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].

• 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]

  […] 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]

• 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]

  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]

  […] 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]

• 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]

• Myoclonic Jerking

  The mother was a 55-year-old woman who had myoclonic jerks of the arms and generalized seizures since the age of 37 years. At age 47 years, she was moderately demented. Muscle weakness and ataxia were not apparent. [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]

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.

• Karyotype Abnormal

  When considered cytogenetically, the lipomas were characterized by a mixture of karyotypically abnormal and normal cells. An identical del(6)(q24) was found in two tumors. [ncbi.nlm.nih.gov]

• 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]

• 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]

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