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Myoclonus with epilepsy with ragged red fibers(MERRF)

MedGen UID:
56486
Concept ID:
C0162672
Disease or Syndrome
Synonyms: Fukuhara syndrome; MERRF; Merrf syndrome; Myoclonic epilepsy associated with ragged-red fibers; Myoencephalopathy ragged-red fiber disease
Modes of inheritance:
Mitochondrial inheritance
MedGen UID:
165802
Concept ID:
C0887941
Genetic Function
Sources: HPO, OMIM, Orphanet
A mode of inheritance that is observed for traits related to a gene encoded on the mitochondrial genome. Because the mitochondrial genome is essentially always maternally inherited, a mitochondrial condition can only be transmitted by females, although the condition can affect both sexes. The proportion of mutant mitochondria can vary (heteroplasmy).
Mitochondrial inheritance (HPO, OMIM, Orphanet)
SNOMED CT: Myoclonus epilepsy AND ragged red fibers (68448003); MERRF (68448003); MERRF - Myoclonic epilepsy - ragged red fibers (230426003); Myoclonic epilepsy - ragged red fibers (230426003); Fukuhara syndrome (57254004)
 
Genes (locations): MT-TF; MT-TI; MT-TK; MT-TL1; MT-TP
OMIM®: 545000
Orphanet: ORPHA551

Definition

A mitochondrial encephalomyopathy characterized clinically by a mixed seizure disorder, myoclonus, progressive ataxia, spasticity, and a mild myopathy. Dysarthria, optic atrophy, growth retardation, deafness, and dementia may also occur. This condition tends to present in childhood and to be transmitted via maternal lineage. Muscle biopsies reveal ragged-red fibers and respiratory chain enzymatic defects. (From Adams et al., Principles of Neurology, 6th ed, p986) [from MeSH]

Additional descriptions

From GeneReviews
MERRF (myoclonic epilepsy with ragged red fibers) is a multisystem disorder characterized by myoclonus (often the first symptom) followed by generalized epilepsy, ataxia, weakness, and dementia. Onset is usually in childhood, occurring after normal early development. Common findings are hearing loss, short stature, optic atrophy, and cardiomyopathy with Wolff-Parkinson-White (WPW) syndrome. Pigmentary retinopathy and lipomatosis are occasionally observed.  https://www.ncbi.nlm.nih.gov/books/NBK1520
From GHR
Myoclonic epilepsy with ragged-red fibers (MERRF) is a disorder that affects many parts of the body, particularly the muscles and nervous system. In most cases, the signs and symptoms of this disorder appear during childhood or adolescence. The features of MERRF vary widely among affected individuals, even among members of the same family.MERRF is characterized by muscle twitches (myoclonus), weakness (myopathy), and progressive stiffness (spasticity). When the muscle cells of affected individuals are stained and viewed under a microscope, these cells usually appear abnormal. These abnormal muscle cells are called ragged-red fibers. Other features of MERRF include recurrent seizures (epilepsy), difficulty coordinating movements (ataxia), a loss of sensation in the extremities (peripheral neuropathy), and slow deterioration of intellectual function (dementia). People with this condition may also develop hearing loss or optic atrophy, which is the degeneration (atrophy) of nerve cells that carry visual information from the eyes to the brain. Affected individuals sometimes have short stature and a form of heart disease known as cardiomyopathy. Less commonly, people with MERRF develop fatty tumors, called lipomas, just under the surface of the skin.  https://ghr.nlm.nih.gov/condition/myoclonic-epilepsy-with-ragged-red-fibers

Clinical features

Papilledema
MedGen UID:
10565
Concept ID:
C0030353
Finding
Papilledema refers to edema (swelling) of the optic disc secondary to any factor which increases cerebral spinal fluid pressure.
Optic disc pallor
MedGen UID:
108218
Concept ID:
C0554970
Finding
A pale yellow discoloration of the optic disk (the area of the optic nerve head in the retina). The optic disc normally has a pinkish hue with a central yellowish depression.
Leber optic atrophy
MedGen UID:
182973
Concept ID:
C0917796
Disease or Syndrome
Mitochondrial diseases are a clinically heterogeneous group of disorders that arise as a result of dysfunction of the mitochondrial respiratory chain. They can be caused by mutation of genes encoded by either nuclear DNA or mitochondrial DNA (mtDNA). While some mitochondrial disorders only affect a single organ (e.g., the eye in Leber hereditary optic neuropathy [LHON]), many involve multiple organ systems and often present with prominent neurologic and myopathic features. Mitochondrial disorders may present at any age. Many individuals with a mutation of mtDNA display a cluster of clinical features that fall into a discrete clinical syndrome, such as the Kearns-Sayre syndrome (KSS), chronic progressive external ophthalmoplegia (CPEO), mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS), myoclonic epilepsy with ragged-red fibers (MERRF), neurogenic weakness with ataxia and retinitis pigmentosa (NARP), or Leigh syndrome (LS). However, considerable clinical variability exists and many individuals do not fit neatly into one particular category, which is well-illustrated by the overlapping spectrum of disease phenotypes (including mitochondrial recessive ataxia syndrome (MIRAS) resulting from mutation of the nuclear gene POLG, which has emerged as a major cause of mitochondrial disease. Common clinical features of mitochondrial disease – whether involving a mitochondrial or nuclear gene – include ptosis, external ophthalmoplegia, proximal myopathy and exercise intolerance, cardiomyopathy, sensorineural deafness, optic atrophy, pigmentary retinopathy, and diabetes mellitus. Common central nervous system findings are fluctuating encephalopathy, seizures, dementia, migraine, stroke-like episodes, ataxia, and spasticity. A high incidence of mid- and late pregnancy loss is a common occurrence that often goes unrecognized.
Large central visual field defect
MedGen UID:
871312
Concept ID:
C4025800
Finding
Sudden loss of visual acuity
MedGen UID:
893113
Concept ID:
C4072828
Finding
Severe loss of visual acuity within hours or days. This is characteristic of Leber hereditary optic neuropathy.
Sensorineural hearing loss
MedGen UID:
9164
Concept ID:
C0018784
Disease or Syndrome
A type of hearing impairment in one or both ears related to an abnormal functionality of the cochlear nerve.
Cerebellar ataxia
MedGen UID:
849
Concept ID:
C0007758
Sign or Symptom
Cerebellar ataxia refers to ataxia due to dysfunction of the cerebellum. This causes a variety of elementary neurological deficits including asynergy (lack of coordination between muscles, limbs and joints), dysmetria (lack of ability to judge distances that can lead to under- oder overshoot in grasping movements), and dysdiadochokinesia (inability to perform rapid movements requiring antagonizing muscle groups to be switched on and off repeatedly).
Seizure Disorders
MedGen UID:
4506
Concept ID:
C0014544
Disease or Syndrome
A brain disorder characterized by episodes of abnormally increased neuronal discharge resulting in transient episodes of sensory or motor neurological dysfunction, or psychic dysfunction. These episodes may or may not be associated with loss of consciousness or convulsions.
Myoclonic seizures
MedGen UID:
4988
Concept ID:
C0014550
Disease or Syndrome
Seizures with sudden, brief (< 100 msec) involuntary single or multiple contraction(s) of muscles(s) or muscle groups of variable topography (axial, proximal limb, distal).
Headache
MedGen UID:
9149
Concept ID:
C0018681
Sign or Symptom
Cephalgia, or pain sensed in various parts of the head, not confined to the area of distribution of any nerve.
Spasticity
MedGen UID:
7753
Concept ID:
C0026838
Sign or Symptom
A form of muscle hypertonia associated with upper MOTOR NEURON DISEASE. Resistance to passive stretch of a spastic muscle results in minimal initial resistance (a "free interval") followed by an incremental increase in muscle tone. Tone increases in proportion to the velocity of stretch. Spasticity is usually accompanied by HYPERREFLEXIA and variable degrees of MUSCLE WEAKNESS. (From Adams et al., Principles of Neurology, 6th ed, p54)
Myoclonus
MedGen UID:
10234
Concept ID:
C0027066
Sign or Symptom
A rapid, involuntary jerk of a muscle or group of muscles.
Spasticity
MedGen UID:
7753
Concept ID:
C0026838
Sign or Symptom
A form of muscle hypertonia associated with upper MOTOR NEURON DISEASE. Resistance to passive stretch of a spastic muscle results in minimal initial resistance (a "free interval") followed by an incremental increase in muscle tone. Tone increases in proportion to the velocity of stretch. Spasticity is usually accompanied by HYPERREFLEXIA and variable degrees of MUSCLE WEAKNESS. (From Adams et al., Principles of Neurology, 6th ed, p54)
Myopathy
MedGen UID:
10135
Concept ID:
C0026848
Disease or Syndrome
A disorder of muscle unrelated to impairment of innervation or neuromuscular junction.
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.
Muscle weakness
MedGen UID:
811372
Concept ID:
C3714552
Sign or Symptom
Reduced strength of muscles.
Increased serum lactate
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.
Increased serum pyruvate
MedGen UID:
376596
Concept ID:
C1849488
Finding
An increased concentration of pyruvate in the blood.
Abnormality of metabolism/homeostasis
MedGen UID:
867398
Concept ID:
C4021768
Finding

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
  • CROGVMyoclonus with epilepsy with ragged red fibers
Follow this link to review classifications for Myoclonus with epilepsy with ragged red fibers in Orphanet.

Recent clinical studies

Etiology

Lamperti C, Zeviani M
Epileptic Disord 2016 Sep 1;18(S2):94-102. doi: 10.1684/epd.2016.0846. PMID: 27618766
Altmann J, Büchner B, Nadaj-Pakleza A, Schäfer J, Jackson S, Lehmann D, Deschauer M, Kopajtich R, Lautenschläger R, Kuhn KA, Karle K, Schöls L, Schulz JB, Weis J, Prokisch H, Kornblum C, Claeys KG, Klopstock T
J Neurol 2016 May;263(5):961-972. Epub 2016 Mar 19 doi: 10.1007/s00415-016-8086-3. PMID: 26995359
Mancuso M, Orsucci D, Angelini C, Bertini E, Carelli V, Comi GP, Minetti C, Moggio M, Mongini T, Servidei S, Tonin P, Toscano A, Uziel G, Bruno C, Caldarazzo Ienco E, Filosto M, Lamperti C, Martinelli D, Moroni I, Musumeci O, Pegoraro E, Ronchi D, Santorelli FM, Sauchelli D, Scarpelli M, Sciacco M, Spinazzi M, Valentino ML, Vercelli L, Zeviani M, Siciliano G
Neurology 2013 May 28;80(22):2049-54. Epub 2013 May 1 doi: 10.1212/WNL.0b013e318294b44c. PMID: 23635963
Bindoff LA, Engelsen BA
Epilepsia 2012 Sep;53 Suppl 4:92-7. doi: 10.1111/j.1528-1167.2012.03618.x. PMID: 22946726
Zhou L, Chomyn A, Attardi G, Miller CA
J Neurosci 1997 Oct 15;17(20):7746-53. PMID: 9315896

Diagnosis

Lorenzoni PJ, Scola RH, Kay CS, Silvado CE, Werneck LC
Arq Neuropsiquiatr 2014 Oct;72(10):803-11. PMID: 25337734
Blakely EL, Alston CL, Lecky B, Chakrabarti B, Falkous G, Turnbull DM, Taylor RW, Gorman GS
Neuromuscul Disord 2014 Jun;24(6):533-6. Epub 2014 Apr 1 doi: 10.1016/j.nmd.2014.03.011. PMID: 24792523Free PMC Article
Emmanuele V, Silvers DS, Sotiriou E, Tanji K, DiMauro S, Hirano M
Muscle Nerve 2011 Sep;44(3):448-51. doi: 10.1002/mus.22149. PMID: 21996807Free PMC Article
Orcesi S, Gorni K, Termine C, Uggetti C, Veggiotti P, Carrara F, Zeviani M, Berardinelli A, Lanzi G
J Child Neurol 2006 Jan;21(1):79-82. doi: 10.1177/08830738060210010901. PMID: 16551460
Szuhai K, Ouweland J, Dirks R, Lemaître M, Truffert J, Janssen G, Tanke H, Holme E, Maassen J, Raap A
Nucleic Acids Res 2001 Feb 1;29(3):E13. PMID: 11160915Free PMC Article

Therapy

Chang JC, Liu KH, Chuang CS, Su HL, Wei YH, Kuo SJ, Liu CS
Cytotherapy 2013 Dec;15(12):1580-96. doi: 10.1016/j.jcyt.2013.06.008. PMID: 24199594
Bindoff LA, Engelsen BA
Epilepsia 2012 Sep;53 Suppl 4:92-7. doi: 10.1111/j.1528-1167.2012.03618.x. PMID: 22946726
Mancuso M, Petrozzi L, Filosto M, Nesti C, Rocchi A, Choub A, Pistolesi S, Massetani R, Fontanini G, Siciliano G
Biochem Biophys Res Commun 2007 Mar 23;354(4):1058-60. Epub 2007 Jan 26 doi: 10.1016/j.bbrc.2007.01.099. PMID: 17275787
Mancuso M, Galli R, Pizzanelli C, Filosto M, Siciliano G, Murri L
J Neurol Sci 2006 Apr 15;243(1-2):97-9. Epub 2006 Jan 18 doi: 10.1016/j.jns.2005.11.021. PMID: 16414077
Kaufmann P, Shungu DC, Sano MC, Jhung S, Engelstad K, Mitsis E, Mao X, Shanske S, Hirano M, DiMauro S, De Vivo DC
Neurology 2004 Apr 27;62(8):1297-302. PMID: 15111665

Prognosis

Catteruccia M, Sauchelli D, Della Marca G, Primiano G, Cuccagna C, Bernardo D, Leo M, Camporeale A, Sanna T, Cianfoni A, Servidei S
J Neurol 2015 Mar;262(3):701-10. Epub 2015 Jan 6 doi: 10.1007/s00415-014-7632-0. PMID: 25559684
Hallmann K, Zsurka G, Moskau-Hartmann S, Kirschner J, Korinthenberg R, Ruppert AK, Ozdemir O, Weber Y, Becker F, Lerche H, Elger CE, Thiele H, Nürnberg P, Sander T, Kunz WS
Neurology 2014 Dec 2;83(23):2183-7. Epub 2014 Oct 31 doi: 10.1212/WNL.0000000000001055. PMID: 25361775
Mancuso M, Orsucci D, Angelini C, Bertini E, Catteruccia M, Pegoraro E, Carelli V, Valentino ML, Comi GP, Minetti C, Bruno C, Moggio M, Ienco EC, Mongini T, Vercelli L, Primiano G, Servidei S, Tonin P, Scarpelli M, Toscano A, Musumeci O, Moroni I, Uziel G, Santorelli FM, Nesti C, Filosto M, Lamperti C, Zeviani M, Siciliano G
Mov Disord 2014 May;29(6):722-8. Epub 2014 Feb 7 doi: 10.1002/mds.25839. PMID: 24510442
Monden Y, Mori M, Kuwajima M, Goto T, Yamagata T, Momoi MY
Brain Dev 2013 Jun;35(6):582-5. Epub 2012 Sep 13 doi: 10.1016/j.braindev.2012.08.006. PMID: 22981260
Nakamura M, Yabe I, Sudo A, Hosoki K, Yaguchi H, Saitoh S, Sasaki H
J Med Genet 2010 Oct;47(10):659-64. Epub 2010 Jul 7 doi: 10.1136/jmg.2009.072058. PMID: 20610441

Clinical prediction guides

Hallmann K, Zsurka G, Moskau-Hartmann S, Kirschner J, Korinthenberg R, Ruppert AK, Ozdemir O, Weber Y, Becker F, Lerche H, Elger CE, Thiele H, Nürnberg P, Sander T, Kunz WS
Neurology 2014 Dec 2;83(23):2183-7. Epub 2014 Oct 31 doi: 10.1212/WNL.0000000000001055. PMID: 25361775
Mancuso M, Orsucci D, Angelini C, Bertini E, Carelli V, Comi GP, Minetti C, Moggio M, Mongini T, Servidei S, Tonin P, Toscano A, Uziel G, Bruno C, Caldarazzo Ienco E, Filosto M, Lamperti C, Martinelli D, Moroni I, Musumeci O, Pegoraro E, Ronchi D, Santorelli FM, Sauchelli D, Scarpelli M, Sciacco M, Spinazzi M, Valentino ML, Vercelli L, Zeviani M, Siciliano G
Neurology 2013 May 28;80(22):2049-54. Epub 2013 May 1 doi: 10.1212/WNL.0b013e318294b44c. PMID: 23635963
Chen HF, Chen CY, Lin TH, Huang ZW, Chi TH, Ma YS, Wu SB, Wei YH, Hsieh M
FEBS J 2012 Aug;279(16):2987-3001. Epub 2012 Jul 23 doi: 10.1111/j.1742-4658.2012.08678.x. PMID: 22742457
Horvath R, Kley RA, Lochmüller H, Vorgerd M
Neurology 2007 Jan 2;68(1):56-8. doi: 10.1212/01.wnl.0000250334.48038.7a. PMID: 17200493
Mancuso M, Galli R, Pizzanelli C, Filosto M, Siciliano G, Murri L
J Neurol Sci 2006 Apr 15;243(1-2):97-9. Epub 2006 Jan 18 doi: 10.1016/j.jns.2005.11.021. PMID: 16414077

Recent systematic reviews

Virgilio R, Ronchi D, Bordoni A, Fassone E, Bonato S, Donadoni C, Torgano G, Moggio M, Corti S, Bresolin N, Comi GP
J Neurol Sci 2009 Jun 15;281(1-2):85-92. Epub 2009 Mar 10 doi: 10.1016/j.jns.2009.01.025. PMID: 19278689
Campanella G, Filla A, De Michele G
Acta Neurol (Napoli) 1992 Aug-Dec;14(4-6):408-19. PMID: 1293984

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