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Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 3(PEOA3)

MedGen UID:
373087
Concept ID:
C1836439
Disease or Syndrome
Synonym: PROGRESSIVE EXTERNAL OPHTHALMOPLEGIA, AUTOSOMAL DOMINANT 3
 
Gene (location): TWNK (10q24.31)
 
Monarch Initiative: MONDO:0012241
OMIM®: 609286

Definition

Progressive external ophthalmoplegia is characterized by multiple mitochondrial DNA deletions in skeletal muscle. The most common clinical features include adult onset of weakness of the external eye muscles and exercise intolerance. Patients with C10ORF2-linked adPEO may have other clinical features including proximal muscle weakness, ataxia, peripheral neuropathy, cardiomyopathy, cataracts, depression, and endocrine abnormalities (summary by Fratter et al., 2010). For a general phenotypic description and a discussion of genetic heterogeneity of autosomal dominant progressive external ophthalmoplegia, see PEOA1 (157640). PEO caused by mutations in the POLG gene (174763) are associated with more complicated phenotypes than those forms caused by mutations in the SLC25A4 (103220) or C10ORF2 genes (Lamantea et al., 2002). [from OMIM]

Additional description

From MedlinePlus Genetics
Progressive external ophthalmoplegia is a condition characterized by weakness of the eye muscles. The condition typically appears in adults between ages 18 and 40 and slowly worsens over time. The first sign of progressive external ophthalmoplegia is typically drooping eyelids (ptosis), which can affect one or both eyelids. As ptosis worsens, affected individuals may use the forehead muscles to try to lift the eyelids, or they may lift up their chin in order to see. Another characteristic feature of progressive external ophthalmoplegia is weakness or paralysis of the muscles that move the eye (ophthalmoplegia). Affected individuals have to turn their head to see in different directions, especially as the ophthalmoplegia worsens. People with progressive external ophthalmoplegia may also have general weakness of the muscles used for movement (myopathy), particularly those in the neck, arms, or legs. The weakness may be especially noticeable during exercise (exercise intolerance). Muscle weakness may also cause difficulty swallowing (dysphagia).

Progressive external ophthalmoplegia is part of a spectrum of disorders with overlapping signs and symptoms. Similar disorders include ataxia neuropathy spectrum and Kearns-Sayre syndrome. Like progressive external ophthalmoplegia, the other conditions in this spectrum can involve weakness of the eye muscles. However, these conditions have many additional features not shared by most people with progressive external ophthalmoplegia.

When the muscle cells of affected individuals are stained and viewed under a microscope, these cells usually appear abnormal. These abnormal muscle cells contain an excess of cell structures called mitochondria and are known as ragged-red fibers.

Although muscle weakness is the primary symptom of progressive external ophthalmoplegia, this condition can be accompanied by other signs and symptoms. In these instances, the condition is referred to as progressive external ophthalmoplegia plus (PEO+). Additional signs and symptoms can include hearing loss caused by nerve damage in the inner ear (sensorineural hearing loss), weakness and loss of sensation in the limbs due to nerve damage (neuropathy), impaired muscle coordination (ataxia), a pattern of movement abnormalities known as parkinsonism, and depression.  https://medlineplus.gov/genetics/condition/progressive-external-ophthalmoplegia

Clinical features

From HPO
Fatigue
MedGen UID:
41971
Concept ID:
C0015672
Sign or Symptom
A subjective feeling of tiredness characterized by a lack of energy and motivation.
Myalgia
MedGen UID:
68541
Concept ID:
C0231528
Sign or Symptom
Pain in muscle.
Exercise intolerance
MedGen UID:
603270
Concept ID:
C0424551
Finding
A functional motor deficit where individuals whose responses to the challenges of exercise fail to achieve levels considered normal for their age and gender.
Premature ovarian insufficiency
MedGen UID:
9963
Concept ID:
C0025322
Disease or Syndrome
Amenorrhea due to loss of ovarian function before the age of 40. Primary ovarian inssuficiency (POI) is a state of female hypergonadotropic hypogonadism. It can manifest as primary amenorrhea with onset before menarche or secondary amenorrhea.
Limb muscle weakness
MedGen UID:
107956
Concept ID:
C0587246
Finding
Reduced strength and weakness of the muscles of the arms and legs.
Cardiac arrhythmia
MedGen UID:
2039
Concept ID:
C0003811
Finding
Any cardiac rhythm other than the normal sinus rhythm. Such a rhythm may be either of sinus or ectopic origin and either regular or irregular. An arrhythmia may be due to a disturbance in impulse formation or conduction or both.
Bradycardia
MedGen UID:
140901
Concept ID:
C0428977
Finding
A slower than normal heart rate (in adults, slower than 60 beats per minute).
Cardiomyopathy
MedGen UID:
209232
Concept ID:
C0878544
Disease or Syndrome
A myocardial disorder in which the heart muscle is structurally and functionally abnormal, in the absence of coronary artery disease, hypertension, valvular disease and congenital heart disease sufficient to cause the observed myocardial abnormality.
Dysphagia
MedGen UID:
41440
Concept ID:
C0011168
Disease or Syndrome
Difficulty in swallowing.
Progressive hearing impairment
MedGen UID:
331224
Concept ID:
C1842138
Finding
A progressive form of hearing impairment.
Depression
MedGen UID:
4229
Concept ID:
C0011581
Mental or Behavioral Dysfunction
Frequently experiencing feelings of being down, miserable, and/or hopeless; struggling to recover from these moods; having a pessimistic outlook on the future; feeling a pervasive sense of shame; having a low self-worth; experiencing thoughts of suicide and engaging in suicidal behavior.
Dysarthria
MedGen UID:
8510
Concept ID:
C0013362
Mental or Behavioral Dysfunction
Dysarthric speech is a general description referring to a neurological speech disorder characterized by poor articulation. Depending on the involved neurological structures, dysarthria may be further classified as spastic, flaccid, ataxic, hyperkinetic and hypokinetic, or mixed.
Seizure
MedGen UID:
20693
Concept ID:
C0036572
Sign or Symptom
A seizure is an intermittent abnormality of nervous system physiology characterised by a transient occurrence of signs and/or symptoms due to abnormal excessive or synchronous neuronal activity in the brain.
Areflexia
MedGen UID:
115943
Concept ID:
C0234146
Finding
Absence of neurologic reflexes such as the knee-jerk reaction.
Cerebral atrophy
MedGen UID:
116012
Concept ID:
C0235946
Disease or Syndrome
Atrophy (wasting, decrease in size of cells or tissue) affecting the cerebrum.
Sensory ataxia
MedGen UID:
66020
Concept ID:
C0240991
Sign or Symptom
Incoordination of movement caused by a deficit in the sensory nervous system. Sensory ataxia can be distinguished from cerebellar ataxia by asking the patient to close his or her eyes. Persons with cerebellar ataxia show only a minimal worsening of symptoms, whereas persons with sensory ataxia show a marked worsening of symptoms.
Parkinsonism
MedGen UID:
66079
Concept ID:
C0242422
Disease or Syndrome
Characteristic neurologic anomaly resulting from degeneration of dopamine-generating cells in the substantia nigra, a region of the midbrain, characterized clinically by shaking, rigidity, slowness of movement and difficulty with walking and gait.
Dementia
MedGen UID:
99229
Concept ID:
C0497327
Mental or Behavioral Dysfunction
A loss of global cognitive ability of sufficient amount to interfere with normal social or occupational function. Dementia represents a loss of previously present cognitive abilities, generally in adults, and can affect memory, thinking, language, judgment, and behavior.
Global developmental delay
MedGen UID:
107838
Concept ID:
C0557874
Finding
A delay in the achievement of motor or mental milestones in the domains of development of a child, including motor skills, speech and language, cognitive skills, and social and emotional skills. This term should only be used to describe children younger than five years of age.
Gait disturbance
MedGen UID:
107895
Concept ID:
C0575081
Finding
The term gait disturbance can refer to any disruption of the ability to walk. In general, this can refer to neurological diseases but also fractures or other sources of pain that is triggered upon walking. However, in the current context gait disturbance refers to difficulty walking on the basis of a neurological or muscular disease.
Hyporeflexia
MedGen UID:
195967
Concept ID:
C0700078
Finding
Reduction of neurologic reflexes such as the knee-jerk reaction.
Sensory axonal neuropathy
MedGen UID:
334116
Concept ID:
C1842587
Finding
An axonal neuropathy of peripheral sensory nerves.
Proximal muscle weakness
MedGen UID:
113169
Concept ID:
C0221629
Finding
A lack of strength of the proximal muscles.
Progressive muscle weakness
MedGen UID:
68704
Concept ID:
C0240421
Finding
Ragged-red muscle fibers
MedGen UID:
477048
Concept ID:
C3275417
Finding
An abnormal appearance of muscle fibers observed on muscle biopsy. Ragged red fibers can be visualized with Gomori trichrome staining as irregular and intensely red subsarcolemmal zones, whereas the normal myofibrils are green. The margins of affect fibers appear red and ragged. The ragged-red is due to the accumulation of abnormal mitochondria below the plasma membrane of the muscle fiber, leading to the appearance of a red rim and speckled sarcoplasm.
Multiple mitochondrial DNA deletions
MedGen UID:
479006
Concept ID:
C3277376
Finding
The presence of multiple deletions of mitochondrial DNA (mtDNA).
Cytochrome C oxidase-negative muscle fibers
MedGen UID:
867360
Concept ID:
C4021724
Finding
An abnormally reduced activity of the enzyme cytochrome C oxidase in muscle tissue.
EMG: myopathic abnormalities
MedGen UID:
867362
Concept ID:
C4021726
Pathologic Function
The presence of abnormal electromyographic patterns indicative of myopathy, such as small-short polyphasic motor unit potentials.
Subsarcolemmal accumulations of abnormally shaped mitochondria
MedGen UID:
871128
Concept ID:
C4025597
Anatomical Abnormality
An abnormally increased number of mitochondria in the cytoplasma adjacent to the sarcolemma (muscle cell membrane), whereby the mitochondria also possess an abnormal morphology.
Diabetes mellitus
MedGen UID:
8350
Concept ID:
C0011849
Disease or Syndrome
A group of abnormalities characterized by hyperglycemia and glucose intolerance.
Dysphonia
MedGen UID:
282893
Concept ID:
C1527344
Mental or Behavioral Dysfunction
Difficulty in speaking due to a physical disorder of the mouth, tongue, throat, or vocal cords. Associated with a known physical or neurological cause.
Hypogonadism
MedGen UID:
5711
Concept ID:
C0020619
Disease or Syndrome
A decreased functionality of the gonad.
Abnormality of the thyroid gland
MedGen UID:
1378579
Concept ID:
C4317107
Finding
An abnormality of the thyroid gland.
Ptosis
MedGen UID:
2287
Concept ID:
C0005745
Disease or Syndrome
The upper eyelid margin is positioned 3 mm or more lower than usual and covers the superior portion of the iris (objective); or, the upper lid margin obscures at least part of the pupil (subjective).
Cataract
MedGen UID:
39462
Concept ID:
C0086543
Disease or Syndrome
A cataract is an opacity or clouding that develops in the crystalline lens of the eye or in its capsule.
Progressive external ophthalmoplegia
MedGen UID:
102439
Concept ID:
C0162674
Disease or Syndrome
Progressive external ophthalmoplegia is a condition characterized by weakness of the eye muscles. The condition typically appears in adults between ages 18 and 40 and slowly worsens over time. The first sign of progressive external ophthalmoplegia is typically drooping eyelids (ptosis), which can affect one or both eyelids. As ptosis worsens, affected individuals may use the forehead muscles to try to lift the eyelids, or they may lift up their chin in order to see. Another characteristic feature of progressive external ophthalmoplegia is weakness or paralysis of the muscles that move the eye (ophthalmoplegia). Affected individuals have to turn their head to see in different directions, especially as the ophthalmoplegia worsens. People with progressive external ophthalmoplegia may also have general weakness of the muscles used for movement (myopathy), particularly those in the neck, arms, or legs. The weakness may be especially noticeable during exercise (exercise intolerance). Muscle weakness may also cause difficulty swallowing (dysphagia).\n\nProgressive external ophthalmoplegia is part of a spectrum of disorders with overlapping signs and symptoms. Similar disorders include ataxia neuropathy spectrum and Kearns-Sayre syndrome. Like progressive external ophthalmoplegia, the other conditions in this spectrum can involve weakness of the eye muscles. However, these conditions have many additional features not shared by most people with progressive external ophthalmoplegia.\n\nWhen the muscle cells of affected individuals are stained and viewed under a microscope, these cells usually appear abnormal. These abnormal muscle cells contain an excess of cell structures called mitochondria and are known as ragged-red fibers.\n\nAlthough muscle weakness is the primary symptom of progressive external ophthalmoplegia, this condition can be accompanied by other signs and symptoms. In these instances, the condition is referred to as progressive external ophthalmoplegia plus (PEO+). Additional signs and symptoms can include hearing loss caused by nerve damage in the inner ear (sensorineural hearing loss), weakness and loss of sensation in the limbs due to nerve damage (neuropathy), impaired muscle coordination (ataxia), a pattern of movement abnormalities known as parkinsonism, and depression.

Recent clinical studies

Etiology

Yu-Wai-Man P, Griffiths PG, Gorman GS, Lourenco CM, Wright AF, Auer-Grumbach M, Toscano A, Musumeci O, Valentino ML, Caporali L, Lamperti C, Tallaksen CM, Duffey P, Miller J, Whittaker RG, Baker MR, Jackson MJ, Clarke MP, Dhillon B, Czermin B, Stewart JD, Hudson G, Reynier P, Bonneau D, Marques W Jr, Lenaers G, McFarland R, Taylor RW, Turnbull DM, Votruba M, Zeviani M, Carelli V, Bindoff LA, Horvath R, Amati-Bonneau P, Chinnery PF
Brain 2010 Mar;133(Pt 3):771-86. Epub 2010 Feb 15 doi: 10.1093/brain/awq007. PMID: 20157015Free PMC Article
Carrozzo R, Hirano M, Fromenty B, Casali C, Santorelli FM, Bonilla E, DiMauro S, Schon EA, Miranda AF
Neurology 1998 Jan;50(1):99-106. doi: 10.1212/wnl.50.1.99. PMID: 9443465
Melberg A, Arnell H, Dahl N, Stålberg E, Raininko R, Oldfors A, Bakall B, Lundberg PO, Holme E
Muscle Nerve 1996 Dec;19(12):1561-9. doi: 10.1002/(SICI)1097-4598(199612)19:12<1561::AID-MUS5>3.0.CO;2-8. PMID: 8941270
DiMauro S, Moraes CT
Arch Neurol 1993 Nov;50(11):1197-208. doi: 10.1001/archneur.1993.00540110075008. PMID: 8215979

Diagnosis

Rahman S, Copeland WC
Nat Rev Neurol 2019 Jan;15(1):40-52. doi: 10.1038/s41582-018-0101-0. PMID: 30451971Free PMC Article
Martikainen MH, Hinttala R, Röyttä M, Jääskeläinen S, Wendelin-Saarenhovi M, Parkkola R, Majamaa K
Neuroepidemiology 2012;38(2):114-9. Epub 2012 Feb 24 doi: 10.1159/000336112. PMID: 22377773
Hirano M, Vu TH
Brain Pathol 2000 Jul;10(3):451-61. doi: 10.1111/j.1750-3639.2000.tb00277.x. PMID: 10885664Free PMC Article
Melberg A, Arnell H, Dahl N, Stålberg E, Raininko R, Oldfors A, Bakall B, Lundberg PO, Holme E
Muscle Nerve 1996 Dec;19(12):1561-9. doi: 10.1002/(SICI)1097-4598(199612)19:12<1561::AID-MUS5>3.0.CO;2-8. PMID: 8941270
DiMauro S, Moraes CT
Arch Neurol 1993 Nov;50(11):1197-208. doi: 10.1001/archneur.1993.00540110075008. PMID: 8215979

Therapy

Vu TH, Tanji K, Pallotti F, Golzi V, Hirano M, DiMauro S, Bonilla E
Muscle Nerve 2000 Jan;23(1):80-5. doi: 10.1002/(sici)1097-4598(200001)23:1<80::aid-mus10>3.0.co;2-v. PMID: 10590409
Kaukonen JA, Amati P, Suomalainen A, Rötig A, Piscaglia MG, Salvi F, Weissenbach J, Fratta G, Comi G, Peltonen L, Zeviani M
Am J Hum Genet 1996 Apr;58(4):763-9. PMID: 8644740Free PMC Article

Prognosis

Korhonen JA, Pande V, Holmlund T, Farge G, Pham XH, Nilsson L, Falkenberg M
J Mol Biol 2008 Mar 28;377(3):691-705. Epub 2008 Jan 26 doi: 10.1016/j.jmb.2008.01.035. PMID: 18279890
Hudson G, Schaefer AM, Taylor RW, Tiangyou W, Gibson A, Venables G, Griffiths P, Burn DJ, Turnbull DM, Chinnery PF
Arch Neurol 2007 Apr;64(4):553-7. doi: 10.1001/archneur.64.4.553. PMID: 17420318
Lewis S, Hutchison W, Thyagarajan D, Dahl HH
J Neurol Sci 2002 Sep 15;201(1-2):39-44. doi: 10.1016/s0022-510x(02)00190-9. PMID: 12163192

Clinical prediction guides

Martin-Negrier ML, Sole G, Jardel C, Vital C, Ferrer X, Vital A
Eur J Neurol 2011 Mar;18(3):436-41. Epub 2010 Sep 29 doi: 10.1111/j.1468-1331.2010.03171.x. PMID: 20880070
Korhonen JA, Pande V, Holmlund T, Farge G, Pham XH, Nilsson L, Falkenberg M
J Mol Biol 2008 Mar 28;377(3):691-705. Epub 2008 Jan 26 doi: 10.1016/j.jmb.2008.01.035. PMID: 18279890
Li FY, Tariq M, Croxen R, Morten K, Squier W, Newsom-Davis J, Beeson D, Larsson C
Neurology 1999 Oct 12;53(6):1265-71. doi: 10.1212/wnl.53.6.1265. PMID: 10522883
Melberg A, Arnell H, Dahl N, Stålberg E, Raininko R, Oldfors A, Bakall B, Lundberg PO, Holme E
Muscle Nerve 1996 Dec;19(12):1561-9. doi: 10.1002/(SICI)1097-4598(199612)19:12<1561::AID-MUS5>3.0.CO;2-8. PMID: 8941270
Wallace DC
J Bioenerg Biomembr 1994 Jun;26(3):241-50. doi: 10.1007/BF00763096. PMID: 8077179

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