Objective: To characterize the genetic basis of an autosomal dominant leukodystrophy (ADLD) without lamin B1 (LMNB1) mutations. Material and methods: ADLD is an adult-onset form of leukodystrophy so far associated with duplications of LMNB1 gene. Disease onsets in the 4th decade with autonomic dysfunctions and diffuse demyelination of the CNS. Here we present a pedigree, previously described by Quattrocolo et al. in 1997, segregating an ADLD-like phenotype. A genome-wide linkage analysis mapped the disease in 5q23.2-q23.3, a region including 11 proteincoding genes among which LMNB1. Lamin B1 was screened by direct sequencing, real-time PCR, MLPA, and Southern blot, and its transcript evaluated by quantitative PCR.We also sequenced the coding exons of the remaining 10 genes. Results: In this family, the disease onset in the 4th-5th decade with pyramidal/pseudobulbar signs or tremor, as confirmed by the recent examination of three affected subjects. In contrast to ADLD cases with LMNB1 duplications, autonomic disturbances at onset are never reported andMRI shows relative sparing of the cerebellum.We found neither gene copy-number defects nor point mutations in LMNB1, and excluded point mutations in the coding exons of the other ten genes in the candidate region. However, lamin B1 expression was significantly increased in patients’ lymphoblasts. Conclusions: We report an ADLD family linked to chromosome 5q23.2-q23.3, whose phenotype is somewhat different from ADLD cases due to lamin B1 duplication. Although our data exclude LMNB1 mutations, the increased level of its mRNA suggests its involvement in the pathogenesis.

Autosomal dominant adult–onset leukodystrophy (ADLD) without LMNB1 mutations: a new variant?

BRUSSINO, Alessandro;DI GREGORIO, ELEONORA;BRADAC, Gianni Boris;PINESSI, Lorenzo;BRUSCO, Alfredo
2009-01-01

Abstract

Objective: To characterize the genetic basis of an autosomal dominant leukodystrophy (ADLD) without lamin B1 (LMNB1) mutations. Material and methods: ADLD is an adult-onset form of leukodystrophy so far associated with duplications of LMNB1 gene. Disease onsets in the 4th decade with autonomic dysfunctions and diffuse demyelination of the CNS. Here we present a pedigree, previously described by Quattrocolo et al. in 1997, segregating an ADLD-like phenotype. A genome-wide linkage analysis mapped the disease in 5q23.2-q23.3, a region including 11 proteincoding genes among which LMNB1. Lamin B1 was screened by direct sequencing, real-time PCR, MLPA, and Southern blot, and its transcript evaluated by quantitative PCR.We also sequenced the coding exons of the remaining 10 genes. Results: In this family, the disease onset in the 4th-5th decade with pyramidal/pseudobulbar signs or tremor, as confirmed by the recent examination of three affected subjects. In contrast to ADLD cases with LMNB1 duplications, autonomic disturbances at onset are never reported andMRI shows relative sparing of the cerebellum.We found neither gene copy-number defects nor point mutations in LMNB1, and excluded point mutations in the coding exons of the other ten genes in the candidate region. However, lamin B1 expression was significantly increased in patients’ lymphoblasts. Conclusions: We report an ADLD family linked to chromosome 5q23.2-q23.3, whose phenotype is somewhat different from ADLD cases due to lamin B1 duplication. Although our data exclude LMNB1 mutations, the increased level of its mRNA suggests its involvement in the pathogenesis.
2009
13th Congress of the European Federation of Neurological Societies
Florence, Italy
September 12-15, 2009
16
suppl 3
300
300
http://www.efns.org/efns2009
LMNB1; autosomal dominant leukodystrophy; Lamin B
G. Vaula; A. Brussino; M. Seri; E. Di Gregorio; S. Leombruni; D. Daniele; G.B. Bradac; L. Pinessi; A. Brusco
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2318/132710
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