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Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 4(PEOA4)

MedGen UID:
350480
Concept ID:
C1864668
Disease or Syndrome
Synonym: PROGRESSIVE EXTERNAL OPHTHALMOPLEGIA, AUTOSOMAL DOMINANT 4
 
Gene (location): POLG2 (17q23.3)
 
Monarch Initiative: MONDO:0012415
OMIM®: 610131

Definition

Progressive external ophthalmoplegia-4 (PEOA4) 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). [from OMIM]

Clinical features

From HPO
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.
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.
Left bundle branch block
MedGen UID:
7286
Concept ID:
C0023211
Disease or Syndrome
A conduction block of the left branch of the bundle of His. This manifests as a generalized disturbance of QRS morphology on EKG.
Ventricular bigeminy
MedGen UID:
75503
Concept ID:
C0262662
Finding
An electrocardiographic finding of a normal QRS followed by a premature ventricular contraction; a rhythmic pairing of normal and atypical beats originating in the ventricles in a 1-1 ratio such that an ectopic ventricular beat follows each regular heartbeat.
Failure to thrive
MedGen UID:
746019
Concept ID:
C2315100
Disease or Syndrome
Failure to thrive (FTT) refers to a child whose physical growth is substantially below the norm.
Constipation
MedGen UID:
1101
Concept ID:
C0009806
Sign or Symptom
Infrequent or difficult evacuation of feces.
Gastroparesis
MedGen UID:
101809
Concept ID:
C0152020
Disease or Syndrome
Decreased strength of the muscle layer of stomach, which leads to a decreased ability to empty the contents of the stomach despite the absence of obstruction.
Abnormality of the liver
MedGen UID:
893061
Concept ID:
C4021780
Finding
An abnormality of the liver.
Gastroesophageal reflux
MedGen UID:
1368658
Concept ID:
C4317146
Finding
A condition in which the stomach contents leak backwards from the stomach into the esophagus through the lower esophageal sphincter.
Seizure
MedGen UID:
20693
Concept ID:
C0036572
Sign or Symptom
A seizure is an intermittent abnormality of nervous system physiology characterized by a transient occurrence of signs and/or symptoms due to abnormal excessive or synchronous neuronal activity in the brain.
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.
Cerebellar atrophy
MedGen UID:
196624
Concept ID:
C0740279
Disease or Syndrome
Cerebellar atrophy is defined as a cerebellum with initially normal structures, in a posterior fossa with normal size, which displays enlarged fissures (interfolial spaces) in comparison to the foliae secondary to loss of tissue. Cerebellar atrophy implies irreversible loss of tissue and result from an ongoing progressive disease until a final stage is reached or a single injury, e.g. an intoxication or infectious event.
Hypotonia
MedGen UID:
10133
Concept ID:
C0026827
Finding
Hypotonia is an abnormally low muscle tone (the amount of tension or resistance to movement in a muscle). Even when relaxed, muscles have a continuous and passive partial contraction which provides some resistance to passive stretching. Hypotonia thus manifests as diminished resistance to passive stretching. Hypotonia is not the same as muscle weakness, although the two conditions can co-exist.
Progressive muscle weakness
MedGen UID:
68704
Concept ID:
C0240421
Finding
Facial palsy
MedGen UID:
87660
Concept ID:
C0376175
Disease or Syndrome
Facial nerve palsy is a dysfunction of cranial nerve VII (the facial nerve) that results in inability to control facial muscles on the affected side with weakness of the muscles of facial expression and eye closure. This can either be present in unilateral or bilateral form.
Generalized hypotonia
MedGen UID:
346841
Concept ID:
C1858120
Finding
Generalized muscular hypotonia (abnormally low muscle tone).
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.
Impaired glucose tolerance
MedGen UID:
852424
Concept ID:
C0151671
Finding
An abnormal resistance to glucose, i.e., a reduction in the ability to maintain glucose levels in the blood stream within normal limits following oral or intravenous administration of glucose.
Elevated circulating creatine kinase concentration
MedGen UID:
69128
Concept ID:
C0241005
Finding
An elevation of the level of the enzyme creatine kinase (also known as creatine phosphokinase (CK; EC 2.7.3.2) in the blood. CK levels can be elevated in a number of clinical disorders such as myocardial infarction, rhabdomyolysis, and muscular dystrophy.
Glucose intolerance
MedGen UID:
75760
Concept ID:
C0271650
Disease or Syndrome
Glucose intolerance (GI) can be defined as dysglycemia that comprises both prediabetes and diabetes. It includes the conditions of impaired fasting glucose (IFG) and impaired glucose tolerance (IGT) and diabetes mellitus (DM).
Increased circulating lactate concentration
MedGen UID:
332209
Concept ID:
C1836440
Finding
Abnormally increased level of blood lactate (2-hydroxypropanoic acid). Lactate is produced from pyruvate by lactate dehydrogenase during normal metabolism. The terms lactate and lactic acid are often used interchangeably but lactate (the component measured in blood) is strictly a weak base whereas lactic acid is the corresponding acid. Lactic acidosis is often used clinically to describe elevated lactate but should be reserved for cases where there is a corresponding acidosis (pH below 7.35).
Elevated circulating hepatic transaminase concentration
MedGen UID:
338525
Concept ID:
C1848701
Finding
Elevations of the levels of SGOT and SGPT in the serum. SGOT (serum glutamic oxaloacetic transaminase) and SGPT (serum glutamic pyruvic transaminase) are transaminases primarily found in the liver and heart and are released into the bloodstream as the result of liver or heart damage. SGOT and SGPT are used clinically mainly as markers of liver damage.
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).
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\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.\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.
Cerebral visual impairment
MedGen UID:
890568
Concept ID:
C4048268
Pathologic Function
A form of loss of vision caused by damage to the visual cortex rather than a defect in the eye.

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
Löfberg M, Lindholm H, Näveri H, Majander A, Suomalainen A, Paetau A, Sovijärvi A, Härkönen M, Somer H
Neuromuscul Disord 2001 May;11(4):370-5. doi: 10.1016/s0960-8966(00)00205-4. PMID: 11369188
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

Therapy

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

Clinical prediction guides

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
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

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