Chronic progressive external ophthalmoplegia (CPEO) is considered to be one of the diseases enclosed in the group of mitochondrial disorders in the adult population [1]. Various mutations in the mitochondrial DNA, either in a familial or sporadic pattern, present the underlying cause of the disease [2] [3]. CPEO is by some authors regarded as a part of the continuum of the mitochondrial myopathy disease spectrum, together with CPEO plus and Kearns-Sayre syndrome [4]. The clinical presentation develops as a result of progressive muscle weakness [1] [4]. Extraocular muscle weakness is the cardinal manifestation of chronic progressive external ophthalmoplegia, manifesting as bilateral ptosis and limited eye movements [5]. Cataracts can sometimes be observed [5]. In addition to ocular symptoms, mitochondrial DNA mutations affect other structures including the skeletal muscles, the retina, and the cerebellum [1]. Generalized fatigue and painful movements of the limbs is reported by the majority of patients, which may be severe enough to limit daily activities and significantly impair the quality of life [1]. These complaints are the probable reason why depression may be encountered, another important constituent of the clinical presentation of CPEO [1] [5]. Defects of the cerebellum and the vestibulocochlear system may lead to symptoms such as ataxia and hearing loss [1] [4] [5]. Heart conduction disorders are also reported in a significant number of cases and are the hallmarks of a more severe phenotype of the disease.

• Weakness

  Before the treatment, except bilateral ptosis and external ophthalmopelgia, this patient presented bulbar muscle weakness and neck muscle weakness. [ncbi.nlm.nih.gov]

  @article{f8cb53383c8342d6803dc306d7dfc56d, title = "RE: “Unilateral Ptosis and Homolateral Hemifacial Weakness in Chronic Progressive External Ophthalmoplegia”", author = "Yen, {Michael T.} and Jennifer Murdock and Thyparampil, {Preeti Joseph}", year [scholars.northwestern.edu]

  The clinical presentation develops as a result of progressive muscle weakness. Extraocular muscle weakness is the cardinal manifestation of chronic progressive external ophthalmoplegia, manifesting as bilateral ptosis and limited eye movements. [symptoma.com]

• Fatigue

  CPEO patients reported a high frequency of severe fatigue (67.9%), pain (96.2%), depression (32.1%) and dependency in daily life (46.4%). [ncbi.nlm.nih.gov]

  […] p.Asn322LysfsX4 9 Yes 15 PEO, ptosis, dysphagia and fatigue 54 64 Mother, sister n.d. n.d. c.965dupA p.Asn322LysfsX4 9 Yes 15.1 Severe PEO, ptosis, facial weakness, fatigue and respiratory failure 60 s 74 Sister of Patient 15 COX deficient/RRF LRPCR [doi.org]

  Medial rectus 15 44 5 Single mtDNA deletion 2.3-kb deletion 54 No −3 Severe Mild myopathy, fatigue, migraine Levator 10 55 6 Single mtDNA deletion 2.9-kb deletion 49 No −3 Severe Mild myopathy, fatigue, cerebellar dysfunction Levator 15 50 7 Multiple [iovs.arvojournals.org]

  We ask about general symptoms (anxious mood, depressed mood, fatigue, pain, and stress) regardless of condition. Last updated: May 13, 2019 [patientslikeme.com]

• Progressive Ophthalmoplegia

  Retrospective review of the ophthalmic examination and genetic studies of a patient with chronic progressive ophthalmoplegia. [ncbi.nlm.nih.gov]

  Mitochondrial DNA deletions in progressive external ophthalmoplegia and Kearns-Sayre syndrome. N Engl J Med. 1989 May 18;320(20):1293-9. [disorders.eyes.arizona.edu]

  Acta Neurol Scand 58: 9–34 Google Scholar Bastiaensen LAK (1978) Chronic Progressive External Ophthalmoplegia,. Alphen a/d Rijn, Stafleu. [link.springer.com]

  Chronic progressive ophthalmoplegia with large-scale mtDNA rearrangement: can we predict progression?. Brain. 2007. Genetic and Rare Diseases Information Center, NIH [healthguideinfo.com]

  We report a case of an 18 year old male who had chronic progressive external ophthalmoplegia diagnosed as Kearns – Sayre syndrome. [ispub.com]

• Respiratory Insufficiency

  The patient had normal cardiac function, but a hypoxic restrictive respiratory insufficiency requiring mechanical, not invasive ventilation. A short trial with levodopa was ineffective. [academic.oup.com]

  Clinical presentation occurs in the first 6 months of life, with a multisystem disorder characterized by muscle hypotonia and weakness, seizures, gastrointestinal dysmotility, respiratory insufficiency, hearing loss, lactic acidosis, renal tubulopathy [doi.org]

• Vomiting

  […] breakdown of medium-chain fatty acids into acetyl-CoA → accumulation of fatty acyl- CoA in the blood → hypoketotic hypoglycemia Symptoms usually triggered by Clinical features Onset: within the first years of life Dehydration, poor feeding Hypotonia Vomiting [amboss.com]

  • Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) – Autosomal recessive CPEO in association with peripheral neuropathy, leukoencephalopathy and gastrointestinal symptoms (nausea, vomiting, diarrhea) • Myelonic epilepsy with ragged-red [entokey.com]

  Parikh is the Co-Director of the Cleveland Clinic Mitochondrial Clinic and the Cyclic Vomiting Syndrome Clinic. In 2007, Dr. Parikh was selected as one of "America's Best Doctors." [my.clevelandclinic.org]

  […] autonomic nervous system, and the enteral neural plexus may all be affected, leading to gastrointestinal tract manifestations, namely those involving disorders of peristalsis.[ 13-16 ] Typical manifestations include delayed gastric emptying with nausea and vomiting [bcmj.org]

  In addition to proximal muscle weakness, ataxia, and the eye signs, these patients have recurrent attacks of nausea, vomiting and abdominal pain that mimic intestinal obstruction, starting in young adulthood. [neuroophthalmology.ca]

• Nausea

  • Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) – Autosomal recessive CPEO in association with peripheral neuropathy, leukoencephalopathy and gastrointestinal symptoms (nausea, vomiting, diarrhea) • Myelonic epilepsy with ragged-red [entokey.com]

  This may be associated with nausea and headaches. Hearing loss, trouble with balance and coordination, seizures and learning deficits are common features of mitochondrial disease. [mda.org.au]

  […] the autonomic nervous system, and the enteral neural plexus may all be affected, leading to gastrointestinal tract manifestations, namely those involving disorders of peristalsis.[ 13-16 ] Typical manifestations include delayed gastric emptying with nausea [bcmj.org]

  In addition to proximal muscle weakness, ataxia, and the eye signs, these patients have recurrent attacks of nausea, vomiting and abdominal pain that mimic intestinal obstruction, starting in young adulthood. [neuroophthalmology.ca]

• Hearing Impairment

  A thirty-two year old female had chronic progressive external ophthalmoplegia (CPEO), exertional fatigue, dysarthria, dysphagia, and bilateral hearing impairment. [ncbi.nlm.nih.gov]

  "A novel mutation in the mitochondrial tRNA(Ser(UCN)) gene in a family with non-syndromic sensorineural hearing impairment". Journal of Medical Genetics 37(9):692-694. 74. Pulkes, T., Siddiqui, A., Morgan-Hughes, J. A. and Hanna, M. G. (2000). [mitomap.org]

• Blepharoptosis

  We present our experience with a case of blepharoptosis in CPEO. A 61-year-old woman presented with slowly progressive bilateral blepharoptosis. [ncbi.nlm.nih.gov]

  Author(s): Jonathan, Dutton, M.D., USA, M.D., Chapel Hill NC ICD10-Code: H49.4 Path: Lids -> Ptosis(Blepharoptosis) and Retraction -> Ptosis Additional keywords: Image ID: 5031 -------------------------- -------------------------- -------------------- [atlasophthalmology.net]

• Prolapse

  Mitral valve prolapse and ophthalmoplegia: a progressive, cardioneurologic syndrome. Ann Intern Med. Jun 1980;92(6):735-741. 13. Mullie MA, Harding AE, Petty RK, Ikeda H, Morgan-Hughes JA, Sanders MD. [eyewiki.aao.org]

  Cardiac abnormalities include idiopathic hypertrophic subaortic stenosis, mitral valve prolapse, and conduction block, and are responsible for sudden early deaths. Myopathic weakness of the face and limbs may occur. [neuroophthalmology.ca]

• Myopathy

  Discussion Kearns-Sayre Syndrome is a form of mitochondrial myopathy. [ispub.com]

  In conclusion, mitochondrial myopathy was definitely diagnosed. [ncbi.nlm.nih.gov]

  All mitochondrial myopathy patients in the control group had a normal duration of the cold-water test. Conclusions The study shows that dysphagia is a common problem in patients with CPEO and LSDs of mtDNA. [research.ku.dk]

• Muscle Weakness

  Before the treatment, except bilateral ptosis and external ophthalmopelgia, this patient presented bulbar muscle weakness and neck muscle weakness. [ncbi.nlm.nih.gov]

  (mild) and proximal muscle weakness 60 Died age 66 None 8% COX deficient/1% RRF LRPCR c.121C>T p.Arg41Trp 2 No 5 PEO, ptosis, ataxia, proximal muscle weakness, bulbar symptoms, facial weakness, IHD and sleep disorder 38 64 Sister 8% COX deficient/3% [doi.org]

  The clinical presentation develops as a result of progressive muscle weakness. Extraocular muscle weakness is the cardinal manifestation of chronic progressive external ophthalmoplegia, manifesting as bilateral ptosis and limited eye movements. [symptoma.com]

  Because the muscle weakness is symmetric, patients do not complain of diplopia. Rarely, ophthalmoplegia can be seen in the absence of ptosis. [mussenhealth.us]

• Chronic Progressive External Ophthalmoplegia

  Chronic Progressive External Ophthalmoplegia (CPEO) Diagnosis: Chronic Progressive External Ophthalmoplegia (CPEO) Comment to photo: Chronic progressive external ophthalmoplegia is a genetically inherited disorder characterized by upper eyelid ptosis [atlasophthalmology.net]

  Ophthalmoplegia (CPEO) Brief Description: This is a video presentation of the eyelid and eye movement findings in chronic progressive external ophthalmoplegia. [morancore.utah.edu]

  1 Teaching Video NeuroImages: MT-TL1 mutation presenting as chronic progressive external ophthalmoplegia. ( 30665919 ) 2019 2 Intracranial hypotension mimicking chronic progressive external ophthalmoplegia. ( 29300676 ) Vahdani K....Garrott H. 2018 3 [malacards.org]

  […] edit English chronic progressive external ophthalmoplegia human disease CPEO progressive external ophthalmoplegia PEO chronic progressive external ophthalmoplegia [Ambiguous] progressive external ophthalmoplegia (disorder) chronic progressive external [wikidata.org]

• Ataxia

  Extensive myasthenia and mitochondrial testing was unrevealing in addition to testing for the most common spinocerebellar ataxias. She was diagnosed with CPEO and cerebellar ataxia of unclear etiology. [collections.lib.utah.edu]

  2001 13 M PEO, ataxia 28 90 None 3% COX- deficient fibres LRPCR +ve c.1529C>T p.Ala510Val 11 McDermott et al., 2001 14 M Ataxia, spasticity u/k 55 MS (maternal uncle); mother -walking difficulties 1% COX- deficient fibres LRPCR +ve c.1067C>T p. [doi.org]

  It is defined by triad of clinical findings: onset before age 20, CPEO, pigmentary retinopathy plus any one of following: complete heart block, CSF protein>1.0g/I, cerebellar ataxia 1. Some patients may not fulfill all the criteria for KSS. [ispub.com]

  In conclusion, the SPG7 gene should be screened in patients in whom a disorder of mitochondrial DNA maintenance is suspected when spastic ataxia is prominent. [ncbi.nlm.nih.gov]

• Peripheral Neuropathy

  Numerous darkly staining central regions were noted in the ocular muscle fibers of a patient with Stephens syndrome (CPEO, peripheral neuropathy, and cerebellar disease) and in the reinnervated muscle. [ncbi.nlm.nih.gov]

  […] muscle weakness, sensorineural hearing loss, ataxia, peripheral Neuropathy, cardiomyopathy, cataracts, depression, and endocrine abnormalities. [annalsofian.org]

  Progression of the disorder is associated with specific neurological syndromes such as familiar form of spastic plegia, spinocerebellar disorder and sensorimotor peripheral neuropathy. [ic.steadyhealth.com]

  Peripheral neuropathy may affect sensory, motor, reflex, or blood vessel function. (For more information on this disorder, choose “peripheral neuropathy” as your search term in the Rare Disease Database.) [rarediseases.org]

  Peripheral neuropathy in patients with CPEO associated with single and multiple mtDNA deletions. Neurol Genet 2016;2:e113. 2. Kural MA, Pugdahl K, Fuglsang-Frederiksen A, Andersen H, Tankisi H. [ng.neurology.org]

• Cerebellar Ataxia

  This case highlights the cerebellar ataxia can occur in CPEO plus. [ncbi.nlm.nih.gov]

  It is defined by triad of clinical findings: onset before age 20, CPEO, pigmentary retinopathy plus any one of following: complete heart block, CSF protein>1.0g/I, cerebellar ataxia 1. Some patients may not fulfill all the criteria for KSS. [ispub.com]

  Key words: spinocerebellar ataxias, cerebellar atrophy, genotype, phenotype. [scielo.br]

  Extensive myasthenia and mitochondrial testing was unrevealing in addition to testing for the most common spinocerebellar ataxias. She was diagnosed with CPEO and cerebellar ataxia of unclear etiology. [collections.lib.utah.edu]

• Dysarthria

  We report a 44 years old male patient with more than 20 years of chronic progressive bilateral ptosis and limitation of eye movements manifested dysarthria, dysphagia and neck muscle weakness for 3 years. [ncbi.nlm.nih.gov]

  Initially, there was mild horizontal gaze limitation with mild gaze-evoked nystagmus and slow saccades, and over the years, gait ataxia and dysarthria (mainly a scanning quality to her speech) developed, and her ophthalmoparesis and slow saccades worsened [collections.lib.utah.edu]

  Dysarthria was common (four patients). [doi.org]

To make the diagnosis of a mitochondrial myopathy, the physician must perform a thorough clinical assessment, starting with a proper patient history. The onset of symptoms, their progression, as well as severity must be covered, as they can provide vital clues toward the diagnosis of myopathic disorders. When generalized weakness accompanied by muscle pain, ocular deficits, impaired coordination, and hearing loss are present, a more detailed investigation should be sought. An electrocardiogram (ECG) is useful for detecting heart conduction abnormalities. Imaging studies such as magnetic resonance imaging (MRI) of the head and MR spectroscopy may show atrophy of the cerebrum and cerebellum, as well as a reduced size of the extraocular muscles [4] [6] [7]. Nevertheless, these changes, although suggestive of mitochondrial myopathy, are not specific to CPEO [4]. For this reason, muscle biopsy and subsequent histopathological examination need to be performed [3] [5] [8] [9]. The biopsy will usually depict the presence of ragged red fibers and cytochrome c oxidase (COX)-deficient fibers, which are highly specific for a mitochondrial disease [5]. Approximately 25% of patients will have normal biopsy results, thus molecular genetic studies are considered to be the main method of confirming chronic progressive external ophthalmoplegia [3] [5] [8] [9].

The study shows that increased awareness of this symptom should be given to address appropriate treatment interventions and avoid complications such as social isolation, malnutrition and aspiration pneumonia. [research.ku.dk]

Effective treatment does not exist, and corrective surgery of the ptosis as a palliative measure is a treatment option. This was a retrospective study of 10 years' duration gathering patients with the diagnosis. [ncbi.nlm.nih.gov]

[…] for CPEO and treatment is mainly symptomatic. – Surgical treatment of severe ptosis can be beneficial in patients with CPEO. [entokey.com]

The prognosis and aetiology of the condition are discussed. [ncbi.nlm.nih.gov]

Prognosis Luckily, people with CPEO have a good prognosis and the disease should not effect other aspects of health. While the disease is progressive and symptoms tend to get worse over time, the severity of the disease differs with each patient. [healthguideinfo.com]

The MTTL1 gene is most often associated with the mitochondrial inheritance pattern, along with other mtRNA and mtDNA genes. [14] Prognosis The prognosis is guarded with a generally progressive disorder. [emedicine.com]

Conduction abnormalities have been successfully managed with pacemaker implantation. 6 In cases of severe cardiac dysfunction, heart transplant is an option. 28 Prognosis The visual prognosis for Kearns-Sayre syndrome is relatively good. [eyewiki.aao.org]

Significant pain, proptosis, or pupil involvement are not features of CPEO and should prompt evaluation for alternative etiologies. Mitochondrial DNA mutations are increasingly being recognized as the etiology for CPEO syndromes. [ncbi.nlm.nih.gov]

Alpha-1 antitrypsin deficiency (AAT deficiency) Definition : a congenital disorder characterized by the accumulation of defective alpha-1 antitrypsin enzyme Epidemiology : more common in individuals of European descent [1] Etiology : mutations in SERPINA1 [amboss.com]

In both cases, hematological studies and neuroimaging ruled out alternative etiologies, whereas muscle biopsy showed findings of mitochondrial myopathy. No Reference information available - sign in for access. [ingentaconnect.com]

April 2014 Volume 55, Issue 13 Free ARVO Annual Meeting Abstract | April 2014 A national epidemiological study of chronic progressive external ophthalmoplegia in the United Kingdom - molecular genetic features and neurological burden Author Affiliations [iovs.arvojournals.org]

MeSH terms, Substance MeSH terms Adult Audiometry, Pure-Tone DNA, Mitochondrial/genetics Evoked Potentials, Auditory Female Gene Deletion Hearing Loss, Sensorineural/epidemiology* Hearing Loss, Sensorineural/etiology* Hearing Loss, Sensorineural/physiopathology [ncbi.nlm.nih.gov]

Alpha-1 antitrypsin deficiency (AAT deficiency) Definition : a congenital disorder characterized by the accumulation of defective alpha-1 antitrypsin enzyme Epidemiology : more common in individuals of European descent [1] Etiology : mutations in SERPINA1 [amboss.com]

EPIDEMIOLOGY Incidence CPEO typically have an onset in childhood or early adolescence but they can occur at any age. [entokey.com]

Diagnosis: Chronic Progressive External Ophthalmoplegia (CPEO) - Kearns Sayre Syndrome EPIDEMIOLOGY Rare cause of chronic ptosis + ophthalmoplegia Usually present in 2nd decade of life SIGNS Ptosis with poor levator function Loss of Bell’s reflex (eyes [webeye.ophth.uiowa.edu]

Definition : a congenital disorder characterized by the accumulation of defective alpha-1 antitrypsin enzyme Epidemiology : more common in individuals of European descent [1] Etiology : mutations in SERPINA1 gene [1] Inheritance : autosomal codominant Pathophysiology [amboss.com]

Article navigation 1 1 Dino Ferrari Centre, Neuroscience Section, Department of Pathophysiology and Transplantation (DEPT), University of Milan, Neurology Unit, IRCCS Foundation Ca’ Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy Search for other [doi.org]

PATHOPHYSIOLOGY • The mitochondria is responsible for production of ATP by oxidative phosphorylation, the detoxification of reactive oxygen species, regulation of cell apoptosis, and other functions such iron metabolism, fatty acid oxidation, and amino [entokey.com]

Pathophysiology Mitochondrial DNA (mtDNA) encodes for essential components of the respiratory chain. [emedicine.com]

Retinal evaluation reveals disruption and atrophy of retinal photoreceptors as well as aberrant pigment distribution in all layers of the retina. 4, 5 Spongiform degeneration of the brain has been reported in multiple patients at autopsy. 6 Pathophysiology [eyewiki.aao.org]

A thorough ophthalmic history and examination before ptosis surgery may prevent the corneal complications resulting from surgical intervention. [ncbi.nlm.nih.gov]

In 2014, the Tax Increase Prevention Act passed, requiring the IRS to create a voluntary certification program (CPEO) for PEOs or companies that supply human resource benefits for their client’s workers. [surety1.com]

Research is ongoing to develop a way to prevent the transmission of mitochondrial DNA mutations to future children. [mda.org.au]

Are these tumors related to the MERRF and is there any way to try and prevent their growth? Speaker_-_Dr__Sumit_Parikh: Fatty tumors (lipomas) can be seen more commonly in certain mitochondrial disorders. There is no way to prevent these. [my.clevelandclinic.org]

1. Smits BW, Fermont J, Delnooz CC, Kalkman JS, Bleijenberg G, van Engelen BG. Disease impact in chronic progressive external ophthalmoplegia: more than meets the eye. Neuromuscul Disord. 2011;21(4):272-278.
2. Auré K. Ogier de Baulny H, Laforêt P, Jardel C, Eymard B, Lombès A. Chronic progressive ophthalmoplegia with large-scale mtDNA rearrangement: can we predict progression? Brain. 2007;130(Pt 6):1516-1524.
3. Wabbels B, Ali N, Kunz WS, Roggenkämper P, Kornblum C. Chronic progressive external ophthalmoplegia and Kearns-Sayre syndrome : interdisciplinary diagnosis and therapy [Article in German] Ophthalmologe. 2008;105(6):550-556.
4. Heidenreich JO, Klopstock T, Schirmer T, Saemann P, Mueller-Felber W, Auer DP. Chronic progressive external ophthalmoplegia: MR spectroscopy and MR diffusion studies in the brain. AJR Am J Roentgenol. 2006;187(3):820-824.
5. Chen T, Pu C, Shi Q, et al. Chronic progressive external ophthalmoplegia with inflammatory myopathy. Int J Clin Exp Pathol. 2014;7(12):8887-8892.
6. Wray SH, Provenzale JM, Johns DR, et al. MR of the brain in mitochondrial myopathy. Am J Neuroradiol 1995;16:1167-1173.
7. Carlow TJ, Depper MH, Orrison WW. MR of extraocular muscles in chronic progressive external ophthalmoplegia. Am J Neuroradiol 1998;19:95-99.
8. Kornblum C, Kunz WS, Klockgether T, Roggenkämper P, Schröder R. Diagnostic value of mitochondrial DNA analysis in chronic progressive external ophthalmoplegia (CPEO) [Article in German] Klin Monbl Augenheilkd. 2004;221(12):1057-1061.
9. Sundaram C, Meena AK, Uppin MS, et al. Contribution of muscle biopsy and genetics to the diagnosis of chronic progressive external opthalmoplegia of mitochondrial origin. J Clin Neurosci. 2011;18(4):535-538.