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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
Hearing loss resulting from damage to the COCHLEA and the sensorineural elements which lie internally beyond the oval and round windows. These elements include the AUDITORY NERVE and its connections in the BRAINSTEM.
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
Epilepsy is a brain disorder that causes people to have recurring seizures. The seizures happen when clusters of nerve cells, or neurons, in the brain send out the wrong signals. People may have strange sensations and emotions or behave strangely. They may have violent muscle spasms or lose consciousness. Epilepsy has many possible causes, including illness, brain injury, and abnormal brain development. In many cases, the cause is unknown. Doctors use brain scans and other tests to diagnose epilepsy. It is important to start treatment right away. There is no cure for epilepsy, but medicines can control seizures for most people. When medicines are not working well, surgery or implanted devices such as vagus nerve stimulators may help. Special diets can help some children with epilepsy. NIH: National Institute of Neurological Disorders and Stroke.
Epilepsies, Myoclonic
MedGen UID:
4988
Concept ID:
C0014550
Disease or Syndrome
A clinically diverse group of epilepsy syndromes characterized either by myoclonic seizures or by myoclonus in association with other seizure types. Myoclonic epilepsy syndromes are divided into three subtypes based on etiology: familial, cryptogenic, and symptomatic (i.e., occurring secondary to known disease processes such as infections, hypoxic-ischemic injuries, trauma, etc.).
Headache
MedGen UID:
9149
Concept ID:
C0018681
Sign or Symptom
Almost everyone has had a headache. Headache is the most common form of pain. It's a major reason people miss days at work or school or visit the doctor. The most common type of headache is a tension headache. Tension headaches are due to tight muscles in your shoulders, neck, scalp and jaw. They are often related to stress, depression or anxiety. You are more likely to get tension headaches if you work too much, don't get enough sleep, miss meals, or use alcohol. Other common types of headaches include migraines, cluster headaches, and sinus headaches. Most people can feel much better by making lifestyle changes, learning ways to relax and taking pain relievers. Not all headaches require a doctor's attention. But sometimes headaches warn of a more serious disorder. Let your health care provider know if you have sudden, severe headaches. Get medical help right away if you have a headache after a blow to your head, or if you have a headache along with a stiff neck, fever, confusion, loss of consciousness, or pain in the eye or ear. NIH: National Institute of Neurological Disorders and Stroke.
Spasticity
MedGen UID:
7753
Concept ID:
C0026838
Sign or Symptom
A motor disorder characterized by a velocity-dependent increase in tonic stretch reflexes with increased muscle tone, exaggerated (hyperexcitable) tendon reflexes.
Myoclonus
MedGen UID:
10234
Concept ID:
C0027066
Sign or Symptom
Involuntary shock-like contractions, irregular in rhythm and amplitude, followed by relaxation, of a muscle or a group of muscles. This condition may be a feature of some CENTRAL NERVOUS SYSTEM DISEASES; (e.g., EPILEPSY, MYOCLONIC). Nocturnal myoclonus is the principal feature of the NOCTURNAL MYOCLONUS SYNDROME. (From Adams et al., Principles of Neurology, 6th ed, pp102-3).
Spasticity
MedGen UID:
7753
Concept ID:
C0026838
Sign or Symptom
A motor disorder characterized by a velocity-dependent increase in tonic stretch reflexes with increased muscle tone, exaggerated (hyperexcitable) tendon reflexes.
Myopathy
MedGen UID:
10135
Concept ID:
C0026848
Disease or Syndrome
Your muscles help you move and help your body work. Different types of muscles have different jobs. There are many problems that can affect muscles. Muscle disorders can cause weakness, pain or even paralysis. . Causes of muscle disorders include. -Injury or overuse, such as sprains or strains, cramps or tendinitis . -A genetic disorder, such as muscular dystrophy. -Some cancers. -Inflammation, such as myositis. -Diseases of nerves that affect muscles. -Infections. -Certain medicines. Sometimes the cause is not known.
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.
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
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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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