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Facioscapulohumeral dystrophy A distinct regional myopathy with a novel molecular pathogenesis.

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NEUROLOGICAL PROGRESS
Facioscapulohumeral Dystrophy: A Distinct
Regional Myopathy with a Novel
Molecular Pathogenesis
Rabi Tawil, MD,* Denise A. Figlewicz, PhD,* Robert C. Griggs, MD,* Barbara Weiffenbach, PhD,t
and the FSH Consortium$
Facioscapulohumeral muscular dystrophy (FSHD) is one of the most common inherited diseases of muscle. Until recently, FSHD had received little attention because of its relatively benign course and the perception that it represented
a syndrome rather than a distinct myopathy. Research interest into this disease was reignited with the demonstration of
linkage of FSHD to chromosome 4q35 in 1990. Clinical and molecular genetic research in FSHD has since helped define
it as a distinct clinical entity, outlined its natural history, and defined the primary molecular defect associated with the
condition. FSHD is now known to be associated with large deletions of variable size on chromosome 4q35. These
deletions, however, do not appear to disrupt a transcribed gene but are thought to interfere with the expression of a gene
or genes located proximal to the deletions. These observations complicate the search for the FSHD gene but also imply
the presence of a potentially novel molecular pathognesis.
Tawil R, Figlewicz DA, Griggs RC, Weiffenbach B, the FSH Consortium. Facioscapulohumeral dystrophy:
a distinct regional myopathy with a novel molecular pathogenesis. Ann Neurol 1998;43:279-282
Facioscapulohumeral dystrophy (FSHD) is the third
most common hereditary disease of muscle after Duchenne and myotonic dystrophy with an estimated
incidence of 1:20,000.’ FSHD is recognized by its
characteristic regional involvement and pattern of progression. Although generally considered a benign form
of muscular dystrophy, FSHD is severely disabling for
the more than 15% of individuals who eventually become wheelchair-bound. Except for the landmark thesis by Padberg,’ FSHD received little attention in the
past two decades until its linkage to human chromosome 4q35 in 1990.’ The molecular genetic defect has
now been well defined, but the gene or genes affected
by the deficit have not been identified. Virtually all
cases of FSHD are associated with deletions of variable
size on distal 4q35. There are, however, no genes
within the deleted region. Thus, the deletions themselves do not appear to disrupt a functional gene.
These observations point to a potentially novel diseasecausing mechanism.
This review summarizes current knowledge in
FSHD: the clinical definition and diagnosis; the molecular genetic defect and its use in diagnosis; and the
natural history and potential treatments.
From the *Department of Neurology and the Wayne C. Gorrell J r
Molecular Biology Laboratory, University of Rochester School of
Medicine and Dentistry, Rochester, NY, and tGenome Therapeutics Corporation, Waltham, MA.
$See the appendix on page 281 for the FSH Consortium.
Clinical Features
Symptoms of weakness can appear from infancy to late
life, but most affected individuals become symptomatic
in the second decade. In general, the disease initially involves the face and scapular fixators, followed by the
foot dorsiflexors and finally the hip girdles. Side-to-side
asymmetry of muscle involvement is frequent and often
striking.2 Bulbar, extraocular, and respiratory muscles
are spared. Few extramuscular manifestations occur.
Only high-frequency hearing loss and retinal vascular
tortuosities are noted, and these remain subclinical in
most instances.”* Cardiac muscle is clinically uninvolved; a predilection for atrial tachyarrhythmias has
been r e p ~ r t e d .The
~ , ~ rate of disease progression is variable but is usually very
Most affected individuals
remain able to work, often adapting remarkably well to
profound weakness. Up to one third of patients have no
symptoms, but weakness can be found in over 95% of
affected individuals by age 20.
Clinical Diagnosis
FSHD was at one time considered to be a syndrome
that comprised several disorders. Various scapuloperoneal disorders as well as both neurogenic and myo-
Received Aug 6, 1997 and in revised form Nov 11. Accepted for
publication Nov 17, 1997.
Address correspondence to Dr Tawil, Wayne C. Gorrell Jr Molecular Biology Laboratoly, University of Rochester School of Medicine and Dentistiy, Rochester, NY 14642.
Copyright 0 1998 by the American Neurological Association
279
pathic FSHD-like disorders were considered to
present diagnostic confusion. Definition of the molecular defect has clarified the situation. Patients with
characteristic facial and shoulder weakness and an autosomal dominant family history almost always have
the same molecular defect. In sporadic cases, patients
who lack a family history of the disease occasionally
have other diseases that can be excluded by muscle
biopsy, including nemaline myopathy, desmin storage, mitochondria1 myopathy, polymyositis, and centronuclear myopathy.2 The autosomal dominant
scapuloperoneal syndromes are clinically distinguishable from FSHD. This distinction has become clear
by studies in which such families have been shown to
be unlinked to chromosome 4q35 and to lack the
molecular defect.’ In the sporadic case in which biopsy is unavailable or unhelpful, careful attention to
the patterns of involvement and progression invariably distinguishes these conditions from FSHD.
Genetics
The gene or genes that are affected by the molecular
defect in FSHD are still undefined, although the chromosomal abnormality responsible for the disease has
been defined.9 After linkage of FSHD to chromosome
4q35 in 1990,” a marker (p13E-11) that mapped to
4q35 revealed shorter fragments in genomic DNA digested with the EcoRI restriction enzyme in patients
with FSHD compared with control individuals.’ The
region detected by p 13E- 11 contains repetitive DNA
sequences that are 3.3 kb. Despite extensive sequencing
of the deleted region, no genes have been identified.
Moreover, the repeat region appears to be part of telomeric heterochromatin, which is compacted, usually
transcriptionally inactive DNA.’ If the deletion does
not disrupt a functioning gene, how then does it result
in a disease phenotype? Winokur and colleagues’’ suggested position effect variegation (PEV) as a possible
explanation for this paradox. PEV postulates that a
change in chromosomal structure can influence the
function of proximally located genes. Attention was
then turned to the region proximal to the deletion in
the search for the FSHD gene. Two candidate genes
have thus far been identified, but it has not been possible to establish that either gene is in fact the FSHD
gene. 12,13
Molecuhzr Diagnosis
The 4q35 deletion that causes FSHD can be identified
in 86 to 95% of cases with the disease. The identification of a 4q35 deletion is more than 98% specific for
the disease. FSHD molecular diagnosis is performed on
leukocyte DNA, which is digested simultaneously with
the restriction enzymes EcoRIIBlnI and hybridized with
the probe p13E-11. Affected individuals have smaller
restriction fragments of 10 to 35 kb containing the de-
280
Annals of Neurology
Vol 43
No 3
March 1998
letion, whereas unaffected individuals have restriction
fragments of 50 to 300 kb.’*,15
The 5 to 14% of affected individuals in whom a deletion cannot be identified is attributable to (1) technical
difficulties with degraded or partially digested DNA, (2)
translocation between 4q35 and homologous regions on
1O q complicating the interpretation of the Southern blot
data, and, rarely, (3) FSHD not linked to 4q (locus heterogeneity). In such cases, if the clinical suspicion of
FSHD remains high, further testing with other 4q35
and 1Oq probes as well as more extensive study of the
hndred with linkage analysis may be required.
In summary, whereas no single molecular diagnostic
test will identify 100% of FSHD patients, detection of
a 4q35 deletion in affected individuals in familial
FSHD or its appearance de novo in sporadic cases is
considered confirmatory.
Non-4q35 FSHD
Less than 2% of FSHD kindreds appear not to be
linked to the locus at 4q35.I6 Speer and colleagues are
carrying out a genome-wide screening for linkage for a
single large non-4q35 FSHD kindred. To date, better
than 90% of the genome has been excluded.
FSHD Animal Model
Identification and sequencing of an animal equivalent
to the FSHD gene could greatly facilitate the identification of its human homologue. The myodystrophic
(myd) mouse is proposed to be a model for FSHD.
Myd mice demonstrate muscle weakness as well as dystrophic changes on muscle histology and sensorineural
hearing loss.” Moreover, the myd mutation maps to a
region of mouse chromosome 8, which is homologous
to human 4q.” To date, however, the myd gene has
not been identified.
Genotype-Phenotype Correlations
Although the FSHD gene remains unknown, the variable size of the FSHD-associated deletion provided a
potential explanation for its phenotypic variability.
Thus it was found that sporadic patients, many of
whom have an earlier age at onset, have a smaller
EcoRI fragment size (ie, larger deletion) than those patients with familial FSHD.” Similarly, when time at
disease onset, time to becoming wheelchair-bound, and
quantitative measurement of strength were used as indices of severity in familial and sporadic cases, an inverse correlation was found between severity and fragment
Thus, the larger the deletion, the more
severe the disease manifestation.
Variability in disease expression within families
could not be accounted for by the gender of the parent
transmitting the FSHD mutation.” FSHD does, however, seem to become more severe with each generation. This generational effect (anticipation) was ob-
served when comparing either age at onset or degree
of weakness in consecutive generations in familial
FSHD. 8320 The molecular mechanism for anticipation
in FSHD is not clear. Whereas anticipation in some
triplet repeat diseases is explained by the instability of
the mutation with expansion of the repeats, the FSHD
deletion size remains stable when transmitted to subsequent generations.
Natural History
Charting the natural history of FSHD is important to
provide valid and reliable measures of disease state and
progression as well as providing guidelines for sample
size calculations in FSHD clinical trials. A recently
completed, prospective quantitative natural history
study followed 81 patients for up to 3 years using standardized protocols for manual muscle testing (MMT)
and maximum voluntary isometric contraction testing
(MVICT). Decline in strength was slow but detectable
by M M T and MVICTat 1 year of follow-up.'
Treatment
There is no specific treatment for the weakness of
FSHD. Because of the limited knowledge of disease
pathophysiology, any proposed treatment will by necessity be empirical.
Corticosteroids have been tried in FSHD. Inflammatory infiltrates are seen in as many as 40% of FSHD
biopsy specimens.' Several patients with FSHD have
been treated with prednisone with variable succ e s 21-23 The improvement in strength provided by
prednisone in Duchenne dystrophy led to renewed interest in its use in FSHD.24 An open label trial of
prednisone given over a 3-month period demonstrated
no significant improvement in either strength or musd e mass.25
More recently, an open label trial of albuterol was
completed.26 The P,-adrenergic agents have been
shown to increase lean body mass and skeletal muscle
protein content in normal animals27 as well as to retard
loss of muscle mass in several animal models of muscle
wasting and an animal model of Duchenne dystrophy.28-30 Two studies in humans without an underlying muscle disease showed modest but consistent improvement in ~ t r e n g t h . ~ ' Fifteen
,~~
patients with
FSHD were treated with a slow-release form of oral
albuterol for 3 months. A statistically significant increase in lean body mass as measured by dual-energy
x-ray absorptiometry (DEXA) and in strength as measured by MVICT was observed after 3 months of thera ~ y . ~A' 1-year, randomized, double-blind, placebocontrolled of albuterol is in progress.
Appendix
Members of the International Consortium Participating in
The International Conference on the Cause and Treatment
of FSHD:
Michael Altherr, Los Alamos National Laboratory, Los
Alamos, NM; Kiichi Arahata, Masanori Funakoshi, National
Institute of Neuroscience, Tokyo, Japan; Lucian0 Felicetti,
Enzo Ricci, Instituto di Biologica Cellulare, Rome, Italy;
Rune Frants, Siluer van der Maarel, Leiden University, Leiden, The Netherlands; Jane Hewitt, University of Manchester Medical School, Manchester, UK; John Kissel and Jerry
Mendel, The Ohio State University Hospitals, Columbus,
OH; Peter Lunt, Bristol Royal Hospital for Sick Children,
Bristol, UK; Kathy Mathews, University of Iowa Hospitals,
Iowa City, IA; Richard Orrel and lames Forrester, University
of Rochester School of Medicine, Rochester, NY; George
Padberg, University of Nijmegen, Nijmegen, The Netherlands; Mary Speer, Duke University Medical Center,
Durham, NC; Meena Upadhyaya, University of Wales College of Medicine, Cardiff, UK; Michael van Geel, Roswell
Park Cancer Institute, Buffalo, NY; Mayana Zatz and Marie
Sueb, Universitade de SZo Paolo, S5o Paolo, Brazil.
This report summarizes the findings of an International Conference
on the Cause and Treatment of FSHD (Boston, April 12, 1997).
The conference was supported by grants from the FSH Society Inc,
the Muscular Dystrophy Association, and NIH grant #1 R13
NS35435-01A1 (award funded by NINDS, NIAMS, and the Office
of Rare Diseases).
The authors thank Lisa Oppelt for her expert effort in organizing
the FSHD conference and assistance in the preparation of this
manuscript.
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