Facioscapulohumeral muscular dystrophy type 2: an update on the clinical, genetic, and molecular findings

Fangzhi Frank Jia; Alexander P Drew; Garth Alexander Nicholson; Alastair Corbett; Kishore Raj Kumar

doi:10.1016/j.nmd.2021.09.010

Facioscapulohumeral muscular dystrophy type 2: an update on the clinical, genetic, and molecular findings

Neuromuscul Disord. 2021 Nov;31(11):1101-1112. doi: 10.1016/j.nmd.2021.09.010. Epub 2021 Oct 2.

Authors

Fangzhi Frank Jia¹, Alexander P Drew², Garth Alexander Nicholson³, Alastair Corbett⁴, Kishore Raj Kumar⁵

Affiliations

¹ Department of Neurology, Concord Repatriation General Hospital, Concord, New South Wales 2139, Australia.
² Kinghorn Centre for Clinical Genomics, Garvan Institute of Medical Research, Darlinghurst, New South Wales 2010, Australia.
³ Department of Neurology, Concord Repatriation General Hospital, Concord, New South Wales 2139, Australia; Molecular Medicine Laboratory, Concord Repatriation General Hospital, Concord, New South Wales 2139, Australia; Northcott Neuroscience Laboratory, ANZAC Research Institute, Concord, New South Wales 2139, Australia; Sydney Medical School, University of Sydney, Camperdown, New South Wales 2050, Australia.
⁴ Department of Neurology, Concord Repatriation General Hospital, Concord, New South Wales 2139, Australia; Sydney Medical School, University of Sydney, Camperdown, New South Wales 2050, Australia.
⁵ Department of Neurology, Concord Repatriation General Hospital, Concord, New South Wales 2139, Australia; Kinghorn Centre for Clinical Genomics, Garvan Institute of Medical Research, Darlinghurst, New South Wales 2010, Australia; Molecular Medicine Laboratory, Concord Repatriation General Hospital, Concord, New South Wales 2139, Australia; Sydney Medical School, University of Sydney, Camperdown, New South Wales 2050, Australia. Electronic address: kkum4618@uni.sydney.edu.au.

PMID: 34711481
DOI: 10.1016/j.nmd.2021.09.010

Abstract

Facioscapulohumeral muscular dystrophy (FSHD) is a common genetic disease of the skeletal muscle with a characteristic pattern of weakness. Facioscapulohumeral muscular dystrophy type 2 (FSHD2) accounts for approximately 5% of all cases of FSHD and describes patients without a D4Z4 repeat contraction on chromosome 4. Phenotypically FSHD2 shows virtually no difference from FSHD1 and both forms of FSHD arise via a common downstream mechanism of epigenetic derepression of the transcription factor DUX4 in skeletal muscle cells. This results in expression of DUX4 and target genes leading to skeletal muscle toxicity. Over the past decade, major progress has been made in our understanding of the genetic and epigenetic architecture that underlies FSHD2 pathogenesis, as well as the clinical manifestations and disease progression. These include the finding that FSHD2 is a digenic disease and that mutations in the genes SMCHD1, DNMT3B, and more recently LRIF1, can cause FSHD2. FSHD2 is complex and it is important that clinicians keep abreast of recent developments; this review aims to serve as an update of the clinical, genetic, and molecular research into this condition.

Keywords: DNMT3B; DUX4; Epigenetic derepression; Facioscapulohumeral muscular dystrophy type 2; LRIF1; SMCHD1.

Publication types

Research Support, Non-U.S. Gov't
Review

MeSH terms

Chromosomal Proteins, Non-Histone / genetics
Epigenesis, Genetic
Homeodomain Proteins / genetics
Humans
Muscle Fibers, Skeletal / pathology
Muscle, Skeletal / pathology
Muscular Dystrophy, Facioscapulohumeral / genetics*
Mutation
Phenotype

Substances

Chromosomal Proteins, Non-Histone
Homeodomain Proteins
SMCHD1 protein, human