Numerous inherited disorders result in neuro-ophthalmic signs. Certain myopathies and neurocutaneous syndromes (phakomatoses) are the most common inherited systemic conditions. Inherited optic neuropathies are discussed in Chapter 4.
The extraocular muscles are affected by several inherited conditions that result in mitochondrial dysfunction.
Chronic progressive external ophthalmoplegia
Chronic progressive external ophthalmoplegia (CPEO) is an inherited mitochondrial myopathy characterized by slowly progressive, symmetric ophthalmoplegia with or without ptosis (Video 14-1; Fig 14-4). The majority of patients with CPEO have mitochondrial DNA (mtDNA) deletions or point mutations, but nuclear DNA mutations can also cause CPEO. Thus, the mode of inheritance can be mitochondrial (maternal), autosomal, or sporadic (most common), and the disorder may not be transmissible to the next generation. Patients often initially present with ptosis and do not generally complain of diplopia. However, the majority of patients have visual impairment and difficulty with reading. At presentation, myasthenia gravis may be considered in the differential diagnosis, but in contrast to patients with CPEO, MG patients typically have variable signs and symptoms. Clinical findings usually develop in patients between 18–40 years of age. Systemic symptoms may include generalized muscle weakness. Genetic testing is available for detection of abnormalities in the mtDNA. Histologic examination of muscle biopsy specimens shows the characteristic “ragged red fibers” (Fig 14-5) and mitochondrial proliferation, and electron microscopic studies show inclusion body abnormalities of the affected mitochondria.
Chronic bilateral external ophthalmoplegia with bilateral ptosis.
Courtesy of M. Tariq Bhatti, MD.
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Figure 14-4 Chronic progressive external ophthalmoplegia in a 42-year-old with a 2-year history of progressive ptosis and bilateral external ophthalmoplegia.
(Courtesy of Steven A. Newman, MD.)
Figure 14-5 Histologic examination of a muscle biopsy specimen shows ragged red fibers (modified Gomori trichrome stain).
(Courtesy of Marjorie R. Grafe, MD.)
Kearns-Sayre syndrome is also an inherited mitochondrial myopathy. It includes CPEO, pigmentary retinopathy, and cardiac conduction abnormalities, and it variably includes cerebellar ataxia, deafness, and elevated CSF protein levels. Cardiac evaluation is essential to rule out conduction defects; this evaluation should be obtained for all patients with CPEO.
Yu Wai Man CY, Smith T, Chinnery PF, Turnbull DM, Griffiths PG. Assessment of visual function in chronic progressive external ophthalmoplegia. Eye (Lond). 2006;20(5):564–568.
Oculopharyngeal dystrophy is a hereditary condition, usually autosomal dominant, with onset in the fifth and sixth decades of life. The typical presentation is progressive bilateral ptosis followed by dysphagia and proximal muscle weakness. Most patients have an external ophthalmoplegia that, when asymmetric, may be accompanied by diplopia. Pathologic studies show a vacuolar myopathy. The disease is classically observed in patients of French Canadian ancestry. The only causative mutation described to date is a triplet repeat expansion consisting of 2–7 additional base triplets in a repeat sequence in exon 1 of the polyadenine binding protein, nuclear 1 gene (PABPN1), located on chromosome 14.
Myotonic dystrophy, a dominantly inherited multisystem disorder, also produces ophthalmoplegia that may mimic CPEO. Two types have been identified: type 1, resulting from mutation on chromosome 19, and type 2, resulting from mutation on chromosome 3. Symptoms usually start in late childhood or early adulthood with myotonia that is exacerbated by excitement, cold, and fatigue. The myotonia can be easily detected by asking the patient to shake hands; the patient will not be able to quickly release his or her grasp. This myopathy is unusual in that it affects distal limb musculature first. Wasting of the temporalis and masseter muscles produces the typical “hatchet face.” The myopathic facies, frontal balding, and ptosis cause a distinct and remarkably characteristic appearance.
Ocular findings include ptosis, pigmentary retinopathy, ophthalmoparesis, and polychromatic lenticular deposits (“Christmas tree” cataracts). The pupils are miotic and respond sluggishly to light. Other features of this dystrophy include low intelligence, insulin resistance, hearing loss, cardiomyopathy, cardiac conduction abnormalities, testicular atrophy, and uterine atony. Electromyographic studies can demonstrate characteristic myotonic discharges, and genetic testing can confirm the diagnosis of myotonic dystrophy.
Turner C, Hilton-Jones D. The myotonic dystrophies: diagnosis and management. J Neurol Neurosurg Psychiatry. 2010;81(4):358–367.
Excerpted from BCSC 2020-2021 series: Section 5 - Neuro-Ophthalmology. For more information and to purchase the entire series, please visit https://www.aao.org/bcsc.