MERRF Syndrome
Fukuhara Disease
MERRF syndrome, also known as Myoclonus Epilepsy with Ragged-Red Fibers is a very rare multisystem disorder, part of the mitochondrial encephalomyopathies cluster, due to mitochondrial abnormalities (mutations in mitochondrial deoxyribonucleic acid) that mainly affects the muscular and nervous systems and becomes symptomatic during childhood or adolescence, affecting patients in an unequal manner, even if related.
WIKIDATA, CC BY 2.0
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].
National Library of Medicine, 2021 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. [openmd.com]
(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]
Myoclonic epilepsy with red ragged fibers (MERRF). Reference article, Radiopaedia.org (Accessed on 05 Dec 2022) https://doi.org/10.53347/rID-39666 Myoclonic epilepsy with red ragged fibers (MERRF) is a rare, multisystem mitochondrial disorder. [radiopaedia.org]
Antiepileptic drugs are given for myoclonic seizures and epilepsy. [ncbi.nlm.nih.gov]
[…] their most prominent features: MELAS (Mitochondrial encephalomyopathy, Lactic acidosis, and Stroke-like episodes) MERRF (Myoclonic epilepsy with Ragged red fibers) MELAS syndrome signs and symptoms: muscle weakness and pain recurrent headaches seizures vomiting [medschool.lsuhsc.edu]
[…] 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]
MELAS can lead to stroke-like episodes at a young age (usually before 40), seizures, dementia, headaches, vomiting, unsteadiness, and ill effects from exercise. [mitochondrialdiseases.org]
Mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS) Onset: Childhood to early adulthood Symptoms: MELAS causes recurrent stroke-like episodes in the brain, migraine-type headaches, vomiting and seizures, and can lead to permanent [mda.org]
Symptoms: Seizures, apnea, bradycardia, vomiting, lethargy, coma, enlarged liver, limb weakness, myoglobin in the urine, Reye-like symptoms triggered by fasting. Cause: Autosomal recessive. [umdf.org]
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]
[…] 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]
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]
[…] 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]
On hospital day 22, the patient was transferred to the hospital floor from the ICU due to improved tachycardia and decreased O2 demand. [clinmedjournals.org]
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]
[…] and multiple myocardial infarctions with an implanted cardio defibrillator, and dysphagia with G-tube dependence who presented to the emergency department in May of 2020 as a transfer from a skilled nursing facility with respiratory distress, severe hypotension [clinmedjournals.org]
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 aids and cochlear implants can improve hearing impairments. Physical therapy, occupational therapy and aerobic exercise may help to improve muscle weakness, stiffness, and motor function. [rarediseases.org]
The disease also can cause hearing impairment and short stature. [mda.org]
Hearing impairment is common in various phenotypes of the mitochondrial DNA A3243G mutation. Arch Neurol. 2001 Nov;58(11):1885-8. doi: 10.1001/archneur.58.11.1885. Citation on PubMed DiMauro S. Mitochondrial diseases. [medlineplus.gov]
Symptoms LHON can result in complete blindness in one or both eyes, within about 6 months of initial symptoms. [lhsc.on.ca]
Myopathy
S2CID 12265373. ^ a b "Mitochondrial myopathies: Clinical features and diagnosis". www.uptodate.com. [en.wikipedia.org]
Onset is in the neonatal period, with mental deterioration, intention tremor, myoclonic epilepsy, spasticity, ataxia, muscle weakness and atrophy, myopathy, and sensory neural hearing loss. [accessanesthesiology.mhmedical.com]
Nature 348:651–653 Google Scholar Kobayashi Y, Momoi MY, Tominaga K, Momoi T, Nihei K, Yanagisawa M, Kagawa Y, Ohta S (1990) A point mutation in the mitochondrial tRNALeu(UUR) gene in MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis and [link.springer.com]
[…] syndrome Supergrp Progressive myoclonic epilepsy [DS:H00810] Mitochondrial disease [DS:H01427] Description Myoclonic Epilepsy and Ragged-Red Fiber Disease (MERRF) is a mitochondrial encephalomyopathy characterized by myoclonic seizures, cerebellar ataxia, myopathy [genome.jp]
Due to their low prevalence, patients with mitochondrial myopathies are poorly studied, and therefore developing standardized treatment for these cases is difficult. [clinmedjournals.org]
[…] headaches seizures vomiting abdominal pain hearing loss stroke-like episodes MERRF syndrome signs and symptoms: muscle twitches muscle weakness (abnormal muscle cells are ragged red figers) recurrent seizures uncoordinated movements hearing loss vision [medschool.lsuhsc.edu]
Brief, sudden, jerking muscle spasms (myoclonus) is usually the first symptom of MERRF syndrome followed by seizures (generalized epilepsy), impaired ability to coordinate movements (ataxia), muscle weakness (myopathy) and exercise intolerance. [rarediseases.org]
It also causes muscle weakness, with prominent effects on swallowing, speech and eye movements. [mda.org]
Nocturnal Enuresis
She had nocturnal enuresis until age 14 y and menarche at age 13 y with normal periods thereafter. At age 17 y, recurrent, spontaneous myocloni of all four limbs began. A first generalised tonic-clonic seizure occurred at age 19 y. [hindawi.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]
Myoclonus may be intermittent or continuous. It is often photosensitive and aggravated by action and stimuli. Most of these patients also experience other types of seizures in addition to myoclonus. [ncbi.nlm.nih.gov]
At a glance MERRF is an acronym that stands for Myoclonus Epilepsy Ragged-Red Fibers. It is part of a larger spectrum of muscular disorders called mitochondrial encephalomyopathies. [accessanesthesiology.mhmedical.com]
[…] based on clinical symptoms (myoclonus, epilepsy, ataxia) and ragged-red fibers on muscle biopsy 3. [radiopaedia.org]
Despite VPA, seizures recurred with a frequency of 1-2 seizures/month. In addition to generalised seizures, she rarely experienced focal seizures (Figure 1). [hindawi.com]
Traditional anticonvulsant drugs are used to help prevent and control seizures associated with MERRF syndrome. Valproic acid should be avoided in the treatment of seizures. [rarediseases.org]
Seizure. 2017 Aug;50:166-170. [PubMed: 28686997] 5. [ncbi.nlm.nih.gov]
The most frequent symptom is myoclonic seizures that are usually sudden, brief, jerking spasms that can affect the limbs or the entire body. [accessanesthesiology.mhmedical.com]
Antiepileptic drugs are given for myoclonic seizures and epilepsy. [statpearls.com]
Cerebellar Ataxia
Patients usually present in late adolescence or early adulthood with 1-3 myoclonus epilepsy cerebellar ataxia intellectual disability vision and/or hearing loss cardiomyopathy with Wolff-Parkinson-White syndrome short stature The diagnosis of MERRF is [radiopaedia.org]
MERRF is characterized by myoclonic seizures (brief, sudden twitching muscle spasms), weakness (myopathy), cerebellar ataxia, progressive spasticity and dementia. [secure.ssa.gov]
ataxia, myopathy, and ragged-red fibers (RRFs) on muscle biopsy. [genome.jp]
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]
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]
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 the age of 20 years, clear symptoms of MERRF syndrome developed, including myoclonic seizures, generalized tonic-clonic seizures, and paroxysmal hearing disturbance. [omim.org]
Valproate is the first-line antiepileptic drug for generalized seizures and myoclonic epileptiform abnormalities 49. [doi.org]
Limb Weakness
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]
Exercise intolerance, limb weakness, hearing loss, and diabetes may also precede the occurrence of the stroke-like episodes. [umdf.org]
Case report A 25-year-old male presented with paroxysmal left upper limb tics and weakness that had been ongoing for two years. [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]
Generalized epileptiform discharges in 84.2% of patients, while focal discharges were present in ten patients. One of the patient had multifocal epileptiform activity. [bioline.org.br]
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 stimulation2727. [scielo.br]
Muscle Biopsy Abnormal
Biopsy: Abnormal mitochondria from under the muscle tissue membrane appear as "ragged red fibres" under a microscope Chemical staining identifies diseased mitochondria, appearing as "ragged red fibres". [lhsc.on.ca]
Muscle Biopsy showing Ragged-Red Fibers
Patients exhibit myoclonus epilepsy (involuntary muscle contractions) and show signs of ragged-red fibers in muscle biopsy. Less prevalent symptoms include deafness, exercise intolerance, dementia, and cardiomyopathies. [mitochondrialdiseasenews.com]
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]
MERRF syndrome Directions to Hospitals Treating MERRF syndrome Risk calculators and risk factors for MERRF syndrome Healthcare Provider Resources Symptoms of MERRF syndrome Causes & Risk Factors for MERRF syndrome Diagnostic studies for MERRF syndrome Treatment [wikidoc.org]
Management and treatment As with other mitochondrial encephalomyopathies, there is no specific treatment for MERRF syndrome. [orpha.net]
[citation needed] Treatment[edit] Like many mitochondrial diseases, there is no cure for MERRF, no matter the means for diagnosis of the disease. The treatment is primarily symptomatic. [en.wikipedia.org]
Prognosis The prognosis for patients with MERRF syndrome is globally poor because of the progressive nature of the disease. [orpha.net]
The prognosis for MERRF varies widely depending on age of onset, type and severity of symptoms, organs involved, and other factors. [umdf.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 is generally quite poor. [lhsc.on.ca]
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]
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]
Objectives: Identify the etiology and inheritance pattern of myoclonic epilepsy with red-ragged fibers. Review the multisystem involvement in patients with myoclonic epilepsy with red-ragged fibers. [ncbi.nlm.nih.gov]
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]
The epidemiology of mitochondrial disorders—past, present and future. Biochim Biophys Acta BBA - Bioenerg. 2004;1659(2):115-120. doi:10.1016/j.bbabio.2004.09.005 11. Hameed S, Tadi P. Myoclonic Epilepsy and Ragged Red Fibers. In: StatPearls. [eyewiki.aao.org]
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]
Epidemiology The epidemiologic data of MERRF is largely unknown, but it is widely considered that the prevalence of MERRF is probably less than 1:100,000. [ncbi.nlm.nih.gov]
Pathophysiology Defect of the respiratory chain enzymes, mainly complexes I and IV. Diagnosis Clinical and laboratory confirmation of elevated pyruvate and lactate. [accessanesthesiology.mhmedical.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]
Pathophysiology Mitochondria are known as the powerhouse of the cells, and mtDNA is required for the MRC to generate ATP. [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]
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]
A diagnosis of MERRF syndrome can help guide surveillance, treatment of symptoms and possibly aid in prevention of disease progression. [rarediseases.org]
Patients are usually prescribed therapeutic compounds to alleviate symptoms, but these do not prevent the disease from progressing. [mitochondrialdiseasenews.com]
Although higher proportions of the mutation in the blood of the mother result in a higher risk of having a child with severe phenotype, there are many examples of extreme segregation of the mutation from mother to child, which prevent efficient genetic [orpha.net]
Molnar MJ, Perenyi J, Siska E, et al. The typical MERRF (A8344G) mutation of the mitochondrial DNA associated with depressive mood disorders. J Neurol. 2009;256:264–265.
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.
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.
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.
Vastagh I, Gal A, Remenyi V, et al. A8344G mutation of the mitochondrial DNA with typical mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes syndrome. Ideggyogy Sz. 2011;64:399–403.
Mancuso M, Orsucci D, Angelini C, et al. Phenotypic heterogeneity of the 8344A>G mtDNA "MERRF" mutation. Neurology. 2013;80:2049–2054.
Peng Y, Crumley R, Ringman JM. Spasmodic dysphonia in a patient with the A to G transition at nucleotide 8344 in mitochondrial DNA. Mov Disord. 2003;18:716–718.
Erol I, Alehan F, Horvath R, et al. Demyelinating disease of central and peripheral nervous systems associated with a A8344G mutation in tRNALys. Neuromuscul Disord. 2009;19:275–278.
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.
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.
Marotta R, Chin J, Quigley A, et al. Diagnostic screening of mitochondrial DNA mutations in Australian adults 1990-2001. Intern Med J. 2004;34(1-2):10-19.
Finsterer J. Mitochondrial ataxias. Can J Neurol Sci. 2009;36(5):543-553.
DiMauro S, Hirano M, Kaufmann P, et al. Clinical features and genetics of myoclonic epilepsy with ragged red fibers. Adv Neurol. 2002;89:217-229.
Ito S, Shirai W, Asahina M, et al. Clinical and brain MR imaging features focusing on the brain stem and cerebellum in patients with myoclonic epilepsy with ragged-red fibers due to mitochondrial A8344G mutation. AJNR Am J Neuroradiol. 2008;29(2):392-395.
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.
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.
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.