Myoclonus epilepsy with ragged-red fiber (MERRF) patients present with symptoms related to the central and peripheral nervous system, ocular and cardiovascular apparatus and subcutaneous tissues. The main trait of this disease is myoclonus, consisting of involuntary, brief, sudden spasms affecting extremities. Other peripheral nervous system involvement signs include muscle weakness, as an expression of myopathy, progressive muscular spasticity, peripheral neuropathy, optic nerve atrophy or progressive external ophthalmoplegia and hearing loss. Central nervous system involvement causes seizures, ataxia, depression [1] and dementia, as well as the presence of pyramidal signs on evaluation.

The cardiovascular system is involved with patients developing a form of dilative cardiomyopathy after a period of normal development [2]. Affected individuals also have heart rhythm abnormalities, a type of preexcitation syndrome known as Wolff-Parkinson-White syndrome, premature ventricular contractions, incomplete left bundle branch block and other, unrelated findings such as a short stature, lipomas, abdominal pain, recurrent vomiting, fatigue, exercise intolerance, dyspnea (caused by lactic acid accumulation) and pigmentary retinopathy. Cardiac involvement may progress to subclinical left ventricular dysfunction or overt heart failure. Cases of stroke [3] [4] or stroke-like episodes [5] have also been described. This condition may also be associated with other diseases, such as atypical Charcot-Marie-Tooth and Leigh syndrome, diabetes mellitus and migraine headaches [6].

Other unusual manifestations include spasmodic dysphonia [7], acute demyelinating disease [8] and sudden infant death syndrome [9].

• Epilepsy

  (MERRF syndrome) myoclonic epilepsy with ragged red fibers Fukuhara syndrome Myoclonus with epilepsy and with Ragged Red Fibers Myoclonic epilepsy - ragged red fibers Myoclonus epilepsy AND ragged red fibers MYOCLONIC EPILEPSY ASSOCIATED WITH RAGGED-RED [wikidata.org]

  There are no guidelines available for the management of epilepsy in MERRF syndrome but several expert opinions and general recommendations for the treatment of mitochondrial epilepsy have been published. [ncbi.nlm.nih.gov]

• Vomiting

  […] prominent features: MELAS ( M itochondrial e ncephalomyopathy, L actic a cidosis, and S troke-like episodes) MERRF ( M yoclonic e pilepsy with R agged r ed f ibers) MELAS syndrome signs and symptoms: muscle weakness and pain recurrent headaches seizures vomiting [medschool.lsuhsc.edu]

  The patient might have also had a gastrointestinal condition which could have been due to liver disease, as well as episodes of nausea or vomiting. [en.wikipedia.org]

  […] abnormalities, a type of preexcitation syndrome known as Wolff-Parkinson-White syndrome, premature ventricular contractions, incomplete left bundle branch block and other, unrelated findings such as a short stature, lipomas, abdominal pain, recurrent vomiting [symptoma.com]

  She presented with a complex phenotype characterized by progressive cerebellar ataxia, frequent myoclonus seizures, recurrent stroke-like episodes, migraine-like headaches with nausea and vomiting, and elevated resting lactate blood level. [link.springer.com]

  People with MERRF syndrome have an accumulation of lactic acid in the blood (lactic acidosis) and often complain of vomiting, abdominal pain, fatigue, muscle weakness and difficulty breathing. [rarediseases.org]

• Nausea

  The patient might have also had a gastrointestinal condition which could have been due to liver disease, as well as episodes of nausea or vomiting. [en.wikipedia.org]

  She presented with a complex phenotype characterized by progressive cerebellar ataxia, frequent myoclonus seizures, recurrent stroke-like episodes, migraine-like headaches with nausea and vomiting, and elevated resting lactate blood level. [link.springer.com]

  […] headache/migraine, developmental delay, regression, dementia, tremo r, bradykinesia, retinopathy, optic atrophy, ophthalmoplegia Constitutional: exercise intolerance, growth failure, microcephaly, cachexia, lac tic acidosis, hyperalaninemia, SIDS GI: nausea [slideshare.net]

  […] psychiatrist, ophthalmologist There is no medication to slow the progression of the disease and treatments only target at controlling the symptoms Lactic acidosis is treated by sodium bicarbonate or sodium citrate Antiemetic drugs are used to treat nausea [lhsc.on.ca]

• Tachycardia

  Click Here to download this mito profile (PDF) Links: NINDS OMIM, X-linked: OMIM, Adult-onset: OMIM Symptoms: Hypermetabolism, with fever, heat intolerance, profuse perspiration, polyphagia, polydipsia, ragged-red fibers, and resting tachycardia. [umdf.org]

• Night Blindness

  blindness Tunnel vision Loss of central vision Caused by damage to the light sensing photoreceptor cells of the retina known as rods and cones (usually damage to the rods) Testing Lab Testing: Muscle biopsy: Abnormal mitochondria from muscle tissue may [lhsc.on.ca]

• Hearing Impairment

  Among them, action myoclonus was seen in five; short stature, muscle weakness, and mental retardation in four; lactic acidosis, hearing impairment, and ataxia in two; and seizures in one. [ncbi.nlm.nih.gov]

  Hearing impairment is common in various phenotypes of the mitochondrial DNA A3243G mutation. Arch Neurol. 2001; 58:1885–8. DOI: 10.1001/archneur.58.11.1885. PMID: 11708999. [ CrossRef ] [ Google Scholar ] 6. [e-sciencecentral.org]

  The disease also can cause hearing impairment and short stature. [mda.org]

  impairment 0000407 30%-79% of people have these symptoms Cognitive impairment Abnormality of cognition Cognitive abnormality Cognitive defects Cognitive deficits Intellectual impairment Mental impairment Mutations in the MT-TK gene are the most common [rarediseases.info.nih.gov]

• Myopathy

  The human mitochondrial tRNA mutations are associated with a variety of diseases including mitochondrial myopathies. [en.wikipedia.org]

  One of the predominant phenotypic features in addition to myopathy is epilepsy. [ncbi.nlm.nih.gov]

  […] fibers Hearing Sensorineural hearing loss Metabolic Abnormality Defect in translation of all mtDNA-encoded genes Serum pyruvate or pyruvate and lactate elevated Muscle Muscle weakness Neurologic Abnormality Ataxia Myoclonus epilepsy Spasticity Ocular Myopathy [datagenno.com]

  Mitochondrial metabolism disorders 2016 2017 2018 2019 Non-Billable/Non-Specific Code Type 1 Excludes disorders of pyruvate metabolism ( E74.4 ) Kearns-Sayre syndrome ( H49.81 ) Leber's disease ( H47.22 ) Leigh's encephalopathy ( G31.82 ) Mitochondrial myopathy [icd10data.com]

• Muscle Weakness

  Among them, action myoclonus was seen in five; short stature, muscle weakness, and mental retardation in four; lactic acidosis, hearing impairment, and ataxia in two; and seizures in one. [ncbi.nlm.nih.gov]

  They are named after their most prominent features: MELAS ( M itochondrial e ncephalomyopathy, L actic a cidosis, and S troke-like episodes) MERRF ( M yoclonic e pilepsy with R agged r ed f ibers) MELAS syndrome signs and symptoms: muscle weakness and [medschool.lsuhsc.edu]

  Myoclonus is usually the first symptom followed by seizures, ataxia, muscle weakness and dementia. [rarediseases.org]

  weakness Neurologic Abnormality Ataxia Myoclonus epilepsy Spasticity Ocular Myopathy [datagenno.com]

• Myoclonus

  […] fibers (disorder) Myoclonus epilepsy AND ragged red fibers (disorder) Myoclonus with epilepsy and with Ragged Red Fibers (MERRF syndrome) myoclonic epilepsy with ragged red fibers Fukuhara syndrome Myoclonus with epilepsy and with Ragged Red Fibers Myoclonic [wikidata.org]

  LEV may benefit myoclonus in PME of mitochondrial origin without altering mitochondrial function, and it could be considered the drug of first choice for the treatment of myoclonus in MERRF. [ncbi.nlm.nih.gov]

  If the individual has been experiencing myoclonus, the doctor will run a series of genetic studies to determine if it is a mitochondrial disorder. [en.wikipedia.org]

• Seizure

  The most frequent seizure type in MERRF is generalised myoclonic seizure but also focal myoclonic, focal atonic, generalised tonic-clonic, generalised atonic, generalised myoclonic-atonic, typical absences, or tonic-clonic seizures of unknown onset have [ncbi.nlm.nih.gov]

  The primary features displayed on a person with MERRF include myoclonus, seizures, cerebellar ataxia, myopathy, and ragged red fibers (RRF) on muscle biopsy, leading to the disease's name. [en.wikipedia.org]

  […] most prominent features: MELAS ( M itochondrial e ncephalomyopathy, L actic a cidosis, and S troke-like episodes) MERRF ( M yoclonic e pilepsy with R agged r ed f ibers) MELAS syndrome signs and symptoms: muscle weakness and pain recurrent headaches seizures [medschool.lsuhsc.edu]

• Cerebellar Ataxia

  Abstract Myoclonic epilepsy and ragged-red fibers (MERRF) syndrome is a rare disorder characterized by myoclonus, muscle weakness, cerebellar ataxia, heart conduction block, and dementia. [ncbi.nlm.nih.gov]

  The primary features displayed on a person with MERRF include myoclonus, seizures, cerebellar ataxia, myopathy, and ragged red fibers (RRF) on muscle biopsy, leading to the disease's name. [en.wikipedia.org]

  Diagnostic criteria for MERRF include typical manifestations of the disease: myoclonus, generalized epilepsy, cerebellar ataxia and ragged red fibers (RRF) on muscle biopsy. [scielo.br]

  She presented with a complex phenotype characterized by progressive cerebellar ataxia, frequent myoclonus seizures, recurrent stroke-like episodes, migraine-like headaches with nausea and vomiting, and elevated resting lactate blood level. [link.springer.com]

  Involuntary muscle twitches, generalized epilepsy, and cerebellar ataxia — these symptoms are typically indicative of a mitochondrial myopathy. [mitochondrialdiseasenews.com]

• Generalized Seizure

  Abstract Myoclonus epilepsy associated with ragged-red fibers (MERRF) is a mitochondrial disorder characterized by myoclonus epilepsy, generalized seizures, ataxia and myopathy. [ncbi.nlm.nih.gov]

  At age 55 years, she developed blindness after an episode of generalized seizure, and thereafter was bedridden and severely demented; the phenotype suggested stroke-like episodes consistent with MELAS syndrome. [omim.org]

  Valproate is the first-line antiepileptic drug for generalized seizures and myoclonic epileptiform abnormalities 49. [doi.org]

• Limb Weakness

  Exercise intolerance, limb weakness, hearing loss, and diabetes may also precede the occurrence of the stroke-like episodes. [umdf.org]

  Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) Onset: Usually before age 20 Symptoms: This disorder causes PEO, ptosis (droopy eyelids), limb weakness and gastrointestinal (digestive) problems, including chronic diarrhea and abdominal pain [mda.org]

  The patient had approximately 10 attacks per day, which were accompanied by limb weakness. A magnetic resonance imaging (MRI) scan was performed initially and was found to be normal. [spandidos-publications.com]

  An individual with the MT-TF m.611G A pathogenic variant had mild truncal and proximal limb weakness, cerebellar ataxia, bilateral Babinski sign, and frequent myoclonic jerks [ Mancuso et al 2004 ]. Table 2. [ncbi.nlm.nih.gov]

The diagnosis of MERRF is indicated by clinical examination and confirmed by molecular genetic testing and microscopic examination of the muscle biopsy specimen with modified Gomori trichrome or succinate dehydrogenase staining. This last method will show the presence of cytochrome c oxidase negative muscle fibers and ragged red fibers, while genetic tests will detect mitochondrial deoxyribonucleic acid mutations in white blood cells, urine, saliva, hair follicles, skin or muscle.

Blood workup reveals increased lactate and pyruvate concentrations in the blood and cerebrospinal fluid [10], which also has high protein concentration [11]. Creatine kinase levels may be slightly increased [12], but this is not a specific disease characteristic.

Brain imaging techniques like magnetic resonance imaging are able to diagnose stroke, brainstem atrophy [13], cerebellar atrophy [14] and basal ganglia calcification [15], while magnetic resonance spectroscopy detects brain lactate levels.

The electrocardiogram highlights rhythm and conduction abnormalities, if present. The electroencephalogram usually reveals generalized spike and wave discharges or focal epileptiform waves. The electromyogram and nerve conduction velocity may have either a myogenic or neurogenic aspect.

Genetic analysis may reveal MT-TL1, MT-TK, MT-TP, MT-TF or MT-TI mutations. Combined respiratory chain defects [16] and cytochrome c oxidase deficiency [17] have also been described.

• Epileptiform Activity

  The EEG of patients with MERRF usually exhibits variation in the degree of slowing of background activity and generalized epileptiform activity, which may worsen with intermittent photic stimulation 27, 33, 49, 50, 51. [doi.org]

  One of the patient had multifocal epileptiform activity. [bioline.org.br]

• Muscle Biopsy showing Ragged-Red Fibers

  Most importantly, a muscle biopsy shows ragged-red fibers in over 92% of patients, lending the disease its name. No matter the means for diagnosing the disease, there remains no specific cure for MERRF. [mitochondrialdiseasenews.com]

• Muscle Biopsy Abnormal

  biopsy: Abnormal mitochondria from muscle tissue may appear as “ragged red fibres” under a microscope Chemical staining identifies diseased mitochondria, appearing as “ragged red fibres”. [lhsc.on.ca]

The treatment of progressive myoclonic epilepsy (PME) is largely empirical, even though valproic acid (VPA) is usually considered the drug of first choice. [ncbi.nlm.nih.gov]

There is very little success with these treatments as therapies in hopes of improving mitochondrial function. The treatment only alleviates symptoms, and these do not prevent the disease from progressing. [en.wikipedia.org]

Genes involved include MT-TK, MT-TL1, MT-TH, MT-TS1, MT-TS2, and MT-TF. [1] Differentiating MERRF syndrome from Other Diseases Epidemiology and Demographics Risk Factors Screening Natural History, Complications, and Prognosis Diagnosis Diagnostic Criteria [wikidoc.org]

Prognosis - MERRF Syndrome Not supplied. Treatment - MERRF Syndrome The condition is caused by mutations - that can be detected with genetic testing in 90% of affected individuals - in the mitochondrial gene called MT-TK. [checkorphan.org]

Prognosis The prognosis for patients with MERRF syndrome is globally poor because of the progressive nature of the disease. [orpha.net]

Prognosis The prognosis depends heavily on the underlying etiology and the epilepsy syndrome. Patients with a benign syndrome typically respond well to medication and may outgrow their epilepsy. [emedicine.medscape.com]

Prognosis is generally quite poor. [lhsc.on.ca]

Certain conditions have both an underlying etiology and multiple body system manifestations due to the underlying etiology. [icd10coded.com]

Etiology Seizures associated with early myoclonic encephalopathy can be due to a number of etiologies. [emedicine.medscape.com]

Etiology MERRF syndrome is caused by mutations in the mitochondrial DNA. Over 80% of individuals with MERRF syndrome carry the 8344A G mutation in the lysine transfer RNA ( tRNA Lys ) gene ( MTTK ). [orpha.net]

Mitochondrial respiratory chain defects: underlying etiology in various epileptic conditions. Epilepsia. 2008 ;49: 685 – 690. Google Scholar Crossref Medline ISI 19. Waldbaum, S, Patel, M. Mitochondria, oxidative stress and temporal lobe epilepsy. [doi.org]

Is the tRNA(Leu(UUR)) gene an etiologic hot spot? J Clin Invest. 1993 Dec;92(6):2906-15. Nakamura M, Nakano S, Goto Y, Ozawa M, Nagahama Y, Fukuyama H, Akiguchi I, Kaji R, Kimura J. [ghr.nlm.nih.gov]

The epidemiology of pathogenetic mitochondrial DNA mutations. Ann Neurol 2000 ; 48 : 188 –93. Darin N, Oldfors A, Moslemi A-R, et al. [jnnp.bmj.com]

Genes involved include MT-TK, MT-TL1, MT-TH, MT-TS1, MT-TS2, and MT-TF. [1] Differentiating MERRF syndrome from Other Diseases Epidemiology and Demographics Risk Factors Screening Natural History, Complications, and Prognosis Diagnosis Diagnostic Criteria [wikidoc.org]

Summary Epidemiology The prevalence in the general population of Europe has been estimated at 0.9 in 100 000, but the disease seems to be more common in the USA. [orpha.net]

Epidemiology of A3243G, the mutation for mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes: prevalence of the mutation in an adult population. [ncbi.nlm.nih.gov]

Epidemiology The incidence of myoclonic epilepsy is approximately 1 case in 40,000 children. Typically, the onset of these disorders is during the first 3 years of life. [emedicine.medscape.com]

[…] following characteristics: progressive myoclonic epilepsy clumps of diseased mitochondria accumulate in the subsarcolemmal region of the muscle fiber and appear as "ragged-red fibers" when muscle is stained with modified Gomori trichrome stain short stature Pathophysiology [wikidoc.org]

This model is useful to clarify the pathophysiology and biomolecular mechanisms of MERRF syndrome. [nature.com]

Familial mitochondrial encephalomyopathy (MERRF): genetic, pathophysiological and biochemical characterization of a mitochondrial DNA disease. Cell. 1988 ;55: 601 – 610. Google Scholar Crossref Medline ISI 13. [doi.org]

Familial mitochondrial encephalomyopathy (MERRF): genetic, pathophysiological, and biochemical characterization of a mitochondrial DNA disease. Cell 55: 601-610, 1988. [ncbi.nlm.nih.gov]

Import of a tRNALys with a mutation in the anticodon preventing recognition of the lysine codons does not lead to any rescue, whereas downregulation of the transgenic tRNAs by small interfering RNA (siRNA) transiently abolishes the functional rescue, [ncbi.nlm.nih.gov]

Demographics Risk Factors Screening Natural History, Complications, and Prognosis Diagnosis Diagnostic Criteria History and Symptoms Physical Examination Laboratory Findings Imaging Findings Other Diagnostic Studies Treatment Medical Therapy Surgery Prevention [wikidoc.org]

Source: Genetics Home Reference, Wikipedia Prevention - MERRF Syndrome Not supplied. [checkorphan.org]

The treatment only alleviates symptoms, and these do not prevent the disease from progressing. Patients with concomitant disease, such as diabetes, deafness, or cardiac disease, are treated in combination to manage symptoms. [en.wikipedia.org]

Patients are usually prescribed therapeutic compounds to alleviate symptoms, but these do not prevent the disease from progressing. [mitochondrialdiseasenews.com]

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2. Wahbi K, Larue S, Jardel C, et al. Cardiac involvement is frequent in patients with the m.8344A>G mutation of mitochondrial DNA. Neurology. 2010;74:674–677.
3. Naini AB, Lu J, Kaufmann P, et al. Novel mitochondrial DNA ND5 mutation in a patient with clinical features of MELAS and MERRF. Arch Neurol. 2005;62:473–476.
4. Melone MA, Tessa A, Petrini S, et al. Revelation of a new mitochondrial DNA mutation (G12147A) in a MELAS/MERRF phenotype. Arch Neurol. 2004;61:269–272.
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9. Vallance HD, Jeven G, Wallace DC, et al. A case of sporadic infantile histiocytoid cardiomyopathy caused by the A8344G (MERRF) mitochondrial DNA mutation. Pediatr Cardiol. 2004;25:538–540.
10. Ozawa M, Goto Y, Sakuta R, et al. The 8,344 mutation in mitochondrial DNA: a comparison between the proportion of mutant DNA and clinico-pathologic findings. Neuromuscul Disord. 1995;5(6):483-488.
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15. Orcesi S, Gorni K, Termine C, et al. Bilateral putaminal necrosis associated with the mitochondrial DNA A8344G myoclonus epilepsy with ragged red fibers (MERRF) mutation: an infantile case. J Child Neurol. 2006;21:79–82.
16. Coquet M, Degoul F, Vital A, et al. MERRFf family with 8344 mutation in tRNA (lys). Evidence of a mitochondrial vasculopathy in muscle biopsies. Neuromuscul Disord. 1993;3(5-6):593-597.
17. Hasegawa H, Matsuoka T, Goto Y, et al. Cytochrome c oxidase activity is deficient in blood vessels of patients with myoclonus epilepsy with ragged-red fibers. Acta Neuropathol. 1993;85(3):280-284.