Facioscapulohumeral disease

Padberg, G.W.A.M.

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Padberg, G. W. A. M. (1982, October 13). Facioscapulohumeral disease. Retrieved from
https://hdl.handle.net/1887/25818

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The handle http://hdl.handle.net/1887/25818 holds various files of this Leiden University

dissertation.

Author: Padberg, George Waltherus Adrianus Maria

Title: Facioscapulohumeral disease
Issue Date: 1982-10-13
Chapter 2

Facioscapulohumeral disease: review of the

literature

2.1. Introduction

Chung and Morton ( 1959) classified a large number of

patients with hereditary neuromuscular disorders according to the
pattern of inheritance. They found that the patients with pedi-
grees suggesting autosomal dominant inheritance fitted the
clinical picture of FSHD, as outlined by Wal ton and Nattrass
(1954). Patients with pedigrees suggesting other patterns of
inheritance demonstrated only a slight overlap of clinical find-
ings with FSHD. Chung and Morton (1959) concluded that nearly all
cases of FSHD could be diagnosed on clinical criteria only.
Statistical comparison of anamnestic and clinical data revealed a
high degree of resemblance of cases within one family, while a
significant difference was found when families were compared
among each other. This was interpreted as possibly due to multi-
ple alleles or alternative loci determining FSHD, although the
possibility could not be excluded that the apparent similarities
of sibs were the result of systematic biases in reporting the
onset of the disease. Chung and Morton (1959) could not separate
the group of patients with autosomal dominant inheritance into
more homogeneous subcategories of the basis of the available
evidence. The evidence consisted of personal cases collected in
the Sta te of Wisconsin and of cases selected from the literature,
including the reports of Sjovall (1936) from Sweden, Levison
(1951) from Denmark, Stevenson (1953; 1955) from Northern
Ireland, Beck er ( 1953) from Bad en, Germany, La my and Grouchy
(1954) from France, and Walton (1955) from Durham and
Northumberland, England . These studies still from much of the
basis of our kno wledge of the clinical picture of FSHD . Only few
other family studies of FSHD were reported since 1950. (Tyler and
Stephens, 1950; Boyes, 1950; Walton, 1956; Kazakov et al., 1974).
 - 21 -

Many authors though, have written on neuromuscular disorders and

commented on FSHD from personal experiences.

2.2. Presenting symptoms

Facial weakness wil l often go unnoticed: in over 60% of

Walton's cases (1955) neither the patients nor their families
were aware of it. Inability to whistle or to close the eyes
completely when asleep, are often considered a mild quirk of
nature. Chung and Morton (1959) reported facial onset of FSHD in
20% of their cases. I t is unclear whether they accepted inability
to whistle as a symptom indicating facial weakness. Several
authors like Brooke (1977), suggested a higher frequency of
facial onset by pointing out that many patients with FSHD never
had been able to whistle . The frequency of this symptom in an
unselected population is unknown nor is it clear how often this
symptom is due to facial muscle weakness . If facial onset is
present, it is a strong argument for the diagnosis FSHD, since it
was not noticed in any other type of muscular dystrophy as
described by Chung and Morton (1959).
The most frequently encountered presenting symptoms are
those of shoulder girdle weakness Chung and Morton (1959)
reported shoulder girdle onset in 77% of their cases. Difficul-
ties at gymnastics while climbing a rope or using the trapeze or
the bars, excessive fatigue when writing on a blackboard, dif-
ficulties in placing objects on a shelf or working above shoulder
level , and drooping of the shoulders are the complaints most
often heard. Combing hair or shaving will require special tricks
like resting the arms on a table. Several articles mention pain
in the shoulder girdle in relation to the development or a
exacerbation of the disease (Dubowitz and Brooke, 1973; Bradley,
1979). The significance of this symptom is not known. It may be
related to the extensive inflammatory infiltrates occasionally
found in the muscle biopsies of patients with FSHD (Munsat et
al., 1972) . Quite often it may take a fair degree of shoulder
girdle weakness before complaints arise. Judging the onset of the
 - 22 -

disease by symptoms is likely to result in a much higher age of

onset than if the onset could be estimated from the first detec-
table signs. If peroneal weaknes is present early in the course,
occasionally this may lead to the first symptoms, such as
tripping over small obstacles, or difficulty running.
Chung and Morton (1959) reported pelvic girdle onset in 12%
of their cases, but Becker (1953) never noted symptoms suggesting
pelvic girdle onset. He stressed the descending order of muscle
involvement in FSHD. This descending course was also reported by
Tyler and Stephens (1950).

2.3. Presenting signs

Knowledge of the presenting signs in FSHD is important for

the discussion of the differential diagnosis (see chapter 3):
FSHD may start either in the racial muscles or in the shoulder
girdle muscles, as was demonstrated in the first family described
by Landouzy and Dejerine (1885). The exact number of cases with
facial onset probably will never be known, since facial weakness
frequently remains unnoticed. One finds facial weakness as the
only sign of the disease when abortive cases are discovered
during a family examination or when anxious parents, who are
familiar with the disease, bring a child to the doctor. The most
common presenting signs are facioscapular weakness and atrophy
(Tyler and Stephens, 1950). Probably next in frequency is
shoulder girdle weakness, although accurate numbers are not
known. Humeral i . e. upper arm weakness will develop later in the
course of the disease and is never reported to be the presenting
sign in FSHD. In those cases where peroneal weakness gives rise
to the presenting symptoms, on clinical examination shoulder
girdle weakness is also found. Therefore (facio )scapuloperoneal
weakness may be the presenting syndrome in FSHD, and the
disorders described as scapuloperoneal syndromes, should be
included in the differential diagnosis of FSHD. Pelvic girdle
weakness being the sole and presenting sign of FSHD has not been
reported.
 - 23 -

2.4. Precipitating factors

Trauma, especially to the shoulder girdle, has been

implicated by physicians (Boyes et al., 1950) and by patients
(Becker, 1953) to precipitate the disease. Becker (1953) noticed
this phenomenon to be more frequent in his group of sporadic
cases of FSHD and thought this the result of a need of explana-
tion when visible heredity was lacking. Boyes et a1 . (1950) also
considered unusual physical strain as a possible provoking
mechanism in individuals who are "genetically susceptible" to the
disease . This could explain the asymmetric onset of the disease
in the right arm of a waitress who was under his care . Becker
(1953) who discussed the problem of physical strain at length,
was very sceptical about this mechanism and did not accept this
explanation in hereditary cases .
Other factors which, especially in the older literature,
were considered to play a role were infectious diseases. Becker
(1953) had found no infectious diseases in relation to the onset
of symptoms in his autosomal dominant cases but cited Robinson
(1925) who had observed that typhoid fever in one case and
influenza in tho other cases had aggravated the muscle weakness.
Becker (1953) concluded that the evidence was too flimsy to
accept a causal relation. Tyler and Stephens (1950) noted that
intercurrent illnesses had little effect on the rate of progres-
sion but that immobilisation, paricularly by body casts, resulted
in rapid progression of the muscular atrophy. The latter obser-
vation has been confirmed by many authors. At present no one
believes in a particular precipitating factor in the onset of
FSHD.

2 . 5. The facial muscles

In the majority of cases , facial weakness is present early

in the course of the disease, but facial weakness is not obliga-
 - 24 -

tory to the diagnosis FSHD. Becker (1953) found the facial

muscles to be spared in 18.7% of his cases of autosomal dominant
FSHD, and Chung and Morton (1959) in 16.8% of their collected
cases. This implies that in families with FSHD quite a few
members will start with shoulder girdle weakness while facial
weakness may develop later or not at all. Tyler and Stephens
(1950) found the zygomaticus and orbicularis oris muscles the
first to be affected, although the early detection of weakness in
these muscles may be related to their particular function.
Weakness of the zygomaticus muscles results in an inability to
raise the corners of the mouth and, when the patient smiles, his
mouth moves in a horizontal direction producing a grin more than
a smile, thereby depriving the smile of its emotional quality
( "rire en travers" or transverse smile). When the orbicularis
oris is weak, pursing of the lips, whistling, and retaining air
under pressure becomes impossible. When viewed from the side, the
lips have a pouting appearance due to loss of the normal upward
curvature of the lower lip. In many cases the lips appear to be
thickened (Becker, 1953). In severe cases the upper lips lose all
their mobility and appear to be elongated forming the so-called
"bouche de tapir". Brooke (1977) drew attention to the small
dimples that sometimes are present on both sides of the corners
of the mouth. They deepen when the patient smiles or tries to
show his teeth.
The orbicularis oculi muscles generally seem to be less
affected than the muscles of the lower part of the face. In the
beginning the eyelashes cannot be buried completely on forceful
closure of the eyes. If the weakness progresses, a small rim of
the sclera becomes visible on an attempt to close the eyes,
because the extraocular muscles are never involved in this
disease and a normal Bell's phenomenon can occur. In these cases
usually blinking is slowed and incomplete. At this stage other
facial muscles may become involved as well, resulting in an
unlined forehead and a smooth and expressionless face, that
originated the term "facies myopathica" or myopathic face
(Landouzy and Dejerine, 1885). A frequent finding is the occur-
rence of an asymmetric involvement of the facial muscles some-
 - 25 -

times resulting in an awkward expression. The literature offers

no expl anation for the asymmetric facial weakness. Data on the
frequency of asymmetric involvement are not available. There are
also no data on the degree of facial weakness. Probably this is
partl y due to the fact that there is no proper grading system for
weakness of the facial muscless. Although the degree of facial
involvement is quite variable, severe weakness without involve-
ment of the shoulder girdle muscles has never been reported. The
early and servere involvement of the facial muscles as described
in the f'1rst family of Landouzy an Dejerine (1885) has led
several authors like Erb, Levison, and Becker to remark explicit-
ly that they never had observed this phenomenon. On clin1car and
post-mortem examination the muscles innervated by the trigeminal,
the glossopharyngeal, the vagal and the hypoglossal nerve were
never found to be affected. Bradley (1979) reported weakness of
the masseter and tongue muscles in a small percentage of his
cases, but his numbers are sometimes misleading since he included
the family with a FSH syndrome previously reported by Hudgson et
al. (1972) in his series. This family had a mitochondrial myo-
pathy (see section 3.5.), and the clinical findings were defi-
nite l y distinct from the ones in FSHD as were the
histopathological and biochemical examinations. Therefore,
Bradley's figures are not quite representative for FSHD.
A progressive ptosis and extraocular weakness are no part of
FSHD. The patient reported by Winkler and Van Der Weijde (1889)
as FSHD with progressive ophthalmoplegia was probably suffering
from another disease. 'Ihese same authors suggested a defect in
the motor end plate in this case, a rather modern view at that
time.

2 . 6. The upper extremities, shoulder girdle and neck muscles

It is convenient to describe the weakness and atrophy in

FSHD in sections on the upper extremities, the trunk and the
l ower extremities respectively, as this is the general course of
spread of the disease. I t is impossible to describe the spread
 - 26 -

from one muscle to another, since there is no constant sequence.

This descending course and the autosomal dominant inheritance are
the main features of FSHD (Becker , 1953) .
Grading of muscle weakness by manual testing has only been
done by a few authors (Bradley, 1979). The reasons for this are
obvious. The axial muscles are difficult to grade if one uses a
system like the M.R.C. scale. If the scapula loses its fixation,
proper testing of shoulder girdle muscles becomes extremely
difficult. The causes of the change of position of the scapula
have not been properly described. It is not clear if this is the
result of a lack of strength of certain muscles or relatively too
much strength of other muscles or bOth . If the scapula cannot be
fixed, with a certain manoeuvre one might not be testing the same
muscles as in the case of an unaffected person. One could over-
come this problem by testing only certain skills and abilities as
suggested by Brooke (1977), but then one tests functions and not
individual muscles. Manual muscle testing may only be more or
less accurate and reproducible in testing extremity muscles.
Mechanical testing of muscles in FSHD has never been reported.
Apart from facial muscle weakness, one of the earliest findings
in FSHD is the gradual loss of fixation of the scapula . The
muscles involved are the rhomboids, the lower part of the trape-
zius and the serratus anterior muscles. This will result in
several visible changes. The scapulae rotate slightly laterally,
and move upward, laterally and anteriorly over the thorax. If the
rhomboid and serratus weakness progresses, scapulae alatae
appear. The change of position of the scapulae contributes to the
development of drooping of the shoulders. The clavicles lose
their normal upward slope, assuming a horizontal position, rotate
anteriorly for reasons poorly explained and ultimately sometimes
they may even slope downwards. Another early finding in FSHD is
the involvement of the latissimus dorsi and the sternocostal part
of the pectoralis muscles (Tyler and Stephens, 1950; Chyatte et
al . , 1966). Wasting of the latter will result in a flattened out-
line of the anterior thoracic wall, with a change of the direc-
tion of the axillary crease, running more horizontally instead of
vertically, and pointing at the sternoclavicular joint . In more
 - 27 -

advanced cases wasting of the ante~io~ neck muscles and the

pecto~alis muscles ~esult in a distinct p~ominence of the
clavicles at the base of the neck (B~ooke, 1977). When the
patient is seen f~om the f~ont a small, typical, but unexplained
lump may sometimes be seen in the contou~ of the t~apezius on its
slope to the ac~om1on. At~ophy of the sup~aspinatus and inf~asi­
natus may be visible and, due to the localisation of these musc-
les, quite st~iking. Landouzy and Deje~ine (1885) found these
muscles to be spared but most subsequent authors noted weakness
and wasting of these muscles, the f~equency of which amounted to
90% of B~adley ' s cases (1979). If the scapula has lost its
fixation, the deltoid muscle cannot be properly tested, but if
the scapula is held to the thorax by the examine~ ' s hand, the
deltoid muscle is often obse~ved to be minimally affected. The
sparing of the deltoid muscle which Chyatte et al. (1966) thought
characteristic of FSHD, occasionally, and falsely, induces the
unwary physician to pose the diagnosis of hypertrophy, parti-
cularly so when the su~rounding muscles are conspicuously
atrophic. Others found incomplete sparing of the deltoid muscles
(Tyler and Stephens, 1950; Bradley, 1979) and noted proximal
atrophy with distal sparing or atrophy of only the posterior
muscle bellies. Another feature on inspection may be the internal
rotation of the arms so that the backs of the hands are presented
when one sees the patient from the front. This may be due to the
changed position of the scapula but it is not clear if relatively
strong internal rotators play a role as well. Chyatte et al.
(1966) pointed out specifically that the teres major and
subscapularis muscles , just like the deltoid muscles, are spared
in FSHD . This has not been confirmed by others. The teres major
and subscapularis muscles were often not specifically mentioned
(Tyler and Stephens, 1950; Bradley, 1979). The time between the
onset of shoulder gi~dle weakness and the onset of uppe~ a~m
weakness may be quite variable. The atrophy in the upper arms may
become quite seve~e sometimes even ea~ly in the cou~se of the
disease resulting in so-called "Popeye" arms, because of the
~elative sparing of the lower a~m muscles.

The visible signs as desc~ibed so fa~ all ~eflect a certain

 - 28 -

degree of involvement. Early detection of shoulder girdle

weakness is difficult. There appears to be a great variety of
shoulder build. In many slender people the scapula may be pro-
minent and many healthy women have horizontal clavicles. Sloping
of the shoulders becomes more prominent with age and also the
distance between the medial margins of the scapulae varies
greatly, depending, among others, upon thoracic build. Testing of
individual muscles, as described for instance by Kendall et al.
(1971) , is often very helpful but is not quite reliable for
testing the shoulder fixators in FSHD since these tests depend
upon a good function of other shoulder girdle muscles. The
shoulder g irdle emerges from this picture as a complex structure
in which no muscle ever acts on its own. A large number of varia-
bles are involved in any position and movement of the scapula,
and this is the reason why t here is still debate about normal
scapular function, let alone the function in pathological states .
Therefore, many clinicians rely on functional tests like the
ability to slowly elevate the arm to a vertical position, and the
ability to hold the arm horizontally against pressure. A slowly
lowering of the raised arms is a sensitive test for minimal
serratus anterior weakness (Brooke, 1977) demonstrating a light
degree of scapula alata in this manoeuvre. If the scapula
fixation becomes weaker , the arms cannot be raised completely but
are swung up to catch an object that is above shoulder height. If
the hands are clasped together, the arms can be raised more
easily , a phenomenon r epeatedly described, but never properly
ex plained. When scapular fixation and especially the serratus
function worsens, elevation of the arm above shoulder level
becomes impossible . At attempts at abduction of the arms, the
scapulae ride upwards over the back and their upper borders rise
high up into the normal location of the trapezius muscles. '!his
phenomenon is said to be typical of FSHD (Brooke, 1977), but an
explanation was never offered. A factor that could be important
in the genesis of this sign is the fact that the del to id muscle
in FSHD remains strong for a long time, producing a maximum rise
of the completely unfixed scapula. The extremity muscles are more
accessible for manual testing of individual muscles which will be
 - 29 -

so- called prime movers in certain defined circumstances . Tyler

and Stephens (1950) noted the brachioradialis muscles to be af-
fected in a very early stage, even before the involvement of the
biceps and triceps muscles, a finding not confirmed by others.
Although affected later, the biceps and triceps muscles atrophy
rather faster, resulting in a remarkable thin upper arm amid
relatively spared del to id and lower arm muscles . In general the
forearm muscles retain their strength for a long time . Only in
severe cases weakness of the wrist extensors may develop,
occasionally leading to a wristdrop. The wrist and finger flexors
will maintain good strength much longer. The instrinsic muscles
of the hand will only be affected in severe cases (Becker, 1953).
Bradley (1979) noticed involvement of these muscles in more than
50% of his cases with more than 20 years duration of the disease.
Chyatte et al. (1966) found that the extensors of the neck were
always spared but Bradley (1979) observed that these muscles were
affected as well in several cases. He even noticed weakness of
the neck flexors in as much as 75% of his patients. This
contrasts sharply with the experiences of Van Wijngaarden and
Bethlem (1973), who found the neck flexors rarely involved in
FSHD. They even used this as a criterion for the diagnosis. The
sternocleidomastoid muscles may become weak quite early in the
course of the disease (Tyler and Stephens, 1950), but they are
almost never absent contrary to their early and severe involve-
ment in myotonic dystrophy.

2.1. The truncal muscles

Little has been written about the truncal muscles in FSHD.

Tyler and Stephens (1950) noted that the abdominal muscles were
involved only after the disease had spread to the foot extensors
and glutaeal muscles. Others, on the other hand, (Wintzen, 1979)
found the abdominal muscles often affected rather early in the
course of the disease resulting in a protruding abdomen. Weakness
of the abdominal muscles adds to the pelvic tilt and the increa-
sed lumbar lordosis. Weakness of the glutaeus maximus muscles may
 - 30 -

play a role as well. Also part of the increased lordosis may be a

compensatory mechanism to retain balance while standing or
walking.
In more severely affected patients the increased lumbar
lordosis can result in an almost horizontal sacrum, and the line
of weight bearing from shoulders to feet passes posteriorly to
the sacrum. In this form, the increased lumbar lordosis was
already described by Landouzy and Dejerine and demonstrated in
their case "Leon M." (1885). Duchenne (1868) had suggested that
the lumbar hyperlordosis in FSHD was caused by normally
functioning erector trunci muscles unopposed in their action by
the abdominal muscles. It is not clear if ligamentous or other
factors also play a role in producing this extreme lordosis in
FSHD, since this has never been studied. Carroll (1979) stated
that this lordosis becomes more marked when a patient is bound to
a wheelchair, whereas patients with other types of hereditary
myopathies tend to become more scoliotic when they are in a
wheelchair, but he fails to explain why or to document how often
this phenomenon, typical for FSHD, does occur. A thoracic
kyphosis is rarely found in FSHD and a scoliosis, if present, is
usually very mild, probably because the major symptoms of the
disease usually develop after the spinal growth is completed.

2.8. The lower extremities and the pelvic girdle muscles

Weakness of the anterior tibial muscles was mentioned in the

earliest descriptions of FSHD (Landouzy and Dejerine, 1885; 1886)
and it was the sole finding in the legs in many cases reported by
Boyes et al. (1950) but 1t was not recognised as an early sign
until the publication of the extensive family of Tyler and
Stephens (1950). Chyatte et al. (1966) and Vignos et al. (1967)
found early weakness of the anterior tibial muscles unique and
typical for their group of FSHD patients. Seitz (1957) and
Erbsl~h (1958) paid special attention to this sign and confirmed
Ty1er's and Stephen ' s experience, but at the same time Becker
(1953), Walton and Nattrass (1954), Chung and Morton (1959) and
 - 31 -

Walton and Gardner-Medwin (1974) still found the pelvic girdle

and the proximal muscles of the legs the main sites of involve-
ment in the lower part of the body . Kazakov et al. (1974) studied
55 personal cases and 145 cases from literature and found that
the disease could spread in two different ways to the lower part
of the body. The first type, which they called "the gradually
descending variety", spread initially to the pelvic girdle
muscles and then gradually to the upper and lower leg muscles .
The second type, which they called "the descending type with a
jump ", first spread to the lower legs, especially the anterior
tibial muscles and from there on to the upper legs and pe_l vic
girdle muscles . The second type was said to be more common. These
authors stated that within each family only one type occurred and
they argued that this homology or clinical similarity within
families indicated that FSHD was genetically heterogeneous and
consisted of at least two diseases. Carron (1979) stated that
these findings could not be confirmed, but did not mention on
what grounds. Walton and Gardner- Medwin (1981) argued that the
patients of Kazakov et al. (197 4) were not studied up to modern
standards and might very well have included cases with neurogenic
atrophy . Weakness of the peroneal muscles will develop somewhat
later than the anterior tibial weakness , and by the time this i s
found, weakness of the gluteal, quadriceps and hamstrings muscles
will be clinically present as well. In the majority of cases the
calf muscles remain unaffected for a long time: they become
involved in the latest stages of the disease only (Tyler and
Stephens, 1950) . The extensor digitorum brevis muscles remain
unaffected for a long period and are sometimes found to be hyper-
trophied (Brooke, 1977) as a compensatory mechanism for an early
foot drop. This finding can be helpful in distinguishing FSHD
from neurogenic atrophy . The other intrinsic foot muscles were
reported unaffected by Tyler and Stephens (1950) . These muscles
are only involved in cases with diseases of long duration
(Bradley, 1979). Weakness of the foot extensors interferes with
walking, resulting in a steppage gait and inability t o run.
Patients tend easily to trip over small objects , falling for ward
on their knees. If pelvic girdle weakness develops , a waddling
 - 32 -

gait will be visible and gradually rising from a chair or clim-

bing stairs becomes more and more difficult.
The waddling steppage gait with the impressive lumbar
lordosis, the drooping shoulders and the myopathic face are very
characteristic for FSHD. Finally, walking and standing becomes
impossible and the patient becomes wheelchair-bound .

2.9. Pseudohypertrophy of muscles

Pseudohypertrophy is not a hallmark of FSHD (Wal ton and

Gardner- Medwin, 1981). Landouzy and Dejerine (1885; 1886) obser-
ved pseudohypertrophy in the supraspinatus and infraspinatus
muscles of several cases and considered this to be typical of
FSHD. Fur t her observations could not confirm this. Becker (1953)
observed one case with pseudohypertrophy of the deltoid muscles
but most authors mention a seeming hypertrophy as the deltoid
muscle remains intact for a long time amid rather atrophic
muscles: the same can be said of the calf muscles. Pseudo-
hypertrophy of the glutaei muscles was occasionally observed by
Becker (1953) but is was not mentioned by others. True hypertro-
phy was described in the extensor digitorum brevis muscle by
Brooke (1977) as a compensatory mechanism for an early foot drop.
This has not been reported before. Histological studies on these
muscles were not undertaken.

2.10 . Reflexes

The stretch reflexes diminish rather early in the course of

the disease and may eventually disappear. This is a common, but
ill- explained finding in myopathic disorders. There are no speci-
fic studies on the stretch reflexes in FSHD . Pathological
reflexes do not occur in FSHD. Sensory and cerebellar functions
are invariably intact.
 - 33 -

2.11. Contractures

Contractures are said to be very rare in FSHD (Walton and

Nattrass, 1954). Exact numbers and sites are not reported .
Occasionally ankle contractures are found. If contractures are a
prominent sign in a patient, other diagnoses must be considered,
as will be discussed in the next chapter.

2 . 12. Asymmetry of muscle invo lvement

An important feature of FSHD is a distinct asymmetry of

muscle involvement (Carroll , 1979). This can be present in the
facial as well as in the shoulder girdle muscles , and in t he
extremities.
Mingazzini (1912) and Becker (1953) mentioned a case of
unilateral involvement. Seeker (1953) noted that the right side
was more involved than the left one in 30% of his cases, the left
side more than the right one in 15%, while in 55% of his cases
both sides were more or less equally affected . He was careful not
to draw any conclusions from these figures, since the criteria on
which asymmetry was decided were rather crude. These criteria
were an asymmetric configuration of the shoulder, an asymmetr i c
strength on arm abduction and an asymmetric onset of muscles
weakness. If he also included asymmetry of facial or pelvic
girdle muscles, very few symmetric cases remained. Becker consi-
dered this asymmetry to be a strong argument for environmental
influences on the expression of the gene. He did not mention the
possibility of a relation with right or left handedness.

2 . 13. Skeletal deformities

Skeletal deformities are rare in FSHD. Tyler and Stephens

(1950) noted a pectus excavatum in most of their severely disa-
bled patients. This was also present in one unaffected indivi-
dual. These findings have not been confirmed by others. A mild
 - 34 -

scoliosis is often found in the more advanced cases but numbers

about its frequency are lacking . Occasionally a kyphoscoliosis
has been reported. The increased lumbar lordosis may be a result
of muscle weakness itself, and a mechanism compensating for a
pelvic tilt in order to maintain balance. The increased lordosis
is present in most cases where the disease has spread beyond the
shoulder region but again, precise figures are not available. The
autopsy case described by Landouzy and Lortat Jacob (1909) had a
pectus excavatum, severe muscle contractures, and an increased
lumbar lordosis attributed to skeletal changes , but an autosomal
dominant pattern of inheritance was not apparent in the family of
this patient. Foot deformities are no part of FSHD.

2.14. The cardiac muscles in FSHD

Cardiac involvement in FSHD is considered to be rare. There

are only few and no recent reports on this subject . The older
literature is hampered by an absent or an inadequate classifica-
tion of the hereditary myopathies. Most studies report only a few
cases of FSHD (Rubin and Buchberg, 1952; Weisenfeld and
Messinger, 1952). Schott et al. (1955) studied three patients
with FSHD and emphasized the absence of electrocardiographic ab-
normalities. Manning and Cropp (1958) reported ten patients with
"adult type muscular dystrophy ". Five of them had left axis
deviation which was attributed to rheumatoid heart disease in one
case and to coronary sclerotic heart disease in another patient.
In the remaining three patients, left axis deviation may have
reflected cardiomyopathy. The classification of the myopathy in
these cases has been disputed (Perloff et al., 1966 ; 1971).
Gailani et al. (1958) reported on a thyroidectomized FSHD patient
with a first degree A- V block , a QRS prolongation and a right
branch block, who had a slightly reduced cardiac output. The case
discussed by Lisan et al. (1959) had P and T wave abnormalities,
a radiological cardiomegaly and congestive heart failure at the
age of 32. In this case the diagnosis of FSHD is doubtful because
of the early and severe involvement of the triceps surae muscle.
 - 35 -

Kilburn et al. (1959) made no distinction between the "limb

girdle type" and the "FSH type" of muscular dystrophy . Only two
of this eight patients had facial weakness and predominantly
shoulder girdle weakness as well. Both had thoracic muscle weak-
ness and pulmonary restrictive defects. One of them had a normal
ECG and the other had an incomplete right bundle branch block.
The four patients reported by Welsh et al. (1963) had no history
of cardiac complaints. They all had normal blood pressure and an
normal chest X-ray. One female patient had a heart rate of 52 and
a six-year old boy a tachycardia of 102 . In another patient a
left ventricular conduction delay and a left ventricular hyper-
trophy "were suggested but not all criteria were present to
establish a definite diagnosis". Otherwise the ECG ' s in these
patients were normal. Perloff et al. (1966) studied three
patients with FSHD . One of them, a 36- year old woman, had both
atrial and third heart sounds and an abnormal brachial arterial
response to the Valsalva manoeuvre that could be " compatible with
occult cardiac failure". Another patient had a slightly elevated
wedge pressure . There were no other findings in these patients
suggesting cardiomyopathy. There are three reports of persistent
atrial paralysis (PAP) associated with FSHD (Bloomfield et al. ,
1965; Caponetto et al., 1968; Balwin et al., 1973). All three
patients were men. Autosomal dominant inheritance could not be
demonstrated and photographs of the patients suggested abduction
contractures of the shoulder joints. These patients most likely
suffered from what has been described as X- linked recessive
scapuloperoneal syndrome with cardiomyopathy, in which the ex-
treme rare condition of PAP is know to develop with age. This
syndrome will be discussed in the next chapter. Autopsy reports
on FSHD patients are rare. Landouzy and Dejerine (1885) could not
detect any cardiac abnormality on macroscopical examination. In
the case described by Landouzy and Lortat Jacob (1909) the condi-
tion of the heart was not discussed. The case reported by Justin-
Besanscon et al. (1964) demonstrated tuberculous lesions in the
pericard but the myocard was found to be normaL In summary , no
specific cardiac complaints and no specific abnormalities
concerning cardiac function are known to occur in FSHD.
 - 36 -

2.15 . Concomitant diseases

Few authors studied the association of FSHD with other

diseases. Tyler and Stephens (1950) mentioned thyreotoxicosis in
nine of their patients but thought the association fortuitous.
Becker (1953) noticed a goitre in nine of the 94 cases under
study. The same author found mental retardation to be present in
five patients with FSHD. This association has never been
confirmed. There were also two cases (a father and a son) with
Huntington's chorea in Becker's series; mitral valve disease was
present in three patients, and myocarditis and hypertension each
in another patient , but these findings could not be related to
the muscle disease. Tyler and Stephens (1950) noted hypertension
in six patients of which two had suffered a myocardial
infarction. Rheumatic fever was also frequently present in their
patients but they found no statistically significant difference
between the incidence of rheumatic manifestations in FSHD
patients and in unaffected persons.

2.16. Abortive cases

Davidenkow (1930) was the first who drew attention to the

frequent occurrence of mildly affected cases in FSHD . He stressed
the fact that often neither these patients nor their families
were aware that they had the disease. Tyler and Stephens (1950)
noted absence of symptoms in 24 out of 58 patients (48%).
Thirteen patients were 20 years or older of whom four had
"minimal involvement" defined as "just detectable on exami-
nation". Walton and Nattrass (1954) were very impressed by these
mildly affected cases and introduced the term "abortive" . They
reported five stationary or abortive cases out of 15 studied
(33%). Kazakov et al. (1974) reported 22 (11%) asymptomatic cases
among 200 cases of FSHD most of which were taken from the litera-
ture. The lack of definition of abortive cases makes it difficult
 - 37 -

to study the frequency of this phenomenon in the literature . It

should be noted that neither Becker (1953) nor Chung and Morton
(1959) mentioned abortive cases in their material. The best
definition of abortive cases appears to be "without symptoms but
found affected on clinical examination". This definition also
includes young persons in whom the disease has just started and
who will develop complaints later. A definition of abortive cases
such as "without symptoms and beyond the mean age of first
complaints" probably would be more correct but is unpractical
because the mean age of onset of FSHD is not quite established.
In this study the first definition will be used. The clinical
picture of abortive cases might then include facial weakness
and/or slight shoulder girdle weakness with atrophy. On clinical
examination in a rare case, minimal foot extensor weakness might
be present as well. Although several authors (Davidenkow, 1930)
suggest that FSHD runs a milder course in women, there are no
data that would indicate that there are more female than male
abortive cases .

2.17 The infantile form

If Duchenne 's famous case Henri Juliard (1862) suffered from

FSHD -which is likely because of the clinical picture and the
pattern of heredity in his family- he represented the earliest
report of congenital facial weakness in FSHD. This patient was
seen by Duchenne at the age of 13 because of shoulder girdle
weakness, noticed one year earlier. He was, l ike his mother
reportedly born with facial weakness . When his mother was
examined at the age of 30 the disease had not spread beyond the
facial muscles. Her mother and her brother both had shoulder
girdle weakness and atrophy as wel l . The first patient of
Landouzy and Dejerine (1885) developed facial weakness at the age
of three and shoulder girdle weakness when 15 years old: his sis-
ter had suffered from facial weakness since the age of four.
Hanson and Rowland (1971) described similar patients. Three
unrelated cases were diagnosed as M~bius' syndrome because of
 - 38 -

facial weakness found to be present in the first years of life.

All these cases passed the motor milestones at normal ages and
developed severe muscle weakness in the first years of the second
decade. EMG and muscle biopsy supported the diagnosis FSH myo-
pathy. The first patient had a mother wi th facial weakness and
two brothers who were minimally affected. The second patient had
a sister with facial weakness but other family members could not
be examined. In the third patient, the father and one sibling
were not available for examination; the mother and three siblings
were unaffected. Autosomal dominant inheritance has not been
ruled out and could very well be present in these cases.
Brooke (1977) was the first to describe infantile FSHD as a
special form of this disease. He suggested a specific clinical
course and mode of inheritance in this presentation of FSHD, but
he omitted to give precise numbers and data. It is unclear how
many patients he studied, but he reported that facial weakness is
noted in the first two years of life in all cases, leading to an
early facial paraly sis . Weakness of the shoulder girdle and
pelvic girdle muscles develop early, and the progression is so
fast that according to h i m, most children are dependent on a
wheel chair by the end of the first decade . The expressionless
face limits the emoti onal, non-verbal communication and isolates
the child, making it (in Brooke 's experience) more depressed than
children with other comparable diseases. The most interesting
aspect of Brooke ' s descr iption is the way this infantile form is
transmitted. In all cases except one , Brooke observed in one of
the parents slight facial weakness as the only sign of the
disease. There was no comment on the exception nor on other
members of the fami lies of these patients. Brooke suggested a
modifying gene to be present in the non - affected parent of
these patients, but in view of the limited data such conclusions
appear to be rather premature. At present there is no basis to
assume that infantile FSHD is a distinct form of FSHD.
 - 39 -

2 . 18 The late onset adult form

In his monograph on neuromuscular disorders, Brooke (1977)

described another extreme of the clinical spectrum of FSHD as the
late onset adult form of FSHD. This clinical variety involves
patients with a lifelong mild facial weakness having a rapid
progression at some stage in their life, commonly in middle age,
leading to severe shoulder and pelvic girdle weakness within a
couple of years. Muscle biopsy may reveal inflammatory changes,
but, according to Brooke, they differ from polymyositis. These
patients seem not to respond to corticosteroid treatment . The
lifelong presence of facial weakness was suspected upon
heteroanamnestic information and induced Brooke to consider this
presentation a variant of FSHD. In an earlier publication he
suggested that these cases were sporadic ones (Dubowitz and
Brooke, 1973) . In 1977 he did not comment upon the pattern of
inheritance in these cases. Also lacking are data regarding
family members . Thus the description of this variant is
incomplete and vague, as Brooke himself did admit .

2.19. Age of onset

The onset of FSHD has never been observed objectively. The

reported age of onset is therefore based on anamnestic data. Such
an approach leaves out the abortive cases because they are with-
out complaints . It is also known from family studies that
patients with a considerable amount of facial and shoulder girdle
weakness and atrophy, may nevertheless be without complaints.
Therefore, the true age of onset of the disease may be several
years earlier than is indicated by the complaints of patients.
Another problem around the age of onset lies in the involvement
of the facial muscles. Most patients are not aware of their
facial weakness, nor do they appreciate the meaning of signs,
l ike inability to whistle, or inability to close their eyes
completely. Occasionally someone else -a doctor, a mother or an
attentive family member- has pointed this out to them. In those
 - 40 -

cases the onset of the disease is likely to be reported much

earlier. Many people with FSHD will tell that they were never
able to whi stle . This could indicate facial weakness but, on the
other hand, they may never have tried to whistle for various
r easo ns, so this symptom is of little help as it has not been
properly studied . The reported age of onset reflects more upon
the age of a wareness of the disease in patient s than upon a true
begi nning of t he disease .
The diagnosis of FSHD may be difficult in the early stages
of the disease.Faci al weakness may go unnoticed even for a
trained phys i cian (Walton, 1955). Atrophy and weakness of the
scapular fi xators may be difficult to diagnose early in the
cour se of t he disease, particularly when the patient is young.
Tyler and Stephens (1950) and Becker (1953) all claimed that they
were unable to diagnose the disease with certainty below the age
of seven. On the other hand, facial weakness was found at the age
of three in the proband of Landouzy and Dejerine's first descrip-
t i on (1885) . Hanson and Rowl and (1971) reported patients with
congenital facial weakness, later developing FSHD . Also Brooke ' s
(1 977) cases , repor t ed as the infantile presentation of FSHD, had
facial weakness in the first years of life .
Tyler and Stephens (1950) observed in one large pedigree
with 58 living pat i ents that the symptoms or signs recognizable
by t he patient or his family usually developed between the ages
of seven and 20 years, the most common age of onset being between
13 and 15 years. Only five persons (9%) were older than 20 years
when they firs t noticed symptoms . Becker (1953) examined 11
families with autosomal dominant (facio )scapulohumeral muscular
dystrophy . The age of onset was thought to be between seven and
27 years, with a peak around 15- 16 vears. There were only four
persons (5%) with an onset later than 27 years (29, 31, 39 and 49
respectively) . By the age of 21, 85% of all his cases had been
diagnosed as such. Walton and Nattrass (1954) found two cases
among 15 with the onset at seven and nine years respectively , ten
with the onset in the second decade and three with the onset at
22 , 26 and 27 years respectively. It was concluded that the age
of onset could "vary from infancy untill late in adult life".
 - 41 -

Chung and Morton (1959) presented the ages of onset in a

diagram (Fig. 2.1.). I t shows that 87% of all patients can be
diagnosed at the age of 20 and 93% at the age of 30 years. The
diagram is also used to estimate the risk for individuals in
families with FSHD to become affected under the assumption that
all gene carriers will develop detectable signs of the disease at
a certain time in their lives. The probability that a child of a
patient will carry the abnormal gene is 0.5 in autosomal dominant
diseases, and the risk of such a child, that is unaffected at age
z, to develop the disease does not exceed the ratio 100 - G(z) :
200 - G(z) in which G(z) is the percentage of gene carr~ers
clinically affected at that age. This risk is probably even
lower, because G(z) in this study was based on recollection data
and the disease can be d iagnosed on clinical examination years
before the onset of first symptoms. In addition Chung and Morton
noted a significant higher mean age at ons~t for males (16. 8
years) than for females (13.7 years); they suggested that puberty
might be a factor in precipitating the onset of the disease.
Becker (1953) found that the age of onset, based on anamnestic
data, in ten sporadic cases of FSHD ranged from 15 to 32 years,
with an average of 22 years. This figure differed from the
average age of onset in the group with proven autosomal dominant
inheritance. This difference could reflect genetic heterogeneity
but could also be the result of the unexpected playing an impor-
tant role in the late recognition of symptoms.

f igure 2.1 Cumulative distribution of age of

onset among 95 patients with FSHD
(adopted from Chung and Morton.1959)
9

>
(.)
9
i

f--
__, -
c
Q)
8
::l
er e7
!!!
..._

I
,... /
I
I
age of onset
 - 42 -

2.20 The mode of inheritance

An autosomal dominant pattern of inheritance was found by

most authors who reported on FSHD (Landouzy and DeJerine, 1885;
1886; Pearson, 1933; Boyes et al., 1950; Tyler and Stephens,
1950; Becker, 1953; Walton and Nattrass, 1954; Walton, 1956;
Chung and Morton, 1959; Kazakov et al., 1974). Myopathies with an
autosomal recessive mode of inheritance and presenting themselves
with shoulder girdle muscle weakness have been described, but are
uncommon (Walton and Gardner-Medwin, 1981). In general, these
cases are included in the 11mb- girdle group of muscular
dystrophy . A small percentage of these cases appear to develop
facial weakness in the course of their disease. Yet, an autosomal
recessive myopathy identical to FSHD has been poorly documented.
Brown (1951) reported on in-patients but did not study their
families. Therefore her report cannot be accepted as an argument
for the existence of a recessive form of FSHD. Stevenson (1953)
studied nine families with shoulder girdle and facial muscle
weakness in Northern Ireland. In one family a father and a
daughter were affected: in the other families the patients only
occur red in single sib ships. Stevenson did not describe clearly
which of the supposedly unaffected persons were examined . In some
families the parents were not examined and in others it is evi-
dent that he could have studied only one of them. Stevenson's
conclusion that FSHD is inherited in an autosomal recessive way
is unwarranted on the basis of the data presented. Moser et al.
(1966) described four patients in two families suggestive of
autosomal recessive inheritance . Only one patient had shoul der
girdle onset with facial weakness. In the other three patients
the disease had started in the lower extremities. All in all, it
appears that an autosomal recessive myopathy, clinically iden-
tical to FSHD, has never been properly described .
Apparent sex limitation was only mentioned by Walton (1955)
who studied a family wi th seven affected females in two gene-
rations. The same author (1981) referred to a report of a family
with an autosomal dominant neuromuscular disorder affecting five
 - 43 -

women in two generations (Hertrich 1957). The disorder always had

started in the shoulder girdle muscles . Only one patient had a
questionable facial weakness . Muscle biopsies were not performed .
As long as chance factors cannot be excluded, such families are
no proof of sex-limited inheritance .
Sporadic cases of a facioscapulohumeral myopathy constitute
another problem . A careful examination of the parents and their
families is such cases is always warranted, particularly if
genetic advice is sought, while one should have to be sure that
non-paternity is excluded . But even when the offspring of such a
patient is not affected, a new mutation to FSHD cannot be
excluded. Becker (1953) suggested that the 11 sporadic cases of
his group of descending shoulder girdle myopathy were different
from his autosomal dominant group because of a later age at
onset. But is not quite clear whether all these cases were
sporadic ones, because in several instances the families could
not be examined properly, while in other cases there was a his-
tory suggestive of more affected persons in the family, and in
one case (family 15) the mother of the proband had a paresis of
the orbicularis oris muscle. Walton and Nattrass (1954) included
sporadic cases in their limb-girdle group, which was shown to be
heterogeneous (Chung and Morton, 1959) and in which sporadic
cases with autosomal recessive inheritance could be distinguis-
hed. Moser et al. (1966) reported three sporadic cases with
facioscapulohumeral myopathy of which two had facial onset of the
disease; one of these two patients had no children and her
parents and only brother were dead: the parents and the two
children of the other patient were examined and found to be
healthy.
The literature clearly suggests, that the approach of the
clinician who tries to attach modes of inheritance to sets of
signs leads to more discussion and confusion than that of the
geneticist , who describes the signs at a given mode of inheri-
tance. The geneticist ' s approach avoids an a priori discussion on
semantic problems, such as the meaning of the term facioscapulo-
humeral, and has the advantage that the patterns of inheritance
are well defined. As this approach is felt to be more fruitful ,
 - 44 -

we should like to define FSHD as an autosomal dominant neuro-

muscular disorder. Moreover it can be concluded that autosomal
recessive disorders closly resembling FSHD have not been properly
documented; sporadic cases, resembling FSHD, have been described
and might be mutants or phenocopies.

2 . 21. The penetrance

The penetrance of FSHD was always thought to be complete but

this was based on the findings in relatively small pedigrees.
Only some authors studied large kindreds. Tyler and Stephens
(1950) found the ratio of affected versus non-affected sibs in
their large kindred close to 1 : 1 (the actual numbers were 130
versus 143). No correction for the probands could have been made,
because they were not indicated in this study. Several patients
had died, and only 58 living patients had been examined . Still
the authors considered these results to be compatible with
complete penetrance. Becker (1953) made corrections for the pro-
bands and found that in sibships with at least one affected
person, 41% of the sibs were affected and that 46% of the sibs of
an affected parent were affected themselves. These figures did
not differ significantly from the expected 50% and therefore the
penetrance was thought to be complete . Similar numbers were
reported by Kazakov et al. (1979) who studied 55 personal cases
and 145 histories taken from the literature. They found 49% of
the children to be affected if one of the parents had FSHD . These
authors stated that FSHD occasionally skipped a generation but
they did not document this observation. I f their statement is
based on published reports only, such as the first family of
Landouzy and Dejerine (1885), it is of little value because the
skipped generation in this family was never examined .
 - 45 -

2.22 Sex influence

Since the recognition of muscle disorders, clinicians have

been intrigued by the differences between the sexes . This was
largely caused by the presence of the X-linked myopathies . But
even when these were separated from the other myopathies, the
question remained if the X-chromosome or the hormonal or other
biochemical differences between males and females had any
influence on the onset or the expression of the hereditary muscle
diseases. Several authors have discussed thi s matter when repor-
ting on FSHD. Becker (1953) found more females than males affec-
ted but the numbers did not differ significan tly from the
expected 1 1 ratio . Wal ton (1955) reported on 17 females and
five males in four families but considered the informa t ion too
limited to draw firm conclusions . Most au t hors agree tha t men are
as frequently affected as women.
Chung and Morton (1959) reported a s t atistically signi ficant
difference in the mean age of onset in males and females . The
authors suggested that the onset of puberty might play a role.
However these findings have never been confirmed by others .
Several authors like Davidenkow (1930) had the impression
that FSHD runs a milder cour se in females, but only Becker (1953)
came with evidence from his own material. Using pelvic gir dle
involvement as a criterion for the severity of the disease, he
found that 80% of the males and 23% of the females in his study
were severely affected . The difference in frequency i s statist i -
cally significant. But, again, nobody so far has confirmed these
observations. Bradley (1979) - using his own inde x of severity-
found women to be slightly more severely affected than men, but
his material does not consist purely of FSHD .

2 . 23. Linkage studies

Linkage or association with a known trait or disease has

never been observed in FSHD . Tyler and Stephens (1950) did not
find linkage of FSHD with the loci of the ABO , MN and RH blood
 - 46 -

groups in their large kindred. Chung and Morton (1959) anal ysed
Walton's (1955) limited data on the bloodgroups ABO, RH, MN, P,
FY, and JK in more detail but, again, no suggestion for linkage
was found .

2 . 24 Prevalence and incidence

The prevalence of a disease is defined as the frequency of

affected individuals in a population at a given time. The preva-
lence of FSHD reported by different authors is quite variabl e,
suggesting lar ge regional differences, even if one assumes that
not all affected persons are ascertained in the regions with the
reported low prevalence . Morton and Chung (1959) reported the
prevalence of FSHD being 1 per 435.000 in Wisconsin, after cor-
rection had been made for an estimated ascertainment probability,
and 1 per 179.000 when based on pooled data from several surveys.
Becker (1953) reported a prevalence of 1 per 17 . 000 in South-
Baden (Germany), calculated from familial and non-familial cases.
If the 11 sporadic cases were excluded, the prevalence of FSHD
amounted to 1 per 20 . 000 approximately. Walton and Nattrass
( 1954) reported 22 affected persons in a population of approxi-
mately 2 million (1 per 91.000) . Moser et al. (1966) found two
patients with FSHD among the 910.000 inhabitants of the Kanton
Bern in Switzerland , i.e • • 1 per 455 . 000. Prot (1971) reported
the prevalence of FSHD in the region of Warsaw (Poland) to be 1
per 250 . 000 individual s .
There are several definitions of incidence. The incidence
might be defined as the frequency of new occurrences of a disease
among individuals of a specific population within a certain
period of time , or as the frequency of individuals born in a cer-
t ain population who wi l l become affected. If the latter defini-
tion is used , the incidence is always higher than the preval ence
because it may take some years for a defective gene to come to
expression, and such a gene may lead to an earl y dea t h . Morton
and Chung (1959) made a correction for the ascertainment proba-
bility and found the incidence of FSHD in Wisconsin to be 1 per
 - 47 -

263.000 individuals born, and for their combined sources as

mentioned in section 2.1., 1 per 109.000 .

2.25 Fitness

Fitness is defined as the ability to transmit one's genes to

the next generation and have them survive in that generation to
be passed on to the next. Seeker (1953) reported a normal fitness
in patients with FSHD, based on the ratio of children of affected
and non-affected sibs. Morton and Chung (1959) stressed the
biased ascertainment of more fertile persons, and the possible
difference in fertility between non- affected sibs and the general
population. Using methods which reduce these biases , they esti-
mated the relative fitness coefficient for patients with FSHD to
be about o. 741. (Morton et al., 1963). Emery and Walton (1967)
reported a normal fitness if affected sibs were compared with
unaffected sibs, but Prot (1971) reported a relative fitness
coefficient of 0 . 80 for her patients with FSHD, when compared
with healthy sibs .

2 . 26 Mutation rate

Seeker and Lenz (1955, 1956), using the direct method,

estimated the mutation rate of FSHD to be 4.7. x 10 - 6 per gene
per generation. Assuming a relative fitness coeffic ient of 0.89
they arrived at a mutation rate of 5.0 x 10 -6 by an indirect
method . Morton and Chung (1959) found a mutation rate of 5.0 x
10- 7 by an indirect estimate and Prot (1971) reported a mutat i on
rate of 3. 0 x 10-1 per gene per generation. These large
differences are related to the reported regional differences in
the prevalence of FSHD, and apart from the problems of complete
ascertainment of this rare and relatively mild disease , many
sources of error such as illegitimacy , low expressivity , and
possibly incomplete penetrance are involved in establishing the
correct number of mutations in a population.
 - 48 -

2.21 Clinical course and disabilty

There are no longitudinal studies of FSHD. The clinical

course of FSHD has been judged f['Om anamnestic data, and is
thought to be slowly progressive in most cases, covering many
decades (Tyler and Stephens, 1950). Most authors agree that long
periods of arrest are not unconunon (Wal ton and Nattrass , 1954),
but occasionally a rapid progression is noted (Brooke, 1977). The
time lapse between involvement of the upper part and lowe[' part
of the body varies g['eatly from patient to patient. Exact figures
are rarely given. Walton and Natt['ass (1954) mentioned a duration
of 20- 30 years before the disease had sp['ead to the pelvic girdle
muscles . In a late[' text, Walton and Ga['dner-Medwin (1981) stated
that some cases may run a rapid cou['se, while in others long
periods of appa['ent arrest may be noted. In some instances the
pelvic girdle muscles will never be involved. Becker (1953) found
that if the pelvic girdle becomes affected, this will happen in
38% of the cases within five years and in 62% within 15 yea['S
after the onset of the disease .
Kazakov et al. ( 197 4) studied the way the disease could
spread to involve the lower part of the body (see 2.8.). "The
descending type with a jump" and "the g['adually descending type"
never occurred within one family and those two types were thought
to suggest genetic heterogeneity of FSHD.
Becker (1953) studied the severity of the disease and
suggested that the sex and physique had an influence on the
course and severity of the disease. He found that women were
significantly less severely affected than men, using pelvic
gi['dle weakness as the criterion for severe involvement (see
2.22) . When the disease was studied in relation to the physical
build, he found that in general the onset of the disease was
later and the disease ran a milder course in the pycnic type,
whi le the leptosome type was affected earlier and more severely.
The group of the athletic types and the group of the aspecific
types had an onset and a course of the disease somewhere in
between the t wo other groups. There were 76% leptosome types and
24% pycnic and pycno-a thletic types in the severely affected
 - 49 -

group with pelvic girdle weakness, while there were 71% pycnic
and pycno-athletic types and 29% leptosome types in the group of
mildly and moderately affected persons.
Other factors that might influence the course of the disease
are rarely mentioned. Infectious deseases and traumata are
believed to have no influence (Tyler and Stephens, 1950; Becker,
1953). Immobilisation for a long time may aggravate muscle
weakness. Boyes et al. (1950) suggested that physical strain
could aggravate the disease, but Becker (1953) rejected such
explanations.
The degree of disability in FSHD at a certain age is
dependent on the clinical course of the disease and is therefore
extremely variable. There is no current grading of the disability
in FSHD in use, nor is there a generally accepted agreement on
the grading of the severity of this disease. Pelvic girdle
involvement occurred in 56% of Seeker's cases (1953), in 45% of
Walton's cases (1955), in 59% of Chung and Morton's cases (1959)
and in 60% of the cases described by Ricker and Mertens (1968).
Their figures included all age groups. Sometimes inability to
walk is considered an indication of severe disability. This was
noted to occur in three out of 51 men (6%) and in six out of 72
(8%) women in Becker's material. Ricker and Mertens (1968)
observed this in two out of 30 patients ( 7%), and then only in
later life . It can be concluded from this limited information
that the frequency of serious disease and disability appears
higher at older age. Tyler and Stephens (1950) made similar
general statements, and most authors agree with their conclusion
that FSHD is a relatively benign disease, even if reports about
the infantile form of FSHD (Brooke, 1977) are taken into account.

2.28 Therapy

The best way to preserve muscle strength is through normal

daily physical activity . Vignos and Watkins (1966) suggested that
an active excercise program, particularly in the early stages of
FSHD, could increase muscle strength. The degree of improvement
 - 50 -

in strength was correlated with the initial strength of the

exercised muscles . Prevention of obesity is of great importance
since excessive weight gain has adverse effects on the ability to
maintain independent ambulation (Vignos, 1979). Contractures
should be treated with stretching. There is no information about
the results of Achilles' tendon elongation operation in FSHD,
probably because such contractures do not occur frequently in
this disease. Experiences with patients with Duchenne type of
muscular dystrophy suggest that such operations are contrain-
dicated in the ambulatory phase because the contractures recur
rapidly; the postoperative immobilisation might result in disuse
a trophy, and the mechanism to maintain ex tension of the knee
might become disturbed, resulting in loss of ambulation (Spencer ,
1967).
Operations to improve the function of the arm by stabili-
sation of the shoulder have been designed specifically for FSHD .
In many cases abduction and anteflexion of the arms are impaired
quite early in the course of the disease because of a severe
paresis of the scapular fixators . In patients with relatively
strong deltoid muscles, manual fixation of the scapula will show
a remarkable improvement of these functions. In these patients
surgical fixation of the scapula might be warranted . The optimal
position of fixation appears to be at 20 degrees e x ternal rota-
tion. Two techniques have been proposed recently: thoracoscapular
bony fusion (Bunch, 1973; Copeland and Howard, 1978) and thoraco-
scapular immobilisation by fastening the scapula to several
underlying ribs with fascia (Ketenjian, 1978) . With the former
technique the patient will be in a shoulder spica for several
weeks, while the la t tcr technique has the advantage that early
shoulder motion is allowed postoperatively with the arm supported
in a sling . All authors claimed excellent results with their
techniques.

2 . 29 Life expectancy and causes of dea t h

As cardiac and respiratory functions are usually spared , the

 - 51 -

life expectancy of patients with FSHD does not differ

significantly from the average in the general population. (Chung
and Morton, 1959; Prot, 1971). The cause of death does not appear
to be related to the myopathy (Seeker, 1953) but extensive and
systematical studies with regard to this problem are lacking.
Walton and Gardner-Medwin (1981) remarked that death through
respiratory failure may occur but happens rarely.

2 . 30 Biochemical studies

The number of biochemical studies specifically on FSHD is

rather small. A mild creatinuria is often present with FSHD :
being a rather non-specific finding in patients with neuro-
muscular disorders, it has little importance .
Hurwi tz et al. (1967) reported a family in which FSHD and
aminoaciduria inherited independently as autosomal dominant
disorders . There was an increased excretion of lysine, cystine,
ornithine and arginine as a result of a renal tubular defect . An
increase of urinary excretion of several aminoacids has been
reported in other myopathies but these findings were inconsistent
and appeared to be non-specific (Pennington, 1981). An increase
of creatine kinase (CK) activity in the serum was found to be the
most sensitive biochemical characteristic of neuromuscular dis-
order . The greatest increase of serum CK activity is found in the
rapidly evolving myopathies while smaller elevations or even nor-
mal values are found in slowly progressive myopathies like FSHD
and denervating disorders . Several other intramuscular enzymes
including aldolase, SGOT (serum glutamic oxaloacetic
transaminase), SGPT (serum glutamic pyruvic transaminase) and LD
(lactic dehydrogenase) are elevated in chronic muslce disease but
to a smaller extent than CK. Munsat et al. (1972) found an ele-
vation of the serum LD activity in 20% of his patients with FSHD.
The serum aldolase activity was elevated in 15% and the SGOT and
the SGPT activities were both elevated in 5% of his cases.
Fowler and Pearson (1964) found the serum CK activity only
occasionally raised . Munsat et al. (1972) reported an elevation
 - 52 -

in 50% of his cases with FSHD but these values were never higher
than four times the upper limit of normal. The same range of CK
activity was found by Hughes (1971) in 13 out of 19 cases (68%)
with FSHD. Bradley (1979) reported the serum CK levels to be
above normal in most cases, but his material included patients
with a mitochondrial myopathy resembling FSHD. Hughes (1971)
observed CK levels to have a tendency to be raised in subjects up
to the age of 45- 50 years and to have a gradual drop to normal in
older age. There was apparently no correlation between the level
of CK activity and the severity of the disease. Munsat et al.
(1972) found no correlation between the levels of CK activity and
the age of the patients or the duration of the disease. Bradley
(1979) was the only author who reported a relation between the
level of the CK activity and the rate of progression of the
disease. Hughes' (1971) hopes that the serum CK activity would
serve to distinguish FSHD and neurogenic atrophy came to nothing
since similar elevations of CK activity were observed in spinal
muscular atrophy, motor neuron disease and other denervating
disorders (Munsat et al., 1973), in the same percentage of cases
(Williams et al., 1970; Welch et al., 1972) as in FSHD. Therefore
the determination of the serum CK activity is of little help to
the differential diagnosis of FSHD (Munsat et al., 1973). Walton
and Gardner -Medwin (1981) stated the serum enzyme levels are not
raised in preclinical cases.
Many studies have been carried out on the serum CK
isoenzymes in muscle diseases, but few included FSHD patients.
Jockers-Wretou (1976) found the serum CK-MB fraction in one
patient to be 7% of the total serum CK activity which was 54 U/1
(normal values up to 50 U/1). Elevation of the CK-MB fraction,
which should not exceed 6% (Klapdor et al. , 1977), is frequently
observed in muscular dystrophies, and is felt to reflect skeletal
muscle disease rather than cardiac muscle disease ( Silverman et
al., 1976). Zweig et al. (1980) observed an increased serum CK-MM
and CK- BB fraction activity in one patient with FSHD, which they
attribu t ed to "leakage of degenerating and regenerating muscl e
fibres" .
Ibrahim et al. (1981) studied serum enzymes and the serum LD
 - 53 -

isoenzymes in seven male patients with FSHD. All patients had a

mild elevation of the serum CK, aldolase, SGOT and LD activities:
also the average serum activity of the fifth LD isoenzyme
fraction was significantly raised in these patients.
Elevated serum pyruvate kinase (PK) levels were found in
seven out of ten patients with FSHD, all of whom had normal serum
CK levels (Alberts and Samaha, 1974). These ten patients showed
an average 12-fold elevation of serum PK activity when compared
to their controls. Seay et al. (1978) could not confirm these
observations: three of their seven patients with FSHD had an
elevated serum CK activity and five of them had an elevated serum
PK activity. But Zats et al. (1978) found an increased serum PK
activity in 18 out of 20 patients with FSHD while only nine had
an elevated serum CK activity. Only one patient had normal
activities of both enzymes. These authors suggested that the
determination of the serum PK activity might be a more sensitive
test than the determination of the serum CK activity in some
neuromuscular disorders and particularly in FSHD.
Hische and Van Der Helm (1979) studied the serum myoglobin
concentrations in 230 patients with neuromuscular diseases of
which eight patients had FSHD. In six of these eight patients
both CK and myoglobin levels were raised, in one patient both
were normal, and in one patient the serum CK activity only was
raised. I t appeared that the estimation of the serum myoglobin
concentration was not a more sensitive test than the deter-
mination of the serum CK activity for the detection of patients
with FSHD .
Ionasescu et al. (1972) reported on ribosomal protein
synthesis in muscle extracts of patients with FSHD. In a previous
in vitro study they had found an abnormally large synthesis of
collagen by muscle polyribosomes in contact with soluble enzymes
derived from the same muscles of patients with Duchenne type of
muscular dystrophy. This could not be demonstrated in FSHD but
they did find an increased incorporation of labelled aminoacids
in the muscle polyribosomes in four patients who were in an early
stage of the disease, whereas three patients in advanced stages
of the disease showed a lowered, and in one case a normal, incor-
 - 54 -

poration of these aminoacids. These findings suggested an

increased protein synthesis in muscles in the early stages of
FSHD and the authors speculated that this could be the synthesis
of a contractile (but possibly inactive) protein, and that the
increased protein synthesis thus reflected a failing attempt at
regeneration (Ionasescu et al., 1975). This abnormality appeared
controlled by an undetermined factor belonging to the so l uble
(non-ribosomal) fraction of muscle homogenates . (Ionasescu and
Zellweger, 1979).

2 .31. Electromyography

At present i t is impossible to differentiate the clinical

varieties of muscular dystrophy from each other by electrodiag-
nostic methods. The principal value of electromyography (EMG) is
to differentiate the myopathies from the neurogenic a trophies
with which they may be confused. The EMG abnormalities in the
myopathies are explained in general by the loss of individual
muscle fibres within a motor unit while the total number of motor
units that can be activated remain unchanged. In needle EMG a
polyphasic motor unit action potential is observed as a result of
non-synchronous firing of remaining muscle fibres. On an average
the action potentials of myopathic muscles are of shorter dura-
tion than those of healthy muscles. This is explained by the
lowered muscle fibre density in the motor units reducing the
early and late components of the action potential at first
(Buchthal et al., 1960). The voltage of the motor unit action
potentials is usually normal or slightly diminished. On maximal
effort, a full interference pattern of normal or slightly reduced
amplitude is obtained in most instances. In severely affected
muscles the disproportion between the degree of weakness and the
reduction in the interference pattern provides an argument for a
myopathic disorder. Automatic frequency analysis of the inter-
ference pattern may reveal a shift to the higher frequencies in
the myopathies, but this is of limited diagnostic value as a
substantial shift of frequencies is usually accompanied by a
 - 55 -

recognisable excess of polyphasic motor unit action potentials.

Most authors use the term "myopathic EMG" when an
interference pattern of motor unit potentials of brief duration
and small amplitude with an excess (> 12%) of polyphasic poten-
tials is found (Buchthal and Kamieniecka, 1982). Engel (1975)
criticized this term since, theoretically, brief small abundant
polyphasic potentials (BSAPP) can be present as well in neuro-
genic disorders. Introduction of new terms like BSAPP- pattern are
equally unsatisfactory (Daube, 1978) because the value of the
term lies solely in the meaning it carries to the reader, and it
does not absolve the electromyographist to describe in detail all
the findings of his examination.
Spontaneous activity has been described in cases of muscular
dystrophy (Buchthal and Rosenfalck, 1963) and consists of brief
discharges of repetitive activity following insertion or movement
of the needle electrode and of fibrillation potentials. 'lhis
spontaneous activity is rather uncommon in muscular dystrophy but
it is frequently found in polymyositis. In polymyositis positive
sharp waves may be present as well. Munsat et al. (1972) found
them in patients with FSHD who had rather extensive cellular
infiltrations, histologically resembling polymyositis.
Fasciculations have never been found in FSHD. Motor nerve
conduction is said to be normal in FSHD when measured by conven-
tional methods, but Bethlem et al . (1973) reported slowing of the
peroneal nerve conduction velocity in two of their seven cases.
Hausmanova-Petrusewicz and Jedrzedowska (1972) demonstrated
enlargement of the motor unit territories , large po tentials and
pseudomyotonic discharges in some of their patients with muscular
dystrophy, features normally indicative of neurogenic disorders.
In many instances of FSHD, on routine EMG examination McComas
(1977) found in some muscles "myopathic " a,nd in other muscles
"neuropathic" features in the same patient: or in some members of
a family "myopathic " and in other members of the same family
"neuropathic" characteristics : but, unfortunately , these findings
are not specified.
Sica and McComas (1971) advanced arguments for a neurogenic
factor in FSHD. Using a method described earlier, (McComas et al .
 - 56 -

1971) they found a reduced number of functioning motor units in

the extensor d1g1torum brevis muscle in three out of four
patients with FSHD. The size of the motor unit was normal in all
four cases. Isometric twitch studies showed decreased twitch ten-
sion in two cases, a prolonged contraction time in four cases and
a prolonged relaxation time in three cases. These findings were
thought to be compatible with chronic partially denervated musc-
les. Maximal impulse conduction velocities and terminal 1atenc1es
in the peroneal nerves were normal. In the discussion of their
results, Sica and McComas (1971) treated patients with FSHD and
patients with a 11mb-girdle myopathy as one group, which led them
to premature conclusions about FSHD, since their actual studies
on those four patients showed only minor abnormalities, often
only in a couple of patients. The technique, methods and inter-
pretations have been severely cri t1cized by Panayiotopoulos et
al. (1974; 1976) who were unable to reproduce the findings in 50
patients including three patients with FSHD after appropriate
modification of the technique (Panayiotopoulos and Scarpalezos,
1977).
Ballantyne and Hansen (1974) used a computerized method to
estimate the quantity of motor units and found this within normal
range in the extensor d1gitorum brevis muscles in three cases of
FSHD. The number of motor units was reduced only in cases of
myotonic dystrophy. The authors thought that S1ca and McComas
(1971) had arrived at low numbers of motor units because their
method failed in diseases where quantitative alteration in the
configuration of the motor unit potentials occurred. A computer
method was also used for analysis of evoked motor unit potentials
(Ballantyne and Hansen, 1975). These potentials were recorded
from surface electrodes over the extensor d1g1torum brevis
muscles and evoked by stimulation of the deep peroneal nerve at
the ankle. The latencies and duration of the motor unit
potentials were significantly increased in cases with FSHD as
compared to controls, which is in contrast to the findings of
conventional needle electromyography. The fastest motor
conduction velocities were significantly reduced and the shortest
distal motor latencies were significantly prolonged in patients
 - 57 -

with FSHD. These findings seemed to support the hypothesis of a

neurogenic factor in FSHD , but Jennekens et al. (1972)
demonstrated with muscle biopsies that, from the second decade
onwards and increasing with age, neurogenic features such as type
grouping and group atrophy were observed in the extensor
digitorum brevis muscles of individuals who had not suffered from
neuromuscular disorders. These findings were explained as the
result of a slow proces of denervation and reinnervation,
occurring as part of the normal ageing processes . This study
suggested that the extensor digitorum brevis muscle is not quite
suitable for EMG studies such as the ones mentioned above .

2 . 32. Muscle biopsy studies

Muscle biopsy in FSHD occasionally shows no abnormalities ;

in classical, slowly progressive cases the changes can be mini-
mal. All histological findings traditionally attributed to
myopathies can be found in FSHD. Histochemical studies of the
muscle biopsies have contributed a great deal to our knowledge of
muscle diseases but these studies included only fe w cases of FSHD
(Brooke and Engel, 1966: five patients; Dubowitz and Brook e,
1973: 11 patients; Bethlem et al., 1973: seven patients; Buchthal
and Kamieniecka, 1982 : 21 patients) . Therefore the histopathology
in FSHD is not as clearly established as in the Duchenne type of
muscular dystrophy (Munsat , 1972) . The reason could be that FSHD
is a rare disease and that many patients are not interested in
extensive studies once the diagnosis is made in a family member
and once they kno w the relatively good prognosis.
First , the organisation of the muscle fibres (i.e . changes
in size and distribution) and secondly , the structural changes
will be discussed.

2!:~~!:!!~~~!~!:!
A very constant finding on histological examination is an
increased variation in fibre size with rounding of the fibres.
Dubowitz and Brooke (1973) frequently observed an increase of the
 - 58 -

mean fibre diameter of all fibre types. Abnormal hypertrophy

factors were more often found than abnormal atrophy factors. The
same authors noted small angulated fibres scattered between large
fibres in 70% of their biopsies. "They were frequently not the
heavily stained angulated fibres seen in denervation, but merely
normally staining very minute fibres". Buchthal and Kamieniecka
(1982) did not observe small angulated fibres in 21 biopsies of
patients with FSHD. The significance of small angulated fibres in
FSHD is uncertain. A neurogenic lesion cannot be ruled out
although most authors (Buchthal and Kamieniecka, 1982) appear to
accept only dark angular fibres that stain intensely with the
NADH- tetrazo lium reductase stain, as a definite proof of dener-
vation in FSHD. Groups of atrophic fibres were not observed by
Brooke and Engel (1966) nor by Dubowitz and Brooke (1973) who
specifically stated that "this would serve to differentiate from
classical denervation" . Bethlem (1970) did not mention angulated
fibres in relation with FSHD, but later (1977) he stated that
small groups of small angular fibres are sometimes present.
Hausmanowa-Petrusewicz and J edrzedowska (1971), and Das tur and
Razzak (1973) also reported small groups of atrophic fibres in
cases of muscular dystrophy but it was not clear if cases of FSHD
were included. If fibre type predominance is present, type 2
predominance is more frequently observed than type 1 predomi-
nance . This helps to differentiate FSHD from other myopathies
which have a tendency to type 1 predominance (Dubowitz and
Brooke, 1973). Engel and Kossman (1963) reported a case of FSHD
with selective involvement of type 1fibres .

~~£~£~~£~~- ~~~~~~~
Hyaline fibres and necrotic fibres with phagocytosis are fre-
quently, but not abundantly, present. They are apparently more
prominent in the rapidly progressive cases. Basophilic fibres
with vesicular nuclei and prominent nucleoli can be found which
are regarded to represent regeneration. Internally located nuclei
are present in some biopsies but this is never a prominent fea-
ture. Increase of fat and endomysical fibrosis, which can be
found in an early phase of the Duchenne type of muscular
 - 59 -

dystrophy, is only rarely present in FSHD and never to a great

extent (Ionasescu et al ., 1972; Dubowitz and Brooke, 1973).
A rather distinct inflammatory reaction is a remarkable and
not unusual finding in FSHD (Brooke and Engel, 1966; Munsat et
al ., 1972; Dubowitz and Brooke, 1973; Bethlem, 1977) . This reac-
tion may be so prominent that it resembles polymyositis. Munsat
et al. (1972) reported four rather severe cases of FSHD: two
showed a clearly autosomal dominant pattern of inheritance in
their families, and in the two other cases the family data were
inadequate. The perivascular and interstitial inflammatory
responses found on histopathological examination wer e so exten-
sive that they were treated with corticosteroids. Three patients
showed a clinical improvement but later reports (Munsat and
Bradley, 1977) attest that this improvement was transient and
deterioration ensued as in other cases with FSHD. Lowering of
serum CK activity was observed during corticosteroid treatment
but the authors stressed that this did not imply therapeutic
benefit. Munsat et al. (1972) suggested that the imflammatory
reactions they observed were only a stage in the development of
FSHD.
Papapetropoulos and Bradley (1974) observed inflammatory
infiltrations in six patients with different types of muscular
dystrophy (three cases of FSHD, three sporadic cases of other
types). They suggested that this was an immunological reaction
secondary to the underlying muscle degeneration, leading to
muscle damage in its own right. A similar explanation was given
by Jennekens et al. (1975) for the inflammatory responses they
found in the muscle biops ies of five members of their two
families with autosomal dominant neurogenic atrophy in a scapulo-
personeal distribution, accompanied by a cardiomyopathy at a more
advanced age. These two families are rather exceptional indeed as
they do not fit properly in any known category . They will be dis-
cussed later.
Target fibres and targetoid fibres have never been described
in FSHD. Moth-eaten fibres seem to be present in more than half
of the cases (Dubowitz and Brooke , 1973). These small fibres are
predominantly type 1 fibres, in which the intermyofibrillar net-
 - 60 -

work that normally has a very regular pattern, assumes a whorling

appearance with areas that do not stain with oxidative enzyme
reactions. These fibres appear to be identical to the lobulated
fibres described by Bethlem et al. (1973). The authors found that
bundles of myofi brils ran an aberrant course in these fibres and
that accumulations of normal mitochondria and glycogen were found
in between these bundles. The significance of these moth-eaten
fibres is unclear as they were observed in other myopathies, in
spi nal muscular atrophies (Bethlem et al . , 1973) and in diseases
like Parkinson ' s disease and polymyalgia rheumatica (Dubowitz and
Brooke , 1973). Yet their frequency in FSHD is remarkable: Bethlem
et al. (1973) observed moth-eaten fibres in 13 out of 300 biop-
sies . Seven out of 11 patients with FSHD showed moth- eaten
fibres.
Ringed fibres are occasionally discovered in FSHD: their
presence suggest a myopathy although they are observed in
diseases such as spinal muscular atrophy and rheumatoid arthritis
(Dubowitz and Brooke , 1973) and also in normal muscles (Behtlem
and Van Wijngaarden, 1963) .
Ultrastructural abnormalities characteristic of FHSD have
not been reported (Ma i r and Tome, 1972; Price and Van De Velde,
1981) .

2.33 . Summary

FSHD shares with other autosomal dominant disorders such as,

for example, Huntington's chorea or myotopnic dystrophy, a con-
fusing history of descriptions of the diseases. After the first
report many observations were made, each emphasizing a peculair
aspect of the variable clinical picture. This often led to sug-
gestions that different diseases were hidden under one clinical
presentation. But autosomal dominant disorders tend to favour the
"lumpers" above the "splitters" and , at present , a variable
clinical picture appears to be a feature of autosomal dominant
disorders . The same applies to FSHD. Still there are some charac-
teristic findings in FSHD:
 - 61 -

- The main features of the disease are early weakness and atrophy
of the shoulder girdle muscles, in many instances preceded by
facial weakness, although, apparently, facial weakness is ab-
sent in approximately 20% of the cases.
- There is an early 'spread of the disease to the muscles of the
upper arms and to the foot elevators . The further extension to
other muscles is variable.
- Pelvic girdle involvement is usually a late stage in the course
of the disease .
- Asymmetry of muscle involvement is very common.
- Pseudohypertrophy of muscles is extremely rare.
- Contractures and skeletal deformities are not common, but exact
figures are lacking.
- Cardiac involvement has never been properly described.
- Abortive cases with minimal or mild muscle involvement and
without complaints related to muscle weakness are quite common.
- The mode of inheritance is autosomal dominant . Autosomal
recessive myopathies , clinically identical to FSHD, have never
been sufficiently documented. Sporadic cases with a myopathy
identical to FSHD have been described. As long as it cannot be
proven or disproven that they are mutants of FSHD , their
classification remains an open question.
- The penetrance of the abnormal gene appears to be complete .
- Men and women appear equally frequently affected . There are no
solid grounds to assume that either sex is more severel y
affected than the other.
- Serum CK activitity is mildly elevated in approximately 50% of
all cases but is rarely more than four times the upper limit of
normal.
- FSHD runs a benign course, leading to a severe disability in
only a small percentage of cases . Only a few persons become
wheelchair- bound, and if so, mostly at an older age .
- The patients' ages at death do not differ significantly from
the average.
 - 62 -

Apart from these characteristic findings, there are several as-

pects of FSHD that lack the quality of constancy.

- The sequence in which individual muscles become affected is

quite variable.
- The rate of progression of the disease differs from case to
case: in some instances the disease is steadily progressive, in
others l ong periods of arrest are noted . Occasionally a rapid
progression within years is observed .
- The age of onset may vary from the first year of life till late
in middl e life . There are no good grounds to assume that the
infantile form of FSHD constitutes a separate entity.
- The prevalence of FSHD in different parts of the world is quite
variable, ranging from 1 in 20 . 000 to 1 in 455.000 individuals
in a population.
- EMG mostly shows abnormalities thought to be compatible with
myopathic disorders i.e. an interference pattern with brief,
small and polyphasic action potentials . Occasionally recordings
suggesting a neurogenic lesion have been reported .
- Muscle biopsies often demonstra t e mild changes, that are
compatible with primary muscle disease . Sometimes inflammatory
reactions of an impressive degree are found . In a number of
cases small angulated f i bres are seen, suggesting a neurogenic
factor in FSHD.

Finally three negative remarks are pertinent to the definition of

the present state of kno wledge of FSHD .

- Factors precipitating the onset of the disease are not known ,

although physi cal exertion has been implied to play a role in
the development of asymmetric muscle involvement.
- Association or linkage with a specific disease or genetic
marker has never been reported.
- The pathogenesis and the cause of this disease are not known .