British Jouirnial of Ophthalmology, 1977, 61, 683-689

Structural alterations of extraocular muscle

associated with Apert's syndrome
SHEILA MARGOLIS, BRUCE R. PACHTER, AND GOODWIN M. BREININ
From the Department of Ophthalmology, New York University Medical Center, New York

SUMMARY An inferior oblique muscle from a patient with Apert's syndrome was examined by
light and electron microscopy. Alterations in the muscle fibres, the myoneural junctions, and
intramuscular nerves were observed. These data are not compatible with the widespread notion
that motility disturbances in this syndrome are solely due to mechanical limitations.

Apert's disease, or acrocephalosyndactyly (Apert, OCULAR EXAMINATION

1906), consists of oxycephaly (tower skull), exoph- Cycloplegic refraction of the OD was + 2 00
thalmos, strabismus, antimongoloid fissures, maxil- -0425 x 90 and OS + 2-25 sphere with visual acuity
lary hypoplasia, optic atrophy, and syndactyly (fusion OD 20/40 and OS 20/30. Two years later examina-
of fingers 2 to 4). Ocular motility disturbances occur tion showed a corrected vision of 20/25 OU. The
frequently in Apert's disease. It has been reported patient had antimongoloid fissures with shallow
that at least 45 to 78 % of patients seen with Apert's orbits and prominent globes which measured at base
and Crouzon's diseases, both craniofacial dysos- 110 by exophthalmometer OD 20 mm and OS
tosis, have strabismus (Davis, 1925; Laitinen et al., 19 mm. Further examination showed an interpupil-
1956). Overacting inferior oblique muscles and slight lary distance of 70 5 mm with an intercanthal
underaction of superior oblique muscles occurred distance of 39 mm. No nystagmus was evident. The
frequently, It has been suggested (Lloyd, 1975;
Miller and Folk, 1975) that these motility anomalies
result from mechanical limitations of the globe
which are secondary to the bony malformation of
the orbit. In the present investigation, the first to
directly examine the structure of extraocular muscle
associated with Apert's syndrome, light and electron
microscopic evidence is indicative of morphological
abnormality.
Case report
The patient was a 13-year-old girl who had oxyce-
phaly resulting from complete closure of the coronal
sutures, shallow orbits, bilateral exophthalmos (Fig.
1), and syndactyly of the hands (Fig. 2) and feet.
Consequently, she had a craniotomy to open the
coronal sutures, and a follow-up examination showed
normal motor progression, and good preservation of
vision, with normal speech and intelligence. Over the
years various surgical procedures had been per-
formed to correct the physical deformities typical of
Apert's syndrome-cleft palate, bifid uvula, and
fusion of fingers.
Requests for reprints to: Dr Bruce R. Pachter, Department of
Ophthalmology, New York University Medical Center, Fig. 1 Patient with Apert's syndrome showing
550 First Avenue, New York, New York 10016, USA antimongoloid fissures, exophthalmos, and hypertelorism
683
684 Sheila Margolis, Bruce R. Pachter, and Goodwiii M. Breinin

scopy by curing a layer of Epon on to them within a

sandwich of polystyrene film (Davidowitz et al.,
1976). The complete muscle biopsy could thus be
initially surveyed by phase contrast for the detection
of disrupted fibres and with particular emphasis on
locating the neuromuscular junctions. Sections of
interest were freed from the plastic sandwich and
remounted for further 1 [um and ultrathin sectioning.
Results
LIGHT MICROSCOPY
Scattered among the predominantly normal-ap-
pearing fibres were cells in varying stages of degenera-
Fig. 2 Syndactyly offingers tion (Fig. 3). Many fibres were enlarged and hya-
linised. These and other cells frequently contained
NPC was 40 mm. The anterior segment was un- vacuolated regions and showed loss of myofibrillar
remarkable except for bilateral transillumination of organisation. Inflammatory infiltrates and lympho-
the iris base. In addition it was noted in both eyes cytic collections were not observed.
that the lens and vitreous were normal. Except for a
suggestion of pallor of the right disc temporally, the ELECTRON MICROSCOPY
optic nerves and blood vessels were normal. There The hyalinised fibres typically contained large
were good foveal reflexes in both eyes, with decrease clusters of mitochondria and showed loss of myo-
in the retinal pigmentation, which allowed for in- fibrillar organisation (Fig. 4). The mitochondria in
creased visibility of the underlying choroidal vessels such clusters often appeared swollen, disrupted, and
anterior to the equator in the superior temporal and vacuolated; their cristae showed fragmentation.
inferior nasal quadrants. Other fibres showed varying degrees of vacuolar
A 'V' pattern esotropia was present. On upward aggregations. Such vacuoles most probably repre-
gaze there was an ET 25, RHT 14, and on downward sented swollen sarcoplasmic reticulum and/or
gaze an ET 40, RHT 14 for distance and near. The resulted from mitochondrial breakdown. In Fig. 5 a
patient had bilateral elevation in adduction, with vacuolar aggregate is seen in a muscle fibre showing
overacting inferior obliques OU and underacting minor myofibrillar disruption. In an advanced
superior obliques OU. There was also decreased stage of cellular degeneration the vacuolar aggre-
abduction OU with 3 mm of bared sclera. Sensory gates become increased in amount and there is loss of
evaluation showed alternating suppression. Surgery myofibrillar organisation (Fig. 6). Quite often,
for correction of strabismus was performed, which necrotic myofibrils were fused into an amorphous
was 4 mm recession of left medial rectus, 8 mm mass, which form electron-dense serpentine strands.
recession of left lateral rectus, as well as bilateral Various nuclear abnormalities were seen. They
inferior oblique disinsertions. included highly involuted configurations, often with
Laboratory tests: ERG, EOG, serum tyrosine, various pseudoinclusions (Fig. 7), as well as pyknotic
and phenylalanine levels and chromosome studies nuclei.
were all normal. Subsarcolemmal inclusions were frequently ob-
served. One type was composed of finely granular,
Materials and methods particulate matter, which formed regular clustering
about foci which tend to be spaced at approximately
The right inferior oblique was completely disinserted, 1200-1400 A (Fig. 8). Their electron density varied
and a segment of approximately 8 mm was taken from light (Fig. 8) to moderate (Fig. 9). A second
from its belly portion and initially fixed in I % type of inclusion appears to be a Hirano body (Fig.
paraformaldehyde/1 % glutaraldehyde in phos- 10).
phate buffer for 4 hours, then transferred to 4 % Neuromuscular junctions were seen on apparently
glutaraldehyde overnight. The muscle segment was normal and disrupted fibres. In some cases the
postfixed in I % osmium tetroxide, dehydrated in axonal terminals appeared highly pyknotic (Fig. 11).
graded alcohols, and embedded whole in Epon 812. These axonal terminals occasionally showed some
The embedded muscle segment was serially sectioned loss of their axolemma.
at 15 rm by steel knife on a sliding microtome. The intramuscular nerves at times showed altera-
These thick sections were cleared for light micro- tions. In many cases such nerve twigs contained
 t'
Structural alterations of extraocular muscle associated with Apert's syndrome 685

5fRVW.. ... ....1X

-,waW
T§
s BF/ ''' z ' 4 " N,:,,
- :

Fig. 4 Marked clustering of mitrochondria, which are in

Fig. 3 Inferior oblique muscle. Hyalinised, vacuolated, various stages of disruption. The myofibrillar organisation
and necrotic fibres are seen (methylene blue, x 260) is indistinct (x 15 000)

If

Fig. 5 A large vacuolar aggregate, consisting presumably

of dilated sarcoplasmic reticulum components and Fig. 6 Necrotic fibre with vacuolar aggregates and loss
mitochondria which have degenerated (x 15 000) of myofibrillar material (x 15 000)
686 Sheila Margolis, Bruce R. Pachter, and Goodwin M. Breinint

Fig. 7 A large nuclear pseudoinclusion containing an

inclusion body and lipofuscin material ( x 11 000) --.z 9S.' .:; Y.'w f. ..: ..; .:-' __ ,

Fig. 8 Subsarcolemmal inclusion body, non-membrane

bound, composed offinely granular particulate material
in an apparently normal muscle fibre (x 15 000)

~4T laminated structures (Luse bodies) characterised

by a definite periodicity. Such structures appeared to
arise from or to be in close association with the base-
.A.bt ment membrane of the Schwann cell (Fig. 12).
Schwann cell inclusions were also seen (Fig. 13).
AO~~~~~~ These appeared similar to the 7t granule of Reich.
The axons within the nerve twigs occasionally
showed significant myelin degeneration (Fig. 14).
Discussion
The high frequency of various alterations in muscle
cell structure observed here strongly suggests a
pathological state.
In the present study mitochondrial aggregates
were observed in the fibres of both the orbital and
the global regions. In a recent study of overacting
inferior oblique from patients with various types of
strabismus by Mukuno et al. (1976) myopathic
alterations were observed, prominent among which
Fig. 9 Subsarcolemmal inclusion body, non-membrane were central cores of closely packed aggregates of
bound, and moderate electron density in a disrupted mitochondria. These were mostly seen in small-
muscle fibre ( x 15 000) diameter fibres on the orbital surface and were rare
 %'C45*HRtSXxse\
Structural alterationis of extraoclular mutscle associated with Apert's syndrome 687

Fig. I I Motor endplate showing two axonal terminals

(AT, and A T2) which appear pyknotic. One axonal
terminal (AT2) shows a focal loss of its axolemma; the
subjunctional region shows some degeneration (arrow)
(x 15 000)
%0- t:*/ ,^..;t5
:*. + ,
c f
X 4
*t ;
s ;, ,.. .,*.,.,

Fig. 10 A subsarcolemmal Hirano body inclusion r .,A

.. $
( x 21 000)

.5

4.
6

*:X.
*.w.5

I r:}

R '1

10

A4A

Fig. 12 Intramuscular nerve showing a Luse body

(elongated laminated structure) apparently attached to Fig. 13 Intramuscular nerve, the Schwann cell of which
the basement membrane of the Schwann cell (x 21 000) contains several inclusion bodies ( x 27 000)
688 Sheila Margolis, Bruce R. Pachter, and Goodwin M. Breinin

Fig. 14 Intramuscular nerve

showing myelin degeneration
(x 13 000)

in the global region. Mitochondrial abnormalities, Reich. Luse bodies have been reported in pathologic
such as aggregation, distension, vacuolation, and extraocular muscle (Martinez and McNeer, 1976),
fragmentation, have been described in both myo- as well as in neurogenic tumours (Friedmann et al.,
pathic and neurogenic diseases with altered ocular 1965). The r granules of Reich have been described
movements (Sakimoto, 1970; Adachi et al., 1973). in nerves of patients with various neuromuscular
Subsarcolemmal inclusions of finely granular disorders (Evans et al., 1965) and in nerves from
structures and Hirano bodies were frequently ob- patients with hypothyroid neuropathy (Dyck and
served in this study. Comparable granular structures Lambert, 1970).
have been previously described in extraocular muscle It thus seems likely that, at least in this case of
from patients with myotonic dystrophy (Culebras Apert's syndrome, the motility disturbance may in
and Merk, 1975), from ageing individuals (Miller, part be related to abnormality of the extraocular
1975), as well as other neuromuscular disorders muscles themselves rather than be due to mechanical
(Mair and Tome, 1972). Hirano bodies have been factors alone.
seen in myasthenic extraocular muscle (Sakimoto,
1968) and in a clinically overacting inferior oblique The authors acknowledge the skilful technical
from a patient with exotropia (Martinez and assistance of Miss Barbara Zimmer.
McNeer, 1976). They also occur in cortical neurons This study has been supported by National Institutes
showing neurofibrillary degeneration and granulo- of Health Grant EY-00309 from the National Eye
vacuolar bodies in patients with Guam amyotrophic Institute.
lateral sclerosis-parkinsonism-dementia complex
(Hirano, 1965). References
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