BACKGROUND AND PURPOSE: Duplications of lamin B1 (LMNB1) at 5q23 are implicated 
in adult-onset autosomal dominant leukodystrophy (ADLD) having been described in 
six families with diverse ethnic background but with a homogeneous phenotype. In 
a large Italian family, we recently identified a variant form of ADLD 
characterized clinically by absence of the autonomic dysfunction at onset 
described in ADLD and, on MRI, by milder cerebellar involvement with sparing of 
hemispheric white matter. Aim of this study was to investigate the genetic basis 
of this variant form of ADLD.
METHODS: We carried out a genome-wide linkage analysis using microsatellite 
markers, and the genes in the candidate region were screened for point 
mutations. LMNB1 was also screened for deletions/duplications by real-time PCR, 
multiplex ligation-dependent probe amplification and Southern blot.
RESULTS: We mapped the variant ADLD locus to 5q23.2-q23.3, a genomic region 
containing 11 genes including LMNB1. Neither gene copy-number defects nor point 
mutations in the LMNB1 gene were found. We also excluded point mutations in the 
coding exons of the other ten genes in the candidate region. However, expression 
of lamin B1 evaluated in lymphoblastoid cells was higher in patients than in 
healthy controls, and was similar to the lamin B1 expression levels found in a 
patient with LMNB1 duplication.
CONCLUSIONS: This observation suggests that a mutation in an LMNB1 regulatory 
sequence underlies the variant ADLD phenotype. Thus, adult forms of ADLD linked 
to 5q23 appear to be more heterogeneous clinically and genetically than 
previously thought.