LMNB1 – Adult-Onset Autosomal Dominant Demyelinating Leukodystrophy

Adult-onset autosomal dominant demyelinating leukodystrophy (ADLD) is a rare, progressive white matter disorder caused by tandem duplications of the lamin B1 gene (LMNB1) leading to increased LMNB1 dosage and protein overexpression. First described in six European families, LMNB1 duplications have now been reported in >20 affected individuals from >10 unrelated pedigrees, all showing autosomal dominant inheritance and consistent CNS white matter demyelination on MRI ([PMID:21225301]).

Genetic evidence for LMNB1-ADLD is robust: germline LMNB1 gene duplications were identified by SNP array or MLPA in 20 probands across 10 families with segregation in multiple generations, meeting the ClinGen genetic cap for a strong classification ([PMID:21225301], [PMID:23681646]). No pathogenic point mutations in LMNB1 coding regions have been reported in ADLD, and non-LMNB1 linkage in one locus underscores regulatory heterogeneity ([PMID:19961535]).

Phenotypically, ADLD patients present initially with autonomic dysfunction—orthostatic hypotension (HP:0001278), micturition urgency (HP:0000012), constipation (HP:0002019), erectile dysfunction (HP:0000802)—followed by pyramidal signs (HP:0007256), cerebellar ataxia (HP:0001251), spastic paraplegia (HP:0001258), tremor (HP:0001337) and progressive brain atrophy (HP:0012444) ([PMID:20719577], [PMID:21225301]). Delayed autonomic onset variants broaden the clinical spectrum ([PMID:23681646]).

Functional studies demonstrate that LMNB1 duplications mediate overexpression of lamin B1 in patient leukocytes and fibroblasts by Western blot and immunohistochemistry, correlating with selective loss of noradrenergic fibers on skin biopsy and absent muscle sympathetic nerve activity on microneurography ([PMID:21225301], [PMID:26896090]). Advanced MRI, proton MRS, and DTI reveal microstructural white matter changes and elevated CSF lactate consistent with active demyelination ([PMID:26189928]).

Mechanistically, LMNB1 overexpression disrupts nuclear lamina integrity, impairing oligodendrocyte function and myelin maintenance. A mouse Lmnb1 insertional mutant exhibits nuclear envelope defects, supporting haploinsufficiency of nuclear architecture as a pathogenic mechanism ([PMID:15232008]).

No studies have refuted the LMNB1-ADLD association, and negative screening in multiple sclerosis cohorts confirmed specificity ([PMID:19348623]).

Integrating genetic and experimental data, LMNB1 duplications cause a dose-dependent leukodystrophy with a consistent clinical and imaging phenotype. Further work may identify regulatory non-coding variants, but current evidence meets ClinGen criteria for a definitive gene-disease relationship. Key take-home: testing for LMNB1 copy number gains is essential for diagnosis and genetic counseling in adult leukodystrophy.

References

• Neurogenetics • 2011 • Genomic duplications mediate overexpression of lamin B1 in adult-onset autosomal dominant leukodystrophy (ADLD) with autonomic symptoms PMID:21225301
• Autonomic neuroscience : basic & clinical • 2016 • A longitudinal study of a family with adult-onset autosomal dominant leukodystrophy: Clinical, autonomic and neuropsychological findings PMID:26896090
• Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology • 2022 • Adult-onset autosomal dominant leukodystrophy and neuronal intranuclear inclusion disease: lessons from two new Chinese families PMID:35419641
• Journal of neurology • 2013 • Adult-onset autosomal dominant leukodystrophy without early autonomic dysfunctions linked to lamin B1 duplication: a phenotypic variant PMID:23681646
• Autonomic neuroscience : basic & clinical • 2011 • Isolated noradrenergic failure in adult-onset autosomal dominant leukodystrophy PMID:20719577
• European journal of neurology • 2009 • Mutations in the lamin B1 gene are not present in multiple sclerosis PMID:19348623
• Proceedings of the National Academy of Sciences of the United States of America • 2004 • Lamin B1 is required for mouse development and nuclear integrity PMID:15232008

Evidence Based Scoring (AI generated)