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MERRF syndrome(MERRF)

MedGen UID:
56486
Concept ID:
C0162672
Disease or Syndrome
Synonyms: Fukuhara syndrome; MERRF; Myoclonic epilepsy associated with ragged-red fibers; Myoclonus with epilepsy with ragged red fibers; Myoencephalopathy ragged-red fiber disease
SNOMED CT: Myoclonic epilepsy with ragged red fibers (230426003); MERFF - myoclonic epilepsy with ragged red fibers (230426003); Fukuhara syndrome (230426003)
Modes of inheritance:
Mitochondrial inheritance
MedGen UID:
165802
Concept ID:
C0887941
Genetic Function
Source: 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).
 
Genes (locations): MT-TF; MT-TI; MT-TK; MT-TL1; MT-TP
 
Monarch Initiative: MONDO:0010790
OMIM®: 545000
Orphanet: ORPHA551

Definition

MERRF (myoclonic epilepsy with ragged red fibers) is a multisystem disorder characterized by myoclonus (often the first symptom) followed by generalized epilepsy, ataxia, weakness, exercise intolerance, and dementia. Onset can occur from childhood to adulthood, occurring after normal early development. Common findings are ptosis, hearing loss, short stature, optic atrophy, cardiomyopathy, cardiac dysrhythmias such as Wolff-Parkinson-White syndrome, and peripheral neuropathy. Pigmentary retinopathy, optic neuropathy, diabetes mellitus, and lipomatosis have been observed. [from GeneReviews]

Additional description

From MedlinePlus Genetics
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://medlineplus.gov/genetics/condition/myoclonic-epilepsy-with-ragged-red-fibers

Clinical features

From HPO
Sensorineural hearing impairment
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
Disease or Syndrome
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- or overshoot in grasping movements), and dysdiadochokinesia (inability to perform rapid movements requiring antagonizing muscle groups to be switched on and off repeatedly).
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
Finding
Very brief, involuntary random muscular contractions occurring at rest, in response to sensory stimuli, or accompanying voluntary movements.
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.
Generalized myoclonic seizure
MedGen UID:
892704
Concept ID:
C4021759
Disease or Syndrome
A generalized myoclonic seizure is a type of generalized motor seizure characterized by bilateral, sudden, brief (<100 ms) involuntary single or multiple contraction of muscles or muscle groups of variable topography (axial, proximal limb, distal). Myoclonus is less regularly repetitive and less sustained than is clonus.
Myopathy
MedGen UID:
10135
Concept ID:
C0026848
Disease or Syndrome
A disorder of muscle unrelated to impairment of innervation or neuromuscular junction.
Muscle weakness
MedGen UID:
57735
Concept ID:
C0151786
Finding
Reduced strength of muscles.
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.
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).
Increased serum pyruvate
MedGen UID:
376596
Concept ID:
C1849488
Finding
An increased concentration of pyruvate in the blood.

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
Follow this link to review classifications for MERRF syndrome in Orphanet.

Professional guidelines

PubMed

Finsterer J
Expert Opin Pharmacother 2019 Jul;20(10):1289-1297. Epub 2019 May 7 doi: 10.1080/14656566.2019.1609941. PMID: 31063406
Finsterer J, Zarrouk-Mahjoub S
Seizure 2017 Aug;50:166-170. Epub 2017 Jun 24 doi: 10.1016/j.seizure.2017.06.010. PMID: 28686997
Finsterer J
Eur J Neurol 2009 Nov;16(11):1178-84. Epub 2009 Sep 23 doi: 10.1111/j.1468-1331.2009.02789.x. PMID: 19780807

Recent clinical studies

Etiology

Cohen BH
Neurotherapeutics 2013 Apr;10(2):227-42. doi: 10.1007/s13311-013-0188-3. PMID: 23549648Free PMC Article
Bindoff LA, Engelsen BA
Epilepsia 2012 Sep;53 Suppl 4:92-7. doi: 10.1111/j.1528-1167.2012.03618.x. PMID: 22946726
DiMauro S
Biochim Biophys Acta 2004 Jul 23;1658(1-2):80-8. doi: 10.1016/j.bbabio.2004.03.014. PMID: 15282178
Schmiedel J, Jackson S, Schäfer J, Reichmann H
J Neurol 2003 Mar;250(3):267-77. doi: 10.1007/s00415-003-0978-3. PMID: 12638015
DiMauro S, Moraes CT
Arch Neurol 1993 Nov;50(11):1197-208. doi: 10.1001/archneur.1993.00540110075008. PMID: 8215979

Diagnosis

Finsterer J, Zarrouk-Mahjoub S, Shoffner JM
Pediatr Neurol 2018 Mar;80:8-23. Epub 2017 Dec 13 doi: 10.1016/j.pediatrneurol.2017.12.005. PMID: 29449072
Cohen BH
Neurotherapeutics 2013 Apr;10(2):227-42. doi: 10.1007/s13311-013-0188-3. PMID: 23549648Free PMC Article
Finsterer J
J Neurol Sci 2011 May 15;304(1-2):9-16. Epub 2011 Mar 13 doi: 10.1016/j.jns.2011.02.012. PMID: 21402391
Satishchandra P, Sinha S
Neurol India 2010 Jul-Aug;58(4):514-22. doi: 10.4103/0028-3886.68660. PMID: 20739785
Schmiedel J, Jackson S, Schäfer J, Reichmann H
J Neurol 2003 Mar;250(3):267-77. doi: 10.1007/s00415-003-0978-3. PMID: 12638015

Therapy

Finsterer J
Expert Opin Pharmacother 2019 Jul;20(10):1289-1297. Epub 2019 May 7 doi: 10.1080/14656566.2019.1609941. PMID: 31063406
Finsterer J, Zarrouk-Mahjoub S, Shoffner JM
Pediatr Neurol 2018 Mar;80:8-23. Epub 2017 Dec 13 doi: 10.1016/j.pediatrneurol.2017.12.005. PMID: 29449072
Finsterer J, Zarrouk-Mahjoub S
Seizure 2017 Aug;50:166-170. Epub 2017 Jun 24 doi: 10.1016/j.seizure.2017.06.010. PMID: 28686997
Bindoff LA, Engelsen BA
Epilepsia 2012 Sep;53 Suppl 4:92-7. doi: 10.1111/j.1528-1167.2012.03618.x. PMID: 22946726
Finsterer J, Zarrouk Mahjoub S
Seizure 2012 Jun;21(5):316-21. Epub 2012 Mar 27 doi: 10.1016/j.seizure.2012.03.003. PMID: 22459315

Prognosis

Magner M, Kolářová H, Honzik T, Švandová I, Zeman J
Dev Period Med 2015 Oct-Dec;19(4):441-9. PMID: 26982751
Seo HE, Hwang SK, Choe BH, Cho MH, Park SP, Kwon S
J Korean Med Sci 2010 Mar;25(3):449-53. Epub 2010 Feb 17 doi: 10.3346/jkms.2010.25.3.449. PMID: 20191046Free PMC Article
Reed UC
Arq Neuropsiquiatr 2009 Mar;67(1):144-68. doi: 10.1590/s0004-282x2009000100038. PMID: 19330236
Huang CC, Wai YY, Chu NS, Liou CW, Pang CY, Shih KD, Wei YH
Eur Neurol 1995;35(4):199-205. doi: 10.1159/000117128. PMID: 7671979
Buchhalter JR
J Child Neurol 1994 Oct;9 Suppl 1:S12-9. doi: 10.1177/0883073894009001041. PMID: 7822747

Clinical prediction guides

Štufková H, Kolářová H, Lokvencová K, Honzík T, Zeman J, Hansíková H, Tesařová M
Genes (Basel) 2022 Jul 14;13(7) doi: 10.3390/genes13071245. PMID: 35886028Free PMC Article
Finsterer J
Expert Opin Pharmacother 2019 Jul;20(10):1289-1297. Epub 2019 May 7 doi: 10.1080/14656566.2019.1609941. PMID: 31063406
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
Kunz WS
Curr Opin Neurol 2002 Apr;15(2):179-84. doi: 10.1097/00019052-200204000-00009. PMID: 11923632
Kim DS, Jung DS, Park KH, Kim IJ, Kim CM, Lee WH, Rho SK
J Korean Med Sci 2002 Feb;17(1):103-12. doi: 10.3346/jkms.2002.17.1.103. PMID: 11850598Free PMC Article

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