Facioscapulohumeral muscular dystrophy

被引:235
作者
Tawil, Rabi
Van der Maarel, Silvere M.
机构
[1] Univ Rochester, Ctr Med, Neuromuscular Dis Ctr, Rochester, NY 14642 USA
[2] Leiden Univ, Ctr Med, Ctr Human & Clin Genet, Leiden, Netherlands
关键词
chromosome; 4; Coat's syndrome; facioscapulohumeral muscular dystrophy; FSHD; heterochromatin; methylation; muscular dystrophy; position effect;
D O I
10.1002/mus.20522
中图分类号
R74 [神经病学与精神病学];
学科分类号
摘要
Facioscapulohumeral muscular dystrophy (FSHD) is a dominantly inherited disorder with an initially restricted pattern of weakness. Early involvement of the facial and scapular stabilizer muscles results in a distinctive clinical presentation. Progression is descending, with subsequent involvement of either the distal anterior leg or hip-girdle muscles. There is wide variability in age at onset, disease severity, and side-to-side symmetry, which is evident even within affected members of the same family. Although FSHD is considered a relatively benign dystrophy by some, as many as 20% of patients eventually become wheelchair-bound. Associated nonskeletal muscle manifestations include high-frequency hearing loss as well as retinal telangiectasias, both of which are rarely symptomatic. The causal genetic lesion in FSHD was described over a decade ago, raising hope that knowledge about its molecular and cellular pathophysiology was soon to follow. In the vast majority of cases, FSHD results from a heterozygous partial deletion of a critical number of repetitive elements (D4Z4) on chromosome 4q35; yet, to date, no causal gene has been identified. The accumulating evidence points to a complex, perhaps unique, molecular genetic mechanism. The absence of detectable expressed sequences from D4Z4, the association of FSHD-causing 4q35 deletions with a specific distal genomic sequence (4qA allele), altered DNA methylation patterns on 4q35, as well as other direct and indirect evidence point to epigenetic mechanisms. As a consequence, partial deletion of D4Z4 results in a (local) chromatin change and ultimately results in the loss of appropriate control of gene expression. There is at present no effective treatment for FSHD. A better understanding of the underlying pathophysiology is needed to design targeted interventions. Despite these limitations, however, two randomized controlled clinical trials have been conducted on FSHD. These trials, along with a previous natural history study, have helped to better define outcome measures for future trials in FSHD as well as other dystrophies.
引用
收藏
页码:1 / 15
页数:15
相关论文
共 120 条
[91]  
VANDEUTEKOM JCT, 1993, HUM MOL GENET, V2, P2037
[92]   Evidence for subtelomeric exchange of 3.3 kb tandemly repeated units between chromosomes 4q35 and 10q26: Implications for genetic counselling and etiology of FSHD1 [J].
vanDeutekom, JCT ;
Bakker, E ;
Lemmers, RJLF ;
vanderWielen, MJR ;
Bik, E ;
Hofker, MH ;
Padberg, GW ;
Frants, RR .
HUMAN MOLECULAR GENETICS, 1996, 5 (12) :1997-2003
[93]   Identification of the first gene (FRG1) from the FSHD region on human chromosome 4q35 [J].
vanDeutekom, JCT ;
Lemmers, RJLF ;
Grewal, PK ;
vanGeel, M ;
Romberg, S ;
Dauwerse, HG ;
Wright, TJ ;
Padberg, GW ;
Hofker, MH ;
Hewitt, JE ;
Frants, RR .
HUMAN MOLECULAR GENETICS, 1996, 5 (05) :581-590
[94]  
VANDEUTEKORN JCT, 1996, THESIS U LEIDEN LEID
[95]   EFFECT OF EXERCISE IN MUSCULAR DYSTROPHY [J].
VIGNOS, PJ ;
WATKINS, MP .
JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION, 1966, 197 (11) :843-&
[96]   Normal growth and regenerating ability of myoblasts from unaffected muscles of facioscapulohumeral muscular dystrophy patients [J].
Vilquin, JT ;
Marolleau, JP ;
Sacconi, S ;
Garcin, I ;
Lacassagne, MN ;
Robert, I ;
Ternaux, B ;
Bouazza, B ;
Larghero, J ;
Desnuelle, C .
GENE THERAPY, 2005, 12 (22) :1651-1662
[97]   Creatine monohydrate in muscular dystrophies:: A double-blind, placebo-controlled clinical study [J].
Walter, MC ;
Lochmüller, H ;
Reilich, P ;
Klopstock, T ;
Huber, R ;
Hartard, M ;
Hennig, M ;
Pongratz, D ;
Müller-Felber, W .
NEUROLOGY, 2000, 54 (09) :1848-1850
[98]  
WEBER JL, 1990, NUCLEIC ACIDS RES, V18, P2202
[99]  
WEIFFENBACH B, 1992, AM J HUM GENET, V51, P416
[100]   MAPPING THE FACIOSCAPULOHUMERAL MUSCULAR-DYSTROPHY GENE IS COMPLICATED BY CHROMOSOME-4Q35 RECOMBINATION EVENTS [J].
WEIFFENBACH, B ;
DUBOIS, J ;
STORVICK, D ;
TAWIL, R ;
JACOBSEN, SJ ;
GILBERT, J ;
WIJMENGA, C ;
MENDELL, JR ;
WINOKUR, S ;
ALTHERR, MR ;
SCHULTZ, P ;
OLANDT, S ;
FRANTS, RR ;
PERICAKVANCE, M ;
GRIGGS, RC .
NATURE GENETICS, 1993, 4 (02) :165-169