This report describes 'leukodystrophy, demyelinating, adult-onset, autosomal dominant' (ADLD), also called 'autosomal dominant adult-onset leukodystrophy' and 'autosomal dominant leukodystrophy with autonomic disease'. This disease is most commonly associated with a heterozygous tandem genomic duplication resulting in an extra copy of the lamin B1 gene (LMNB1). Lamins are intermediate filaments that are major components of the nuclear lamina on the interior of the nuclear envelope. There are multiple lamins in both humans and flies: the human genes LMNA, LMNB2 and LMNB1 are orthologous to fly genes Dmel\Lam and Dmel\LamC. Classical amorphic alleles, RNAi-targeting constructs, and alleles caused by insertional mutagenesis have been generated for both fly genes.
A UAS construct of the wild-type human Hsap\LMNB1 gene has been introduced into flies. Overexpression of the human gene in different neural tissues results in phenotypes similar to, but much milder than, those observed for overexpression of the Drosophila Lam gene.
The original determination that ADLD can be caused by duplication of the human LMNB1 was supported by work in Drosophila characterizing overexpression phenotypes of Dmel\Lam. Overexpression in the developing eye results in neuroanatomical defects and a neurodegenerative phenotype; pan-neuronal overexpression of Dmel\Lam results in lethality. Many physical and genetic interactions of Dmel\Lam have been described; see below and in the Lam gene report.
[updated Aug. 2018 by FlyBase; FBrf0222196]
[LEUKODYSTROPHY, DEMYELINATING, ADULT-ONSET, AUTOSOMAL DOMINANT, TYPICAL; ADLDTY](https://omim.org/entry/169500)
[LEUKODYSTROPHY, DEMYELINATING, ADULT-ONSET, AUTOSOMAL DOMINANT, TYPICAL; ADLDTY](https://omim.org/entry/169500)
Autosomal dominant leukodystrophy with autonomic disease (ADLD) is a slowly progressive disorder of central nervous system white matter characterized by onset of autonomic dysfunction in the fourth to fifth decade, followed in months to years by pyramidal and cerebellar involvement. [Gene Reviews, Autosomal Dominant Leukodystrophy with Autonomic Disease; 2018.08.20]
Autosomal dominant adult-onset demyelinating leukodystrophy is a slowly progressive and fatal disorder that presents in the fourth or fifth decade of life and is characterized clinically by early autonomic abnormalities, pyramidal and cerebellar dysfunction, and symmetric demyelination of the CNS. [from MIM:169500; 2018.08.20]
Most cases of autosomal dominant adult-onset demyelinating leukodystrophy (ADLD) are caused by a heterozygous tandem genomic duplication resulting in an extra copy of the lamin B1 gene (LMNB1). [from MIM:169500; 2018.08.20]
LMNB1 encodes one of the two B-type lamin proteins in human; lamins are components of the nuclear lamina. [Gene Cards, LMNB1; 2018.08.20]
Lamin B, a component of the interphase nuclear lamina, is required to maintain nuclear shape and mechanical integrity (Goldman et al., 2002; pubmed:11877373). [from MIM:150340; 2018.08.20]
Moderate-scoring ortholog of human genes LMNA, LMNB2 and LMNB1 (2 Drosophila to 3 human). Dmel\Lam shares 36-37% identity and 57-60% similarity with the human genes.
