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Ocular findings in muscular dystrophies

  • Nemours Children’s Health System Orlando FL
Journal of Medicine and Medical Sciences Vol. 6(9) pp. 234-242, December 2015
Available online
DOI: http:/
Copyright © 2015 International Research Journals
Ocular findings in muscular dystrophies
Ferhat Evliyaoglu1, Ahmet Z. Burakgazi2*
1Mus State Hospital, Mus, Turkey
2Section of Neuroscience, Department of Medicine, Virginia Tech Carilion School of Medicine, Roanoke, VA, USA
*Correspondence Author’s Email:
Muscular dystrophies are a heterogeneous class of inherited disorders presenting with different
clinical, genetic, and biochemical features. Muscular dystrophies include Duchennemuscular dystrophy
(DMD) and Becker muscular dystrophy (BMD) myotonic dystrophy (DM), oculopharyngeal muscular
dystrophy (OPMD), facioscapulohumeral muscular dystrophy (FSHD), limb-girdle muscular dystrophy
(LGMD), distal muscular dystrophy, and congenital muscular dystrophy (CMD)types, each with a wide
spectrum of clinical manifestations. Those muscular dystrophies can have similar symptoms or unique
and specific presentations. This abstract will review the prevalence, clinical presentation, and
management of ocular findings in certain muscular dystrophies.
Keywords: Muscular dystrophies, Ocular findings, Duchenne and Becker muscular dystrophies, myotonic
dystrophies, oculopharyngeal muscular dystrophy, facioscapulohumeral muscular dystrophy, limb-girdle
muscular dystrophy, distal muscular dystrophy, and congenital muscular dystrophy
AD: Autosomal dominant
ANO5: Anoctamins 5
AR: Autosomal recessive
DMD: Duchennemuscular dystrophy
BMD: Becker muscular dystrophy
CMD: Congenital muscular dystrophy
MDC1C: Congenital muscular dystrophy 1C
MDC1D: Congenital muscular dystrophy 1D
CPEO: Chronic progressive external ophthalmoplegia
DM: Myotonic dystrophy
EOM: Extraocular muscles
FSHD: Facioscapulohumeral muscular dystrophy
FCMD: Fukuyama congenital muscular dystrophy
GDP: Guanosinediphosphate
GMPPB: Guanosinediphosphate mannose pyrophosphorylase B
LGMD: Limb-girdle muscular dystrophy; MEB: Muscle eye brain disease
OPMD: Oculopharyngeal muscular dystrophy
POMGNT1: ProteinO-linked-mannosebeta-1,2-N-acetylglucosaminyl transferase 1
SP: Smooth pursuit
VOR-S: Vestibulo-ocular reflex suppression
WWS: Walker-Warburg syndrome
Muscular dystrophies are a heterogeneous class of
inherited disorders presenting with different clinical,
genetic, and biochemical features (Mercuri and Muntoni,
2013,Miller 1985). They are characterized by progressive
weakness in facial, limb, and axial muscle groups to a
variable degree. Involvement of other organ systems
such as the brain, inner ear, eyes, or skin can be rarely
seen in muscular dystrophies. (Mercuri and Muntoni,
2013), (Anastasopoulos et al.1996). In this article, we
focus on the prevalence, clinical presentation, and
management of ocular findings in certain muscular
dystrophies including DMD and BMD, DM, OPMD,
FSHD, LGMD, distal muscular dystrophy, and CMD.
Duchenne and Becker Muscular Dystrophies
DMD is the most frequently seen, most severe form of
muscular dystrophy. (Mercuri and Muntoni, 2013) DMD
has an unremitting and progressive course, and mainly
affects males. (Bellayou et al. 2009) Bellayou et al. 2009)
BMD is a less severe formof the disease and has a
slower progression. Bellayou et al. 2009, Aartsma-Rus et
al.2006, Chakkalakal et al. 2005).DMD and BMD are X-
linked muscular dystrophies. The incidence of DMD is
around1 in 3,500 male births (2.9 per 10,000 males),
whereas the incidence of BMDisaround1 in 18,518 male
births (0.5 per 10,000 males). (Emery 1991) The
prevalence of DMD is approximately 1.3 to1.8 per 10,000
males aged 5 through 24 years (Miller et al. 2006).
Dystrophin is an essential protein for the frame of
skeletal muscles and a part of dystrophin-associated
glycoprotein complex (Ervasti and Campbell, 1991),
which is responsible fora critical connection between the
cytoskeleton and extra-cellular matrix. Its absence or
abnormality can cause myofiber necrosis, progressive
muscle weakness, and fatigability. D (Porter and Baker,
1996) MD is caused by a defect in the dystrophin gene,
leading to a lack of dystrophin protein in the affected
individuals. In BMD, an abnormal version of dystrophin
retains some function of the muscle tissues.( Blake et al.
2002) Patients with DMD typically become wheelchair
dependent before the age of twenty. Death usually
occurs by age thirty due to cardio respiratory
complications. (Kaminski et al.1992).
Interestingly, extraocular muscles (EOM) are a few
skeletal muscle groups that retaina normal structure and
function in both DMD and BMD. (Ervasti and Campbell,
1991) EOM’s ability to retain a normal structure and
function in patients diagnosed with DMD and BMDmay
depend on EOM’sindistinct features whichprotect it
fromthe toxic effects of intracellular calcium, which is
related to myofibril necrosis in absence of dystrophin
(Khurana et al. 1995). In addition, saccadic eye
movements in DMD patients are similar when
comparedto individuals who have not been diagnosed
with DMD (Khurana et al. 1995).
The histopathologic analysis of EOM in patients with
DMD revealsEOMshave high mitochondrial contents and
their configurations are different from other skeletal
muscles that provide unique contraction speed and
Evliyaoglu and Burakgazi 235
fatigue resistance in EOMs (Porter and Baker, 1996).
Myosin heavy chain composition and distribution is
different in EOMs thanin limb muscles. Furthermore,
EOM has a slower course of development in the
embyrogenic stage than limb muscles (Pedrosa-Domellof
et al. 2000).
In Porter et al.’s study investigating EOM function of
mdx mice (commercially available dystrophin-deficient
mice), it was demonstrated that the level of utrophin
protein was higher in the EOMs of mdx mice and there
was no specific muscle fiber alteration in EOMs when
compared to limb muscles in mdx mice. It was postulated
that elevated utrophin levels might mediate the rescue of
eye muscle in DMD/BMD (Porter et al. 1998). Although
impairment of EOM in DMD/BMD was shown by
oculography in some studies, it is not supported by
randomized double blind clinical trials (Scelsa et al. 1996,
Lui et al. 2001).
Myotonic Dystrophy
DM is an autosomal dominant, multisystem disorder and
occurs as a result of an unstable triplet expansion of
nucleotides on certain areas of DNA (Brook et al. 1992).
Progressive expansion of the triple insertion with
succeeding generations can cause generic anticipation.
The clinical manifestations of the MD include muscle
wasting, weakness, myotonia (delayed muscle relaxation
following contraction), abnormal cardiac conduction,
mental retardation, testicular atrophy, hyperinsulinemia,
and frontal baldness. The ocular manifestations mainly
include ptosis and cataract, blepharitis and in rare cases,
diplopia or restriction of the range of eye movements
(Miller et al. 2006). Almost one-third ofpatients have
lower than normal intraocular pressure, presumably
resulting from decreased aqueous production. (Walker et
al. 1982) The cataract in MD often contains iridescent
deposits within a thin band of the anterior and posterior
cortex. The red, blue, green, and white flecks are visible
on slit lamp examination and their distribution in the lens
cortex is thought to be highly specific toMD. Those flecks
can distinguish from the more common iridescent
refractile flecks in age-related cataracts. (Miller et al.
2006) Varieties of pupillary abnormalities have been
described in MD, but most patients have normal pupillary
response to light. Pigmentary changes in the macula
resemble those of pattern dystrophy, but are not a
common cause of vision reduction.20 Peripheral retinal
pigment epithelial atrophy and clumping has been
described and probably causes few, if any, clinical
symptoms (Raitta and Karli, 1982, Betten et al. 1971).
Besides these ocular findings, the slowing of saccades
and attenuation of smooth pursuit gain have been
demonstrated in MD patients by means of oculographic
recordings. (Baloh et al. 1975) The decrease in saccadic
eye movements is a subclinical feature of the disease
236 J. Med. Med. Sci.
noted in the literature, but its pathophysiologicmechanism
has remained controversial. It has been postulated that
the decrease in saccadic eye movementsstems from
dystrophic changes in the extraocular muscles. (Oohira rt
al. 1983, Burian and Burns, 1966). The histopathologic
assessment of extraocular muscles reveals dystrophic
changes as well. (Davidson 1961, Kuwabara and Lessell,
1976). The finding of a 'warming-up' phenomenon for
repetitive saccades is explained in terms of myotonia,
(Hansen et al. 1993) which is known to involve the
extraocular eye muscles (Oohira rt al. 1983, Burian and
Burns, 1966). In other traditions, it is hypothesized that
the phenomena may be sourced from a central origin.
(Emre 1985) Anastasopoulos et al. postulatedthat a
central or peripheral origin causes oculomotor
abnormalities in patients with MD.They studied both slow
and fast eye movements and compared smooth pursuit
(SP) performance with theability to suppress the
vestibule-ocular reflex by visual fixation (vestibulo-ocular
reflex suppression (VOR-S). It was concluded that the
parallel degradation of SP and VOR-S in MD patients
might reflect a central deficit (Anastasopoulos et al.
Oculopharyngeal muscular dystrophy
In 1962, Victor and colleagues described a
neuromuscular disease manifesting with unique relation
of progressive externalophthalmoplegia and pharyngeal
weakness that was subsequently namedOPMD. (Victor et
al. 1962) OPMD was first described by Taylor (Taylor
1915) as a progressive cranial neuropathy. OPMD is
caused by a mutation in the PABN1 gene, which is
encoded by the long arm of chromosome 14. (Brais
2003) Selective involvement of ocular and pharyngeal
muscle may depend on a continued remodeling process
in these muscle groups, which make them vulnerable to
the effects of the disease. (Wirtschafter et al. 2004)
Although it is clear that the disease is inherited in an
autosomal dominant (AD) fashion, a few cases of
autosomal recessive (AR) type OPMD have been
reported. (Brais et al.1998) The disease has a regional
disturbance and runsamong families. In the late 1960sin
Quebec, Canada, the estimated prevalence of OPMD
was 1:1000. (Francois 1969) Its prevalence is
around1:600 among the Bukhara Jewish population.
(Blumen et al. 1997) A study analyzing 216 cases of
OPMD in Hispanic populations in New Mexico,
USAdemonstrates that OPMD is not limited to the
French-Canadian population in Quebec and is seen in
Hispanic populations as well (Becher et al. 2001).
OPMDrelated symptomsusually become prominent
around age forty and all patients become symptomatic
before the age of 70. In addition to ptosis and dysphagia,
the affected individuals may suffer from tongue atrophy
and weakness, proximal lower extremity weakness,
dysphonia, limitation of upward gaze, facial muscle
weakness, and proximal upper extremity weakness.
(Bouchard et al. 1997) Levator palpebral muscle
weakness can cause ptosis in OPMD. The first symptom
is usually ptosis in OPMD, followed by dysphagia. Ptosis
is always bilateral in OOPMD.Affected individuals
contract frontal muscles and recline their head to
compensate for disrupted visual fields, so a typical
posture occurs, which is called “asstrologist” posture.
(Ruegg et al. 2005) Although the astrologist posture is
notcommonly used in clinical practice, it may be an
important feature of the disease and may differentiate it
from chronic progressive external ophthalmoplegia
(CPEO), which is also characterized by bilateral ptosis
besides ophthalmoplegia. (Smits et al. 2011) Eyelid
drooling is the most bothering finding in CPEO patients;
fortunately reconstructive surgery usually provides
satisfactory results (Rodrigue and Molgat, 1997).
EOM can be involved in OPMD and may result in
ophthalmoplegia and strabismus. Hill and colleagues
analyzed 31 OPMD patients in the United Kingdom and
reported that half of the patientsthere had some limitation
of EOM, which were graded moderate or severe and
described as ophthalmoplegia. (Hill et al. 2001) Although
ophthalmoplegia is a common sign of the disease, the
(Salvesen and Brautaset, 1996) affected individuals
usually have a slight degree of ophthalmoplegia
(Salvesen and Brautaset, 1996), which becomes
prominent during examination. Full range of external
ophthalmoplegia is rare and intrinsic eye muscles (cilliary
and sphincter muscles of the iris) are not involved in
OPMD. (Tomé 1994) Since the degree of
ophthalmoplegia is slight, diplopia is not a common sign
and may become more prominent in forced movements
of the eye.
Facioscapulohumeral muscular dystrophy
FSHD is one of the most common types of muscular
dystrophy, first described in 1884 by Landouzy and
Dejerine. It is characterized bymuscle weakness and
atrophy, especially in the upper part of the body.
Estimated incidence of the disease is 1 in 15,000 to
20,000 dependingon the population sampled. (44) FSHD
can be classified into two different types based on
genetic defects. In FSHD type 1 (95%)there is a deletion
in the units of D4Z4 DNA repeat sequence, which is
located on the subtelomeric region of the long arm of
chromosome 4 (4q35). (Lee et al. 1995) A small amount
of FSHD cases (less than 5%) are called FSHD type 2,
resulting from a methylation defect in D4Z4 when
compared to the deletion in type 1 (de Greef et al. 2009).
FSHD is a genetic disorder and inherited with AD
fashion. Although it can occasionally be seen in sporadic
form, 90% of affected individuals carry the AD gene.
General signs and symptoms of the disease become
apparent during early adolescence, but onset and
severity of the disease can show extreme variability even
in the same family. Although a vast majority of
casespresent during adolescence, rare forms of severe
FSHD can present during early childhood, with some mild
forms of FSHD becomingapparent by or around age forty.
Muscle weakness and atrophy are first seen in facial
muscles and one side of the face is usually affectedmore
severelythan the other side. Affected individuals have
difficulty closing their eyes and smiling, which results in a
transverse smile. Whistling and drinking is difficult due to
weakness of muscles around the mouth as well. Shoulder
weakness is another common symptom of the disease,
presenting with winging scapuladue to weakness ofthe
surrounding muscles. Bilateral tibialis anterior
involvement is highly characteristic of the disease,
resulting in gait disturbance. Muscle pain is also reported
in FSHD and can be seen as a prominent symptom of the
disease. (Bushby et al. 1998) Pain is usually located
around the joints where affected muscles are located.
(Bushby et al. 1998).
Although extra-ocular muscle involvement is extremely
rare in FSHD and sparing of extra-ocular muscle
involvement is accepted as one of the diagnostic criteria
of FSHD (Padberg et al. 1991), three FSHD patients with
progressive external ophthalmoplegia have been
reported in literature. (Krasnianski et al. 2003).
Eyelid weakness is seen in FSHD and FSHD patients
may not be able to close their eyelids tightly, leading to
lagophthalmos. Exposure keratopathy is a potential
complication of this situation if appropriate treatment is
not given. Besides medical treatment, surgical
intervention may be considered in severe situation with
gold implants in the eyelid (Sansone et al. 1997).
FSHD patients frequently suffer from Coats’ disease of
the eye, which is characterized by telengectasic vessels
in the peripheral retina (Small 1968, Statland et al. 2013).
It was first described by Small (Small 1968) in four
siblings with exudative telangiectasia of the retina and
FSHD in 1968. Fitzsimons et al. performed detailed
examinations including fundus angiography inthe eyes of
75 FSHD patients and demonstrated peripheral retinal
capillary abnormalities including telangiectasia, leakage
and micro aneurysm formation (Fitzsimons et al. 1987).
(Padberg et al. 1995) also demonstrated retinal
vasculopathy in 49% of patients with FSHD by using
retinal angiography. (Padberg et al. 1995)Two exudative
retinal detachments due to retinal telangiectasia in FSHD
were reported in the literature. (Pauleikhoff et al. 1992)
Since retinal detachment is a severe complication of
Coats’ disease, clinicians should carefully perform eye
examination in patients with FSHD to prevent a potential
visual loss with laser treatment applied to theinvolved
areas of the retina. Previous studies demonstrated a
clear relationship between Coats ‘disease and FSHD.
However, a recent survey study reported that Coats’
disease was a rare complication of FSHD-1 in patients
Evliyaoglu and Burakgazi 237
with a large deletion of D4Z4. A survey of 357 patients
with FSHD-1 conducted a found that only 14 had Coats
disease. This study suggests a need for closer
surveillance for retinal complications in patients with
small amounts of D4Z4 fragments (15 kb) (Statland et
al. 2013).
Limb-girdle muscular dystrophy
LGMD is a heterogenic group of diseases that usually
involvethe shoulder and the hip girdle muscles,sparing
the facial muscles. (van der Kooi et al. 1996) LGMD is
sub-classified into two main categories according to their
inheritance. LGMD type 1 is inherited as AD fashion while
LGMD type 2 is inherited in ARform. (Van der Kooi et al.
1996, Urtasun et al. 1998). The AR form is more common
and accounts for almost 90% of the presented type of the
disease. Although it is difficult to estimate prevalence of
LGMD due to its many subtypes; it is estimated at
1:14,500 to 1:123,000for all subtypes. (van der Kooi et al.
1996,Urtasun et al. 1998).
Facial muscles are almost exclusively spared in
LGMD. LGMD1C is a subtype of LGMD that is caused by
a mutation in the caveolin 3 gene, which is responsible
for producing a protein called caveolin 3 that has an
important role in the formation of muscle fibers (Minetti et
al. 1998). although it presents with proximal muscle
weakness like other types of LGMD, ophthalmoplegia,
exophthalmos and blepharoptosis have been reported in
LGMD1C (Filosto et al. 2009). Guanosinediphosphate
mannose (GDP-mannose) pyrophosphorylase B.
(GMPPB ) is an enzyme that catalyzes the formation
of GDP-mannose from guanosine triphosphate and
mannose-1-phosphate that is required in glycosylation
pathways (Carss et al. 2013). A defect in the GMPPB
gene specifically may cause brain and eye problems
(Carss et al. 2013). In a study investigating eight cases
with a GMPPB gene defect, LGMD and congenital
muscular dystrophy were diagnosed in some of the
cases.LGMD with GMPPB gene defect manifests with
mental retardation, microcephaly, epilepsy, and ocular
findings including childhood cataract formation, ptosis,
strabismus, nystagmus and retinal diseases (Carss et al.
Anoctamins are related to calcium activated chloride
channels and consist of 10 members (Hartzell et al.
2009). A recessive mutation in anoctamins 5 (ANO5)
results in a subtype of LGMD,which is coded as LGMD2L
(6). A case study with macular dystrophy was reported in
one of two siblings with LGMD2L with ANO5 mutation
(Vaz-Pereira et al. 2014). Although the association is not
clearly demonstrated, it may be due to a dysfunction in
calcium activated chloride channel in retinal pigment
epithelium (Vaz-Pereira et al. 2014).
POMGNT1 (Protein O - linked – mannosebeta -1,2-N-
acetyl glucosaminyltransferase 1) is an enzyme encoded
238 J. Med. Med. Sci.
by the POMGNT1 gene. The product of the POMGNT1
gene participates in synthesis of O-mannosylglycan
(Akasaka-Manya et al. 2011). A mutation in the
POMGNT1 can cause Muscle eye brain disease (MEB)
and LGMD2O, which is a rare subtype of LGMD.
Although POMGNT1 mutation may be associated with
congenital glaucoma, retinal dysplasia, and high rates of
myopia in literature, reported cases of LGMD2O did not
have eye problems except one case, where the patient
presented with severe myopia (Clement et al. 2008,
Raducu et al. 2012).
LGMD is a progressive disease and no specific
treatment is available for any subtypes of LGMD. The
primary aim in LGMDis to prevent complications of the
disease and improve the patient’s quality of life. Physical
therapy and occupational therapy have a major role in
treatment of LGMD. In a novel study, it is reported that
chronic oral administrationof angiotensin 1-7 (Ag1-7) may
improve skeletal muscle function in patients with
LGMD2F (Sabharwal et al. 2014). Gene therapy also has
promising results in patients with LGMD2D, which is used
adenovirus associated vector and showed six months of
sustained α-sarcoglycan gene expression in 2 of 3
patients’ that were defected in LGMD2D subtype
(Mendell et al. 2010).
Distal muscular dystrophy
Distal muscular dystrophies (distal myopathy) are a group
of inherited muscular diseases primarily affecting the
hands and feet (Lu et al. 2008). Distal muscular
dystrophy is a common name.Almost 20 different entities
of distal muscular dystrophies have been genetically
determined, but well-known types include Welander,
Finnish (tibial), Miyoshi, Nonaka, Gowers-Laing,
hereditary inclusion-body myositis type 1, distal myopathy
with vocal cord and pharyngeal weakness, and ZASP-
related myopathy (Lu et al. 2008, Udd 2009). Clinical
presentation and inheritance pattern of these myopathies
are not uniform. In literature, there are some rare types
of distal muscular dystrophies but the classificationsare
difficult to make because some subtypes are not well
documented and retrospective analysis has not been
performed properly (Udd 2009, Pitceathly et al. 2013).
Distal muscular dystrophies generally present with
progressive weakness in the legs, hands and feet.
Mutated genes are responsible from sarcomeric protein
production that causes the disease. Affected individuals
usually have normal or slightly increased levels of
creating kinase. Ocular involvement is not typically seen
in distal muscular dystrophy. In literature there area few,
very rare cases presenting with ocular muscle
involvement in distal muscular dystrophy. Two patients
with upper limb predominant distal myopathy presented
with progressive external ophthalmoplegia and had
cataract operation in early life (Pitceathly et al. 2013).
Further investigation showed novel pathogenic
heterozygous POLG missense mutations causing mt
DNA depletion and representing itself in upper limb
predominant distal myopathy with ocular involvement
(Pitceathly et al. 2013). Distal myopathy and progressive
external ophthalmoplegia were reported in the same
patient but a type of distal myoptahy was not reported in
this case (Damian 1993). Oculopharyngodistal myopathy
is a rare clinical entity and is accepted as a distal
myopathy. It is characterized byptosis, external
ophthalmoplegia, dysphagia, and distal weakness.
Although oculopharyngodistal myopathy has a similar
presentation toOPMD, genetic features are different
between the two diseases (Minami et al. 2001). In a
study, oculopharyngodistal myopathy was reported in 47
patients from 9 unrelated Turkish families (Durmus et al.
2011). The common initial symptom was ptosis, followed
by oropharyngeal symptoms and distal muscular
weakness (Durmus et al. 2011). Both AD and AR traits
were reported, but no clinical differences were found
between AD and AR types (Durmus et al. 2011).The AR
form of the disease is rare and was previously reported in
two Japanese brothers and two Dutch siblings (Uyama et
al. 1998, van der Sluijs et al. 2004). It is shown that a
patient with the AR form of the disease has more severe
presentation and earlieronset of the disease in
comparison to the AD form (van der Sluijs et al. 2004).
Furthermore, external ophthalmoplegia, dysphagia,
distal weakness and atrophy in all extremities have been
reported in Chinesefamilies.That clinical entity was also
accepted as oculopharyngodistal myopathy. The
histopathologic examination of a muscle biopsy revealed
numerous tubulofilamentous inclusions in both the
sarcoplasm and nucleus (Lu et al. 2008). Each type of
distal muscular dystrophy has its own presentation so
management of the disease changes according to the
clinical concern. Occupational therapy, physiotherapy
and some types of braces may be effective when there
isdistal muscular involvement, while surgical therapy may
be requiredforocular involvement, especially in cases
where there is severe blepharoptosis and facial palsy
(Shimizu et al. 2013).
Congenital muscular dystrophy
CMD is clinically and genetically a heteregenous group of
diseases in which affected individuals have its related
symptoms atbirth. It has a progressive nature and
affected individuals may improve, worsen, or stabilize
duringthe acute period of the disease.Due to general
worsening of muscle weakness over time, some kind of
joint deformities and contractures, such as spinal
deformities, can be seen. It is difficult to estimate the
prevalence of CMD due to a lack of exact diagnosis with
genetic confirmation but it is reported as ranging from
0.68 to 2.5 per 100,000 in a few studies (Darin 2000,
Norwood et al. 2009).
Hypotonia may be noted in utero and in birth. Further
developmental delays can be seen over time. Joint and
spinal deformities are prominent features of CMD.
Although arrest or delay in motor abilities is marked in
many individuals, it can be difficult to estimate the onset
of disease but the diagnosis is usually made before two
years of age. Muscle weakness is a prominent feature of
CMD but the affected individualsmayhave some serious
complications such as feeding difficulty and respiratory
failure. Furthermore, central nervous system, heart and
eye involvements can be seen in some subtypes (Sparks
et al. 1993).
CMD can be divided into four main groups according
to the affected type of proteins: structural proteins,
glycosylation proteins, endoplasmic reticulum proteins,
and nuclear envelope proteins. The four main groups can
be further divided into many subtypes by involved gene,
which may cause variability in phenotypes. Eye
abnormalities are almost exclusively specific for
dystroglycanopathy, which is caused by a defect in
glycosylation (Sparks et al. 1993). There are five well-
known types of dystroglycanopathy:
a) Fukuyama congenital muscular dystrophy (FCMD)
FCMD is an AR form of CMD and characterized by
generalized muscle weakness, severe brain involvement
with impaired cognitive function, seizure and abnormal
eye function (Muntoni and Voit 2004). In affected
individuals, both anterior and posterior segments of the
eye can be affected in addition to ocular muscle
involvement. Eye involvement can be seen in 50% of the
affected individuals. Abnormal eye movements,
strabismus, poor visual pursuits, myopia, hyperopia, and
cataract have been reported in FCMD. Retinal
detachment and microphthalmos can be seen in some
rare cases (Muntoni and Voit 2004, Yoshioka et al. 1992).
b) Muscle eye brain disease (MEB)
MEB has a similar presentation with FCMD and was first
described by (Santavuori et al. 1989). It is characterized
by congenital muscular dystrophy, brain malformation,
mental retardation, and ocular abnormalities.
Hydrocephalus, lisencephaly, abnormal
electroencephalograms and myoclonic jerks are marked
central nervous system features of MEB. Severe
congenital myopia, congenital glaucoma, pallor of the
optic discs, retinal hypoplasia, retinal detachment,
nystagmus, enophtalmus, microphthalmia, optic atrophy,
juvenile cataracts, and uncontrolled eye movements are
associated ocular findings of MEB (Demir et al. 2009,
Pihko et al. 1995). The flash VEPs were exceptionally
high in MEB, which helps to differentiate it from FCMD
(Santavuori et al. 1989).
Evliyaoglu and Burakgazi 239
c) Walker-Warburg syndrome (WWS)
WWS (also known as cerebroocular dysplasia-muscular
dystrophy) is the most severe form of
dystroglycanopathy. Itwas first described by Walker in
1942 andthe full clinical picture was delineated by
Warburg in 1982.The life expectancy for individuals
affected with WWSis less than 3 years (Walker 1942,
Cormand et al. 2001). WWS is caused by a mutation in
POMT1, which also causes limb-girdle muscular
dystrophy-dystroglycanopathy type C1 (Longman et al.
2003). WWSis also associated with type II cobblestone
lissencephaly, hydrocephalus, cerebellar malformations
and eye abnormalities. The major ocular abnormalities
are buphthalmos, congenital glaucoma, microphthalmia,
cataract, immature anterior chamber angle, retinal
dysplasia with or without retinal detachment, persistent
hyperplastic primary vitreous, optic nerve hypoplasia, and
coloboma. (Cormand et al. 2001, Brasseur-Daudruy et al.
d) Congenital muscular dystrophy 1C (MDC1C) :
MDC1Cis a rare type of CMD that is inherited as AR form
and caused by a defect in the fukutin related protein
gene, which is also defected in LGMD type 2I (Brown et
al. 2004). MDC1C is associated with hypotonia, feeding
difficulties and severe weakness (Brockington et al.
2001). Although facial weakness is associated with
MDC1C, ocular involvement is not a prominent feature of
the disease. The reported ocular findings are strabismus
and ophthalmoplegia in MDC1C (Louhichi et al. 2004).
e) Congenital muscular dystrophy type 1D (MDC1D)
:MDC1D is a novel type of dystroglycanopathy in which
the affected gene is called LARGE (like
glycosyltransferase) (Longman et al. 2003). Horizontal
nystagmus, mild myopia and strabismus have been
reported in MDC1D in addition to central nervous system
and retinal involvements (Longman et al. 2003, Clarke et
al. 2011).
Muscular dystrophies are a heterogeneous group of
inherited disorders. Those muscular dystrophies can
have similar symptoms and can have unique and specific
presentations. We summarize ocular findings in certain
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the range of eye movements. The first symptom is
240 J. Med. Med. Sci.
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Purpose: Myopathic blepharoptoses (ptoses) is a complex group of disorders. To date, no formal categorization scheme has been developed based on associated ocular and systemic findings, genetic fingerprint, treatment, and prognosis for each ptosis in this group. We report a new classification scheme for myopathic ptoses. Methods: Literature review and classification development. Results: A new classification scheme of myopathic ptoses includes isolated static myopathic ptosis (congenital ptosis), static myopathic ptosis associated with aberrant innervation and those associated with periocular abnormalities, and progressive myopathic ptoses that affect the levator muscle and other muscle groups in childhood and adulthood. Conclusions: Making the distinction of myopathic ptosis type early will maximize patient outcomes by optimizing surgical and systemic management and facilitating the recruitment of subspecialists to care for patients with these challenging conditions.
Full-text available
Congenital muscular dystrophies with hypoglycosylation of α-dystroglycan (α-DG) are a heterogeneous group of disorders often associated with brain and eye defects in addition to muscular dystrophy. Causative variants in 14 genes thought to be involved in the glycosylation of α-DG have been identified thus far. Allelic mutations in these genes might also cause milder limb-girdle muscular dystrophy phenotypes. Using a combination of exome and Sanger sequencing in eight unrelated individuals, we present evidence that mutations in guanosine diphosphate mannose (GDP-mannose) pyrophosphorylase B (GMPPB) can result in muscular dystrophy variants with hypoglycosylated α-DG. GMPPB catalyzes the formation of GDP-mannose from GTP and mannose-1-phosphate. GDP-mannose is required for O-mannosylation of proteins, including α-DG, and it is the substrate of cytosolic mannosyltransferases. We found reduced α-DG glycosylation in the muscle biopsies of affected individuals and in available fibroblasts. Overexpression of wild-type GMPPB in fibroblasts from an affected individual partially restored glycosylation of α-DG. Whereas wild-type GMPPB localized to the cytoplasm, five of the identified missense mutations caused formation of aggregates in the cytoplasm or near membrane protrusions. Additionally, knockdown of the GMPPB ortholog in zebrafish caused structural muscle defects with decreased motility, eye abnormalities, and reduced glycosylation of α-DG. Together, these data indicate that GMPPB mutations are responsible for congenital and limb-girdle muscular dystrophies with hypoglycosylation of α-DG.
Full-text available
Eye is the official journal of the Royal College of Ophthalmologists. It aims to provide the practising ophthalmologist with information on the latest clinical and laboratory-based research.
Oculopharyngeal muscular dystrophy (OPMD) is an underdiagnosed late-onset dominant muscular dystrophy with worldwide variable prevalence. It starts with eyelid ptosis and dysphagia in the late forties or early fifties that evolves into a limb-girdle muscular dystrophy. It is caused in the great majority of cases by an expansion of cryptic GCN/alanine repeat in the polyadenylate-binding protein nuclear 1 (PABPN1) gene leading to a lengthening of the N-terminal polyalanine domain that is believed to cause protein aggregation principally in the nuclei. It is one of the few dystrophies where the major symptoms can be significantly alleviated by surgical procedures.
Muscular dystrophies are a heterogeneous group of inherited disorders that share similar clinical features and dystrophic changes on muscle biopsy. An improved understanding of their molecular bases has led to more accurate definitions of the clinical features associated with known subtypes. Knowledge of disease-specific complications, implementation of anticipatory care, and medical advances have changed the standard of care, with an overall improvement in the clinical course, survival, and quality of life of affected people. A better understanding of the mechanisms underlying the molecular pathogenesis of several disorders and the availability of preclinical models are leading to several new experimental approaches, some of which are already in clinical trials. In this Seminar, we provide a comprehensive review that integrates clinical manifestations, molecular pathogenesis, diagnostic strategy, and therapeutic developments.
Myotonic dystrophy in a 58-year-old patient was diagnosed on clinical grounds together with a positive family history. There was a striking dissociation between loss of saccades in the horizontal direction and the preserved ability to generate pursuit movements. Vertical movements were much less affected. The oculomotor deficits point towards brainstem pathology as they cannot be explained by pathology of the motor unit. © 1985 Informa UK Ltd All rights reserved: reproduction in whole or part not permitted.
Oculopharyngodistal myopathy is an extremely rare disease characterised by slowly progressive blepharoptosis, facial and bulbar muscle weakness and distal leg myopathy. We report the case of a 72-year-old woman with severe bilateral blepharoptosis and facial palsy caused by oculopharyngodistal myopathy that was present for more than 29 years. The condition was successfully treated by simple surgical intervention. © 2013 Published by Elsevier Ltd on behalf of British Association of Plastic, Reconstructive and Surgeon.
Objective: To investigate the frequency of Coats syndrome and its association with D4Z4 contraction size in patients with facioscapulohumeral muscular dystrophy type 1 (FSHD1). Methods: We searched a North American FSHD registry and the University of Rochester (UR) FSHD research database, reviewed the literature, and sent surveys to 14 FSHD referral centers in the United States and overseas to identify patients with genetically confirmed FSHD1 with a diagnosis of Coats syndrome. Results: Out of 357 genetically confirmed patients in a North American FSHD registry and 51 patients in the UR database, 3 patients had a self-reported history of Coats disease (0.8%; 95% confidence interval 0.2%-2.2%). In total, we identified 14 patients with FSHD with known genetic contraction size and Coats syndrome confirmed by ophthalmologic examination: 10 from our survey and 4 from the literature. The median age at diagnosis of Coats syndrome was 10 years (interquartile range 14 years). The median D4Z4 fragment size was 13 kilobases (kb) (interquartile range 1 kb). One patient was mosaic (55% 11 kb, and 45% 78 kb). Conclusions: Coats syndrome is a rare extramuscular complication of FSHD1 associated with large D4Z4 contractions. Closer surveillance for retinal complications is warranted in patients with D4Z4 fragments ≤15 kb.
Facioscapulohumeral muscular dystrophy (FSHD) is associated with a deletion on chromosome 4q35. Recent studies have shown that this deletion is found in patients with other phenotypes in addition to those with the classic Landouzy-Dejerine FSHD phenotype. To examine patients with atypical phenotypes and an FSHD deletion on chromosome 4q35. Clinical characterization and genotype-phenotype correlation. University hospital. Forty-one symptomatic subjects with deletions on chromosome 4q35. We found 6 patients with atypical FSHD. Three (from a single family with FSHD) had additional symptoms of chronic progressive external ophthalmoplegia (4q35 EcoRI/BlnI fragment size, 20 kilobase [kb]), and 3 patients (1 with sporadic disease and 2 from a single family) had facial-sparing scapulohumeral dystrophy (4q35 EcoRI/BlnI fragment size, 30 and 34 kb, respectively). The clinical presentations in patients with FSHD-associated short fragments on chromosome 4q35 are not restricted to the classic FSHD form, but constitute a variety of clinical manifestations. There seems to be no clear correlation between the atypical subtype and the DNA fragment size due to the deletion.