Myoclonus epilepsy with ragged-red fibers
Jun. 10, 2021
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Progressive external ophthalmoplegia is a syndrome of diverse causes and is often accompanied by disorders of other tissues other than extraocular muscles. Most are inherited conditions, some are autosomal, and many are mutations of mitochondrial DNA (mtDNA); in fact, progressive external ophthalmoplegia represents the most common mitochondrial phenotype. Progress in understanding pathogenesis is lagging and, like many inherited diseases, treatment is needed. As newly discovered mutations continue to be found, more roads to etiology and pathogenesis continue to emerge.
• Progressive external ophthalmoplegia is a syndrome of diverse causes and is often accompanied by disorders of organ systems other than extraocular muscles. Most are inherited conditions, some are autosomal, and many are caused by mutations of mitochondrial DNA (mtDNA).
• Progressive external ophthalmoplegia represents the most common mitochondrial phenotype.
• Progress in understanding pathogenesis is lagging and, like many inherited diseases, disease-modifying treatments are needed.
Progressive external ophthalmoplegia (PEO) is a syndrome of diverse causes, all sharing the combination of ophthalmoparesis, ptosis of the eyelids, and normal pupils. The syndromes are separated by age at onset, distribution of extraocular weakness, patterns of inheritance, and specific mutations of mitochondrial DNA (mtDNA) or nuclear DNA (See Table 1). The differential diagnosis of these syndromes involves myasthenia gravis, Graves ophthalmopathy with thyroid disease, and ocular myopathies (101).
In 1890 Beaumont introduced the term “progressive nuclear ophthalmoplegia.” For the next half century, it was uncertain whether the cause was neurogenic or myopathic. That question was never resolved because none of the usual methods suffice to make the differentiation--not EMG or biopsy of ocular muscles, or even postmortem examination. In 1968, Rosenberg and colleagues found that 5 of 27 cases of ocular myopathy were associated with neurogenic syndromes, and David A Drachman introduced the term "ophthalmoplegia-plus" because the syndrome was often associated with neurologic multisystem diseases. In 1975, Rowland suggested that Kearns-Sayre syndrome could be defined clinically and noted that it was almost never familial. In the next decade this was debated; many investigators thought it premature to separate individual syndromes because so many patients had symptoms and signs that overlapped classifications. However, with the 1972 recognition by Olson and colleagues that finding “ragged-red fibers” in a muscle biopsy stained with the Gomori method is a sign of mitochondrial proliferation, followed by the later recognition of maternal inheritance in syndromes called “myoclonus epilepsy with ragged red fibers” (ie, MERRF) and “mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes” (ie, MELAS), the importance of mtDNA was recognized (59). In 1988, Holt and colleagues found deletions in some mitochondrial diseases; then, Zeviani, DiMauro, and Schon found major deletions only in Kearns-Sayre syndrome or sporadic cases of progressive external ophthalmoplegia itself. Simultaneously, in 1988 Wallace found a point mutation in Leber hereditary optic neuropathy, and others soon identified point mutations in MELAS and MERRF. Nevertheless, point mutations may cause PEO (82; 07).
In one atypical 10-year-old patient with Kearns-Sayre syndrome, limb weakness, short stature, impaired mental development, and pigmentary retinopathy were evident, but the diagnosis was apparently not made until 28 years of age after a year of recurrent syncope due to complete heart block (and cardiomegaly). Therapy included a pacemaker (63).
These discoveries might have ended the debates and, in a way, they did. The significance of the clinical syndromes is no longer disputed. Pathogenesis is uncertain because a single mutation is often associated with more than one clinical syndrome (phenotypic heterogeneity) (20); conversely, a single clinical disorder is likely to be associated with more than 1 mutation in the same gene (allelic heterogeneity) or different genes (locus heterogeneity). It is still useful to define the syndromes clinically, but mutations of mtDNA or nuclear DNA are being identified more readily and more frequently. As a result, some experts prefer a genetic classification (96). Van Goethem introduced the term “mtDNA maintenance” to account for mutations that lead to depletion of mtDNA or multiple deletions (95).
Sleep disorders may be encountered more often in PEO than in the general population (81), and most mitochondrial myopathies have been autosomal dominant, but autosomal recessive forms are being reported (87; 92). Similarly, esophageal disorders may be uncovered by physiological tests, but frank dysphagia is uncommon (18). Fatigue, pain, and depression may be more common in patients with PEO than in a comparable group with myotonic muscular dystrophy (79). Respiration may be impeded (80).
Single major deletion of the mtDNA is also found in an infantile anemia, the Pearson syndrome. In survivors of that disorder, features of Kearns-Sayre may appear later, and 1 mother with ophthalmoplegia but no other features of Kearns-Sayre had a child with Pearson anemia; both mother and child had the same major mutation (77).
In a parallel path of progress, the clinical features of “oculopharyngeal muscular dystrophy” were first described by Taylor in 1915 (88) and popularized by Barbeau and by Victor and colleagues in the 1960s (04). Tome and Fardeau described the characteristic inclusions in muscle (90). Brais and colleagues mapped the disorder to 14q11 in 1995 and cloned the gene (08).
Oculopharyngodistal myopathy was described by Schotland and Rowland (76), recognized as a specific syndrome in Japan by Satoyoshi and colleagues (75), and named by Fukuhara and colleagues (25).
A. Congenital myopathies: Central core disease, multicore, centronuclear, myotubular, and nemaline myopathies.
II. Juvenile or adult-onset
A. Mitochondrial diseases.
1. Kearns-Sayre syndrome, sporadic, with single deletion of mtDNA.
B. Oculopharyngeal muscular dystrophy, autosomal dominant, gene PABPN1.
Modified from (70)
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 (78), 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 (54). 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 (54). 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 (29). 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” (71).
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 (60).
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 (60). 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%) (60). 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 (60).
With some exceptions, PEO is more likely to be associated with deletions of mtDNA than with point mutations (16)—data confirmed by the Italian Network, where ocular myopathy was positively associated with mtDNA single deletions and polymerase gamma (POLG) mutations (60). 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 (60).
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 (03).
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 (54).
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 (57).
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) (51). 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 (51).
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 (68). 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.
Other neural syndromes with prominent ophthalmoplegia are the mitochondrial neurogastrointestinal encephalomyopathy or “MNGIE” (38; Hirano et al 2016) and sensory ataxic neuropathy with dysarthria and ophthalmoparesis “SANDO” syndrome, with considerable overlap with other progressive external ophthalmoplegia-associated syndromes (54).
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; 48).
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 (43).
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 (66), but also in POLG-related progressive external ophthalmoplegia patients 11% have diabetes and diabetes has also been seen in OPA1 mutations (43). 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 (43).
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 (52; 45). Thus, it is in contrast to other chronic neuromuscular disorders such as DM1, hereditary motor and sensor neuropathy type 1, and facioscapulohumoral dystrophy (41), 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 (45). 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 (45). 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 (80).
Parkinsonism has been described in patients with progressive external ophthalmoplegia, first associated with 3 genes—ANT1 (SLC25A4), Twinkle (PEO1/C10orf2), and mitochondrial DNA POLG (14) and afterwards with MPV17 (27). 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 (46).
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 didn’t show visual complaints, but subclinical loss of retinal nerve fibers at optical coherence tomography (10).
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.
Progressive external ophthalmoplegia is sporadic in approximately 50% of cases, with the remaining 50% inherited through autosomal dominant, autosomal recessive, or maternal transmission.
Sporadic PEO and sporadic Kearns-Sayre syndrome are the most common forms (85) due to a single large de novo mtDNA deletion typically not transmitted to offspring. Sporadic cases may be associated with mutations in tRNA genes (09; 83) or other mtDNA point mutations (44).
Autosomal dominant ophthalmoplegia and autosomal recessive MNGIE are associated with multiple deletions or depletion of mtDNA; the deletions and the clinical syndromes are attributed to impaired interaction between nuclear and mtDNA (36; 93); in fact the maintenance of mtDNA depends of on a number of nuclear gene-encoded proteins that function in mtDNA synthesis and the maintenance of a balanced mitochondrial nucleotide pool. Mutations in at least 7 genes encoded by nuclear DNA cause autosomal dominant PEO, both pure and plus form, including POLG1, POLG2, ANT1, Twinkle (previously designated as C10orf2), RRM2B, DNA2, and OPA1, with POLG1 being the most common (54). There is often a striking variety of phenotypes even within related probands carrying the same mutation. SPG7 has been also described as cause of PEO associated with multiple mtDNA deletions (61).
Autosomal recessive progressive external ophthalmoplegia is less common and is due to mutations in TYMP, POLG1, DGUOK, TK2, MGM1, RRM2B, RNASEH1, and C1QBP genes, leading to either multiple mtDNA deletions or mtDNA depletion. In those disorders, PEO is typically not an isolated syndrome but rather part of a more complex syndrome such as MNGIE, due to TYMP mutations, that causes multiple deletions, depletion, and point mutations of mtDNA, leading to abnormalities of respiratory chain function. The resulting syndrome of young adults comprises PEO, sensorimotor peripheral neuropathy, gastroenteropathy, cachexia, and leukoencephalopathy leading to early death (36; 37; 55; Hirano et al 2016). Above TYMP, RRM2B also encodes a cytosolic enzyme that is involved in nucleotide metabolism and is important for maintaining a balanced mitochondrial nucleotide pool resulting in the reduction of cytosolic synthesis of deoxyribonucleosides, causing the same MNGIE syndrome (19).
Both POLG1 and RRM2B are able to cause both autosomal dominant and autosomal recessive forms of progressive external ophthalmoplegia; pathogenic variants of RRM2B leading to the recessive forms of the disease are predicted to be loss-of-function whereas those associated with dominant inheritance are predicted to have dominant negative effects (19).
Pathogenic variants in POLG1 result in a reduction in polymerase gamma activity leading to stalling at the replication fork finally with mitochondrial DNA maintenance defects. POLG-related syndromes constitute a continuum of phenotypes from childhood to late adulthood. These disorders include, over autosomal recessive and autosomal dominant forms of progressive external ophthalmoplegia, Alpers-Huttenlocher syndrome, childhood myocerebrohepatopathy spectrum, POLG-related MNGIE, myoclonic epilepsy-myopathy-sensory ataxia, ataxia-neuropathy spectrum, and SANDO (Cohen et al 2018).
Maternally-inherited ophthalmoplegia may also be associated with point mutations, especially the m.3243A>G MELAS mutation, with or without other manifestations of that multisystem disease (53; 71; 98; 82) and mutations in other tRNA genes (54). Ophthalmoplegia is less often associated with MERRF (74; 89), being present in about 5% patients in an Italian cohort, whereas eyelid ptosis occurred in 25% of cases (50).
Other forms of ophthalmoplegia are also genetic, including autosomal dominant or recessive oculopharyngeal muscular dystrophy. Oculopharyngeal muscular dystrophy is a late-onset muscle disorder characterized by progressive ptosis of the eyelids, dysphagia, and proximal limb weakness. Most cases are transmitted in an autosomal dominant fashion, although some occur in a recessive or sporadic pattern (49).
Autosomal dominant oculopharyngeal muscular dystrophy is caused by short (GCG) 8-13 triplet-repeat expansions in the polyadenylation binding protein 2 (PABP2) gene, which is localized in chromosome 14q11 (08). In this triplet repeat disease, pathological expansions of the polyalanine tract may cause mutated PABP2 oligomers to accumulate as filamentous inclusions in nuclei. Normal alleles contain 10 GCN trinucleotide repeats. Autosomal dominant alleles range in size from 12 to 17 GCN repeats; autosomal recessive alleles comprise 11 GCN repeats (Trollet et al 2014). The triplet repeat is mitotically and meiotically stable, so expansion of the triplet repeat in meiosis is rare and clinical anticipation is not observed with this disease (Trollet et al 2014).
The variability of age of onset and severity of weakness may depend on the number of (GCN) repeats; this issue is debated. More severe presentations are for autosomal dominant forms; the most severe is reported in individuals who are homozygous for an autosomal dominant variant whereas autosomal recessive forms have a later onset and milder disease (Trollet et al 2014).
Oculopharyngodistal myopathy is characterized by progressive ptosis, external ophthalmoplegia, and weakness of the masseter, facial, pharyngeal, and distal limb muscles. In June 2020, Deng and coworkers identified an abnormal GGC repeat expansion in the 5' UTR of GIPC1 gene (15).
Ophthalmoplegia is common in congenital myopathies (40) and congenital myasthenia gravis (21) but rare in most forms of muscular dystrophy, myotonic dystrophy type 1 and 2, or spinal muscular atrophy (28).
The prevalence of all forms of childhood-onset (< 16 years of age) mitochondrial diseases has been estimated to range from 5 to 15 cases per 100,000 individuals (29).
A study performed in a cohort of North East of England determined that, in adults, the prevalence of mitochondrial diseases caused by mutations in mtDNA is estimated at 9.6 cases per 100,000 individuals and the prevalence of mitochondrial diseases caused by mutations in nDNA is 2.9 cases per 100,000 individuals (30).
In this study the number of adult cases per 100,000 individuals with a single, large-scale mtDNA deletion was 1.5 whereas the prevalence of autosomal dominant progressive external ophthalmoplegia was 0.7, point mutation of mtDNA was 3.5 for 3243A>G and 0.2 for 8344A>G, autosomal dominant OPA1 mutations was 0.4, autosomal recessive POLG-related disorders was 0.3, autosomal dominant RRM2B related disorders was 0.2, and adults with chronic progressive external ophthalmoplegia and multiple mtDNA deletions in muscle that have not been genetically determined was 0.2 (30).
In Italy, single deletions account for about a third of all 228 patients with mtDNA-related disease from the database of the ‘Nationwide Italian Collaborative Network of Mitochondrial Diseases, more than that suggested by a previously reported study (51).
Based again on the Nationwide Italian Collaborative Network of Mitochondrial Diseases database, which is the largest mito-cohort worldwide, among the 1400 patients with a fully reported clinical picture, ocular myopathy with eyelid ptosis and/or ophthalmoparesis was the first clinical feature observed in 42.8%. Among the 722 patients with a definite genetic diagnosis, the term “ocular myopathy” was present in 55.3% of cases, being positively associated with mtDNA single deletions (94.4% of patients with single deletion present ocular myopathy) and POLG mutations (82.6%). Ocular myopathy was less common in patients with OPA1 mutations (93.1% of patients with OPA1 mutation did not present ocular myopathy) and all the mtDNA point mutations (62.9%) (60). Among the patients with ocular myopathy, 32.8% of individuals had also an encephalomyopathy whereas 67.2% had no sign of central nervous system involvement. Age at onset was higher in the progressive external ophthalmoplegia group (28.1 ± 15.9 years) compared to the PEO-encephalomyopathy group (17.6 ± 18.3 years) (P < 0.05). The difference in male proportion (higher in the PEO-encephalomyopathic group) was also significant (p = 0.03) and is fully explained by the already known increased proportions of stroke-like episodes among m.3243A>G male patients, and the male proportion was significantly lower in pure progressive external ophthalmoplegia than PEO-plus (PEO patients with multisystem disease without signs of central nervous system involvement). Patients with “pure” progressive external ophthalmoplegia were 36.6% and did not show a different age at onset nor disease duration from the other progressive external ophthalmoplegia patients. In the PEO-encephalomyopathy group there was an increased prevalence of m.3243A>G carriers (66.7%) whereas single deletions (83.6%) and Twinkle (96%) mutations were associated with the PEO phenotype. Other rare nuclear and mtDNA mutations were usually associated with PEO-encephalomyopathic features (60).
Autosomal dominant oculopharyngeal muscular dystrophy is especially frequent in French Canadians (1:1000), and a founder effect has been demonstrated, but the condition is encountered worldwide. The highest gene frequency in found in Bukharan Jews settled in Israel (1:600); in the French general population, the prevalence is 1:100,000 (23; 01). In the United States the majority of affected individuals are of French-Canadian extraction, though a large number are also of other backgrounds including Jewish Ashkenazi and Spanish American in Texas, New Mexico, and California (Trollet et al 2014).
Autosomal recessive form of oculopharyngeal muscular dystrophy has a prevalence of 1:10,000 in France, Quebec, and Japan (Trollet et al 2014).
Prenatal diagnosis may be possible in Mendelian forms of progressive external ophthalmoplegia. Progressive external ophthalmoplegia itself is not a life-threatening condition, but it can be a serious disability. Kearns-Sayre syndrome is disabling and probably shortens longevity, but few patients have children (31; 69). Because oculopharyngeal muscular dystrophy is autosomal dominant and presymptomatic detection is feasible, genetic counseling should be considered.
The most common forms of ophthalmoplegia are recognized by distinctive clinical patterns and modes of inheritance. Clues to mitochondrial disorders include maternal inheritance and personal or family history of retinopathy, deafness, diabetes mellitus, short stature, or lipomatosis. Finding ragged-red fibers in the muscle biopsy implies a mitochondrial myopathy; vacuolar myopathy with characteristic tubules invokes oculopharyngeal muscular dystrophy. In some patients with oculopharyngeal dystrophy, limb weakness may be the first manifestation (94). The constellation of signs usually makes MNGIE evident, but the neuropathy may be mistaken for chronic inflammatory demyelinating polyneuropathy (CIDP) (06).
Among sporadic cases, a few prove to be due to Graves disease or myasthenia gravis.
Ophthalmic Graves disease may present with diplopia and subacute progression of mild to severely restricted extraocular motility but is recognized by exophthalmos and soft tissue signs; however, these clues are occasionally lacking and appropriate laboratory tests are needed. Extraocular muscles may be thickened on orbital imaging as opposed to atrophic muscles seen in progressive external ophthalmoplegia (84).
Myasthenia gravis can almost always be recognized by features that are not seen in PEO, including diurnal variation in severity of symptoms and signs, lack of lid atrophy, response to edrophonium, and association with thymoma or antibodies to acetylcholine receptor. These distinguishing features are important, because both PEO and myasthenia may be associated with dysarthria, dysphagia, and limb weakness.
When PEO is combined with evidence of multisystem disease (as in Machado-Joseph syndrome or other inherited spinocerebellar ataxias), the condition may be defined clinically, but other tests are needed for complete evaluation, including DNA analysis. Progressive supranuclear palsy is characterized by abnormal eye signs early in the course; this may progress to complete ophthalmoplegia, but by then there is evidence of parkinsonism, dementia, and corticospinal tract disease.
PEO is also associated with ataxia and peripheral neuropathy in abetalipoproteinemia. This can be suspected clinically by the clinical triad: childhood onset, retinopathy, and chronic fatty diarrhea. It can be identified preliminarily by finding a low value for serum cholesterol, finding evidence of malabsorption, and then demonstrating the absence of beta lipoprotein or by DNA analysis.
If the pupils do not react to light, the condition is called “complete ophthalmoplegia” and is not strictly “external”; complete ophthalmoplegia may be seen in some central disorders or in peripheral neuropathies.
Wernicke encephalopathy is characterized by the triad ophthalmoplegia, ataxia, and confusion and is due to thiamine deficiency, so thiamine supplementation can lead to improvement of the symptoms and often complete resolution.
Miller Fisher syndrome is a postinfectious, immune-mediated neuropathy characterized in typical instances by the clinical triad of ataxia, areflexia, and ophthalmoplegia; this disease is considered to be a variant of Guillain-Barre syndrome.
Oculomotor apraxia may simulate ophthalmoparesis. In children with gait and limb ataxia, those with oculomotor apraxia do not fixate normally. If asked to look to 1 side, they turn the head first, with contraversion of the eyes, and then the eyes follow to the same side in slow saccades with head thrusts. Ocular movements on command are slightly limited, and eye movement stops before reaching extreme positions of gaze. These slow eye movements appear equally on lateral and vertical gaze. If the head is immobilized, the eyes cannot move. Blinking is exaggerated. Ocular pursuit movements may be normal at first, but PEO often ensues. In ataxia with oculomotor apraxia type 1 (AOA1) (MIM 208920), the autosomal recessive mutation affects aprataxin (APTX) on chromosome 9p13.3. In a family, there was also CoQ10 deficiency (64; 65).
PEO may sometimes be attributed to environmental toxicity; for instance, the syndrome appeared in 5 patients who had been given antiretroviral therapy for 10 years and had no antibodies to AChR. Orbital MRI showed patchy bright signal within ocular muscles with “conserved volume”, as in PEO (62). It was not clear whether the disorder had been caused by the disease or drug.
Statins may cause myopathic toxicity, also with ptosis, diplopia, and/or ophthalmoplegia, with symptom resolution with drug cessation and possible symptom recurrence with reintroduction of the drug (24).
In the neurogenic multisystem diseases, the progressive ophthalmoplegia could still be myopathic, coexisting with neurogenic disease. One certainly neurogenic form of progressive ophthalmoplegia appears late in survivors of amyotrophic lateral sclerosis (56).
In presence of a positive family history of ophthalmoplegia, it may be possible to make a diagnosis of a mitochondrial disease or of oculopharyngeal muscular dystrophy (01).
All patients with sporadic PEO should have a limb muscle biopsy with specific histologic review for the ragged-red fibers of mitochondrial diseases and the filamentous inclusions of oculopharyngeal muscular dystrophy. A sample should be sent for analysis of mitochondrial DNA and, possibly, assay or mitochondrial enzymes. Muscle biopsy is also needed for the identification of other structurally specific myopathies that may cause ophthalmoplegia, such as central core, multicore, or nemaline myopathies (100). EMG evaluates possible limb myopathy. The family history should be scrutinized for possible evidence of maternal inheritance, considering that the same mutation mitochondrial DNA may be associated with different clinical syndromes in the same family. If MNGIE is a possible diagnosis, assay of blood thymidine level may be diagnostic (58).
Genetic testing may be performed in blood when a nuclear gene defect is suspected. If a mtDNA mutation is suspected, mtDNA sequencing should be performed from muscle specimen. Urine analysis could be useful for testing the m.3243A>G mutation. A new method to study the occurrence of mtDNA single deletion in urine has been presented, and the authors concluded that urine can be used to screen patients suspected clinically of having a single mtDNA deletion (97).
For Kearns-Sayre syndrome, tests include brain CT or MRI, ECG, cerebrospinal fluid examination, EMG, nerve conduction velocity, retinal examination, and audiogram. Identification of diabetes mellitus, hypoparathyroidism, or hypoadrenalism may have implications for treatment. For any mitochondrial disease, the family history should be scrutinized for evidence of maternal inheritance.
Biotin-thiamine-responsive basal ganglia disease is a multisystemic disorder, which may include PEO (86).
For possible myasthenia gravis, all patients with sporadic PEO should have an edrophonium test and measurement of antibodies to the acetylcholine receptor or anti-MUSK. Other tests might include the response to repetitive nerve stimulation and chest CT for possible thymoma. Congenital myasthenia may be manifest primarily by ophthalmoplegia, and there may not be a diagnostic response to edrophonium. Diagnosis depends on evaluation of endplate structure and physiology as well as genetic analysis of mutations in the subunits of the acetylcholine receptor; these sophisticated tests almost always require the collaboration of a research center.
To evaluate possible Graves disease, all patients with PEO should have thyroid function tests, including a test for thyroid-stimulating hormone.
In the correct clinical context, anti-GQ1b antibodies, present in more than 90% of Miller Fisher syndrome patients, are essentially diagnostic of Miller Fisher syndrome and are not associated with progressive external ophthalmoplegia.
In presence of chronic diarrhea or other evidence of malabsorption, tests should be done to evaluate the possibilities of abetalipoproteinemia or mitochondrial gastroneuropathy (ie, MNGIE). If ophthalmoplegia is associated with spinocerebellar or motor neuron signs, the correct diagnosis is usually clinically evident (56).
Although the clinical manifestations of mitochondrial diseases are diverse, only rarely do they replicate syndromes of motor neuron disease (34).
For the most part, management involves the treatment of symptoms. The major questions for all people with PEO are whether to elevate the lid surgically and how to do that. Surgical correction of the ptosis requires careful consideration due to the risks of postoperative corneal exposure or recurrence of ptosis due to the recurrent nature of the conditions.
There is debate about the indications for any surgery and for the different forms of lid surgery (99). Some prefer levator resection (42) or creation of a sling (73).
In a study published in 2013, Doherty and coauthors surgically treated 21 patients with PEO, 7 patients with myotonic dystrophy, and 1 with oculopharyngeal muscular dystrophy with 61 procedures comprising levator resection, brow suspension, anterior lamellar repositioning, lower lid elevation, and upper lid lowering. Palpebral aperture was significantly increased in all patient groups more significantly following brow suspension compared with levator resection. Postoperative complications were few, included corneal exposure and ulceration, ptosis recurrence, arched brow, and sling infection, all of which were successfully treated (17). In selecting the appropriate corrective procedure for these patients, levator function is usually a decisive factor given the progressive nature of the ptosis, such that early levator resection may not correct the ptosis in the long term (17).
Binocular diplopia and strabismus may be treated with prismatic glasses but also with surgery.
Cricopharyngeal myotomy is recommended for severe dysphagia (12), as well as the packaging of a percutaneous external gastrostomy.
Children with Kearns-Sayre syndrome are all candidates for a cardiac pacemaker; the major question is when to implant the pacemaker. Diabetes mellitus, hearing loss, and hypoparathyroidism may require specific treatment (32). Attention has to be given to cerebellar disability and school performance.
The diseases with malabsorption syndromes (abetalipoproteinemia) include severe neurologic disability. Some of the disability in these disorders and Kearns-Sayre syndrome can be reversed by vitamin E therapy, but nothing yet has been effective in other forms of PEO, although coenzyme Q has been given (67).
For MNGIE, beside hemodialysis and peritoneal dialysis, enzyme replacement therapy with encapsulated thymidine phosphorylase within erythrocytes in order to prolong the half-life of circulatory enzyme and reduce the immunogenic reactions has been tested in a single observational study without controls providing class 4 evidence of clinical benefit (05). In 1 patient the graft failed, but in a second patient, nucleoside levels decreased in blood and symptoms improved (35; 47). Based on high thymidine phosphorylase expression in the liver, a 25-year-old severely affected patient underwent liver transplantation. Serum levels of toxic nucleosides rapidly normalized. At 400 days of follow-up, the patient's clinical condition is stable, suggesting liver transplantation as a possible therapy for MNGIE (13).
Mitochondrially targeted zinc finger nucleases have been used for a form of gene therapy to alleviate PEO by site-specific elimination of pathogenic human mitochondrial DNA, with clinical improvement (26).
A small water-soluble mitochondrially-targeted tetrapeptide (D-Arg-dimethylTyr-Lys-Phe-NH2) able to scavenge mitochondrial reactive oxygen species to inhibit the mitochondrial permeability transition pore and to stabilize cardiolipin has been proposed in preclinical studies in heart and renal failure (39; 72), suggesting its possible role in experimental trials in mitochondrial diseases.
Preterm labor and hypertension have been reported (22).
Patients with isolated progressive external ophthalmoplegia usually tolerate general anesthesia without incident. However, in patients with progressive external ophthalmoplegia and more complex multisystem disease it is prudent to have cardiac and pulmonary screen prior to any surgery and anesthesia.
Emma Ciafaloni MD FAAN
Dr. Ciafaloni of the University of Rochester received personal compensation for serving on advisory boards and/or as a consultant for Alexion, Avexis, Biogen, PTC Therapeutics, Ra Pharma, Sarepta, Strongbridge Biopharma PLC, and Wave; and for serving on a speaker’s bureau for Biogen. Dr Ciafaloni also received research and/or grant support from Orphazyme, Santhera, and Sarepta.See Profile
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