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Juvenile myopathy, encephalopathy, lactic acidosis AND stroke(MELAS)

MedGen UID:
56485
Concept ID:
C0162671
Disease or Syndrome
Synonyms: MELAS; MELAS, MT-ND1-Related; MELAS, MT-ND5-Related; MELAS, MT-ND6-Related; MELAS, MT-TF-Related; MELAS, MT-TK-Related; MELAS, MT-TL1-Related; MELAS, MT-TQ-Related; MELAS, MT-TS1-Related; MELAS, MT-TS2-Related; Mitochondrial encephalomyopathy lactic acidosis and stroke-like episodes
SNOMED CT: MELAS - Mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (39925003); MELAS - Mitochondrial encephalopathy, lactic acidosis and stroke-like episodes (39925003); Mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (39925003); Juvenile myopathy, encephalopathy, lactic acidosis AND stroke (39925003); MELAS (39925003)
Modes of inheritance:
Mitochondrial inheritance
MedGen UID:
165802
Concept ID:
C0887941
Genetic Function
Sources: HPO, OMIM
The distribution of mitochondria, including the mitochondrial genome, into daughter cells after mitosis or meiosis, mediated by interactions between mitochondria and the cytoskeleton. [GOC:mcc, PMID:10873824, PMID:11389764]
 
Genes (locations): MT-CO1; MT-CO2; MT-CO3; MT-CYB; MT-ND1; MT-ND5; MT-ND6; MT-TC; MT-TF; MT-TK; MT-TL1; MT-TQ; MT-TS1; MT-TS2; MT-TV; MT-TW
 
Monarch Initiative: MONDO:0010789
OMIM®: 540000
Orphanet: ORPHA550

Definition

MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes) is a multisystem disorder with protean manifestations. The vast majority of affected individuals develop signs and symptoms of MELAS between ages two and 40 years. Common clinical manifestations include stroke-like episodes, encephalopathy with seizures and/or dementia, muscle weakness and exercise intolerance, normal early psychomotor development, recurrent headaches, recurrent vomiting, hearing impairment, peripheral neuropathy, learning disability, and short stature. During the stroke-like episodes neuroimaging shows increased T2-weighted signal areas that do not correspond to the classic vascular distribution (hence the term "stroke-like"). Lactic acidemia is very common and muscle biopsies typically show ragged red fibers. [from GeneReviews]

Additional descriptions

From OMIM
MELAS syndrome, comprising mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes, is a genetically heterogeneous mitochondrial disorder with a variable clinical phenotype. The disorder is accompanied by features of central nervous system involvement, including seizures, hemiparesis, hemianopsia, cortical blindness, and episodic vomiting (Pavlakis et al., 1984; Montagna et al., 1988). Other mitochondrial encephalomyopathies include Leigh syndrome (LS; 256000), Kearns-Sayre syndrome (KSS; 530000), MERRF syndrome (545000), and Leber optic atrophy (535000).  http://www.omim.org/entry/540000
From MedlinePlus Genetics
Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) is a condition that affects many of the body's systems, particularly the brain and nervous system (encephalo-) and muscles (myopathy). The signs and symptoms of this disorder most often appear in childhood following a period of normal development, although they can begin at any age. Early symptoms may include muscle weakness and pain, recurrent headaches, loss of appetite, vomiting, and seizures. Most affected individuals experience stroke-like episodes beginning before age 40. These episodes often involve temporary muscle weakness on one side of the body (hemiparesis), altered consciousness, vision abnormalities, seizures, and severe headaches resembling migraines. Repeated stroke-like episodes can progressively damage the brain, leading to vision loss, problems with movement, and a loss of intellectual function (dementia).\n\nMost people with MELAS have a buildup of lactic acid in their bodies, a condition called lactic acidosis. Increased acidity in the blood can lead to vomiting, abdominal pain, extreme tiredness (fatigue), muscle weakness, and difficulty breathing. Less commonly, people with MELAS may experience involuntary muscle spasms (myoclonus), impaired muscle coordination (ataxia), hearing loss, heart and kidney problems, diabetes, and hormonal imbalances.  https://medlineplus.gov/genetics/condition/mitochondrial-encephalomyopathy-lactic-acidosis-and-stroke-like-episodes

Clinical features

From HPO
Congestive heart failure
MedGen UID:
9169
Concept ID:
C0018802
Disease or Syndrome
The presence of an abnormality of cardiac function that is responsible for the failure of the heart to pump blood at a rate that is commensurate with the needs of the tissues or a state in which abnormally elevated filling pressures are required for the heart to do so. Heart failure is frequently related to a defect in myocardial contraction.
Hypertensive disorder
MedGen UID:
6969
Concept ID:
C0020538
Disease or Syndrome
The presence of chronic increased pressure in the systemic arterial system.
Abnormal left ventricular function
MedGen UID:
7287
Concept ID:
C0023212
Disease or Syndrome
Inability of the left ventricle to perform its normal physiologic function. Failure is either due to an inability to contract the left ventricle or the inability to relax completely and fill with blood during diastole.
Left ventricular hypertrophy
MedGen UID:
57442
Concept ID:
C0149721
Disease or Syndrome
Enlargement or overgrowth of the myocardium of the left ventricle, due to chronic pressure overload.
Arrhythmia
MedGen UID:
167788
Concept ID:
C0855329
Finding
An electrocardiographic finding of a change in cardiac electrical activity.
Stroke-like episode
MedGen UID:
346558
Concept ID:
C1857287
Finding
No consensus exists on what a stroke-like episode is, but these episodes can be functionally defined as a new neurological deficit, occurring with or without the context of seizures, which last longer than 24 hours.
Wolff-Parkinson-White syndrome
MedGen UID:
409600
Concept ID:
C1963282
Finding
Growth abnormality
MedGen UID:
808205
Concept ID:
C0262361
Finding
Episodic vomiting
MedGen UID:
333228
Concept ID:
C1838993
Finding
Paroxysmal, recurrent episodes of vomiting.
Bilateral sensorineural hearing impairment
MedGen UID:
96788
Concept ID:
C0452138
Disease or Syndrome
A bilateral form of sensorineural hearing impairment.
Progressive sensorineural hearing impairment
MedGen UID:
335894
Concept ID:
C1843156
Disease or Syndrome
A progressive form of sensorineural hearing impairment.
Hemiparesis
MedGen UID:
6783
Concept ID:
C0018989
Finding
Loss of strength in the arm, leg, and sometimes face on one side of the body. Hemiplegia refers to a complete loss of strength, whereas hemiparesis refers to an incomplete loss of strength.
Encephalopathy
MedGen UID:
39314
Concept ID:
C0085584
Disease or Syndrome
A functional and/or structural disorder of the brain caused by diseases (e.g. liver disease, kidney disease), medications, chemicals, and injuries.
Migraine
MedGen UID:
57451
Concept ID:
C0149931
Disease or Syndrome
Migraine is the most common type of chronic, episodic headache, as summarized by Featherstone (1985). One locus for migraine with or without aura (MGR1) has been identified on chromosome 4q24. Other loci for migraine have been identified on 6p21.1-p12.2 (MGR3; 607498), 14q21.2-q22.3 (MGR4; 607501), 19p13 (MGR5; 607508), 1q31 (MGR6; 607516), 15q11-q13 (MGR7; 609179), 5q21 (with or without aura, MGR8, 609570; with aura, MGR9, 609670), 17p13 (MGR10; 610208), 18q12 (MGR11; 610209), 10q22-q23 (MGR12; 611706), and the X chromosome (MGR2; 300125). Mutation in the KCNK18 gene (613655) on chromosome 10q25 causes migraine with aura (MGR13; 613656). A subtype of autosomal dominant migraine with aura (MA), familial hemiplegic migraine (FHM; see 141500), is caused by mutation in the CACNA1A gene (601011) on chromosome 19p13 (FHM1; 141500), by mutation in the ATP1A2 gene (182340) on chromosome 1q21 (FHM2; 602481), or by mutation in the SCN1A gene (182389) on chromosome 2q24 (FHM3; 609634). Another locus for FHM has been mapped to chromosome 1q31 (FHM4; see 607516). There is evidence that a polymorphism in the estrogen receptor gene (ESR1; 133430.0005) and a polymorphism in the TNF gene (191160.0004) may confer susceptibility to migraine. A polymorphism in the endothelin receptor type A gene (EDNRA; 131243.0001) may confer resistance to migraine.
Generalized tonic-clonic seizures
MedGen UID:
141670
Concept ID:
C0494475
Disease or Syndrome
A generalized motor seizure is a type of generalized-onset seizure with predominantly motor (involving musculature) signs. The motor event could consist of an increase (positive) or decrease (negative) in muscle contraction to produce a movement.
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.
Stroke-like episode
MedGen UID:
346558
Concept ID:
C1857287
Finding
No consensus exists on what a stroke-like episode is, but these episodes can be functionally defined as a new neurological deficit, occurring with or without the context of seizures, which last longer than 24 hours.
Myopathy
MedGen UID:
10135
Concept ID:
C0026848
Disease or Syndrome
A disorder of muscle unrelated to impairment of innervation or neuromuscular junction.
Mitochondrial myopathy
MedGen UID:
56484
Concept ID:
C0162670
Disease or Syndrome
Episodic mitochondrial myopathy with or without optic atrophy and reversible leukoencephalopathy (MEOAL) is an autosomal recessive neuromuscular disorder characterized mainly by childhood onset of progressive muscle weakness and exercise intolerance. Patients have episodic exacerbation, which may be associated with increased serum creatine kinase or lactic acid. Additional more variable features may include optic atrophy, reversible leukoencephalopathy, and later onset of a sensorimotor polyneuropathy. The disorder results from impaired formation of Fe-S clusters, which are essential cofactors for proper mitochondrial function (summary by Gurgel-Giannetti et al., 2018)
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.
Lactic acidosis
MedGen UID:
1717
Concept ID:
C0001125
Disease or Syndrome
Metabolic acidosis characterized by the accumulation of lactate in the body. It is caused by tissue hypoxia.
Diabetes mellitus
MedGen UID:
8350
Concept ID:
C0011849
Disease or Syndrome
A metabolic disorder characterized by abnormally high blood sugar levels due to diminished production of insulin or insulin resistance/desensitization.
Diabetes mellitus
MedGen UID:
8350
Concept ID:
C0011849
Disease or Syndrome
A metabolic disorder characterized by abnormally high blood sugar levels due to diminished production of insulin or insulin resistance/desensitization.
Developmental cataract
MedGen UID:
3202
Concept ID:
C0009691
Congenital Abnormality
A cataract that occurs congenitally as the result of a developmental defect, in contrast to the majority of cataracts that occur in adulthood as the result of degenerative changes of the lens.
Hemianopia
MedGen UID:
9193
Concept ID:
C0018979
Finding
Partial or complete loss of vision in one half of the visual field of one or both eyes.
Ophthalmoplegia
MedGen UID:
45205
Concept ID:
C0029089
Sign or Symptom
Paralysis of one or more extraocular muscles that are responsible for eye movements.
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.

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
  • CROGVJuvenile myopathy, encephalopathy, lactic acidosis AND stroke
Follow this link to review classifications for Juvenile myopathy, encephalopathy, lactic acidosis AND stroke in Orphanet.

Professional guidelines

PubMed

Authors/Task Force members., Elliott PM, Anastasakis A, Borger MA, Borggrefe M, Cecchi F, Charron P, Hagege AA, Lafont A, Limongelli G, Mahrholdt H, McKenna WJ, Mogensen J, Nihoyannopoulos P, Nistri S, Pieper PG, Pieske B, Rapezzi C, Rutten FH, Tillmanns C, Watkins H
Eur Heart J 2014 Oct 14;35(39):2733-79. Epub 2014 Aug 29 doi: 10.1093/eurheartj/ehu284. PMID: 25173338

Recent clinical studies

Etiology

Galnares-Olalde JA, López-Hernández JC, Benitez-Alonso EO, de Montellano DJD, May-Mas RN, Briseño-Godínez ME, Pérez-Valdez EY, Pérez-Jovel E, Fernández-Valverde F, León-Manríquez E, Vargas-Cañas ES
Neurologist 2021 Jul 6;26(4):143-148. doi: 10.1097/NRL.0000000000000331. PMID: 34190208
Chae HW, Na JH, Kim HS, Lee YM
Eur J Endocrinol 2020 Nov;183(5):505-512. doi: 10.1530/EJE-20-0189. PMID: 33107434
Bhatia KD, Krishnan P, Kortman H, Klostranec J, Krings T
AJNR Am J Neuroradiol 2020 Jan;41(1):167-173. Epub 2019 Dec 5 doi: 10.3174/ajnr.A6325. PMID: 31806591Free PMC Article
Brambilla A, Favilli S, Olivotto I, Calabri GB, Porcedda G, De Simone L, Procopio E, Pasquini E, Donati MA
Int J Cardiol 2019 Feb 1;276:14-19. Epub 2018 Oct 23 doi: 10.1016/j.ijcard.2018.10.051. PMID: 30482630
Toyoshima Y, Tanaka Y, Satomi K
BMJ Case Rep 2017 Sep 11;2017 doi: 10.1136/bcr-2017-220934. PMID: 28893805Free PMC Article

Diagnosis

Baszyńska-Wilk M, Moszczyńska E, Szarras-Czapnik M, Wysocka-Mincewicz M, Wątrobińska U, Kozłowska A, Szalecki M
Pediatr Endocrinol Diabetes Metab 2021;27(3):213-218. doi: 10.5114/pedm.2021.107713. PMID: 34596368
Galnares-Olalde JA, López-Hernández JC, Benitez-Alonso EO, de Montellano DJD, May-Mas RN, Briseño-Godínez ME, Pérez-Valdez EY, Pérez-Jovel E, Fernández-Valverde F, León-Manríquez E, Vargas-Cañas ES
Neurologist 2021 Jul 6;26(4):143-148. doi: 10.1097/NRL.0000000000000331. PMID: 34190208
Chae HW, Na JH, Kim HS, Lee YM
Eur J Endocrinol 2020 Nov;183(5):505-512. doi: 10.1530/EJE-20-0189. PMID: 33107434
Yokota Y, Hara M, Akimoto T, Mizoguchi T, Goto YI, Nishino I, Kamei S, Nakajima H
BMC Neurol 2020 Jun 17;20(1):247. doi: 10.1186/s12883-020-01818-w. PMID: 32552696Free PMC Article
Brambilla A, Favilli S, Olivotto I, Calabri GB, Porcedda G, De Simone L, Procopio E, Pasquini E, Donati MA
Int J Cardiol 2019 Feb 1;276:14-19. Epub 2018 Oct 23 doi: 10.1016/j.ijcard.2018.10.051. PMID: 30482630

Therapy

El-Hattab AW, Emrick LT, Hsu JW, Chanprasert S, Almannai M, Craigen WJ, Jahoor F, Scaglia F
Mol Genet Metab 2016 Apr;117(4):407-12. Epub 2016 Jan 27 doi: 10.1016/j.ymgme.2016.01.010. PMID: 26851065Free PMC Article
El-Hattab AW, Adesina AM, Jones J, Scaglia F
Mol Genet Metab 2015 Sep-Oct;116(1-2):4-12. Epub 2015 Jun 15 doi: 10.1016/j.ymgme.2015.06.004. PMID: 26095523
El-Hattab AW, Emrick LT, Chanprasert S, Craigen WJ, Scaglia F
Int J Biochem Cell Biol 2014 Mar;48:85-91. Epub 2014 Jan 8 doi: 10.1016/j.biocel.2013.12.009. PMID: 24412347
El-Hattab AW, Hsu JW, Emrick LT, Wong LJ, Craigen WJ, Jahoor F, Scaglia F
Mol Genet Metab 2012 Apr;105(4):607-14. Epub 2012 Jan 24 doi: 10.1016/j.ymgme.2012.01.016. PMID: 22325939Free PMC Article
Finsterer J, Barton P
Epileptic Disord 2010 Dec;12(4):330-4. Epub 2010 Nov 9 doi: 10.1684/epd.2010.0338. PMID: 21059492

Prognosis

Brambilla A, Favilli S, Olivotto I, Calabri GB, Porcedda G, De Simone L, Procopio E, Pasquini E, Donati MA
Int J Cardiol 2019 Feb 1;276:14-19. Epub 2018 Oct 23 doi: 10.1016/j.ijcard.2018.10.051. PMID: 30482630
Toyoshima Y, Tanaka Y, Satomi K
BMJ Case Rep 2017 Sep 11;2017 doi: 10.1136/bcr-2017-220934. PMID: 28893805Free PMC Article
Whitehead MT, Wien M, Lee B, Bass N, Gropman A
Pediatr Neurol 2017 Oct;75:61-65. Epub 2017 Jul 12 doi: 10.1016/j.pediatrneurol.2017.06.017. PMID: 28818358
Whitehead MT, Wien M, Lee B, Bass N, Gropman A
Neuroradiology 2017 Aug;59(8):813-818. Epub 2017 Jun 30 doi: 10.1007/s00234-017-1866-3. PMID: 28667360
Bell JD, Higgie K, Joshi M, Rucker J, Farzi S, Siddiqui N
A A Case Rep 2017 Jul 15;9(2):38-41. doi: 10.1213/XAA.0000000000000520. PMID: 28398928

Clinical prediction guides

Kraya T, Neumann L, Paelecke-Habermann Y, Deschauer M, Stoevesandt D, Zierz S, Watzke S
Mitochondrion 2019 Jan;44:53-57. Epub 2017 Dec 29 doi: 10.1016/j.mito.2017.12.012. PMID: 29289801
Felczak P, Lewandowska E, Stępniak I, Ołdak M, Pollak A, Lechowicz U, Pasennik E, Stępień T, Wierzba-Bobrowicz T
Pol J Pathol 2017;68(2):173-181. doi: 10.5114/pjp.2017.65021. PMID: 29025253
Toyoshima Y, Tanaka Y, Satomi K
BMJ Case Rep 2017 Sep 11;2017 doi: 10.1136/bcr-2017-220934. PMID: 28893805Free PMC Article
Whitehead MT, Wien M, Lee B, Bass N, Gropman A
Neuroradiology 2017 Aug;59(8):813-818. Epub 2017 Jun 30 doi: 10.1007/s00234-017-1866-3. PMID: 28667360
El-Hattab AW, Adesina AM, Jones J, Scaglia F
Mol Genet Metab 2015 Sep-Oct;116(1-2):4-12. Epub 2015 Jun 15 doi: 10.1016/j.ymgme.2015.06.004. PMID: 26095523

Recent systematic reviews

Gramegna LL, Cortesi I, Mitolo M, Evangelisti S, Lia T, Cirillo L, Tonon C, Lodi R
J Neuroradiol 2021 Sep;48(5):359-366. Epub 2021 Feb 15 doi: 10.1016/j.neurad.2021.02.002. PMID: 33596430
Finsterer J, Aliyev R
J Neurol Sci 2020 May 15;412:116726. Epub 2020 Feb 7 doi: 10.1016/j.jns.2020.116726. PMID: 32088469
Di Stadio A, Pegoraro V, Giaretta L, Dipietro L, Marozzo R, Angelini C
Orphanet J Rare Dis 2018 Feb 21;13(1):35. doi: 10.1186/s13023-018-0770-1. PMID: 29466997Free PMC Article
Nanau RM, Neuman MG
Clin Biochem 2013 Oct;46(15):1323-38. Epub 2013 Jun 20 doi: 10.1016/j.clinbiochem.2013.06.012. PMID: 23792104

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