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CASE REPORT Table of Contents  
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Progressive external ophthalmoplegia – A case report


 Department of Pathology, SMS Medical College, Jaipur, Rajasthan, India

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Date of Submission05-Sep-2021
Date of Decision11-Jan-2022
Date of Acceptance12-Jun-2022
Date of Web Publication13-Jan-2023
 

   Abstract 


Progressive external ophthalmoplegia is a slowly progressive hereditary mitochondrial myopathy. Most mitochondrial disorders overlap clinically, enzymatically, and genetically. The most common enzyme defect is the combined deficit of complexes I and IV. Progressive external ophthalmoplegia particularly affects the extraocular muscles and is characterised by ophthalmoplegia, and bilateral ptosis. The ptosis and ophthalmoplegia is unresponsive to anticholinergics, with no effective treatment, but corrective surgery for ptosis as a palliative one. In this article, we report a rare case of a 16-year-old female with characterstic histological features consistent with progressive external ophthalmoplegia.

Keywords: Cytochrome-c oxidase negative, mitochondrial, muscle fibres, ophthalmoplegia, progressive external ophthalmoplegia, ragged red fibres


How to cite this URL:
Kaur A, Mathur K, Harsh A, Thakar K. Progressive external ophthalmoplegia – A case report. Indian J Pathol Microbiol [Epub ahead of print] [cited 2023 Feb 2]. Available from: https://www.ijpmonline.org/preprintarticle.asp?id=367711





   Introduction Top


Mitochondrial diseases are a particularly complex group of disorders caused by impairment of the electron transport chain (or respiratory chain) in the mitochondria. Phenotypes may range from pure myopathy to multi-systemic disorders, having a wide ranged age at onset, severity, and progression.[1] Progressive external ophthalmoplegia (PEO) is the most common manifestation of the mitochondrial myopathy, occurring approximately in two-third of patients and progress over 5–15 years.[2]

Von Graefel presented the first ocular condition characterized by progressive ptosis of the bilateral eyelids and progressive paralysis of the oculorotatory muscles in 1868. Later in 1879, Hutchinson described the same disease, and the classical “Hutchinsonian facies” associated with the disease.[3]


   Case Report Top


A16-year-old girl presented with slowly progressive bilateral ptosis starting during her teenage years and then noted progessive visual impairment in both eyes approximately five years prior to presentation. She was short statured and had history of delayed milestones. Family history was noncontributory. Her ptosis began unilaterally (left) at age of 13 years, became noticeably bilateral within a few years, and worsened progressively over the subsequent years. Ptosis showed no diurnal variation or remission or exacerbation. There was no history of diplopia. Ophthalmologic examination revealed marked bilateral ptosis (interpalpebral fissure width 3 mm on the right, 4 mm on the left). Pupils were equal and reactive to light and no relative afferent pupil defect was present. However, both eyes had total bilateral external ophthalmoplegia but retinal examination was normal. Visual acuity was 0.5 in the right eye and 0.4 in the left. An electromyogram showed findings consistent with a myogenic disorder. Magnetic resonance Imaging (MRI) brain was normal. Audiometry showed sensorineural hearing loss. It was low frequency loss in the right ear.

Cardiac tests showed normal ECG. Biopsy of the left vastus lateralis was done. Cryosections show relatively preserved fascicular architecture. There was mild variation in fiber size. No evidence of necrosis or inflammation or regenerating fibres was seen.

Enzyme histochemistry was performed on the cryosections. Cytochrome?c Oxidase (COX) stain shows presence of COX negative fibres. Modified Gomori trichrome stain showed presence of ragged red fibres. [Figure 2]b. Subsarcolemmal deposits are seen on NADHTR stain [Figure 2]c.COX ? SDH stain shows COX negative and SDH positive (blue)fibres. [Figure 2]d. Overall morphological features were in favour of mitochondrial myopathy.
Figure 2: (a) HE stained sections show relatively preserved fascicular architecture. (HE, 10×) (b) Sections show ragged red fibres. (MGT, 40×) (c) Subsarcolemmal deposit highlighted on NADHTR (NADHTR, 20×) (d) High power view showing COX negative, SDH positive fibres.(COX-SDH, 40×)

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The diagnosis of chronic PEO was established in view of clinical features and pathologically, by detection of ragged red fibers on modified Gomori trichrome stain and COX negative fibres in a muscle biopsy specimen.

After the clinical follow-ups with specialists based on clinical findings and biopsy features the patient was diagnosed as isolated PEO and is currently treated with coenzyme q10 and eye drops. She is advised to go for genetic testing by Next Generation Sequencing for confirmation. Her mother was advised to look out for any vision loss, heart symptoms or ataxia. Regular checkups were advised for the same. Corrective surgery for ptosis was also offered which the mother refused for the time.


   Discussion Top


PEO is a mitochondrial disorder characterized by ptosis, ophthalmoparesis, and proximal limb weakness. It affects all ages, but mostly young adults with ages between 18 and 40 years.[2] Onset of clinical manifestations in the present case is although early as compared to classical cases reported in literature but there was no pigmentary retinopathy or vision loss which is seen in Kearns-Sayre Syndrome.

The opthalmic features particularly ptosis was strictly permanent that is throughout the day and not precipitated by exercise or diurnal. Although it was bilateral, it was more prominent on the right side. [Figure 1] There was no fluctuation (exacerbation/remission), moreover treatment with anti-cholinergic drug showed no improvement ruling out myasthenia gravis.[4]
Figure 1: Bilateral ptosis in a patient of progressive external ophthalmoplegia. (right > left)

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Ophthalmoplegia was seen in all directions. As opposed to progressive supranuclear palsy 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.[2] Hutchinson's triad (weakness of frontalis muscle with compensatory chin elevation and bilateral ptosis) is characteristic,[2],[5] which is present in our case. There is usually no diplopia or at most only transient diplopia. PEO is bilateral in majority of cases, but may be unilateral.[2],[6]

The patient also had sensorineural (low frequency) hearing loss (right ear). The vast majority of patients with mitochondrial deafness have absent otoacoustic emission, providing strong evidence that the cochlea is the component most sensitive to mitochondrial dysfunction.[7]

Although HE stained sections showed relatively preserved fasicular architecture, the presence of ragged red fibres and COX negative fibres [Figure 2]d in the biopsy rules out oculopharyngeal muscular dystrophy and confirms the diagnosis of mitochondrial myopathy. Clinical features, against oculopharyngeal muscular dystrophy for young age, were absence of bulbar symptoms (dysphagia) and limb weakness.

Mitochondrial ocular myopathies are divided into two categories: Mitochondrial Ocular myopathies I (PEO & PEO plus) and mitochondrial ocular myopathies II (Pearson syndrome and Kearns-Sayre Syndrome).[1]

The present case has isolated ocular myopathy with neuromuscular involvement hence the diagnosis, PEO, and rules out PEO plus. PEO is associated with single deletion of mitochondrial Deoxyribonucleic acid (DNA) or a DNA Polymerase Gamma (POLG) mutation.

Pearson syndrome is a mitochondrial respiratory chain deficit characterised by exocrine pancreatic insufficiency and refractory sideroblastic anemia which were absent in the present case. Kearns-Sayre Syndrome spectrum comprise classic triad which is PEO, pigmentary retinopathy and age of onset less than 20 years. The extension of the syndrome involves clinical features of multiple systems. Signs and symptoms defining Kearns-Sayre Syndrome include tremor, hearing loss, cognitive involvement, failure to thrive/short stature, and cardiomyopathy,[1],[8] which are not seen in this case.

Chronic PEO 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 mitochondrial DNA. The most frequent molecular defect of PEO is a single large-scale mitochondrial DNA deletion, which is associated with a benign course and without significant risk for other family members.[2]

While the 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.

Although syndromic presentations have been associated with specific genetic alterations, the genotype–phenotype relationship in mitochondrial disorders is particularly complex because a single mutation can cause several different clinical syndromes, while each syndrome can be caused by different genetic alterations. Muscle biopsy is indespensible in unsolved and unclear cases after genetic studies. Hence, it is a cheap and cost effective alternative that can be used to avoid the enormous costly genetic testing required in mitochondrial myopathy.


   Conclusion Top


Clinical heterogeneity associated with mitochondrial disorders makes mitochondrial disorders a remarkably complex group of diseases. Since the mutations are enormous, biopsy is the gold standard and the most cost effective method in diagnosing mitochondrial myopathy.

Mitochondrial myopathy must be considered in any patient with progressive ptosis and loss of extraocular muscle functions, particularly if these problems arise during the early years of life. They should further be investigated by the clinicians for PEO by muscle biopsy and genetic tests and should avoid the use of immunosuppresants.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
   References Top

1.
Orsucci D, Ienco EC, Rossi A, Siciliano G, Mancuso M. Mitochondrial syndromes revisited. J Clin Med 2021;10:1249.  Back to cited text no. 1
    
2.
Maghbooli M, Ghaffarpour M, Ghazizadeh T, Shalbaf NA, MalekMahmoudi G. Clinicogenetical variants of progressive external ophthalmoplegia-An especial review of non-ophthalmic manifestations. Neurol India 2020;68:760-8.  Back to cited text no. 2
[PUBMED]  [Full text]  
3.
Axel HC, Jimmi LH. Chronic progressive external ophthalmoplegia. J Natl Med Assoc 1996;58:436-41.  Back to cited text no. 3
    
4.
Gonzalez-Moron D, Bueri J, Kauffman MA. Progressive external ophthalmoplegia (PEO) due to a mutation in the C10orf2 (PEO1) gene mimicking a myasthenic crisis. BMJ Case Rep 2013;2013:bcr2013010181.  Back to cited text no. 4
    
5.
Moraes CT, DiMauro S, Zeviani M, Lombes A, Shanske S, Miranda AF, et al. Mitochondrial DNA deletions in progressive external ophthalmoplegia and Kearns-Sayre syndrome. N Engl J Med 1989;320:1293-9.  Back to cited text no. 5
    
6.
El-Hattab AW, Adesina AM, Jones J, Scaglia F. MELAS syndrome: Clinical manifestations, pathogenesis, and treatment options. Mol Genet Metab 2015;116:4-12.  Back to cited text no. 6
    
7.
Scarpelli M, Zappini F, Filosto M, Russignan A, Tonin P, Tomelleri G. Mitochondrial sensorineural hearing loss: A retrospective study and a description of cochlear implantation in a MELAS patient. Genet Res Int 2012;2012:287432.  Back to cited text no. 7
    
8.
Mancuso M, Orsucci D, Angelini C, Bertini E, Carelli V, Comi GP, et al. Redefining phenotypes associated with mitochondrial DNA single deletion. J Neurol 2015;262:1301-9.  Back to cited text no. 8
    

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Correspondence Address:
Ashmeet Kaur,
23 Vidyut Nagar A, Prince Road, Ajmer Road, Jaipur, Rajasthan
India
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ijpm.ijpm_893_21



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    -  Mathur K
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    -  Thakar K


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