Presentation and course
The defining feature of progressive external ophthalmoplegia is ptosis, usually but not always with symmetrical and progressive limitation of eye movements, with normal pupils. Sometimes, there is only ptosis--without ophthalmoplegia--for years (81), often leading to the gradual acquisition of a chin-up compensatory head position. Traditionally diplopia is considered to be rare because both eyes are affected simultaneously; however, numerous studies of progressive external ophthalmoplegia patients have found high rates of transient or constant diplopia (56). Facultative suppression preventing diplopia is common among progressive external ophthalmoplegia patients with strabismus and may reflect the long-time course over which ocular misalignment develops (56). On examination, the eyelids may appear thin. The syndrome usually begins in childhood or adolescence, but it may start later.
Whether the disorder is deemed myopathic (ocular myopathy) or neurogenic depends on associated findings. If myopathic changes are found in muscle biopsy, or if there are other myopathic features, clinically or in the electromyogram (EMG), the ophthalmoplegia is also deemed myopathic. Additionally, there may be weakness of face, oropharynx, neck, or limbs or multisystem signs that can represent important red flags for a mitochondrial disease such as cardiomyopathy, peripheral neuropathy, diabetes mellitus, hearing loss, or lipomatosis (30). In the autosomal dominant form, dysphagia is prominent, hence, the term oculopharyngeal muscular dystrophy. Ptosis is common in oculopharyngeal muscular dystrophy, but ophthalmoplegia is not. Limb weakness in oculopharyngeal muscular dystrophy is usually more severe proximally. In contrast, a different distribution of weakness leads to the term oculopharyngodistal myopathy (74).
In mitochondrial diseases, progressive external ophthalmoplegia may appear as the unique/predominant sign of disease, in this case it is denoted as simple PEO, or may be part of a multisystem manifestation of mitochondrial alteration. Ocular myopathy may be a feature of a multisystem mitochondrial encephalomyopathy when associated with central neurologic signs such as myoclonus (MERRF), stroke-like episodes (MELAS), cognitive impairment and ataxia (Kearns-Sayre syndrome), and others, but may also be part of a set of manifestation without involvement of the central nervous system, defined newly as PEO-plus, differently from Drachman, by Orsucci and colleagues (63).
Orsucci and associates performed a retrospective study on mitochondrial ocular myopathy based on the Nationwide Italian Collaborative Network of Mitochondrial Diseases patients web Italian registry of 1300 patients, defining among the progressive external ophthalmoplegia group: pure PEO as the patients with isolated ocular myopathy and PEO-plus as those with ocular myopathy and other features of neuromuscular and multisystem involvement, excluding central nervous system (63). Ocular myopathy was the most common feature in the cohort of mitochondrial patients, representing the 55.3% of patients with definite genetic diagnosis. Pure PEO patients were one third of all progressive external ophthalmoplegia patients. The most common CNS features associated were ataxia (19.8%), cognitive impairment (13.5%), seizures (7.5%), pyramidal signs (7.3%), tremor (4.5%), stroke-like episodes (3.8%), impaired consciousness (3.8%), dystonia (3.5%), microcephaly (3.0%), nystagmus (2.8%), myoclonus (2.3%), and parkinsonism (2.0%) (63). Considering the progressive external ophthalmoplegia patients, ocular myopathy was associated with muscle weakness (42.9%), exercise intolerance (23.1%), muscle wasting (17.5%), hearing loss (15.3%), and swallowing impairment (14.9%) without association with specific genotypes, except for mutations in TYMP that were associated with muscle wasting (63).
With some exceptions, PEO is more likely to be associated with deletions of mtDNA than with point mutations (17)data confirmed by the Italian Network, where ocular myopathy was positively associated with mtDNA single deletions and polymerase gamma (POLG) mutations (63). However, ocular myopathy as manifestation of a multisystem mitochondrial encephalomyopathy was linked to the m.3243A>G mutation with the association of an increased lactate whereas the other PEO patients were associated with mtDNA single deletion and Twinkle mutations (63).
The associated clinical syndrome is more likely to be severe and involve brain, retina and auditory nerves if it starts before 9 years of age, and much less likely to be severe if it starts after 20 years of age (04).
Progressive external ophthalmoplegia, Kearns-Sayre syndrome, and Pearson syndrome are the 3 sporadic clinical syndromes classically associated with single large-scale deletions of mitochondrial DNA. An invariant triad defines Kearns-Sayre syndrome: PEO, pigmentary retinopathy, and onset before 20 years of age. In addition, there should be at least 1 of the following: heart block (with need for pacemaker), cerebrospinal fluid protein content of 100 mg/dl or greater, and a disabling cerebellar syndrome. Cardiac conduction abnormalities may be present at the time of progressive external ophthalmoplegia onset or may develop years later mandating serial cardiac evaluations (56).
However, these classic criteria of Kearns-Sayre syndrome present some limitations: the age limit is arbitrary, CSF protein levels have very limited use in current clinical practice in those patients, multisystem clinical features strongly associated with Kearns-Sayre syndrome are excluded from the current criteria (for instance hearing loss, failure to thrive/short stature, cognitive involvement, tremor, and cardiomyopathy), and finally, many patients with progressive external ophthalmoplegia due to an mtDNA single deletion did not fulfill the criteria for Kearns-Sayre syndrome or for pure progressive external ophthalmoplegia; for instance, progressive external ophthalmoplegia patients (who do not fit the diagnostic criteria of Kearns-Sayre syndrome) may also demonstrate pigmentary retinopathy, often described as a salt and pepper retinopathy with a speckled pattern of retinal pigment epithelium clumping alternating with areas devoid of normal epithelium (59).
To resolve these limitations, the Italian Network of mitochondrial diseases tested in a large cohort of 228 patients from the database of the Nationwide Italian Collaborative Network of Mitochondrial Diseases simplified criteria for a new category which could be defined KSS spectrum (ptosis and/or ophthalmoparesis due to an mtDNA single large-scale deletion and at least 1 of the following: retinopathy, ataxia, cardiac conduction defects, hearing loss, failure to thrive/short stature, cognitive involvement, tremor, cardiomyopathy), as opposed to progressive external ophthalmoplegia (ptosis and/or ophthalmoparesis due to an mtDNA single large-scale deletion not fulfilling the new KSS spectrum criteria or criteria for Pearson syndrome) (53). In this view, classic Kearns-Sayre syndrome represents the most severe extreme of the Kearns-Sayre syndrome spectrum. With the new criteria, it is possible to classify nearly all single-deletion patients: 64.5% progressive external ophthalmoplegia, 31.6% Kearns-Sayre syndrome spectrum (including classic Kearns-Sayre syndrome 6.6%), and 2.6% Pearson syndrome. The deletion length was greater in Kearns-Sayre syndrome spectrum than in progressive external ophthalmoplegia whereas heteroplasmy was inversely related with age at onset (53).
In March 2020, Rodríguez-López and colleagues reported a retrospective analysis of the clinical, pathological, and genetic features of 89 cases with mitochondrial progressive external ophthalmoplegia (71). Although they have observed 3 main phenotypes: pure progressive external ophthalmoplegia (42%), Kearns-Sayre syndrome (10%), and progressive external ophthalmoplegia plus (48%), they have also concluded that phenotype-genotype correlations cannot be brought in mitochondrial progressive external ophthalmoplegia, and a muscle biopsy should be the first step in the diagnostic flow of progressive external ophthalmoplegia when mitochondrial etiology is suspected. Additional national cohorts of mitochondrial progressive external ophthalmoplegia have been reported in Poland (47) and Czech Republic (03).
Other neural syndromes with prominent ophthalmoplegia are the mitochondrial neurogastrointestinal encephalomyopathy or MNGIE (39; 34) and sensory ataxic neuropathy with dysarthria and ophthalmoparesis SANDO syndrome, with considerable overlap with other progressive external ophthalmoplegia-associated syndromes (56).
Progressive external ophthalmoplegia is also among the many reported neuromuscular manifestations exhibited in dominant optic atrophy plus patients in which numerous neurologic sequelae including sensorineural hearing loss, ataxia, and peripheral neuropathy are present in addition to the optic atrophy. Dominant optic atrophy is well known to be caused in 60% to 70% of cases by OPA1 gene mutations, so when bilateral optic atrophy is observed in a patient with progressive external ophthalmoplegia, OPA1 gene mutation should be considered (02; 50).
Although the frequency of diabetes mellitus is probably higher in patients with mitochondrial diseases in general, including PEO, the association is not well understood. Mitochondrial dysfunction might play an important role in diabetes pathophysiology; in fact, when mtDNA defects are located in the pancreas, slow destruction of the β cells may occur, causing decrease in insulin production (as opposed to insulin resistance); however, peripheral skeletal muscle insulin resistance has also been reported in some mitochondrial disorders (44).
Both mtDNA mutations and nuclear genes mutations may be associated with diabetes: maternally-inherited diabetes is likely to be caused by the MELAS m.3243A>G mutation (69), but also in POLG-related progressive external ophthalmoplegia patients 11% have diabetes and diabetes has also been seen in OPA1 mutations (44). Therefore, copy number variations of mtDNA are known to be associated to diabetes; in fact, in looking at all patients with mtDNA deletions causing either Kearns-Sayre syndrome or the milder isolated progressive external ophthalmoplegia, 11% to 14% have diabetes (44).
It is noteworthy that in patients with mitochondrial disease, psychiatric conditions were far more common than in the general population and included major depression, agoraphobia and/or panic disorder, generalized anxiety disorder, social anxiety disorder, and psychotic syndromes (54; 46). Thus, it is in contrast to other chronic neuromuscular disorders such as DM1, hereditary motor and sensor neuropathy type 1, and facioscapulohumoral dystrophy (42), which are not associated with an increased risk of depression, suggesting a causative relation between mitochondrial dysfunction and an increased risk of depression. Correlation studies between psychiatric disorders and mtDNA have been long performed with inconsistent results (46). Studies on somatic mtDNA mutations in tissues have been also performed demonstrating an increase in the level of the common deletion in the brain, especially frontal lobes, of bipolar disorder patients (46). Progressive external ophthalmoplegia patients reported a high frequency of severe fatigue (67.9%), pain (96.2%), depression (32.1%), and dependency in daily life (46.4%); patients with POLG1 mutations had more functional impairments but fatigue severity, depression, and pain did not differ between patients with or without POLG1 mutations (83).
Parkinsonism has been described in patients with progressive external ophthalmoplegia, first associated with 3 genesANT1 (SLC25A4), Twinkle (PEO1/C10orf2), and mitochondrial DNA POLG (15) and afterwards with MPV17 (28). Twinkle-related autosomal dominant progressive external ophthalmoplegia patients have been described to developed late-onset mild and stable parkinsonism, with bilateral postural and rest tremor and mild rigidity of upper limbs and axial muscles typically responsive to L-Dopa (48).
Two families segregating a heterozygous dominant OPA1 mutation associated with a slowly progressive syndrome characterized by progressive external ophthalmoplegia, mitochondrial myopathy, sensorineural deafness, peripheral neuropathy, parkinsonism, and/or cognitive impairment have been reported. Most patients didnt show visual complaints, but subclinical loss of retinal nerve fibers at optical coherence tomography (11).
Prognosis and complications
The prognosis of progressive external ophthalmoplegia depends on the associated features, primarily whether there is severe limb weakness or a cerebellar disorder that may be mild or disabling. In Kearns-Sayre syndrome, the cerebellar and heart involvement are probably the most incapacitating component, and life span may be shortened. When there is myopathic limb weakness in either mitochondrial disease or oculopharyngeal muscular dystrophy, disability is usually mild.
At 60 years of age, a woman noted bilateral ptosis with no diurnal variation or diplopia. Episodes of transient choking once or twice a week led to endoscopy, but no cause was found. She did not lose weight. There was no limb weakness. EMG was consistent with myopathy. She was being treated for hypercholesterolemia with statin drugs, and the serum level of creatine kinase was 508 units (normal was 0 to 165). Cardiac evaluation showed no abnormality.
Her parents were first cousins, and the family, who resided in the United States, originated in Uzbekistan, having been derived from Samarkand Sephardic Jewish people. One sister had eyelid surgery for ptosis. A brother and 2 other sisters were asymptomatic. Her mother died of bone cancer at 80 years of age, but had ptosis and dysphagia for many years. A maternal aunt was asymptomatic, but 2 maternal uncles were said to have had ptosis and dysphagia. There was no information about her grandparents. Her 2 children and the 2 children of her affected sister were asymptomatic at 23 to 33 years of age.
Examination. She had a long, lean face because the temporalis muscles and masseters were small. Bilateral ptosis was evident, and eye closure was weak. She could not puff out her cheeks or whistle forcefully. Eye movements were asymmetric. On lateral gaze in either direction, the adducting eye moved completely, but the abducting eye movement was incomplete. Vertical movements were normal. Speech and oropharynx were normal, as were the sternomastoids and limb muscles. There was no myotonia of grasp or percussion. Tendon reflexes were not elicited.
Diagnostic test. DNA was analyzed for the PABP2 gene (polyalanine-binding protein). Normally there are 6 GCG repeats. The patient had 9 repeats on 1 chromosome and 6 on the other. That is, she was heterozygous for the mutation; the pattern was diagnostic of oculopharyngeal muscular dystrophy. Despite the consanguinity, heterozygosity indicated autosomal dominant inheritance.