Progressive external ophthalmoplegia

Abstract

Progressive external ophthalmoplegia (PEO), characterized by ptosis and impaired eye movements, is a clinical syndrome with an expanding number of etiologically distinct subtypes. Advances in molecular genetics have revealed numerous pathogenic causes of PEO, originally heralded in 1988 by the detection of single large-scale deletions of mitochondrial DNA (mtDNA) in skeletal muscle of people with PEO and Kearns–Sayre syndrome. Since then, multiple point variants of mtDNA and nuclear genes have been identified to cause mitochondrial PEO and PEO-plus syndromes, including mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) and sensory ataxic neuropathy dysarthria ophthalmoplegia (SANDO). Intriguingly, many of those nuclear DNA pathogenic variants impair maintenance of the mitochondrial genome causing downstream mtDNA multiple deletions and depletion. In addition, numerous genetic causes of nonmitochondrial PEO have been identified.

DEFINITION OF PROGRESSIVE EXTERNAL OPHTHALMOPLEGIA

Progressive external ophthalmoplegia (PEO, also known as chronic progressive external ophthalmoplegia [CPEO]) is a clinical syndrome that was defined by Lewis P. Rowland in the 1992 Handbook of Clinical Neurology by the following features: (1) progressive ptosis and impaired mobility of the eyes; (2) bilaterality; (3) affected muscles are innervated by more than one nerve; (4) pupils are spared; (5) gradual progression over months or years; and (6) there are no remissions or exacerbations (Rowland, 1992). In addition, “no evidence of a specific disorder” (e.g., myasthenia gravis, thyroid disorder, or myotonic dystrophy) was an exclusionary criterion. However, in the thirty-plus years since Rowland’s original definition, scientific advances—particularly in molecular genetics—have defined multiple etiologically distinct forms of PEO. Accordingly, exclusion of specific disorders has become less relevant to diagnosing PEO, while inclusion of genetically defined disorders has gained importance in delineating subtypes of this syndrome. Thus, this chapter focuses on molecular advances in our understanding of the causes and reclassification of subtypes of PEO that have been reported since the previous Handbook chapter on this subject. Because many of the PEO variants have been linked to pathogenic variants of mitochondrial or nuclear DNA that are critical for mitochondrial functions, it is appropriate to feature PEO in this Handbook of Clinical Neurology focused on mitochondrial diseases.

HISTORICAL BACKGROUND

The first case of PEO was described 1868 by Dr. Albrech von Gräefe, who reported a woman of unspecified age with partial ptosis and complete rigidity of both eyes, with preservation of pupillary muscles that appeared static over 6 years (Von Gräefe, 1868). The striking isolated symmetric extraocular muscle weakness was associated with absent to mild strabismus, without other systemic clinical manifestations. Dr. von Gräefe attributed the syndrome to defects in the ocular nerves, given muscle from a prior case with diplopia showed no macro- or microscopic abnormalities and because eye movements require little force from muscle. As well-documented in Dr. Rowland’s previous chapter (Rowland, 1992), subsequent reports of progressive ophthalmoplegia primarily attributed the condition to neuronal degeneration (Hutchinson, 1879; Beaumont, 1890; Wilbrand and Saenger, 1900; Langdon and Cadwalader, 1928; Marburg, 1936; Hassler, 1953); however, Dr. Ernst Fuchs suggested that the weakness was due to isolated muscular dystrophy based upon findings in a superior levator biopsy (Fuchs, 1890).

In the 1930s, reports of ophthalmoplegia in association with muscular dystrophy-like limb weakness (Martin, 1936; Elliott, 1939), followed by reports of histological evidence of myopathy (Sandifer, 1946; Kiloh and Nevin, 1951) with absence of pathology in oculomotor nuclei (Beckett and Netsky, 1953; Schwarz and Liu, 1954), indicated myopathic etiologies for PEO. Further complexity of PEO became evident with cases of ocular myopathy with neural involvement, including peripheral neuropathy, ataxia, or spinal cord involvement (Rosenberg et al., 1968), which Dr. David Drachman described as “ophthalmoplegia-plus” (Drachman, 1968). A clinically distinct form of ophthalmoplegia-plus, Kearns–Sayre syndrome, was characterized by the triad of external ophthalmoplegia, retinitis pigmentosa, and heart block (Kearns and Sayre, 1958).

The application of a modified-Gomori trichrome histochemical stain to skeletal muscle revealed ragged-red fibers (RRFs), a sign of abnormal proliferation of mitochondria in subsarcolemmal regions of the skeletal muscle of patients with progressive ophthalmoplegia (Olson et al., 1972), a seminal observation that indicated mitochondrial pathology as a key factor in many cases of PEO.

MITOCHONDRIAL PROGRESSIVE EXTERNAL OPHTHALMOPLEGIA (PEO)

After Dr. William Olson’s initial report of seven individuals with RRFs in “oculocraniosomatic neuromuscular disease,” multiple other case series reinforced the association of PEO with RRFs (DiMauro et al., 1973; Pongratz et al., 1979; Mussini et al., 1984; Petty et al., 1986; Rowland et al., 1991; Serratrice, 1991). The application of cytochrome c oxidase (COX, mitochondrial complex IV) and succinate dehydrogenase (SDH, mitochondrial complex II) histochemical stains revealed that many of the RRFs were COX-deficient and SDH-positive or had excessive SDH activity, so-called ragged-blue fibers (Olson et al., 1972; Muller-Hocker et al., 1983; Yamamoto and Nonaka, 1988; Mita et al., 1989; Reichmann et al., 1991).

PEO is one of the most common clinical manifestations of mitochondrial disease; in the Nation-wide Italian Collaborative Network of Mitochondrial Disease, more than half of the genetically confirmed mitochondrial disease subjects had ocular myopathy (399/722, 55.3%), while in the North American Mitochondrial Disease Consortium (NAMDC) Registry, over 20% of genetically diagnosed participants had ptosis (196/666, 29.4%) or PEO (137/666, 20.6%) (Orsucci et al., 2017; Barca et al., 2020).

Mitochondrial PEO begins insidiously and progresses slowly and symmetrically such that many patients are initially unaware of the problem, in part because many do not develop diplopia; one study reported that 8 of 52 patients (15%) with mitochondrial PEO were aware of abnormal extraocular motility, and only 5 of 49 (10%) with ophthalmoplegia had diplopia (Petty et al., 1986).

The seemingly straightforward task of defining PEO has dissenting opinions. While there is consensus that mitochondrial PEO is defined by the presence of ptosis, progressive external ophthalmoplegia, or, as in most cases, both (Moraes et al., 1989; Rowland et al., 1991; Rowland, 1992; Van Goethem et al., 2003b; Aure et al., 2007; Goldstein and Falk, 2013 [Updated 2019 Jan 31]), some clinicians view this syndrome as a pure extraocular myopathy (Mancuso et al., 2015; Orsucci et al., 2017). Others consider PEO to be a generalized myopathy with extraocular, oropharyngeal, and skeletal muscle involvement (Aure et al., 2007; Barca et al., 2020; Emmanuele et al., 2022). In the majority of mitochondrial PEO, skeletal muscles demonstrate some clinical weakness, mitochondrial histological abnormalities (RRF and COX-deficient myofibers), or genetic defects (e.g., single or multiple deletions or depletion of mtDNA) (Aure et al., 2007). Consequently, consensus criteria for mitochondrial syndromes defined mitochondrial PEO clinically by ptosis, PEO, or both, but noted limb myopathy, exercise intolerance, and dysphagia may also be present (Emmanuele et al., 2022).

In 1988, the ground-breaking identification of single large-scale deletions of mitochondrial DNA (mtDNA) by Drs. Ian Holt, Anita Harding, and John Morgan-Hughes heralded the molecular genetic era of mitochondrial disease research (Holt et al., 1988). Later that year, Drs. Massimo Zeviani, Salvatore DiMauro, Rowland, and colleagues as well as other groups reported the association of mtDNA single deletions with Kearns–Sayre syndrome and with PEO (Fig. 2.1) (Lestienne and Ponsot, 1988; Ozawa et al., 1988; Zeviani et al., 1988; Holt et al., 1989; Johns et al., 1989; Moraes et al., 1989). Subsequently, the phenotypic spectrum of mtDNA single deletions was expanded by the identification of these mutations in infants with Pearson syndrome, a severe, typically infantile onset sideroblastic anemia that is often fatal (Rötig et al., 1990; McShane et al., 1991). Follow-up of long-term survivors of Pearson syndrome developed PEO or KSS further broadening the clinical spectrum of mtDNA single deletions not only across affected individuals but within single patients.

Fig. 2.1.

Ophthalmoparesis in a patient with mitochondrial progressive external ophthalmoplegia due to a single mitochondrial DNA large-scale deletion. The patient has severely impaired upgaze and partially impaired lateral gaze most evident on left lateral gaze with sclera visible on abducting left eye. Mild right ptosis is accentuated on right lateral gaze. Blue arrows denote direction of eye movement.

While it is clear that mtDNA single deletions exhibit phenotypic diversity ranging from Pearson syndrome to isolated PEO and multisystemic KSS, this heterogeneity spans a spectrum rather than discrete entities with overlap cases with PEO-plus manifestations beyond myopathy, albeit not fulfilling criteria for KSS (Berenberg et al., 1977; Rowland et al., 1991; Rowland, 1992; Mancuso et al., 2015; Orsucci et al., 2017; Carelli and La Morgia, 2018).

Although the natural history of mitochondrial PEO has not been prospectively characterized, a retrospective analysis of 69 patients with PEO and mtDNA single large-scale deletions noted that 40 patients with PEO without neurological involvement had later onset (median: 17.5 years-old vs. 12 years-old with neurological manifestations) and slower progression (Aure et al., 2007). Most patients had initial onset of PEO with subsequent development of limb myopathy, dysphagia, and heart involvement, supporting the notion that mitochondrial pure PEO is less common than PEO with myopathy.

MRI scans of extraocular muscle have revealed that increased T1-weighted hyperintensity and T2 prolongation correlated severity of ophthalmoparesis indicating MRI biomarkers may be useful in assessing PEO progression in natural history studies and therapeutic clinical trials (Pitceathly et al., 2016). In a detailed study of 87 patients with single large-scale mtDNA deletions, Drs. John Grady, Robert McFarland and colleagues noted correlations between clinical and histological outcome measures with the size of the deletion, deletion heteroplasmy level, and location of the deletion (Grady et al., 2014); however, application of the mtDNA single-deletion features to predict outcome in individual patient is not yet feasible.

While mtDNA single deletions comprise the most frequent cause of PEO (Moraes et al., 1989; Rodriguez-Lopez et al., 2020), at least 35 distinct mtDNA point mutations as well as pathogenic variants in at least 12 nDNA genes can present with isolated PEO (Table 2.1) (Moraes et al., 1993; Hattori et al., 1994; Seibel et al., 1994; Laforet et al., 1995; Silvestri et al., 1996; Santorelli et al., 1997; Franceschina et al., 1998; Taylor et al., 1998; Tiranti et al., 1999; Kaukonen et al., 2000; Campos et al., 2001; Sahashi et al., 2001; Seneca et al., 2001; Spagnolo et al., 2001; Spelbrink et al., 2001; Van Goethem et al., 2001; Karadimas et al., 2002; Spinazzola et al., 2004; Zsurka et al., 2004; Smits et al., 2007; Sotiriou et al., 2009; Alston et al., 2010; Berardo et al., 2010; Souilem et al., 2010, 2011; Liu et al., 2011; Pinos et al., 2011; Gamba et al., 2012; Wolf et al., 2012; Blakely et al., 2013; Jackson et al., 2014; Hellebrekers et al., 2019; Schlapakow et al., 2019; Tarnopolsky et al., 2019; Joshi et al., 2020; O’Donnell et al., 2020; Rodriguez-Lopez et al., 2020; Visuttijai et al., 2021).

Table 2.1.

Differential diagnosis of mitochondrial progressive external ophthalmoplegia

Ocular myopathies

Mitochondrial progressive external ophthalmoplegia (PEO)

Single mitochondrial DNA deletion

Mitochondrial DNA depletion deletions syndrome (MDDS)

Polymerase gamma (POLG) disease

Thymidine kinase 2 deficiency

Mitochondrial DNA point mutations

Mitochondrial progressive external ophthalmoplegia plus (PEO-plus)

Kearns–Sayre syndrome (KSS)

Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE)

Sensory ataxic neuropathy dysarthria ophthalmoplegia (SANDO)

PEO, optic atrophy, and deafness

Other PEO-plus

Myotonic dystrophy types 1 and 2

Oculopharyngeal muscular dystrophy (OPMD)

Oculopharyngodistal myopathy (OPDM)

Congenital myopathies

Limb-girdle muscular dystrophy (LGMD) with ophthalmoplegia

Graves’ disease

Orbital myositis (orbital pseudotumor)

Neuromuscular Junction Disorders

Myasthenia gravis

Congenital myasthenia gravis

Lambert–Eaton myasthenic syndrome (LEMS)

Neurogenic ophthalmoplegia

Multiple sclerosis

Anti-GQ1b syndrome

Miller–Fisher syndrome

Congenital with facial diplegia (Moebius syndrome)

A-beta lipoproteinemia

Supranuclear ophthalmoplegia

Progressive supranuclear palsy (PSP)

Hereditary ataxias

Hereditary spastic paraplegia (HSP)

Spastic paraplegia 7 (SPG7) and rarely spastic paraplegia 35 (SPG35)

Spinocerebellar ataxia (SCA)

SCA 1, 2, 3, 7, 9, 11, 28

Most of the nuclear genes presenting with PEO are required for mtDNA maintenance as evident by the presence of mtDNA multiple deletions, depletion, or both in muscle and other postmitotic tissues (Lopez-Gomez et al., 2022). Pathogenic variants in POLG are the most frequent nDNA cause of PEO, which may be inherited in an autosomal dominant or recessive manner (Cohen et al., 1993; Van Goethem et al., 2001). While PEO due to POLG pathogenic variants may be the only manifestation, most individuals develop a generalized myopathy with proximal limb weakness, fatigue, and exercise intolerance. Furthermore, after initially presenting with PEO, people with autosomal POLG pathogenic variants often progress to develop PEO-plus with extra-muscular manifestations, such as peripheral neuropathy, ataxia, encephalopathy, and seizures (Van Goethem et al., 2001, 2003a; Lamantea et al., 2002; Horvath et al., 2006). Similarly, some individuals with autosomal dominant POLG pathogenic variants have PEO-plus with variable combinations and severity of sensorineural hearing loss, peripheral neuropathy, ataxia, depression, parkinsonism, hypogonadism, and cataracts (Luoma et al., 2004; Pagnamenta et al., 2006). One recurrent form of PEO-plus due to recessive POLG pathogenic variants is sensory ataxic neuropathy, dysarthria, and ophthalmoplegia (SANDO) (Fadic et al., 1997).

Other nDNA genes that cause PEO include SLC25A4, TWNK, POLG2, SPG7, DNA2, RNASEH1, TOP3A, TK2, DGUOK, RRM2B, and GMPR (Table 2.2) (Kaukonen et al., 2000; Saada et al., 2001; Spelbrink et al., 2001; Longley et al., 2006; Bourdon et al., 2007; Tyynismaa et al., 2009, 2012; Fratter et al., 2011; Ronchi et al., 2012, 2013; Paradas et al., 2013; Pfeffer et al., 2014; Wedding et al., 2014; Reyes et al., 2015; Feichtinger et al., 2017; Martin et al., 2018; Sommerville et al., 2020; Primiano et al., 2022).

Table 2.2.

Nuclear genes with pathogenic variants that cause mitochondrial progressive external ophthalmoplegia

Gene	Protein	PEO Phenotype	Inheritance	Reference
TYMP	Thymidine phosphorylase	MNGIE	AR	Nishino et al. (2000)
SLC25A4	Adenine nucleotide translocator 1	PEO	AD/AR	Kaukonen et al. (2000)
TK2	Thymidine kinase 2	PEO/PEO-plus	AR	Saada et al. (2001) and Garone et al. (2018)
DGUOK	Deoxyguanosine kinase	PEO	AR	Mandel et al. (2001) and Ronchi et al. (2012)
POLG	Polymerase gamma catalytic subunit	PEO/PEO-plus/SANDO/MNGIE-like	AD/AR	Van Goethem et al. (2001) and Van Goethem et al. (2003a)
TWNK	Twinkle	PEO	AD/AR	Spelbrink et al. (2001)
POLG2	Polymerase gamma subunit 2	PEO	AD/AR	Longley et al. (2006)
RRM2B	P53-subunit of ribonucleotide reductase	PEO/KSS/MNGIE-like	AD/AR	Bourdon et al. (2007) and Pitceathly et al. (2012)
OPA1	GTPase mitochondrial fusion	PEO-plus	AD	Hudson et al. (2008)
MGME1	Mitochondrial genome maintenance exonuclease 1	PEO/KSS	AR	Kornblum et al. (2013)
DNA2	DNA replication ATP-dependent	PEO	AD	Ronchi et al. (2013)
SPG7	Paraplegin	PEO-plus	AR	Wedding et al. (2014)
AFGL2	AFG3-like protein 2	PEO-plus	AD	Gorman et al. (2015)
RNASEH1	Ribonuclease H1	PEO/PEO-plus	AR	Reyes et al. (2015) and Bugiardini et al. (2017)
C1QBP	Complement component C1q binding protein	PEO	AR	Feichtinger et al. (2017)
TOP3A	DNA topoisomerase 3 alpha	PEO-plus	AR	Nicholls et al. (2018)
GMPR	GMP reductase 1	PEO	AD	Sommerville et al. (2020)
LIG3	Ligase III	MNGIE-like	AR	Bonora et al. (2021)
RRM1	Ribonucleotide reductase catalytic subunit	PEO/MNGIE-like	AD/AR	Shintaku et al. (2022)

Abbreviations: AD, autosomal dominant; AR, autosomal recessive; KSS, Kearns–Sayre syndrome; MNGIE, mitochondrial neurogastrointestinal encephalomyopathy; PEO, progressive external ophthalmoplegia; SANDO, sensory ataxic neuropathy dysarthria ophthalmoplegia.

Thymidine kinase 2 deficiency (TK2d), due to autosomal recessive TK2 pathogenic variants, presents as a clinical spectrum from early onset (beginning in the 1–4th year of life), rapidly progressive and fatal myopathy to a late-onset (after age 12 years) PEO, which often resembles PEO due to POLG pathogenic variants or single mtDNA deletions (Garone et al., 2018; Wang et al., 2018). However, early respiratory muscle involvement causing severe restrictive lung disease is characteristic of TK2d. Compassionate use of deoxynucleoside in TK2d patients suggests this may be an effective therapy (Dominguez-Gonzalez et al., 2019; Berardo et al., 2022).

KEARNS–SAYRE SYNDROME

The frequently cited historical criteria for KSS are an obligate triad of CPEO, pigmentary retinopathy, and onset before age 20 years plus at least one of the following three manifestations: cardiac conduction block, cerebellar ataxia, and elevated cerebrospinal fluid protein (>100 mg/dL) (Rowland et al., 1983, 1991). Shortcomings of this definition include the age-at-onset requirement, as some cases have had onset after age 20 (Hirano and DiMauro, 1996), and elevated CSF protein, which is rarely performed because molecular genetic testing provides definitive diagnosis is many cases via noninvasive testing (Emmanuele et al., 2022). Thus, a North American consensus paper has reverted to the original definition of KSS composed of the clinical tetrad: 1) PEO; 2) pigmentary retinopathy; 3) cardiac conduction block; and 4) skeletal muscle involvement (Kearns and Sayre, 1958; Emmanuele et al., 2022). While as many as 90% of KSS cases are due to mtDNA single deletions (Moraes et al., 1989), pathogenic variants in nDNA genes or mtDNA point mutations may present as KSS (Wilichowski et al., 1998; Seneca et al., 2001; Nishigaki et al., 2003; Pitceathly et al., 2011; Kornblum et al., 2013).

PEO-PLUS

In addition to the distinct cases of PEO and KSS, there are patients with mtDNA single deletions that have manifestations beyond PEO, but do not fulfill criteria for KSS and are therefore classified as PEO-plus (previously described as ophthalmoplegia-plus) (Table 2.2). Some individuals are transiently PEO-plus until they develop the full KSS phenotype (Aure et al., 2007). Furthermore, it has become clear that distinct PEO-plus syndromes are clinically recognizable and often linked to pathogenic variants in specific nuclear DNA (nDNA) genes, such as mitochondrial neurogastrointestinal encephalomyopathy (MNGIE), which is typically due to TYMP pathogenic variants, while sensory ataxic neuropathy dysarthria ophthalmoplegia (SANDO) has been linked primarily to POLG pathogenic variants (Table 2.2) (Drachman, 1968; Rosenberg et al., 1968; Rowland et al., 1991, 1997; Rowland, 1992; Fadic et al., 1997; Nishino et al., 1999; Hirano et al., 2001; McClelland et al., 2016; Viscomi and Zeviani, 2017; Lopez-Gomez et al., 2022). Pathogenic variants in OPA1 typically cause autosomal dominant optic atrophy; however, a subset of patients develop PEO and other neurological features in addition to optic neuropathy (Ferraris et al., 2008; Hudson et al., 2008; Yu-Wai-Man et al., 2010).

MITOCHONDRIAL NEUROGASTROINTESTINAL ENCEPHALOMYOPATHY (MNGIE)

MNGIE is clinically defined by PEO, gastrointestinal dysmotility, cachexia, peripheral neuropathy, and leukoencephalopathy, and supported by laboratory tests indicating mitochondrial dysfunction (elevated lactate in blood, cerebrospinal fluid, or both; mtDNA multiple deletions, deletions, or somatic point mutations; and RRF, COX-deficient fibers, or both in muscle) (Hirano et al., 2021). Autosomal recessive TYMP pathogenic variants cause loss of thymidine phosphorylase activity leading to accumulation of thymidine and deoxyuridine and mitochondrial deoxynucleoside triphosphate pool imbalances that cause mtDNA instability (Nishino et al., 1999; Spinazzola et al., 2002). Typically, the disease onset is in the late teens and progresses to fatality in the late-30s (Garone et al., 2011). Allogeneic hematopoietic stem cell transplantation (AHSCT) and liver transplantation decrease levels of the toxic nucleosides, thymidine and deoxyuridine, and may lead to stabilization or mild clinical improvements; however, due to high morbidity and mortality after AHSCT, liver transplantation is the more suitable option for most MNGIE patients (Halter et al., 2011; D’Angelo et al., 2020; Hirano et al., 2021). Patients with MNGIE or MNGIE-like phenotypes have been linked to pathogenic variants in POLG, RRM2B, and LIG3 (Van Goethem et al., 2003c; Shaibani et al., 2009; Bonora et al., 2021) as well as mtDNA point mutations (Gamez and Garces-Garmendia, 2005; Keilland et al., 2016).

SENSORY ATAXIC NEUROPATHY DYSARTHRIA OPHTHALMOPLEGIA (SANDO)

Originally reported as a distinct mitochondrial disease phenotype, Sensory Ataxic Neuropathy Dysarthria Ophthalmoplegia (SANDO) was initially linked to autosomal recessive pathogenic variants in POLG (Fadic et al., 1997; Van Goethem et al., 2003a). Rare subsequent cases of SANDO have been identified to be caused by pathogenic variants in C10orf2 and RNASEH1 (Hudson et al., 2005; Hanisch et al., 2015; Bugiardini et al., 2017).

NONMITOCHONDRIAL FORMS OF PEO

In addition to mitochondrial diseases, other neuromuscular disorders manifest PEO and need to be considered in the differential diagnosis of mitochondrial PEO (Table 2.1). Nonmitochondrial ocular myopathies include myotonic dystrophy, oculopharyngeal muscular dystrophy (OPMD), oculopharyngodistal myopathy (OPDM), congenital myopathies, limb-girdle muscular dystrophy, Graves’ ophthalmopathy, and orbital myositis (Rowland, 1992; Rowland et al., 1997). Myotonic dystrophy type 1 characteristically presents as a multisystemic disorder with distal limb weakness, myotonia, early cataracts, cardiac arrhythmias, endocrinopathies, daytime sleepiness, balding, and intellectual disabilities (Bird, 1993). Myotonic dystrophy type 1 is due to autosomal dominant expansions of a CTG trinucleotide repeat in DMPK. In contrast to type 1, type 2 myotonic dystrophy typically affects proximal and axial muscles, and less frequently affects nonmuscle tissues, and is caused by autosomal dominant expansions of a CCTG repeat in CNBP (Schoser, 1993). Oculopharyngeal muscular dystrophy (OPMD) is a late-onset disorder with ptosis, dysphagia, and proximal limb weakness with relatively mild ophthalmoparesis (Brais, 2011; Yamashita, 2021). OPMD is usually inherited in an autosomal pattern due to expansions of a GCN trinucleotide repeat in PABP1 (biallelic 11 repeats cause autosomal recessive OPMD, while heterozygous 12–18 repeats cause autosomal dominant OPMD). Oculopharyngodistal myopathy (OPDM) is an adolescent or adult-onset disorder with extraocular, facial, pharyngeal, and distal limb weakness due to expansions in CGG trinucleotide repeats in four genes: LRP12, GIPC1, NOTCH2NLC, and RIPL1 (Yu et al., 2022). Thus, expansions of tri- or tetra-nucleotide repeats in noncoding regions of genes are emerging as a recurrent cause of myopathies with PEO.

Inherited congenital myopathies that often manifest PEO in addition to limb and axial weakness include central core myopathy due to recessive RYR1 pathogenic variants, centronuclear myopathy due to X-linked recessive variants in MTM1, and autosomal dominant pathogenic variants in DNM2 (Claeys, 2020). Genetic congenital myasthenic syndromes with defects at the neuromuscular junction typically present with generalized weakness with prominent ptosis and ophthalmoparesis, and some forms present with isolated extraocular weakness (Estephan et al., 2022). Congenital fibrosis of extraocular muscles (CFEOM), Duane retraction syndrome, and Mobius syndrome are congenital cranial dysinnervation disorders presenting with ptosis at birth with variable restrictive and paretic strabismus due to genetic defects of embryological development of cranial neuromuscular units (Vivian, 2020).

Among the nongenetic causes of PEO, autoimmune ocular and generalized myasthenia gravis are the most frequent and can be clinically distinguished from genetic forms by acute to subacute onset and prominent fluctuation of symptoms, in contrast to the gradual onset and chronic slow progression of most genetic forms of PEO (Gilhus, 2016; Farmakidis et al., 2018; Pasnoor et al., 2018). The diagnosis can be confirmed in most cases by detection of autoantibodies against the acetylcholine receptor, muscle specific kinase, or lipoprotein-related protein 4 (LRP4), as well as electrophysiological studies. Thyroid-associated ophthalmopathy can present with ophthalmoparesis; however, most cases manifest eyelid retraction with signs of orbital inflammation, such as conjunctival erythema and swelling, periocular edema, and proptosis (Bahn, 2010; Liu et al., 2010).

CONCLUSIONS

In the three decades since the last Handbook of Clinical Neurology chapter on PEO (Rowland, 1992), there has been remarkable progress in delineating multiple genetic causes of this condition. In particular, pathogenic variants in mtDNA and nDNA that impair mitochondrial functions have emerged as frequent causes of isolated PEO, PEO-plus, and specific PEO-plus syndromes such as KSS, MNGIE, and SANDO. Several conclusions can be drawn from the genetic knowledge. Single large-scale deletions of mtDNA are the most frequent causes of sporadic mitochondrial PEO and KSS, while nDNA defects causing secondary defects of mtDNA maintenance are the most frequent causes of autosomal mitochondrial PEO and PEO-plus syndromes. Additional nonmitochondrial forms of PEO have also been genetically linked to expansions of tri- and tetra-nucleotide DNA repeats, as well as defects in genes required for development of the neuromuscular junction or cranial neuromuscular units. Further advances to develop therapies for PEO are needed.