Pontine stroke in a patient with Chronic Progressive External Ophthalmoplegia (CPEO): a case report.

BACKGROUND: Chronic progressive external ophthalmoplegia (CPEO) is a mitochondrial disease with slowly progressive bilateral ptosis and symmetric ophthalmoplegia due to a genetic mutation that results in defective oxidative phosphorylation. Common genes that are implicated in CPEO include POLG, RRM2B, ANT1 and PEO1/TWNK. Here, we report a case of a patient diagnosed with CPEO caused by a novel mutation in PEO/TWNK after suffering a right pontine stroke. CASE PRESENTATION: A 70-year-old man with history of chronic progressive bilateral ptosis and ophthalmoplegia, as well as similar ocular symptoms in his father and grandfather, presented with acute onset of right hemifacial weakness and dysarthria. Brain MRI revealed an acute ischemic stroke in the right dorsal pons. The patient did not experience diplopia due to severe baseline ophthalmoplegia. Creatine kinase was elevated to 6,080 U/L upon admission and normalized over the course of one week; electromyography revealed a myopathic process. Genetic testing revealed a novel mutation c.1510G > A (p. Ala504Thr) in a pathogenic "hot spot" of the C10ORF2 gene (TWNK/PEO1), which is associated with CPEO. The mutation appears to be deleterious using several pathogenicity prediction tools. CONCLUSIONS: This case report describes a patient with late-onset CPEO caused by a novel, likely pathogenic, mutation in the TWNK gene. Although the patient presented with a pontine stroke, it manifested with solely new onset facial palsy, as he had a severe underlying ophthalmoplegia secondary to his CPEO.

Progressive external ophthalmoplegia.

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.

Exophthalmos associated with chronic progressive external ophthalmoplegia.

PURPOSE: Chronic progressive external ophthalmoplegia (CPEO) is a mitochondrial disease characterized by slowly progressive ptosis and limitations in ocular motility. Although exophthalmos is not considered to be a common feature of CPEO, this study focused on the incidence of exophthalmos in patients with CPEO. STUDY DESIGN: Retrospective observational case series METHODS: We reviewed the clinical charts of patients who received a diagnosis of CPEO sometime during the period between January 2010 and December 2018. CPEO was diagnosed on the basis of detection of a deletion of mitochondrial DNA (mtDNA) from saliva, buccal mucosa, or extraocular muscle specimens obtained during strabismus surgery. Horizontal MRI/CT images or Hertel ophthalmometry was used in determining exophthalmos. RESULTS: Seven patients (4 males) were identified. The mean age at diagnosis was 32.6 years (range 13-53 years). mtDNA deletion mutations were detected in the buccal mucous membrane DNA in 5 patients and in the saliva and extraocular muscle DNA in 2 patients. MRI/CT was recorded in 6 patients, four of whom showed exophthalmos (cases 1-4), and case 5 was determined as exophthalmos on the basis of a Hertel ophthalmometer reading. Exophthalmos was bilateral in 4 of the patients (cases 1, 2, 4, and 5) and unilateral in 1 patient (case 3). Exophthalmos was the chief concern of 2 of the patients; however, it was not clinically significant in the other patients. CONCLUSIONS: Although exophthalmos may not be recognized by either the patient or the clinician, it may be one of the common features of CPEO. A large multiethnic study should be performed.

Clinical and molecular spectrum associated with Polymerase-γ related disorders.

BACKGROUND: POLG pathogenic variants are the commonest single-gene cause of inherited mitochondrial disease. However, the data on clinicogenetic associations in POLG-related disorders are sparse. This study maps the clinicogenetic spectrum of POLG-related disorders in the pediatric population. METHODS: Individuals were recruited across 6 centers in India. Children diagnosed between January 2015 and August 2020 with pathogenic or likely pathogenic POLG variants and age of onset <15 years were eligible. Phenotypically, patients were categorized into Alpers-Huttenlocher syndrome; myocerebrohepatopathy syndrome; myoclonic epilepsy, myopathy, and sensory ataxia; ataxia-neuropathy spectrum; Leigh disease; and autosomal dominant / recessive progressive external ophthalmoplegia. RESULTS: A total of 3729 genetic reports and 4256 hospital records were screened. Twenty-two patients with pathogenic variants were included. Phenotypically, patients were classifiable into Alpers-Huttenlocher syndrome (8/22; 36.4%), progressive external ophthalmoplegia (8/22; 36.4%), Leigh disease (2/22; 9.1%), ataxia-neuropathy spectrum (2/22; 9.1%), and unclassified (2/22; 9.1%). The prominent clinical manifestations included developmental delay (n = 14; 63.7%), neuroregression (n = 14; 63.7%), encephalopathy (n = 11; 50%), epilepsy (n = 11; 50%), ophthalmoplegia (n = 8; 36.4%), and liver dysfunction (n = 8; 36.4%). Forty-four pathogenic variants were identified at 13 loci, and these were clustered at exonuclease (18/44; 40.9%), linker (13/44; 29.5%), polymerase (10/44; 22.7%), and N-terminal domains (3/44; 6.8%). Genotype-phenotype analysis suggested that serious outcomes including neuroregression (odds ratio [OR] 11, 95% CI 2.5, 41), epilepsy (OR 9, 95% CI 2.4, 39), encephalopathy (OR 5.7, 95% CI 1.4, 19), and hepatic dysfunction (OR 4.6, 95% CI 21.3, 15) were associated with at least 1 variant involving linker or polymerase domain. CONCLUSIONS: We describe the clinical subgroups and their associations with different POLG domains. These can aid in the development of follow-up and management strategies of presymptomatic individuals.

A novel homozygous frameshift mutation in the DCC gene in a Pakistani family with autosomal recessive horizontal gaze palsy with progressive scoliosis-2 with impaired intellectual development.

Horizontal Gaze Palsy with Progressive Scoliosis-2 with Impaired Intellectual Development (HGPPS2) is a rare congenital disorder characterized by absence of conjugate horizontal eye movements, and progressive scoliosis developing in childhood and adolescence. We report three new patients with HGPPS2 in a consanguineous Pakistani family, presenting varying degrees of progressive scoliosis, developmental delays, horizontal gaze palsy, agenesis of corpus callosum, and absence of cerebral commissures. Analysis of genotyping data identified shared loss of heterozygosity (LOH) region on chromosomes 5p15.33-15.31, 6q11.2-12, and 18q21.1-21.3. A hypothesis-free, unbiased exome data analysis detected an insertion of nucleotide A (c.2399dupA) in exon 16 of the DCC gene. The insertion is predicted to cause frameshift p.(Asn800Lysfs*11). Interestingly, DCC gene is present in the LOH region on chromosome 18. Variant (c.2399dupA) in the DCC gene is considered as the most probable candidate variant for HGPPS2 based on the presence of DCC in the LOH region, previously reported role of DCC in HGPPS2, perfect segregation of candidate variant with the disease, prediction of variant pathogenicity, and absence of variant in variation databases. Sanger Sequencing confirmed the presence of the novel homozygous mutation in all three patients; the parents were heterozygous carriers of the mutation, in accordance with an autosomal recessive inheritance pattern. DCC encodes a netrin-1 receptor protein; its role in the development of the CNS has recently been established. Biallelic DCC mutations have previously been shown to cause HGPPS2. A novel homozygous variant in patients of the reported family extend the genotypic and phenotypic spectrum of HGPPS2.

Cellular alterations identified in pluripotent stem cell-derived midbrain spheroids generated from a female patient with progressive external ophthalmoplegia and parkinsonism who carries a novel variation (p.Q811R) in the POLG1 gene.

Variations in the POLG1 gene encoding the catalytic subunit of the mitochondrial DNA polymerase gamma, have recently been associated with Parkinson's disease (PD), especially in patients diagnosed with progressive external ophthalmoplegia (PEO). However, the majority of the studies reporting this association mainly focused on the genetic identification of the variation in POLG1 in PD patient primary cells, and determination of mitochondrial DNA copy number, providing little information about the cellular alterations existing in patient brain cells, in particular dopaminergic neurons. Therefore, through the use of induced pluripotent stem cells (iPSCs), we assessed cellular alterations in novel p.Q811R POLG1 (POLG1Q811R) variant midbrain dopaminergic neuron-containing spheroids (MDNS) from a female patient who developed early-onset PD, and compared them to cultures derived from a healthy control of the same gender. Both POLG1 variant and control MDNS contained functional midbrain regionalized TH/FOXA2-positive dopaminergic neurons, capable of releasing dopamine. Western blot analysis identified the presence of high molecular weight oligomeric alpha-synuclein in POLG1Q811R MDNS compared to control cultures. In order to assess POLG1Q811R-related cellular alterations within the MDNS, we applied mass-spectrometry based quantitative proteomic analysis. In total, 6749 proteins were identified, with 61 significantly differentially expressed between POLG1Q811R and control samples. Pro- and anti-inflammatory signaling and pathways involved in energy metabolism were altered. Notably, increased glycolysis in POLG1Q811R MDNS was suggested by the increase in PFKM and LDHA levels and confirmed using functional analysis of glycolytic rate and oxygen consumption levels. Our results validate the use of iPSCs to assess cellular alterations in relation to PD pathogenesis, in a unique PD patient carrying a novel p.Q811R variation in POLG1, and identify several altered pathways that may be relevant to PD pathogenesis.

Strabismus surgery for diplopia in chronic progressive external ophthalmoplegia.

BACKGROUND: To report midterm outcomes of strabismus strategy for management of diplopia in chronic progressive external ophthalmoplegia and specific surgical planning rationale. DESIGN: Retrospective interventional case series. RESULTS: Two patients, a 26-year-old male and a 36-year-old female, diagnosed with chronic progressive external ophthalmoplegia presented with blepharoptosis and intermittent diplopia. Ocular motility examination was significant for bilateral profound impairment of adduction with relative preservation of abduction, infraduction and elevation. Control of intermittent exotropia gradually worsened over 3 and 1.5 years of follow-up, respectively, in the presence of documented stability of the angle of exodeviation. Strabismus surgery involving modest amounts of bilateral medial rectus resection and lateral rectus recessions was undertaken. Surgical intervention was successful in controlling alignment in primary position and alleviating diplopia and asthenopia after 9 and 8 years of follow-up time, respectively, despite slow progression of ophthalmoplegia. CONCLUSION: Bilateral selective impairment of adduction and intermittent exotropia may be the presenting ocular motility disturbance in chronic progressive external ophthalmoplegia. Properly designed strabismus surgery may provide sustainable, in the midterm, control of alignment and symptomatic relief in selected patients with CPEO.

Focal Segmental Glomerulosclerosis Associated with Chronic Progressive External Ophthalmoplegia and Mitochondrial DNA A3243G Mutation.

Focal segmental glomerulosclerosis (FSGS) is caused by various etiologies, with mitochondrial dysfunction being one of the causes. FSGS is known to be associated with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS), which is a subclass of mitochondrial disease. However, it has rarely been reported in other mitochondrial disease subclasses. Here, we reported a 20-year-old man diagnosed with FSGS associated with chronic progressive external ophthalmoplegia (CPEO) due to mitochondrial DNA (mtDNA) 3243A>G mutation. He presented with left ptosis, short stature, mild sensorineural deafness, and cardiac conduction block. A renal biopsy sample showed segmental sclerosis and adhesions between capillaries and Bowman's capsule, indicating FSGS. Electron microscopy demonstrated abnormal aggregated mitochondria in podocytes, and the basement membrane and epithelial cells of Bowman's capsule. Skeletal muscle biopsy also showed accumulation of abnormal mitochondria. mtDNA analysis identified heteroplasmic mtDNA 3243A>G mutation with no large-scale deletions. From these findings, we diagnosed the case as CPEO with multi-organ involvement including FSGS. Our report demonstrates that CPEO, as well as MELAS, can be associated with FSGS. Because mitochondrial disease presents with a variety of clinical symptoms, atypical cases with non-classical manifestations are observed. Thus, mitochondrial disease should be considered as an underlying cause of FSGS with systemic manifestations even with atypical phenotypes.

Surgical Technique for Pulled in Two Syndrome: Three Cases With Chronic Progressive External Ophthalmoplegia.

The authors describe three examples of "pulled in two syndrome" (PITS) from a series of 13 patients undergoing strabismus surgery with underlying chronic progressive external ophthalmoplegia (CPEO) and illustrate techniques for recovery of the "pulled in two" extraocular muscle should the complication arise. In all cases, a rectus muscle snapped under minimal tension while held on a strabismus hook during strabismus surgery. Two patients suffered from CPEO as a result of genetic mitochondrial disease, whereas one resulted from presumed mitochondrial toxicity induced by HAART. In cases 1 and 3, the proximal medial rectus segment was retrieved and reattached. In case 2, the fragmented superior rectus muscle was too friable to be reattached. All three patients were satisfied with the outcome, having reduced their angles of misalignment postoperatively. All three had improved cosmesis, and the two who had complained of diplopia preoperatively found their diplopia to be eliminated or improved. With anticipation of muscle friability in patients with previous extraocular surgery or degenerative muscle changes such as CPEO, the likelihood of the complication arising may be reduced. Should it occur, the loss of a snapped rectus muscle may be avoided through careful manipulation of the globe. [J Pediatr Ophthalmol Strabismus. 2017;54:e83-e87.].

Dysphagia is prevalent in patients with CPEO and single, large-scale deletions in mtDNA.

BACKGROUND: The aim of this study was to assess the frequency of subjective and objective dysphagia in patients with chronic progressive external ophthalmoplegia (CPEO) due to single, large-scale deletions (LSDs) of mitochondrial DNA (mtDNA). METHODS: Sixteen patients with CPEO and single LSDs of mtDNA were included in the study and compared to a control group of 12 patients with the m.3243A>G mtDNA mutation. Patients had to drink 80ml of water at 4°C as fast as they could (cold-water test) and fill out a standardized questionnaire about dysphagia. RESULTS: Eight patients (50%) with CPEO and single LSDs of mtDNA had a prolonged cold-water test, including one with a PEG-tube, who was unable to perform the test, and nine patients reported subjective swallowing problems (56.3%). 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. Dysphagia seems to be progressive with age as abnormal swallowing occurred preferentially in persons ≥45years. 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.

Horizontal Gaze Palsy and Progressive Scoliosis With ROBO 3 Mutations in Patients From Cape Verde.

Horizontal gaze palsy with progressive scoliosis (HGPPS) is a rare and autosomal recessive syndrome. We describe 2 cases of HGPPS which are the first documented in patients of African ancestry from an isolated population in Cape Verde. They demonstrated typical findings on neuro-ophthalmic examination and brain magnetic resonance imaging. One patient had novel heterozymous mutations of the ROB0 3 gene.

Correcting myogenic ptosis accompanying extraocular muscle weakness: The "Bobby Pin" procedure.

This article evaluates the "Bobby Pin" procedure in the correction of myogenic ptosis accompanying extraocular muscle weakness. We retrospectively reviewed 26 eyelids of 13 patients who underwent "Bobby Pin" procedure for myogenic ptosis accompanying extraocular muscle weakness. We evaluated the patients' clinical features such as age, etiology of ptosis, symptoms, standard ptosis measurements, associated systemic diseases, additional ophthalmic conditions, complications, and recurrence. Etiology of myogenic ptosis and extraocular muscle weakness was oculopharyngeal dystrophy in 4 (31%) patients, chronic progressive external ophthalmoplegia in 4 (31%) patients, myotonic dystrophy in 2 (23%) patients, and idiopathic in 3 (15%) patients. The mean levator function was approximately 5 mm pre- and post-operatively (range 1 to 12 mm). The mean margin-to-reflex distance 1 increased from -1.1 mm (below the light reflex) pre-operatively to +0.4 mm (above the light reflex) post-operatively. After a mean follow-up of 40 months, only 1 (8%) patient experienced ptosis recurrence. Upper eyelids were symmetric in both contour and height in all patients. Mild superficial keratopathy involving less than 10% of cornea was observed in 4 (31%) patients. The "Bobby Pin" procedure is an effective and long-lasting treatment option for correcting acquired ptosis accompanying extraocular muscle weakness. The procedure is safe, simple, easily learned, time- and cost-effective, and does not require any expensive equipment.

Horizontal gaze palsy and progressive scoliosis in a patient with congenital esotropia and inability to abduct. A case report. / Parálisis de la mirada horizontal y escoliosis progresiva en un paciente con endotropia congénita y limitación de abducción. A propósito de un caso.

CASE REPORT: The case is presented on a 4- year-old child with congenital esotropia, limitation of abduction, cross-fixation, and thoracolumbar scoliosis. Genetic testing of ROBO3 gene confirmed the diagnosis of horizontal gaze palsy and scoliosis (HGPSS) DISCUSSION: HGPPS is a rare congenital disorder characterised by absence of conjugate horizontal eye movements and progressive scoliosis developed in childhood and adolescence. We highlight this motility disorder as a part of the differential diagnosis of early childhood esotropia with cross- fixation and limitation of abduction.

Chronic Progressive External Ophthalmoplegia in the Absence of Ptosis.

Classically defined as bilateral, symmetric, and progressive ophthalmoparesis with myopathic ptosis, chronic progressive external ophthalmoplegia (CPEO) rarely has been reported in the absence of ptosis. We describe 2 patients with CPEO and without ptosis who presented with binocular diplopia related to small-angle esodeviations, poor fusional amplitudes, and slow saccades. In both cases, hematological studies and neuroimaging ruled out alternative etiologies, whereas muscle biopsy showed findings of mitochondrial myopathy.