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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.


Presentation

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].

Falling
  • The classification of this disease varies from patient to patient, since many individuals do not fall into one specific disease category.[en.wikipedia.org]
  • This is true even if your disability falls under the CAL program. In other words, even with a diagnosis of MERRF, automatic approval of benefits is not guaranteed.[disability-benefits-help.org]
  • Although a purely clinical classification can be helpful ( Table 1 ), many individuals do not fall into one specific disease category. The situation is made all the more complex by the poor correlation between genotype and phenotype.[ncbi.nlm.nih.gov]
Severe Clinical Course
  • We describe a girl with MERRF syndrome who had an unusually rapid and severe clinical course, with onset of symptoms at age 7 years and death by age 14 years of overwhelming lactic acidosis.[ncbi.nlm.nih.gov]
Vomiting
  • […] 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]
  • […] 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]
  • 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]
Vascular Disease
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]
  • 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]
  • […] 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]
  • 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.[symptoma.com]
Withdrawn
  • The average myoclonus score improved dramatically, as well as the quality of life and no side effects were observed, even after having withdrawn VPA.[ncbi.nlm.nih.gov]
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]
  • 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]
Chronic Progressive External Ophthalmoplegia
  • Disorders evaluated in Mayo's Mitochondrial Disease Clinic include, among others: Alpers progressive sclerosing poliodystrophy (Alpers disease) Barth syndrome Chronic progressive external ophthalmoplegia (CPEO) Dominant optic atrophy Friedreich's ataxia[mayoclinic.org]
  • "Impairment of mitochondrial tRNA(Ile) processing by a novel mutation associated with chronic progressive external ophthalmoplegia" . Mitochondrion 11(3):488-496. 3.[mitomap.org]
  • 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[ncbi.nlm.nih.gov]
  • KEARNS-SAYRE SYNDROME (KSS) AND CHRONIC PROGRESSIVE EXTERNAL OPHTHALMOPLEGIA (CPEO).[neuropathology-web.org]
  • Links: OMIM Long Name: Chronic Progressive External Ophthalmoplegia Syndrome. Symptoms: Similar to those of KSS plus: visual myopathy, retinitis pigmentosa, dysfunction of the central nervous system. Cause: Single mitochondrial DNA deletions.[umdf.org]
Stupor
  • These episodes were followed by left lateral homonymous hemianopia and left hemiparesis, complex partial seizure, and stupor for a few days.[dx.doi.org]
Dysautonomia
  • Family history may also include neuropathy and dysautonomia, or heart conditions such as cardiomyopathy. The patient's history might also exhibit kidney problems, such as proximal nephron dysfunction.[en.wikipedia.org]

Workup

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.

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]

Treatment

  • 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]
  • RESULTS: Delivered doses of 52.5 μg and 105 μg Pep-1-Mito had better delivered efficiency and mitochondrial biogenesis after 15 days of treatment.[ncbi.nlm.nih.gov]
  • We describe the successful administration of a combined general and epidural anesthesia with sevoflurane maintenance in a patient with myoclonic epilepsy with ragged red fibers (MERRF syndrome) scheduled for surgical treatment of bilateral clubfoot.[ncbi.nlm.nih.gov]
  • 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]
  • A further study revealed that the expression of MMP1 could be further induced by treatment of the skin fibroblasts with 200 microM hydrogen peroxide (H2O2) and inhibited by 1 mM N-acetylcysteine.[ncbi.nlm.nih.gov]

Prognosis

  • 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[wikidoc.org]
  • Prognosis The prognosis for patients with MERRF syndrome is globally poor because of the progressive nature of the disease.[orpha.net]
  • 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]
  • The prognosis for MELAS is poor. Typically, the age of death is between 10 to 35 years, although some patients may live longer.[umdf.org]
  • Clinical phenotype, prognosis and mitochondrial DNA mutation load in mitochondrial encephalomyopathies. J Biomed Sci 2002 ; 9 : 527 –33 Lombes A, Diaz C, Romero NB, et al.[ajnr.org]

Etiology

  • Certain conditions have both an underlying etiology and multiple body system manifestations due to the underlying etiology.[icd10coded.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]
  • Lee YM, Kang HC, Lee JS, Kim SH, Kim EY, et al. (2008) Mitochondrial respiratory chain defects: underlying etiology in various epileptic conditions. Epilepsia 49: 685-690.[omicsonline.org]

Epidemiology

  • 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[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]
  • Josef Finsterer 1 * and Sinda Zarrouk-Mahjoub 2 1 Krankenanstalt Rudolfstiftung, Vienna, Austria 2 Genetics Laboratory, Research Unit “Genetics Epidemiology and Molecular” Faculty of Medicine Tunis, Tunisia Corresponding Author : Josef Finsterer Krankenanstalt[omicsonline.org]
Sex distribution
Age distribution

Pathophysiology

  • […] 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]
  • 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]
  • These findings strengthen the hypothesis that neuronal loss plays an important role in the pathophysiology of these diseases.[doi.org]
  • View Article : Google Scholar : PubMed/NCBI 5 De la Mata M, Garrido-Maraver J, Cotán D, et al: Recovery of MERRF fibroblasts and cybrids pathophysiology by coenzyme Q10. Neurotherapeutics. 9:446–463. 2012.[spandidos-publications.com]

Prevention

  • 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]

References

Article

  1. 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.
  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.
  5. 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.
  6. Mancuso M, Orsucci D, Angelini C, et al. Phenotypic heterogeneity of the 8344A>G mtDNA "MERRF" mutation. Neurology. 2013;80:2049–2054.
  7. 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.
  8. 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.
  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.
  11. 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.
  12. Finsterer J. Mitochondrial ataxias. Can J Neurol Sci. 2009;36(5):543-553.
  13. 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.
  14. 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.
  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.

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Last updated: 2019-07-11 22:01