Childhood onset oculopharyngeal muscular dystrophy
Post on 31-Dec-2016
Childhood Onset Oculopharyngeal Muscular Dystrophy D a v i d L a c o m i s , M D * , W i l l i a m J. K u p s k y , M D t ,
Kar l K. K u b a n , M D * , and L i n d a A. Specht , M D , P h D *
Oculopharyngeal muscular dystrophy is an inherited disorder, usually autosomal dominant, which typically becomes symptomatic during the fifth decade of life with slowly progressive ptosis and dysphagia; child- hood onset has not been reported. A 13-year-old female of French-Canadian descent developed nasal speech and strabismus at 5 years of age; there was no family history of neuromuscular disease. Ptosis and mild fa- cial and proximal muscle weakness were present by 9 years of age. Over the next 4 years, the patient devel- oped dysphagia, palatal paralysis, weight loss, de- creased ocular motility, scoliosis, shortness of breath, and obstructive apnea. Tracheostomy and gastrostomy were required. Creatine kinase and repetitive facial nerve stimulation were normal. Edrophonium testing was negative and electromyography revealed myopath- ic motor units in the iliopsoas muscle. A preponderance of type I fibers and scattered atrophic and angulated muscle fibers were present in 3 muscle biopsies. The clinical presentation and findings are consistent with childhood onset oculopharyngeal muscular dystrophy.
Lacomis D, Kupsky WJ, Kuban KK, Specht LA. Child- hood onset oculopharyngeal muscular dystrophy. Pediatr Neurol 1991;7:382-4.
Oculopharyngeal muscular dystrophy (OPMD) was named and deemed myopathic by Victor et al. in 1962 [1 ], although Taylor initially reported a familial form of pro- gressive ptosis and dysphagia in 1915 . Much of our present knowledge stems from Barbeau's evaluations of kindreds of French-Canadians, the group in which it is most common .
This rare disorder is characterized by adult onset of symptoms, often not until the fifth decade ol litir. The youngest reported patient, a member of an OPMD kindred, developed dysphagia at 19 years of age. Further data were not provided [41. Childhood onset has not been reported.
We report a patient with severe OPMD which presented in early childhood and was initially diagnosed as facio- scapulohumeral (FSH) muscular dystrophy. The clinical features and histopathology are described.
A 13-year-old female of French-Canadian descent had nomml devel- opment and was welt until age 5 years when nasal speech was ob- served. A pharyngeal flap was performed for presumed oropharyngeal incompetence and corrective surgery was undertaken for left esotropia. Ptosis developed; at 8 years of age, mild facial weakness and fatigue with exertion was exhibited. One year later, weight loss, worsening facial weakness, and difficulty climbing stairs were reported. Limila- tion of lateral ocular gaze and mild weakness of the face, neck, and proximal limbs were present on examination. Creatine kinase (CK) was 34 U/L (normal: < 50 U/L). Electromyography (EMG) documented short duration, low-amplitude motor unit action potentials in the del- toid, quadriceps, and facial muscles. A deltoid biopsy revealed scat- tered atrophic and angulated fibers; the patient was believed to have FSH dystrophy. Rapidly progressive scoliosis prompted referral to our medical center at 12 years of age.
Neurologic examination revealed a thin girl with bilateral ptosis, bi- facial weakness, decreased lateral gaze, nasal speech, and absent palate movement. There was marked shoulder girdle atrophy, Severe left con- vex scoliosis, and mild weakness of the neck flexors and proximal muscles of the upper and lower extremities. Hearing, reflexes, coor- dination, and sensation were normal.
EMG demonstrated normal nerve conduction; there was no decre- mental response upon repetitive facial nerve stimulation. Short dura- tion, low-amplitude motor units were present in the right iiiopsoas muscle. An edrophonium test and an acetylcholine receptor antibody screen were negative; serum lactate was normal. The spinal cord and brain appeared normal on magnetic resonance imaging. A diagnosis of OPMD was made.
The parents of the patient were third cousins. "i'here was no family history of neuromuscular disease; neurologic examinations of both par- ents. a 14-year-old brother, and an 18-year-old sister all were normal. EMG of the patient's mother was also normal.
Bilateral ptosis and dysphagia worsened. By age 121/_, years, dyspnea on exertion and symptoms and signs consistent with obstructive s!ee p apnea were present. The partially obstructive pharyngeal flap was re- leased, but nocturnal oxygen desaturation continued. Tracheostomy and intermittent nocturnal mechanical ventilation were required; a gas- trostomy tube was placed to sustain nutritional intake.
Spinal fusion was performed. Biopsies of a paraspinous muscle and the left biceps revealed scattered angulated and atrophic fibers, mild patchy increase in endomysial connective tissue, and a mild prepon- derance of type I fibers (Figs 1A,1B). No ragged-red fibers, abnormal inclusions, rimmed vacuoles, necrotic or regenerating fibers, or inflam- matory infiltrates were observed. Some fibers displayed focally decreased staining with NADH-TR. Electron microscopy revealed atro- phic fibers and a patchy increase in connective tissue, lntranuclear palisading filamentous inclusions were not observed; an intramuscular nerve twig was unremarkable.
From the Departments of *Neurology and tPathology (Neuropathology); Children's Hospital and Harvard Medical School; Boston, Massachusetts.
Communications should be addressed to: Dr. Specht; Fegan 11; Children's Hospital; Longwood Avenue; Boston, MA 02115. Received May 10, 1991; accepted June 20, 1991.
382 PEDIATRIC NEUROLOGY Vol. 7 No. 5
Figure 1. (A) Paraspinal muscle biopsy disclosing scattered atrophic and angulated fibers (arrows): frozen section, hematoxylin and eosin stain. (B) Biceps muscle biopsy revealing scattered atrophic and angulate fibers and an intermixture of fiber types with miM type l fiber predominance (dark fibers). Atrophic/angulate forms include both type I and type ll fibers: frozen section, myofibrillar ATPase (pH 4.6). A,B: original magnification, x250.
The patient's disorder was dominated by ptosis and dys- phagia, suggesting the clinical diagnosis of an "ocular myopathy." Slowly progressive ptosis and dysphagia are the cardinal and presenting features of OPMD, although weakness of facial, extraocular, and proximal or distal limbs occurs, particularly in the later stages of the disease [1,4]. In general, ptosis begins in the fourth to sixth dec- ades of life. Dysphagia typically occurs years later and may become incapacitating. Serum CK usually is normal but may be mildly elevated [4,5]. EMG usually documents myopathic motor unit action potentials in affected mus- cles; however, neurogenic changes have been reported in the literature .
The differential diagnosis includes myasthenia gravis, mitochondrial myopathy (e.g., Kearnes-Sayre syndrome, oculocraniosomatic syndrome), FSH and myotonic dys- trophies, congenital myopathy, and Fazio-Londe disease (progressive juvenile bulbar palsy). Myasthenia gravis was eliminated by a negative edrophonium test, absence of a decremental response upon repetitive nerve stimulation, and the absence of acetylcholine receptor antibodies on serologic studies. Electrophysiologically and clinically, the findings were myopathic. A mitochondrial myopathy was considered; however, the serum lactate was normal and "ragged-red" fibers or abnormal mitochondria were not identified on 3 separate biopsies from different mus- cles. FSH dystrophy and most other dystrophies do not present with ptosis and dysphagia. Myotonia, which should have been present in myotonic dystrophy, was ab- sent clinically and by EMG. The presence of normal hear- ing eliminated the possibility of infantile FSH dystrophy. The electrophysiologic features and lack of upper motor neuron signs excluded Fazio-Londe disease. Finally, the acquired features, absence of characteristic histopatho-
logic findings, and rapidly progressive course are inconsis- tent with congenital myopathy.
In OPMD, histologic evaluation of oculopharyngeal muscles has most frequently demonstrated "dystrophic" changes: variation in fiber size, loss of fibers with replace- ment by fat and connective tissue, increase in number of myofiber nuclei, internal nuclei, and typically rimmed vacuoles similar to those observed in other myopathic processes, such as inclusion body myositis [6,7]. "Ragged- red" fibers, ordinarily a characteristic of mitochondrial myopathies, also have been described, most frequently in extraocular muscles, but are not considered to be a typical feature . Small, angulated fibers (often type I) are fre- quently observed which react strongly with oxidative stains and have suggested an underlying denervating pro- cess . Dystrophic changes also occur in the diaphragm . In limb muscles, dystrophic changes with "rimmed" vacuoles may be observed [6,7,9]; however, occasionally, group atrophy, elongate and angulated fibers, and target fibers have been observed . Inflammation also has been reported, but a superimposed polymyositis could not be excluded in that patient . In many patients, intra- nuclear tubulofilamentous inclusions have been identified by electron microscopy [5,11,12]. The inclusions may serve as a specific marker of OPMD , but similar filaments have also been observed in inclusion body myo- sitis  and, as in this case, the inclusions are not always identified. Atrophic and angulated fibers, present in our patient, are most frequently observed in neurogenic atro- phy, but such fibers have been found in OPMD . There- fore, the histopathology is compatible with OPMD, but the more characteristic "rimmed" vacuoles and intranuclear inclusions were not observed, despite the examination of 3 different muscle biopsies. Biopsy of oculopharyngeal or
Lacomis et al: Oculopharyngeal Muscular Dystrophy 383
ocular muscles may have revea led a more striking patho-
Al though O P M D usually exhibits an autosomal domin-
ant pattern o f inheri tance, our patient may represent an
autosomal recess ive form in v iew of the parental consan-
guini ty . Alternat ively, a new mutat ion is possible. It
is also plausible that 1 parent has not yet expressed the
phenotype and that the inheri tance pattern is autosomal
The early age o f onset is one o f the most striking fea-
tures o f this pat ient . Previous ly , a w o m a n in a large
French-Canadian kindred was reported to exhibi t early
signs o f O P M D at 19 years of age, but ch i ldhood onset has
not been reported . Earl ier literature reported the pre-
sence o f progress ive ptosis and dysphagia (diagnosis un-
known) in chi ldren . Perhaps these patients repre-
sented unrecognized O P M D or mi tochondr ia l disorders.
The cl inical and pathologic features of this patient are
mos t consistent with O P M D of chi ldhood onset, possibly
o f au tosomal recess ive inheri tance; however , only future
advances in uncover ing the molecu la r basis o f O P M D will
a l low def ini t ive classif ication.
 Victor M, Hayes R, Adams RD. Oculopharyngeal muscular dystrophy. N Engl J Med 1962;267:1267-72.
 Taylor EW. Progressive vagus-glossopharyngcal paralysis widl ptosis. A contribution to the group of family diseases J Nerv Merit Dis 1915:42:129-39,
 Barbeau A. The syndrome of hereditary late ~)nsel ~ ptosis alld dysphagia in French-Canada. In: Kuhn E. ed. Symposium uber progres sive muskeldystrophie. Berlin: Springer-Verlag, 1966:102-~).
 Murphy SF, Drachman DB. The oculopharyngeal ~yndrome JAMA 1968;203:99-104.
[51 Bouchard J-P. Gagne F, Tome FM, Brunet 1). Nuclear inclu- sions in oculopharyngeal muscular dystrophy in Quebec. Can J Neurol Sci 1989; 16:446-50.
 Schmitt HP. Gowans JD, Munsat T. An autopsy study of a fa- milial oculopharyngeal muscular dystrophy with distal spread and neu- rogenic involvement. Muscle Nerve 1981:4:296-305.
 Little BW, Perl DE Oculopharyngeal muscular dystrophy. An autopsied case from the French-Canadian kindred. J Neurol Sci 1982; 53:145-8.
 Tome FMS, Fourdeau M. Ocular myopathies. In: Engle AG, Banker BQ, eds. Myology. New York: McGraw Hill; 1986; 1327-34.
 Buckler RA, Pratter MR, Chad DA. Smith TW. Chronic cough as the presenting symptom of oculopharyngeal muscular dystrophy. Chest 1989;95:921-2.
 Bosch EP, Gowans JD, Munsat T. Inflammatory myopathy in oculopharyngeal dystrophy. Muscle Nerve 1979;2:73-7.
 Tome FM, Askansas V, Engel WK, Alvarez RB, Lee C-S. Nu- clear inclusions in innervated cultured muscle fibers from patients with oculopharyngeal muscular dystrophy. Neurology 1989;39:926-39.
 Smith TW, Chad D. Intranuclear inclusions in oculopharyngeat muscular dystrophy. Muscle Nerve 1984;7:339-40.
 Fried K, Arlozorov A, Spira R. Autosomal recessive ocuto- pharyngeal muscular dystrophy. J Med Genet 1975; 12:416-8.
 Bray GM, Kaarsoo M, Ross RT. Ocular myopathy with dys- phagia. Neurology 1965;15:678-84.
384 PEDIATRIC NEUROLOGY Vol. 7 No. 5