PEOA4
MCID: PRG040
MIFTS: 40

Progressive External Ophthalmoplegia with Mitochondrial Dna Deletions, Autosomal Dominant 4 (PEOA4)

Categories: Bone diseases, Ear diseases, Eye diseases, Fetal diseases, Genetic diseases, Metabolic diseases, Neuronal diseases, Rare diseases

Aliases & Classifications for Progressive External Ophthalmoplegia with Mitochondrial Dna...

MalaCards integrated aliases for Progressive External Ophthalmoplegia with Mitochondrial Dna Deletions, Autosomal Dominant 4:

Name: Progressive External Ophthalmoplegia with Mitochondrial Dna Deletions, Autosomal Dominant 4 57 13
Progressive External Ophthalmoplegia with Mitochondrial Dna Deletions, Autosomal Dominant, 4 74 72
Autosomal Dominant Progressive External Ophthalmoplegia with Mitochondrial Dna Deletions 4 29 6
Chronic Progressive External Ophthalmoplegia 74 72
Peoa4 57 74
Ophthalmoplegia, External, Progressive, with Mitochondrial Dna Deletions, Autosomal Dominant, Type 4 40
Progressive External Ophthalmoplegia, Autosomal Dominant 4 57
Progressive External Ophthalmoplegia Autosomal Dominant 4 74
Ocular Myopathy of Von Graefe-Fuchs 74
Mitochondrial Ocular Myopathy 74
Kearns-Sayre Syndrome 72
Graefe Disease 74
Cpeo 74

Characteristics:

OMIM:

57
Inheritance:
autosomal dominant

Miscellaneous:
variable severity
progressive disorder
variable age at onset (range infancy to adult)


HPO:

32
progressive external ophthalmoplegia with mitochondrial dna deletions, autosomal dominant 4:
Inheritance autosomal dominant inheritance
Onset and clinical course variable expressivity progressive adult onset


Classifications:



External Ids:

MeSH 44 D017246
MedGen 42 C1864668
UMLS 72 C0022541 C0162674 C1864668

Summaries for Progressive External Ophthalmoplegia with Mitochondrial Dna...

UniProtKB/Swiss-Prot : 74 Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant, 4: A disorder characterized by progressive weakness of ocular muscles and levator muscle of the upper eyelid. In a minority of cases, it is associated with skeletal myopathy, which predominantly involves axial or proximal muscles and which causes abnormal fatigability and even permanent muscle weakness. Ragged-red fibers and atrophy are found on muscle biopsy. A large proportion of chronic ophthalmoplegias are associated with other symptoms, leading to a multisystemic pattern of this disease. Additional symptoms are variable, and may include cataracts, hearing loss, sensory axonal neuropathy, ataxia, depression, hypogonadism, and parkinsonism.

MalaCards based summary : Progressive External Ophthalmoplegia with Mitochondrial Dna Deletions, Autosomal Dominant 4, also known as progressive external ophthalmoplegia with mitochondrial dna deletions, autosomal dominant, 4, is related to chronic progressive external ophthalmoplegia and kearns-sayre syndrome, and has symptoms including seizures, muscle weakness and myalgia. An important gene associated with Progressive External Ophthalmoplegia with Mitochondrial Dna Deletions, Autosomal Dominant 4 is POLG2 (DNA Polymerase Gamma 2, Accessory Subunit). The drug Ubiquinone has been mentioned in the context of this disorder. Affiliated tissues include skeletal muscle, liver and eye, and related phenotypes are seizures and failure to thrive

OMIM : 57 Progressive external ophthalmoplegia-4 is an autosomal dominant form of mitochondrial disease that variably affects skeletal muscle, the nervous system, the liver, and the gastrointestinal tract. Age at onset ranges from infancy to adulthood. The phenotype ranges from relatively mild, with adult-onset skeletal muscle weakness and weakness of the external eye muscles, to severe, with a multisystem disorder characterized by delayed psychomotor development, lactic acidosis, constipation, and liver involvement (summary by Young et al., 2011). For a general phenotypic description and a discussion of genetic heterogeneity of autosomal dominant progressive external ophthalmoplegia, see PEOA1 (157640). (610131)

Related Diseases for Progressive External Ophthalmoplegia with Mitochondrial Dna...

Diseases in the Progressive External Ophthalmoplegia with Mitochondrial Dna Deletions, Autosomal Recessive 1 family:

Progressive External Ophthalmoplegia with Mitochondrial Dna Deletions, Autosomal Dominant 1 Progressive External Ophthalmoplegia with Mitochondrial Dna Deletions, Autosomal Dominant 2
Progressive External Ophthalmoplegia with Mitochondrial Dna Deletions, Autosomal Dominant 3 Progressive External Ophthalmoplegia with Mitochondrial Dna Deletions, Autosomal Dominant 4
Progressive External Ophthalmoplegia with Mitochondrial Dna Deletions, Autosomal Dominant 5 Progressive External Ophthalmoplegia with Mitochondrial Dna Deletions, Autosomal Dominant 6
Progressive External Ophthalmoplegia with Mitochondrial Dna Deletions, Autosomal Recessive 2 Progressive External Ophthalmoplegia with Mitochondrial Dna Deletions, Autosomal Recessive 3
Progressive External Ophthalmoplegia with Mitochondrial Dna Deletions, Autosomal Recessive 4 Progressive External Ophthalmoplegia with Mitochondrial Dna Deletions, Autosomal Recessive 5

Diseases related to Progressive External Ophthalmoplegia with Mitochondrial Dna Deletions, Autosomal Dominant 4 via text searches within MalaCards or GeneCards Suite gene sharing:

(show top 50) (show all 123)
# Related Disease Score Top Affiliating Genes
1 chronic progressive external ophthalmoplegia 13.1
2 kearns-sayre syndrome 12.4
3 progressive external ophthalmoplegia with mitochondrial dna deletions, autosomal dominant 1 12.1
4 progressive external ophthalmoplegia with mitochondrial dna deletions, autosomal dominant 2 12.1
5 progressive external ophthalmoplegia with mitochondrial dna deletions, autosomal dominant 3 12.1
6 ocular muscular dystrophy 11.9
7 mitochondrial dna-related progressive external ophthalmoplegia 11.9
8 strabismus 11.7
9 progressive external ophthalmoplegia with mitochondrial dna deletions, autosomal recessive 1 11.7
10 progressive external ophthalmoplegia with mitochondrial dna deletions, autosomal recessive 2 11.6
11 ptosis 10.8
12 myopathy 10.8
13 mitochondrial myopathy 10.7
14 mitochondrial disorders 10.6
15 mitochondrial metabolism disease 10.5
16 dysphagia 10.5
17 mitochondrial encephalomyopathy 10.4
18 mechanical strabismus 10.4
19 branchiootic syndrome 1 10.4
20 neuropathy 10.4
21 ataxia and polyneuropathy, adult-onset 10.3
22 optic nerve disease 10.3
23 lactic acidosis 10.3
24 myasthenia gravis 10.3
25 retinitis pigmentosa 10.3
26 aceruloplasminemia 10.3
27 ataxia, combined cerebellar and peripheral, with hearing loss and diabetes mellitus 10.3
28 neuroretinitis 10.3
29 alternating exotropia 10.3
30 exotropia 10.3
31 retinitis 10.3
32 encephalopathy 10.3
33 hereditary optic neuropathy 10.3
34 3-methylglutaconic aciduria, type iii 10.2
35 lagophthalmos 10.2
36 peripheral nervous system disease 10.2
37 keratitis, hereditary 10.1
38 mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes 10.1
39 sensory ataxic neuropathy, dysarthria, and ophthalmoparesis 10.1
40 atrioventricular block 10.1
41 sensorineural hearing loss 10.1
42 movement disease 10.1
43 exophthalmos 10.1
44 exposure keratitis 10.1
45 muscular dystrophy 10.1
46 myotonic dystrophy 10.1
47 mitochondrial encephalomyopathy lactic acidosis and stroke-like episodes 10.1
48 myotonia atrophica 10.1
49 alzheimer disease 10.0
50 progressive familial heart block, type ia 10.0

Graphical network of the top 20 diseases related to Progressive External Ophthalmoplegia with Mitochondrial Dna Deletions, Autosomal Dominant 4:



Diseases related to Progressive External Ophthalmoplegia with Mitochondrial Dna Deletions, Autosomal Dominant 4

Symptoms & Phenotypes for Progressive External Ophthalmoplegia with Mitochondrial Dna...

Human phenotypes related to Progressive External Ophthalmoplegia with Mitochondrial Dna Deletions, Autosomal Dominant 4:

32 (show all 23)
# Description HPO Frequency HPO Source Accession
1 seizures 32 occasional (7.5%) HP:0001250
2 failure to thrive 32 occasional (7.5%) HP:0001508
3 constipation 32 occasional (7.5%) HP:0002019
4 global developmental delay 32 occasional (7.5%) HP:0001263
5 gastroesophageal reflux 32 occasional (7.5%) HP:0002020
6 generalized hypotonia 32 occasional (7.5%) HP:0001290
7 elevated hepatic transaminase 32 occasional (7.5%) HP:0002910
8 gastroparesis 32 occasional (7.5%) HP:0002578
9 cerebellar atrophy 32 occasional (7.5%) HP:0001272
10 cerebral visual impairment 32 occasional (7.5%) HP:0100704
11 ptosis 32 HP:0000508
12 facial palsy 32 HP:0010628
13 arrhythmia 32 HP:0011675
14 myalgia 32 HP:0003326
15 increased serum lactate 32 HP:0002151
16 progressive external ophthalmoplegia 32 HP:0000590
17 exercise intolerance 32 HP:0003546
18 limb muscle weakness 32 HP:0003690
19 progressive muscle weakness 32 HP:0003323
20 cytochrome c oxidase-negative muscle fibers 32 HP:0003688
21 elevated serum creatine kinase 32 HP:0003236
22 impaired glucose tolerance 32 HP:0040270
23 multiple mitochondrial dna deletions 32 HP:0003689

Symptoms via clinical synopsis from OMIM:

57
Head And Neck Eyes:
ptosis
external ophthalmoplegia, progressive (peo)
cortical blindness (1 patient)

Muscle Soft Tissue:
exercise intolerance
limb muscle weakness
muscle pain
facial muscle weakness
muscle weakness, progressive
more
Cardiovascular Heart:
cardiac conduction defects

Growth Other:
failure to thrive (in some patients)

Abdomen Liver:
liver disease (in some patients)

Laboratory Abnormalities:
increased serum lactate
increased serum creatine kinase
abnormal liver enzymes (in some patients)

Endocrine Features:
impaired glucose tolerance

Neurologic Central Nervous System:
seizures (in some patients)
developmental delay (in some patients)
hypotonia (in some patients)
cerebellar atrophy (1 patient)

Abdomen Gastrointestinal:
gastroesophageal reflux (in some patients)
constipation (in some patients)
delayed gastric emptying (in some patients)

Clinical features from OMIM:

610131

UMLS symptoms related to Progressive External Ophthalmoplegia with Mitochondrial Dna Deletions, Autosomal Dominant 4:


seizures, muscle weakness, myalgia, ophthalmoplegia, cerebellar ataxia, facial paresis

Drugs & Therapeutics for Progressive External Ophthalmoplegia with Mitochondrial Dna...

Drugs for Progressive External Ophthalmoplegia with Mitochondrial Dna Deletions, Autosomal Dominant 4 (from DrugBank, HMDB, Dgidb, PharmGKB, IUPHAR, NovoSeek, BitterDB):


# Name Status Phase Clinical Trials Cas Number PubChem Id
1 Ubiquinone

Interventional clinical trials:


# Name Status NCT ID Phase Drugs
1 A Phase Ia/Ib, Multiple-site Study to Assess the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of KL1333 After a Single and Multiple Ascending Oral Doses in Healthy Subjects and Patients With Primary Mitochondrial Disease Recruiting NCT03888716 Phase 1 KL1333;Placebo Oral Tablet
2 Clinical Characteristics and Prognostic Factors of Mitochondrial nt3243 A>G Mutation in Taiwan Unknown status NCT02114554
3 Magnetic Resonance Imaging Study of Patients With Chronic Progressive External Ophthalmoplegia Completed NCT02161848
4 Effect Of The System In The Enriched Fat Metabolism Of The Child Reached Mitochondrial Cytopathy Completed NCT02385565
5 Nutritional Assessment in Patients Affected by Mitochondrial Cytopathy Completed NCT02375438
6 Can Metagenomic and Metadata be Combined Using Bioinformatics and Computational Biology Methods to Personalise Patient Treatment. Completed NCT03213067
7 North American Mitochondrial Disease Consortium Patient Registry and Biorepository (NAMDC) Recruiting NCT01694940
8 Foundation Fighting Blindness Registry, My Retina Tracker Recruiting NCT02435940
9 Rare Disease Clinical Research Network Natural History of Pearson Syndrome North American Mitochondrial Disease Consortium (NAMDC) Enrolling by invitation NCT02327364

Search NIH Clinical Center for Progressive External Ophthalmoplegia with Mitochondrial Dna Deletions, Autosomal Dominant 4

Genetic Tests for Progressive External Ophthalmoplegia with Mitochondrial Dna...

Genetic tests related to Progressive External Ophthalmoplegia with Mitochondrial Dna Deletions, Autosomal Dominant 4:

# Genetic test Affiliating Genes
1 Autosomal Dominant Progressive External Ophthalmoplegia with Mitochondrial Dna Deletions 4 29 POLG2

Anatomical Context for Progressive External Ophthalmoplegia with Mitochondrial Dna...

MalaCards organs/tissues related to Progressive External Ophthalmoplegia with Mitochondrial Dna Deletions, Autosomal Dominant 4:

41
Skeletal Muscle, Liver, Eye, Retina, Brain, Heart, Thyroid

Publications for Progressive External Ophthalmoplegia with Mitochondrial Dna...

Articles related to Progressive External Ophthalmoplegia with Mitochondrial Dna Deletions, Autosomal Dominant 4:

(show top 50) (show all 511)
# Title Authors PMID Year
1
Biochemical analysis of human POLG2 variants associated with mitochondrial disease. 8 71
21555342 2011
2
Mutant POLG2 disrupts DNA polymerase gamma subunits and causes progressive external ophthalmoplegia. 8 71
16685652 2006
3
Mitochondrial DNA Maintenance Defects Overview 71
29517884 2018
4
Analysis of protein-coding genetic variation in 60,706 humans. 71
27535533 2016
5
Exome sequencing identifies a novel missense variant in RRM2B associated with autosomal recessive progressive external ophthalmoplegia. 71
21951382 2011
6
RRM2B mutations are frequent in familial PEO with multiple mtDNA deletions. 71
21646632 2011
7
A PRIMPOL mutation and variants in multiple genes may contribute to phenotypes in a familial case with chronic progressive external ophthalmoplegia symptoms. 38
31348995 2019
8
Chronic Progressive External Ophthalmoplegia and Bilateral Vestibular Hypofunction: Balance, Gait, and Eye Movement Before and After Multimodal Chiropractic Care: A Case Study. 38
31367202 2019
9
Distinct segregation of the pathogenic m.5667G>A mitochondrial tRNAAsn mutation in extraocular and skeletal muscle in chronic progressive external ophthalmoplegia. 38
30962064 2019
10
Optical coherence tomography findings in chronic progressive external ophthalmoplegia. 38
31140991 2019
11
Exophthalmos in Kearns-Sayre syndrome. 38
31158487 2019
12
Muscle pain in mitochondrial diseases: a picture from the Italian network. 38
30710167 2019
13
Late-onset presentation of POLG1-associated mitochondrial disease. 38
30936349 2019
14
[Mitochondrial diseases]. 38
30643957 2019
15
CPEO and Mitochondrial Myopathy in a Patient with DGUOK Compound Heterozygous Pathogenetic Variant and mtDNA Multiple Deletions. 38
30956829 2019
16
A rare case of mitochondriopathy with autosomal dominant progressive external ophthalmoplegia diagnosed through skeletal muscle biopsy. 38
31263856 2019
17
Appendicular skeletal muscle mass: A more sensitive biomarker of disease severity than BMI in adults with mitochondrial diseases. 38
31344055 2019
18
Strabismus surgery for diplopia in chronic progressive external ophthalmoplegia. 38
29582258 2019
19
Teaching Video NeuroImages: MT-TL1 mutation presenting as chronic progressive external ophthalmoplegia. 38
30665919 2019
20
Clinical and demographic features of chronic progressive external ophthalmoplegia in a large adult-onset cohort. 38
29246868 2019
21
Ophthalmoplegia in Mitochondrial Disease. 38
30450853 2018
22
Ant1 mutant mice bridge the mitochondrial and serotonergic dysfunctions in bipolar disorder. 38
29892051 2018
23
Novel mutation in the RNASEH1 gene in a chronic progressive external ophthalmoplegia patient. 38
30340744 2018
24
False positive acetylcholine receptor antibodies in a case of unilateral chronic progressive external ophthalmoplegia: case report and review of literature. 38
29333908 2018
25
Intracranial hypotension mimicking chronic progressive external ophthalmoplegia. 38
29300676 2018
26
[Diagnostic and Therapeutic Approaches for Mitochondrial Diseases]. 38
30248691 2018
27
Phenotypic and Genotypic Heterogeneity of RRM2B Variants. 38
29241262 2018
28
Progressive fat replacement of muscle contributes to the disease mechanism of patients with single, large-scale deletions of mitochondrial DNA. 38
29567350 2018
29
Disclosing the functional changes of two genetic alterations in a patient with Chronic Progressive External Ophthalmoplegia: Report of the novel mtDNA m.7486G>A variant. 38
29398297 2018
30
[Mitochondrial Dysfunctions and Role of Coenzyme Q10 in Patients with Glaucoma]. 38
29448286 2018
31
Mitochondrial Disorder: Kearns-Sayre Syndrome. 38
30578503 2018
32
Outcome of epilepsy in patients with mitochondrial disorders: Phenotype genotype and magnetic resonance imaging correlations. 38
29272804 2018
33
Anesthetic management of a parturient with Kearns-Sayre syndrome, dual-chamber and VVI implantable defibrillator pacemaker/defibrillator, and preeclampsia for cesarean delivery: A case report and review of the literature. 38
29416473 2018
34
Focal Segmental Glomerulosclerosis Associated with Chronic Progressive External Ophthalmoplegia and Mitochondrial DNA A3243G Mutation. 38
29190634 2018
35
[Chronic Progressive External Ophthalmoplegia Ptosis: Problems with Diagnostics and Treatment]. 38
29373868 2018
36
Topoisomerase 3α Is Required for Decatenation and Segregation of Human mtDNA. 38
29290614 2018
37
Mitochondrial mutations in 12S rRNA and 16S rRNA presenting as chronic progressive external ophthalmoplegia (CPEO) plus: A case report. 38
29310369 2017
38
Surgical Technique for Pulled in Two Syndrome: Three Cases With Chronic Progressive External Ophthalmoplegia. 38
29156062 2017
39
Clinical, biochemical, molecular, and histological features of 65 Portuguese patients with mitochondrial disorders. 38
28128857 2017
40
Pure exercise intolerance and ophthalmoplegia associated with the m.12,294G > A mutation in the MT-TL2 gene: a case report. 38
29052516 2017
41
Reply to "Axonal hyperexcitability due to Schwann cell involvement in chronic progressive external ophthalmoplegia". 38
28838816 2017
42
Axonal hyperexcitability due to Schwann cell involvement in chronic progressive external ophthalmoplegia. 38
28811105 2017
43
Use of FGF-21 as a Biomarker of Mitochondrial Disease in Clinical Practice. 38
28825656 2017
44
Mitochondrial dysfunction and cerebral metabolic abnormalities in patients with mitochondrial encephalomyopathy subtypes: Evidence from proton MR spectroscopy and muscle biopsy. 38
28695670 2017
45
Efficacy of frontalis suspension with silicone rods in ptosis patients with poor Bell's phenomenon. 38
29034153 2017
46
A multi-systemic mitochondrial disorder due to a dominant p.Y955H disease variant in DNA polymerase gamma. 38
28430993 2017
47
MtDNA-maintenance defects: syndromes and genes. 38
28324239 2017
48
Nerve excitability changes related to muscle weakness in chronic progressive external ophthalmoplegia. 38
28535487 2017
49
Unilateral Ptosis and Homolateral Hemifacial Weakness in Chronic Progressive External Ophthalmoplegia. 38
28512510 2017
50
RE: "Unilateral Ptosis and Homolateral Hemifacial Weakness in Chronic Progressive External Ophthalmoplegia". 38
28533811 2017

Variations for Progressive External Ophthalmoplegia with Mitochondrial Dna...

ClinVar genetic disease variations for Progressive External Ophthalmoplegia with Mitochondrial Dna Deletions, Autosomal Dominant 4:

6
# Gene Variation Type Significance SNP ID GRCh37 Pos GRCh38 Pos
1 POLG2 NM_007215.4(POLG2): c.1352G> A (p.Gly451Glu) single nucleotide variant Pathogenic rs104894632 17:62474046-62474046 17:64477929-64477929
2 POLG2 NM_007215.4(POLG2): c.614C> G (p.Pro205Arg) single nucleotide variant Pathogenic rs397514659 17:62489087-62489087 17:64492970-64492970
3 POLG2 NM_007215.4(POLG2): c.1423_1424del (p.Leu475fs) deletion Pathogenic 17:62473974-62473975 17:64477857-64477858
4 POLG2 NM_007215.4(POLG2): c.1417G> A (p.Asp473Asn) single nucleotide variant Conflicting interpretations of pathogenicity rs563130304 17:62473981-62473981 17:64477864-64477864
5 POLG2 NM_007215.4(POLG2): c.1343_1347del (p.Thr447_Leu448insTer) deletion Uncertain significance 17:62474050-62474055 17:64477934-64477938
6 POLG2 NM_007215.4(POLG2): c.673C> T (p.Arg225Ter) single nucleotide variant Uncertain significance rs371515325 17:62489028-62489028 17:64492911-64492911
7 POLG2 NM_007215.4(POLG2): c.1105A> G (p.Arg369Gly) single nucleotide variant Likely benign rs201936720 17:62481850-62481850 17:64485733-64485733

UniProtKB/Swiss-Prot genetic disease variations for Progressive External Ophthalmoplegia with Mitochondrial Dna Deletions, Autosomal Dominant 4:

74
# Symbol AA change Variation ID SNP ID
1 POLG2 p.Gly451Glu VAR_029364 rs104894632

Expression for Progressive External Ophthalmoplegia with Mitochondrial Dna...

Search GEO for disease gene expression data for Progressive External Ophthalmoplegia with Mitochondrial Dna Deletions, Autosomal Dominant 4.

Pathways for Progressive External Ophthalmoplegia with Mitochondrial Dna...

GO Terms for Progressive External Ophthalmoplegia with Mitochondrial Dna...

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