurological examinations were unremarkable, with intact cognition (MoCA 27/30) and an EDSS score of 1.0. Over the following year, he developed insomnia, muscle spasms and worsening constipation, leading to rectopexy for rectal prolapse due to severe straining.

Four years after symptom onset, he showed mild pyramidal tract involvement with increased limb tone and brisk reflexes. His MoCA score remained stable, but his EDSS increased to 3.0 mainly attributed to autonomic dysfunction.

Results

Magnetic resonance imaging of the brain demonstrated mild irregular foci of periventricular, subcortical and deep white matter hyperintensities bilaterally. Genetic sequencing revealed a 275.54kb tandem duplication at 5q23.2 [NC_000005.10:g.126637655_126913191dup] comprising 4 genes including the LMNB1 gene and the silencer region (Chr5: 126,778,113 and 126,778,222).

Conclusions

This case presents a distinct clinical manifestation of LMNB1 duplication, with a notably milder phenotype compared to typical LMNB1-related ADLD. The patient, who developed symptoms later in life, did not exhibit hallmark ADLD features such as cerebellar signs, tremors, sensory loss, or pseudobulbar symptoms. Studies in mouse models suggest that silencer regions are critical for down-regulating LMNB1 expression, preventing demyelination, and mitigating the effects of gene overexpression. This regulatory mechanism likely explains the milder presentation observed in this case. The inclusion of silencer elements in the duplication may provide a protective effect, reducing disease severity.

Authors/Disclosures
Savvina Prapiadou, MD PRESENTER	Ms. Prapiadou has nothing to disclose.
Benjamin Yong Qiang Tan	Benjamin Yong Qiang Tan has nothing to disclose.
Jia Dong James Wang	Mr. Wang has nothing to disclose.
Tamara N. Kimball, MD (Mass General Brigham)	Dr. Kimball has nothing to disclose.
Joy Vijayan, MD (Division of Neurology-Department of Medicine-University of Toronto)	Dr. Vijayan has nothing to disclose.

��ɫ��

��ɫ��