Clinicogenetical Variants of Progressive External Ophthalmoplegia - An Especial Review of Non-ophthalmic Manifestations
Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/0028-3886.293454
Source of Support: None, Conflict of Interest: None
Keywords: Genetic, non-ophthalmic, progressive external ophthalmoplegia plus, progressive external ophthalmoplegia
Several mitochondrial disorders with or without PEO have been identified following the first disease attributable to mitochondrial dysfunction in 1962, i.e., the Kuft's disease (asthenia, progressive weakness, profound perspiration, high basic metabolism with large number of abnormal mitochondria in muscles).
In general, bilateral chronic progressive ophthalmoplegia is seen mostly with mitochondrial disorder known as PEO, thyroid ophthalmopathy, and oculopharyngeal/facioscapulohumeral dystrophies; sometimes in patients with myasthenia gravis, Lambert-Eaton syndrome and rarely with paraneoplastic brainstem encephalitis.
PEO is the most common manifestation of the mitochondrial myopathy, occurring approximately in two-third of patients and progress over 5–15 years. It affects all ages, but mostly young adults with ages between 18 and 40 years. As opposed to PSP that affects the vertical gaze and spares horizontal gaze, PEO involves all directions and is usually combined with weakness of eye closure, a combination that almost always indicates myopathy. Hutchinson's triad (weakness of frontalis muscle with compensatory chin elevation and bilateral ptosis) is characteristic. There is usually no diplopia or at most only transient diplopia. PEO is bilateral in majority of cases, but may be unilateral. Facial weakness presents in up to 25% and mild visual impairment in 95% of cases.,
PEO is sometimes a part of Kearns-Sayre or SANDO (sensory ataxic neuropathy, dysarthria, ophthalmoplegia) syndromes. Some patients develop neurological manifestations not fulfilling criteria for syndromes, thus are classified as PEO-plus. Possible association with sideroblastic anemia and exocrine pancreas dysfunction (Pearson syndrome) is other noticeable features.
Mitochondria are under the dual genetic control of both mitochondrial genome (mtDNA) and nuclear DNA. Mitochondrial DNA replicates continuously, so several thousand mtDNA copies with matrilineal transmission in each cell result in mitochondrial genotype. Point mutations of mtDNA exclusively account for the maternal lineage inheritance. Single deletions of mtDNA are often sporadic and have somatic origin, however were reported as maternal inheritance in some cases.,
A wide spectrum of clinical phenotypes ranging from ataxia, myopathy, and severe encephalopathy in infancy and childhood to late-onset PEO (progressive external ophthalmoplegia) are commonly associated with mutations of nuclear genes responsible in maintenance of mtDNA. Expectancy of an association between heterogeneous disorders caused by multiple mtDNA mutations and recessive or dominant mutations of POLG, SLC25A4, OPA1, RRM2B or TWNK genes is strongly increasing.
Adult-onset autosomal dominant PEO (adPEO) most commonly manifest with ptosis and ophthalmoparesis, multiple mtDNA deletions, cytochrome c oxidase (COX)–deficiency, and ragged-red fibers in muscle.
CPEO can be due to maternally inherited point mutations, sporadic single large-scale deletions, or primary autosomal dominant or rarely recessive mutations that cause secondary multiple deletions of mtDNA [Table 1].
Herein, we attempt to exhibit a categorization founded on genetic properties from a clinical point of view [Figure 1].
I. Many patients have an abnormality of mitochondrial DNA. Up to 60% of these cases are associated with large-scale rearrangements of mtDNA. In another 15% of cases the m. 3243G A>G (MT-TL1; tRNALeu) mutation is responsible. Other mtDNA point mutations have been linked to PEO (Twinkle) in isolated cases, which include following subtypes:
II. Autosomal-dominant PEO (adPEO) includes ragged-red muscular fibers with deficiency in respiratory chain and abnormal mitochondria along with multiple mtDNA deletions in post mitotic tissues. It contains variants with different subtypes such as:
Clinical correlation of various common mutations
The variety of clinical associations of CPEO has led to uncertainty about the nature of the disease. Although CPEO may encompass the clinical manifestations of a single metabolic defect, the disease may represent other different neurological components such as primary myopathy or denervation atrophy.
Adult-onset weakness of external eye muscles and exercise intolerance constitute the most frequent presentations of autosomal dominant PEO (adPEO). Wide spectrum of symptoms are allocated to adPEO including sensorineural hearing loss, cataracts, optic atrophy, sensory axonal neuropathy, Parkinsonism, ataxia, depression, and hypogonadism. However, adPEO is characterized by the exclusive or prevalent involvement of skeletal muscles.
Ataxia though being a core presentation of disorders related to POLG mutation and TWNK gene mutation (result in infantile-onset spinocerebellar ataxia), is an additional sign in many mitochondrial disorders. There was a report on a patient with POLG mutations presenting with ataxia, ophthalmoparesis, and some additional features, which was diagnosed based on MRI findings.
Broad spectrum of disorders, including the autosomal dominant and recessive forms of PEO, the autosomal recessive lethal Alpers syndrome, the mitochondrial recessive ataxia syndrome with and without ophthalmoplegia, ataxic neuropathy with dysarthria and ophthalmoparesis (SANDO), parkinsonism, and male infertility have been identified caused by Numerous mutations of POLG gene.
The affected individuals with the Leu98Pro substitution had a relatively mild clinical phenotype (mainly represented by PEO) compatible with a relatively long-life expectancy from a clinical point of view. The mean age at the onset of extraocular muscle involvement in all family members with the Leu98Pro substitution has been lower than that in previously described families with adPEO linked to chromosome 10q24 or SLC25A4.
Olsen et al. in a study of eight PEO patients with a single mtDNA deletion disclosed that six subjects had dystrophic changes in muscles, which deduce high mutation load (over 45% in their group) in PEO patients could be commonly associated with this finding. Other studies also revealed that in those PEO patients who possess a high mutation load, dystrophic involvement of the skeletal muscles was a frequent feature.
Unlike the study of Olsen et al., muscle biopsies of 62 from 86 PEO patients indicated specific mtDNA abnormalities and among them only three cases had this particular association (a much lower frequency, about 4.8%). Remarkable dystrophic changes were detected in skeletal muscles of these patients along with obvious proximal muscular weakness mimicking limb girdle muscular dystrophy (LGMD). There was a patient with dystrophic features, having COX negative fibers and a very high CK level (4762 IU/l), which haven't been reported in previous cases with A3251G mutation.
Inflammatory changes were demonstrated in muscle biopsy of an adult PEO man with an episode of sudden respiratory failure who had 3251A>G mtDNA mutation, which was reported by Mancuso et al.
In sporadic cases of PEO, large rearrangements and point mutations in mtDNA have been reported. In one case of PEO plus who affected by limb weakness, diabetes mellitus, macroglossia, and lipomas, there was a novel m. 4302A>G transition in MTTI.
Experts could not discern clear genotypic/phenotypic correlations in the patients with adPEO- PEO1 defect, and earlier onset of symptoms has not been associated with increased disease severity.
Non-ophthalmoplegic and systemic manifestations
Because of genetic heteroplasmy, the clinical manifestations of mitochondropathies are quite varied.
Autosomal-dominant PEO with onset in adulthood mostly represents as ptosis and ophthalmoparesis and frequently involve other organs (CPEO plus). Autosomal dominant progressive external ophthalmoplegia (adPEO) typically includes a generalized myopathy and often variable degrees of sensorineural hearing loss, axonal neuropathy, ataxia, depression, Parkinsonism, hypogonadism, and cataracts in what has been called “chronic progressive external ophthalmoplegia plus,” or “CPEO+” [Table 2].
Mitochondrial disease associated with inflammatory myopathy is very rare.
Remarkable and subacute progression of disease in a known case of typical PEO was reported, when the patient was 41 years old. There was subacute exacerbation of the symptoms which could not in favor of the disease course of PEO and manifested by difficulties in swallowing, speech, and elevating the head when lying on the bed. These were consequences of bulbar paralysis and weakness of neck extensor muscles. Evolution of oropharyngeal paresis is often occurring insidiously. Despite the routine sparing of axial muscles in course of the disease, severe neck weakness demonstrated in this patient. Subacute progression and the new clinical manifestations are more resembling acquired myopathy like myositis; however, the diagnosis of PEO cannot vindicate these features. Weakness of neck extensor muscles in myositis can lead to head drop. Although rare acute or advanced myositis can represent with dysphagia, choking episodes, and respiratory muscle weakness. In muscle biopsy, Raged-red fibers (RRFs) and COX-negative fibers accompanying with perivascular and perimysial inflammations confirmed the diagnosis. Following further surveys including CD4 and CD68 positive regions in immunohistochemical staining and inflammatory myopathy with mitochondrial dysfunction in pathology, the patient underwent prednisone regimen with a good therapeutic effect (bulbar paralysis and neck weakness were obviously improved). Post-treatment biopsy affirmed disappearance of the inflammation and immunohistochemical staining positive regions, concluding that based on all the evidences the patient involved with both PEO and myositis. Therefore, it isn't classic dermatomyositis or polymyositis and should be identified as inflammatory myopathy.
According to Sweeney et al. report from a family with PEO, there may be psychiatric symptoms and risk of sudden death in early adult life due to respiratory failure following muscle paralysis.
Another young patient died from rapidly progressive myopathy and cardiorespiratory failure but did not suffer from any extraocular muscle weakness.
Ciafaloni et al. reported a family with affected mother and daughter by PEO along with affective disorders in whom muscular tissue declared multiple deletions of mtDNA. They didn't study the brain tissue in their cases. Though a propensity to depression in patient's family members became divulged by the proband since the only one receiving psychiatric treatment.
Houshmand et al. studied 23 clinically diagnosed Iranian patients with CPEO of them 16 (69.6%) patients showed single deletion in the mtDNA, 2 (8.7%) subjects had G1423C mutation in the Twinkle gene without mtDNA multiple deletions and the remaining 5 (21.7%) did not reveal any deletions in the mtDNA or mutation in the Twinkle gene. Their study provides evidence that the investigation of mtDNA and Twinkle gene mutations in CPEO may help with early diagnosis and prevention of the disease. Generalized weakness of the skeletal muscles and sudden unexpected death are common clinical features of AdPEO.
There were rare reports about established dystrophic changes in skeletal muscles in mitochondrial myopathies as following: 1. a patient with Kearns-Sayre syndrome associated with multiple mtDNA deletions, 2.a patient complains from exercise intolerance and growth retardation related to m.4409 T>C mutation, 3.a patient with clinical mimicry of myotonic dystrophy who had m. 5650 G>A mutation.
Although cardiac conduction abnormality is considered as the main cardiovascular system involvement in PEO, some patients show left ventricular dysfunction which necessitate special attention in the management of the disease. Pulsed tissue Doppler imaging (TDI) offers an additional means to conventional echocardiography for assessing left ventricular diastolic function and to identify preclinical systolic myocardial involvement in PEO patients.
Rai N K et al. reported a 32-year-old lady with sporadic PEO with ragged red fibers (RRF) or ragged blue fiber (SDH equivalents) that afflicted by relapsing quadriplegia, cardiac septal hypertrophy, respiratory involvement, and requiring prolonged ventilator support.
A 57-year-old Swedish man was reported with autosomal dominant PEO and hypogonadism. This patient developed acute rhabdomyolysis and renal failure provoked by alcohol consumption. After hemodialysis he made a good recovery. A repeated alcohol intake resulted in a 57-fold increase in serum myoglobin (Mb) levels. This syndrome originally described by Lundberg.
Ohno et al. reported two Japanese brothers with inherited recurrent myoglobinuria provoked by strenuous physical exercise or fasting. They had RRFs, focal COX deficiency, and multiple mtDNA deletions. The Japanese patients did not have PEO or evidence of autosomal dominant inheritance. Multiple mtDNA deletions and the consequent defects of mitochondrial energy-transducing system were proposed causes of recurrent myoglobinuria.
In one case report related to deletion in mitochondrial DNA, asymmetric ophthalmoplegia, and unilateral myopathic facial paresis was depicted as an unusual manifestation of the PEO disease.
In Challa S, et al. study the most common clinical syndrome associated with RRFs on muscle biopsy was PEO with or without other signs in 38 (63%) patients. About 43% had only external ophthalmoplegia and 12 (20%) had PEO plus syndrome including 6 oculopharyngeal weakness, 5 myopathy, and 1 myoneuropathy. Six patients with PEO had associated myoclonus.
Specific syndromes were the presenting feature in 8 (13%); this was Kearns-Sayre syndrome (KSS) in 4 patients. Retinitis pigmentosa was noted in four patients with KSS.
Other reported phenotypes of PEO include rapidly progressive myopathy,,,,,, Esophageal contraction, Parkinsonism, cognitive deficit with behavioral disturbances, Levodopa responsive Parkinsonism, and endocrine dysfunction.
The disease involves both genders equally and children are mostly symptom free at birth. Remarkable features of KSS include early onset PEO and degenerative pigmentary retinopathy (usually during the first decades of life). Retinitis pigmentosa generally presents in atypical form with salt-and-pepper pattern of degeneration without the bony spicule appearance. Another manifestation of the disease is cardiac conduction disturbances (mostly cardiac conduction block) which usually develop after ophthalmoplegia. Other cardiac complications are intraventricular septal hypertrophy, mitral valve prolapse and left ventricle dysfunction. Patients should go under regular cardiovascular checkups, because of the risk of sudden cardiac death. Lactic acidosis may also occur.
The cardinal neurologic findings consist of cerebellar ataxia, obvious rise in CSF protein (>100 mg/dL), vestibular dysfunction, pendular nystagmus, hearing loss, and dementia.
These patients have impressive endocrine abnormalities such as short stature, diabetes, gonadal dysfunction, hypoparathyroidism, and hyperaldosteronism.
Pearson marrow-pancreas syndrome
Pearson syndrome is usually a fatal disorder of infancy that typically occurs in sporadic manner. It comprises sideroblastic anemia, exocrine pancreas dysfunction with or without Ophthalmoplegia. The phenotype often evolves into PEO or KSS in some surviving babies.
SANDO is a subgroup of mitochondrial CPEO-plus disorders associated with multiple mtDNA deletions, predominantly POLG mutation in skeletal muscle and peripheral nerve tissue. The patients have sensory ataxic neuropathy, dysarthria, and ophthalmoparesis with autosomal recessive pattern of inheritance and onset in adulthood. The presenting phenotype of the patients show wide spectrum, even within the same family. Despite various manifestations including seizures, myopathic weakness, and impaired hearing, the most common clinical feature of the disease seems to be sensory ataxia. Another similar disorder is spinocerebellar ataxia with epilepsy (SCAE) which has a higher frequency of migraine headaches and seizures.
PEO with parkinsonism
PEO seems to precede the onset of Parkinsonism, which can develop in various ages from 36 to 75 years. Although there was no correlation between the age of the onset of PEO and the onset of Parkinsonism, Parkinsonism seems to co-segregate with POLG mutations in some families with PEO. PET findings were consistent with dopaminergic neuronal loss and levodopa responsive parkinsonian symptoms. Other symptoms are peripheral neuropathy, cataract, and early menopause presenting in some patients.
An autosomal recessive syndrome named mitochondrial neuro-gastrointestinal encephalomyopathy (MNGIE) is result of a mutation in a gene called “TYMP”, encoding thymidine phosphorylase (TP). This disorder has relentlessly progressive course which usually begins in adolescence and increase tissue and plasma levels of thymidine and deoxy-uridine. Deceased subjects had the mean lifetime of 37 years. The disease often presents with peripheral neuropathy, mitochondrial myopathy with ptosis and PEO. Other important manifestations include severe cachexia caused by gastrointestinal dysmotility and leukoencephalopathy without cognitive regression.
In Infantile-onset spinocerebellar ataxia (IOSCA), children between 9 and 18 months develop acute or subacute ataxia, hypotonia, athetosis, and areflexia. Afflicted babies usually harboring mutations in PEO 1 and became wheelchair-bound until teenage years which can intermingle with other problems like optic atrophy, PEO, mental decline, sensorineural hearing loss, and sensory neuropathy and dysautonomic symptoms. Late-onset manifestations of the disease can vary from psychiatric symptoms to migraine type headaches and severe epilepsy.
The characteristics of each of Especial PEO syndromes with genetic and clinical characteristics are briefly summarized in [Table 3].
Chronic progressive external ophthalmoplegia (PEO) is a mitochondrial disorder characterized by ptosis, ophthalmoparesis, and proximal limb weakness. The most frequent molecular defect is a single large-scale mitochondrial DNA (mtDNA) deletion, which is associated with a benign course and without significant risk for other family members.
On the contrary, autosomal dominant PEO is due to mutations in the nuclear DNA genome and it usually manifests as more heterogeneous phenotypes that range from isolated PEO to multisystem disorders.
This type of PEO expresses exercise intolerance, cataracts, hearing loss, optic atrophy, ataxia, sensory axonal neuropathy, depressive mood, hypogonadism, and Parkinsonism. Most of these cases were initially reported as Kearns-Sayre syndrome (KSS), but KSS is inherited maternally. Other studies reported limb weakness, bulbar palsy, dystrophic muscular changes, anxiety, moderate cognitive dysfunction, sudden death from respiratory failure, tremor, Dupuytren's contractures, myositis, macrocytic anemia, diabetes mellitus, macroglossia, lipomas and reduced total gray matter and cerebellar volumes. Different genetic characteristics play important role in this clinical variability.
In summary, PEO includes a spectrum with three major presentations: pure PEO, special syndromes and PEO plus syndromes [Figure 2]. So, if physicians encounter patients with clinical manifestations of PEO which show additional features, they should further investigate PEO by muscle biopsy and genetic tests and should not rule out PEO at a first glance.
We would like to thank Saeid Latifi-Navid, Ph.D, Associate professor of medical molecular genetics in the University of Mohaghegh Ardabili, for genetic specialist consult and review.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3]