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When should MERRF (myoclonus epilepsy associated with ragged-red fibers) be the diagnosis?

Quando o diagnóstico deveria ser MERRF (epilepsia mioclônica associada com fibras vermelhas rasgadas)?

Abstracts

Myoclonic epilepsy associated with ragged red fibers (MERRF) is a rare mitochondrial disorder. Diagnostic criteria for MERRF include typical manifestations of the disease: myoclonus, generalized epilepsy, cerebellar ataxia and ragged red fibers (RRF) on muscle biopsy. Clinical features of MERRF are not necessarily uniform in the early stages of the disease, and correlations between clinical manifestations and physiopathology have not been fully elucidated. It is estimated that point mutations in the tRNALys gene of the DNAmt, mainly A8344G, are responsible for almost 90% of MERRF cases. Morphological changes seen upon muscle biopsy in MERRF include a substantive proportion of RRF, muscle fibers showing a deficient activity of cytochrome c oxidase (COX) and the presence of vessels with a strong reaction for succinate dehydrogenase and COX deficiency. In this review, we discuss mainly clinical and laboratory manifestations, brain images, electrophysiological patterns, histology and molecular findings as well as some differential diagnoses and treatments.

MERRF; mitochondrial; epilepsy; myoclonus; myopathy


Epilepsia mioclônica associada com fibras vermelhas rasgadas (MERRF) é uma rara doença mitocondrial. O critério diagnóstico para MERRF inclui as manifestações típicas da doença: mioclonia, epilepsia generalizada, ataxia cerebelar e fibras vermelhas rasgadas (RRF) na biópsia de músculo. Na fase inicial da doença, as manifestações clínicas podem não ser uniformes, e correlação entre as manifestações clínicas e fisiopatologia não estão completamente elucidadas. Estima-se que as mutações de ponto no gene tRNALys do DNAmt, principalmente a A8344G, sejam responsáveis por quase 90% dos casos de MERRF. As alterações morfológicas na biópsia muscular incluem uma grande proporção de RRF, fibras musculares com deficiência de atividade da citocromo c oxidase (COX) e presença de vasos com forte reação para succinato desidrogenase e deficiência da COX. Nesta revisão, são discutidas as principais manifestações clínicas e laboratoriais, imagens cerebrais, padrões eletrofisiológicos, histológicos e alterações moleculares, bem como, alguns dos diagnósticos diferenciais e tratamentos.

MERRF; mitocondria; epilepsia; mioclonia; miopatia


In 1973, a group of patients with a unique mitochondrial disease, whose common clinical features included mitochondrial myopathy associated with familial myoclonic epilepsy, were first described1. Tsairis P, Engel WK, Kark P. Familial myoclonic epilepsy syndrome associated with skeletal muscle mitochondrial abnormalities. Neurology. 1973;23(4):408.. In the following decade, additional cases with similar presentations were included in the literature, and on this basis, Fukuhara et al. gave the best characterization of the disease, which they referred to as MERRF (Myoclonus Epilepsy associated with Ragged-Red Fibers)2. Fukuhara N, Tokiguchi S, Shirakawa K, Tsubaki T. Myoclonus epilepsy associated with ragged-red fibers (mitochondrial abnormalities): disease entity or a syndrome. J Neurol Sci. 1980;4791):117-33. http://dx.doi.org/10.1016/0022-510x(80)90031-3
https://doi.org/10.1016/0022-510x(80)900...
. The disease was so named because the patients all had myoclonus epilepsy and mitochondrial dysfunction was found upon muscle biopsy2. Fukuhara N, Tokiguchi S, Shirakawa K, Tsubaki T. Myoclonus epilepsy associated with ragged-red fibers (mitochondrial abnormalities): disease entity or a syndrome. J Neurol Sci. 1980;4791):117-33. http://dx.doi.org/10.1016/0022-510x(80)90031-3
https://doi.org/10.1016/0022-510x(80)900...
.

The MERRF diagnostic criteria described in 1980 by Fukuhara et al included as typical manifestations of the disease the following: myoclonus, generalized epilepsy, cerebellar ataxia and ragged-red fibers (RRF) on muscle biopsy2. Fukuhara N, Tokiguchi S, Shirakawa K, Tsubaki T. Myoclonus epilepsy associated with ragged-red fibers (mitochondrial abnormalities): disease entity or a syndrome. J Neurol Sci. 1980;4791):117-33. http://dx.doi.org/10.1016/0022-510x(80)90031-3
https://doi.org/10.1016/0022-510x(80)900...
.

Cases previously reported in the international literature which fit a possible diagnosis of MERRF were reviewed, reinforcing the presence of the myoclonus, epilepsy, ataxia and RRF as diagnostic criteria required for the disease3. Hirano M, DiMauro S. Clinical features of mitochondrial myopathies and encephalomyopathies. In: Lane RJM, editor. Handbook of muscle disease. New York: Marcel Dekker; 1996. p. 479-504.,4. DiMauro S, Hirano M, Kaufmann P, Tanji K, Sano M, Shungu DC et al. Clinical features and genetics of myoclonic epilepsy with ragged red fibers. Adv Neurol. 2002;89:217-29. http://dx.doi.org/10.1016/b978-0-12-374105-9.00349-x
https://doi.org/10.1016/b978-0-12-374105...
. Although the main manifestation of this group of patients with mitochondrial disease is the presence of myoclonus and epilepsy, other multisystemic alterations can be found as follows: deafness, exercise intolerance, dementia, peripheral neuropathy, short stature, abnormal cardiac conduction, cardiomyopathies, opthalmoparesis, pigmentary retinopathy, and lipoma, among others3. Hirano M, DiMauro S. Clinical features of mitochondrial myopathies and encephalomyopathies. In: Lane RJM, editor. Handbook of muscle disease. New York: Marcel Dekker; 1996. p. 479-504.,4. DiMauro S, Hirano M, Kaufmann P, Tanji K, Sano M, Shungu DC et al. Clinical features and genetics of myoclonic epilepsy with ragged red fibers. Adv Neurol. 2002;89:217-29. http://dx.doi.org/10.1016/b978-0-12-374105-9.00349-x
https://doi.org/10.1016/b978-0-12-374105...
.

In Brazil, the first report of MERRF was made by Arruda et al in 1990 who described a family in which three siblings had myoclonic epilepsy associated with dementia, cerebellar ataxia, muscle weakness and sensory neuropathy5. Arruda WO, Torres LFB, Lombes A, DiMauro S, Cardoso BA, Teive HA et al. Mitochondrial myopathy and myoclonic epilepsy. Arq Neuropsiquiatr. 1990;48(1):32-43. http://dx.doi.org/10.1590/S0004-282X1990000100006
https://doi.org/10.1590/S0004-282X199000...
. The siblings all showed an elevation of lactic acid, electroencephalogram (EEG) with photoparoxysmal response, muscular COX activity deficiency, muscle biopsy with ragged-red fibers (RRF) and abnormal mitochondria as viewed by electron microscopy. Since this first description in Brazil, few MERRF patients have been described in the country to date5. Arruda WO, Torres LFB, Lombes A, DiMauro S, Cardoso BA, Teive HA et al. Mitochondrial myopathy and myoclonic epilepsy. Arq Neuropsiquiatr. 1990;48(1):32-43. http://dx.doi.org/10.1590/S0004-282X1990000100006
https://doi.org/10.1590/S0004-282X199000...
,6. Lorenzoni PJ, Scola RH, Kay CS, Arndt RC, Silvado CE, Werneck LC. MERRF: clinical features, muscle biopsy and molecular genetics in Brazilian patients. Mitochondrion. 2011;11(3):528-32. http://dx.doi.org/10.1016/j.mito.2011.01.003
https://doi.org/10.1016/j.mito.2011.01.0...
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Two other important medical landmarks are ascribed to MERRF. MERRF was the first human disease in which a maternal inheritance pattern was clearly demonstrated, suggesting a defect in mtDNA. MERRF was also the first disease in which a molecular defect was associated with a particular form of epilepsy7. Rosing HS, Hopkins LC, Wallace DC, Epstein CM, Weidenheim K. Maternally inherited mitochondrial myopathy and myoclonic epilepsy. Ann Neurol. 1985;17(3):228-37. http://dx.doi.org/10.1002/ana.410170303
https://doi.org/10.1002/ana.410170303...
,8. Shoffner JM, Lott MT, Lezza A, Seibel P, Ballinger SW, Wallace DC. Myoclonic epilepsy and ragged-red fiber disease (MERRF) is associated with a mitochondrial DNA tRNALys mutation. Cell. 1990;61(6):931-7. http://dx.doi.org/10.1016/0092-8674(90)90059-n
https://doi.org/10.1016/0092-8674(90)900...
,9. Yoneda M, Tanno Y, Horai S, Ozawa T, Miyatake T, Tsuji S. A common mitochondrial DNA mutation in the tRNA-lys of patients with myoclonus epilepsy associated with ragged-red fibers. Biochem Int. 1990;21:789-96..

What is the pathogenesis?

MERRF is a mitochondrial disease caused by pathogenic mutations usually in DNAmt. The pathogenesis of the disease depends upon the relative proportions of mutant and wild-type DNAmt and the threshold of vulnerability to mitochondrial dysfunction of each tissue. Correlations between clinical manifestations and physiopathology in MERRF patients are not fully elucidated, and two main hypotheses have been considered to explain its pathogenesis (Figure 1):

Figure 1
The mechanism of “intracellular eletrolytic disturbance” (sodium, potassium and calcium) proposed to cause neuronal loss and hyperexcitability dysfunction in MERRF patients (adapted with permission from JAMES et al.)1111 . James AM, Sheard PW, Wei YH, Murphy MP. Decreased ATP synthesis is phenotypically expressed during increased energy demand in fibroblasts containing mitochondrial tRNA mutations. Eur J Biochem. 1999;259(1-2):462-9. http://dx.doi.org/10.1046/j.1432-1327.1999.00066.x
https://doi.org/10.1046/j.1432-1327.1999...
.

(1) neuronal hyperexcitability, which suggests the presence of an "intracellular ion disturbance” (sodium, potassium and calcium) triggering an abnormal threshold in the action potential of the neuronal membrane that could lead to changes in the pattern of the neuronal excitability and synaptic transmission in some areas of the brain tissue1010 . Folbergrová J, Kunz WS. Mitochondrial dysfunction in epilepsy. Mitochondrion. 2012;12(1):35-40. http://dx.doi.org/10.1016/j.mito.2011.04.004
https://doi.org/10.1016/j.mito.2011.04.0...
,1111 . James AM, Sheard PW, Wei YH, Murphy MP. Decreased ATP synthesis is phenotypically expressed during increased energy demand in fibroblasts containing mitochondrial tRNA mutations. Eur J Biochem. 1999;259(1-2):462-9. http://dx.doi.org/10.1046/j.1432-1327.1999.00066.x
https://doi.org/10.1046/j.1432-1327.1999...
.

(2) neuronal loss, which suggests that a "mitochondrial cytopathy" triggers an energy failure in some areas of the brain causing neuronal death1010 . Folbergrová J, Kunz WS. Mitochondrial dysfunction in epilepsy. Mitochondrion. 2012;12(1):35-40. http://dx.doi.org/10.1016/j.mito.2011.04.004
https://doi.org/10.1016/j.mito.2011.04.0...
,1111 . James AM, Sheard PW, Wei YH, Murphy MP. Decreased ATP synthesis is phenotypically expressed during increased energy demand in fibroblasts containing mitochondrial tRNA mutations. Eur J Biochem. 1999;259(1-2):462-9. http://dx.doi.org/10.1046/j.1432-1327.1999.00066.x
https://doi.org/10.1046/j.1432-1327.1999...
.

However, neither of these hypotheses alone could explain comprehensively all of major disease manifestations in MERRF patients, and similar presentations can occur in other mitochondrial diseases. The formation of ATP in mitochondria is essential for both the excitability and self preservation of the neuron1010 . Folbergrová J, Kunz WS. Mitochondrial dysfunction in epilepsy. Mitochondrion. 2012;12(1):35-40. http://dx.doi.org/10.1016/j.mito.2011.04.004
https://doi.org/10.1016/j.mito.2011.04.0...
,1111 . James AM, Sheard PW, Wei YH, Murphy MP. Decreased ATP synthesis is phenotypically expressed during increased energy demand in fibroblasts containing mitochondrial tRNA mutations. Eur J Biochem. 1999;259(1-2):462-9. http://dx.doi.org/10.1046/j.1432-1327.1999.00066.x
https://doi.org/10.1046/j.1432-1327.1999...
. Thus, the mechanisms that trigger the main manifestations are correlated with a combination of neuronal loss and hyperexcitability dysfunction, perhaps both, initiated by the failure of oxidative phosphorylation in specific areas of the brain tissue, and they may be responsible for the pathogenesis of the major clinical manifestations of MERRF patients (Figure 2)1010 . Folbergrová J, Kunz WS. Mitochondrial dysfunction in epilepsy. Mitochondrion. 2012;12(1):35-40. http://dx.doi.org/10.1016/j.mito.2011.04.004
https://doi.org/10.1016/j.mito.2011.04.0...
,1111 . James AM, Sheard PW, Wei YH, Murphy MP. Decreased ATP synthesis is phenotypically expressed during increased energy demand in fibroblasts containing mitochondrial tRNA mutations. Eur J Biochem. 1999;259(1-2):462-9. http://dx.doi.org/10.1046/j.1432-1327.1999.00066.x
https://doi.org/10.1046/j.1432-1327.1999...
.

Figure 2
A combination of mechanisms that may be responsible for triggering the major manifestations of MERRF (adapted with permission from Folbergrová and Kunz)1010 . Folbergrová J, Kunz WS. Mitochondrial dysfunction in epilepsy. Mitochondrion. 2012;12(1):35-40. http://dx.doi.org/10.1016/j.mito.2011.04.004
https://doi.org/10.1016/j.mito.2011.04.0...
.

What are the genetic abnormalities?

In 1990, Shoffner et al and Yoneda et al, described a point mutation, affecting the mtDNA gene encoding the RNA transporter of lysine (tRNALys) at position 8344 by exchange of the nucleotide A for G (A8344G), in the muscle of patients with MERRF8. Shoffner JM, Lott MT, Lezza A, Seibel P, Ballinger SW, Wallace DC. Myoclonic epilepsy and ragged-red fiber disease (MERRF) is associated with a mitochondrial DNA tRNALys mutation. Cell. 1990;61(6):931-7. http://dx.doi.org/10.1016/0092-8674(90)90059-n
https://doi.org/10.1016/0092-8674(90)900...
,9. Yoneda M, Tanno Y, Horai S, Ozawa T, Miyatake T, Tsuji S. A common mitochondrial DNA mutation in the tRNA-lys of patients with myoclonus epilepsy associated with ragged-red fibers. Biochem Int. 1990;21:789-96.. This mitochondrial tRNALys gene, also known as MT-TK or TRNK, is located between nucleotides 8295 and 8364 on the mtDNA, and it is responsible for decoding the codons AAR (R = A or G)1212 . Yasukawa T, Kirino Y, Ishii N, Holt IJ, Jacobs HT, Makifuchi T et al. Wobble modification deficiency in mutant tRNAs in patients with mitochondrial diseases. FEBS Lett. 2005;579(13):2948-52. http://dx.doi.org/10.1016/j.febslet.2005.04.038
https://doi.org/10.1016/j.febslet.2005.0...
. After this initial description, other studies have shown that the A8344G mutation is responsible for most cases of MERRF1313 . Hammans SR, Sweeney MG, Brockington M, Morgan-Hughes JA, Harding AE. Mitochondrial encephalopathies: molecular genetic diagnosis from blood samples. Lancet. 1991;33798753):1311-3. http://dx.doi.org/10.1016/0140-6736(91)92981-7.

In the years following the discovery of the A8344G mutation, three additional point mutations have also been found in patients with MERRF in the tRNALys gene of mtDNA as follows: T8356C, G8361A and G8363A1414 . Rossmanith W, Raffelsberger T, Roka J, Kornek B, Feucht M, Bittner RE. The expanding mutational spectrum of MERRF substitution G8361A in the mitochondrial tRNALys gene. Ann Neurol. 2003;54(6):820-3. http://dx.doi.org/10.1002/ana.10753
https://doi.org/10.1002/ana.10753...
,1515 . Santorelli FM, Mak SC, El-Schahawi M, Casali C, Shanske S, Baram TZ et al. Maternally inherited cardiomyopathy and hearing loss associated with a novel mutation in the mitochondrial tRNA(lys) gene (G8363A). Am J Hum. 1996;58(5):933-9.,1616 . Silvestri G, Moraes CT, Shanske S, Oh SJ, DiMauro S. A new mtDNA mutation in the tRNA-lys gene associated with myoclonic epilepsy and ragged-red fibers (MERRF). Am J Hum Genet. 1992;51(6):1213-7.. The T8356C point mutation was found in patients with MERRF who also had stroke-like episodes, suggesting an overlap between MERRF and mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS)1616 . Silvestri G, Moraes CT, Shanske S, Oh SJ, DiMauro S. A new mtDNA mutation in the tRNA-lys gene associated with myoclonic epilepsy and ragged-red fibers (MERRF). Am J Hum Genet. 1992;51(6):1213-7.,1717 . Zeviani M, Muntoni F, Savarese N, et al. A MERRF/MELAS overlap syndrome associated with a new point mutation in the mitochondrial DNA tRNA(Lys) gene. Eur J Hum Genet. 1993;1(1):80-7.. The A8361G point mutation was described in patients associated with MERRF manifesting with deafness and dementia1414 . Rossmanith W, Raffelsberger T, Roka J, Kornek B, Feucht M, Bittner RE. The expanding mutational spectrum of MERRF substitution G8361A in the mitochondrial tRNALys gene. Ann Neurol. 2003;54(6):820-3. http://dx.doi.org/10.1002/ana.10753
https://doi.org/10.1002/ana.10753...
. The G8363A point mutation appears to be related to the presence of cardiomyopathy and deafness in patients with MERRF, and, in some cases, it overlap with Leigh syndrome1515 . Santorelli FM, Mak SC, El-Schahawi M, Casali C, Shanske S, Baram TZ et al. Maternally inherited cardiomyopathy and hearing loss associated with a novel mutation in the mitochondrial tRNA(lys) gene (G8363A). Am J Hum. 1996;58(5):933-9.,1818 . Ozawa M, Nishino I, Horai S, Nonaka I, Goto YI. Myoclonus epilepsy associated with ragged-red fibers: a G-to-A mutation at nucleotide pair 8363 in mitochondrial tRNA(Lys) in two families. Muscle Nerve. 1997:20(3):271-8. http://dx.doi.org/10.1002/(SICI)1097-4598(199703)20:3?ENT(lt)?271::AID-MUS2?ENT(gt)?3.0.CO;2-8
https://doi.org/10.1002/(SICI)1097-4598(...
,1919 . Shtilbans A, Shanske S, Goodman S, Sue CM, Bruno C, Johson TL et al. G8363A mutation in the mitochondrial DNA transfer ribonucleic acidLys gene: another cause of Leigh syndrome. J Child Neurol. 2000;15(11):759-61.,2020 . Virgilio R, Ronchi D, Bordoni A, Fassone E, Bonato S, Donadoni C et al. Mitochondrial DNA G8363A mutation in the tRNA Lys gene: clinical, biochemical and pathological study. J Neurol Sci. 2009;281(1-2):85-92. http://dx.doi.org/10.1016/j.jns.2009.01.025
https://doi.org/10.1016/j.jns.2009.01.02...
.

Over the years, the few point mutations in mtDNA that have been found in patients with MERRF have usually been in the tRNALys gene of mtDNA or have overlapped with other mitochondrial diseases (Table 1). Thus, it is estimated that the A8344G mutation remains responsible for over 80% of MERRF patients: mutations T8356C, G8361A and G8363A account for approximately 10%1313 . Hammans SR, Sweeney MG, Brockington M, Morgan-Hughes JA, Harding AE. Mitochondrial encephalopathies: molecular genetic diagnosis from blood samples. Lancet. 1991;33798753):1311-3. http://dx.doi.org/10.1016/0140-6736(91)92981-7,2121 . Brackmann F, Abicht A, Ahting U, Schröder R, Trollmann R. Classical MERRF phenotype associated with mitochondrial tRNA(Leu) (m.3243A>G) mutation. Eur J Pediatr. 2012;171(5):859-62. http://dx.doi.org/10.1007/s00431-011-1662-8
https://doi.org/10.1007/s00431-011-1662-...
,2222 . Fukuhara N. Clinicopathological features of MERRF. Muscle Nerve. 1995;18(Suppl 14):S90-4. http://dx.doi.org/10.1002/mus.880181419
https://doi.org/10.1002/mus.880181419...
,2323 . Shoffner JM, Wallace DC. Mitochondrial genetics: principles and practice. Am J Hum Genet. 1992;51(6):1179-86.. The remaining mutations account for less than 5% of cases, but up to 10% of MERRF patients have still no identifiable mutations in mtDNA1313 . Hammans SR, Sweeney MG, Brockington M, Morgan-Hughes JA, Harding AE. Mitochondrial encephalopathies: molecular genetic diagnosis from blood samples. Lancet. 1991;33798753):1311-3. http://dx.doi.org/10.1016/0140-6736(91)92981-7,2121 . Brackmann F, Abicht A, Ahting U, Schröder R, Trollmann R. Classical MERRF phenotype associated with mitochondrial tRNA(Leu) (m.3243A>G) mutation. Eur J Pediatr. 2012;171(5):859-62. http://dx.doi.org/10.1007/s00431-011-1662-8
https://doi.org/10.1007/s00431-011-1662-...
,2222 . Fukuhara N. Clinicopathological features of MERRF. Muscle Nerve. 1995;18(Suppl 14):S90-4. http://dx.doi.org/10.1002/mus.880181419
https://doi.org/10.1002/mus.880181419...
,2323 . Shoffner JM, Wallace DC. Mitochondrial genetics: principles and practice. Am J Hum Genet. 1992;51(6):1179-86..

Table 1
Published mutations in mitochondrial (DNAmt) and nuclear (DNAn) DNA associated with MERRF.

The A8344G mutation appears to be specific to patients with MERRF, because this mutation has rarely been described in other mitochondrial diseases, even without the presence of myoclonus or epilepsy2424 . Zeviani M, Amati P, Bresolin N, Antozzi C, Piccolo G, Toscano A et al. Rapid detection of the A-to-G(8344) mutation of mtDNA in Italian families with myoclonus epilepsy and ragged-red fibers (MERRF). Am J Hum Genet. 1991;48(2):203-11.,2525 . Kazakos K, Kotsa K, Yavropoulou M, Dionyssopoulos A, Grabs R, Yovos J, Polychronakos C. Familial clustering strongly suggests that the phenotypic variation of the 8344 A>G lys mitochondrial tRNA mutation is encoded in cis. Ann Hum Genet. 2012;76(4):296-300. http://dx.doi.org/10.1111/j.1469-1809.2012.00711.x
https://doi.org/10.1111/j.1469-1809.2012...
. Additionally, MERRF patients who present with other mutations in mtDNA have usually been reported to present with another mitochondrial disease, such as MELAS, Leigh syndrome, Kearns-Sayre syndrome, NARP, neuropathy, deafness or pigmentary retinopathy (Table 1). Although the mitochondrial diseases caused by point mutations of mtDNA have heterogeneous phenotypes, the phenotype of patients with the A8344G point mutation usually results in MERRF.

In rare cases, the presence of rearrangement type deletion in mtDNA or the presence of recessive missense mutations in polymerase gamma (POLG) gene in nuclear DNA has been associated with MERRF (Table 1).

The proportion of mutant mtDNA appears to be similar in the majority of the different tissues affected in MERRF patients1818 . Ozawa M, Nishino I, Horai S, Nonaka I, Goto YI. Myoclonus epilepsy associated with ragged-red fibers: a G-to-A mutation at nucleotide pair 8363 in mitochondrial tRNA(Lys) in two families. Muscle Nerve. 1997:20(3):271-8. http://dx.doi.org/10.1002/(SICI)1097-4598(199703)20:3?ENT(lt)?271::AID-MUS2?ENT(gt)?3.0.CO;2-8
https://doi.org/10.1002/(SICI)1097-4598(...
,2020 . Virgilio R, Ronchi D, Bordoni A, Fassone E, Bonato S, Donadoni C et al. Mitochondrial DNA G8363A mutation in the tRNA Lys gene: clinical, biochemical and pathological study. J Neurol Sci. 2009;281(1-2):85-92. http://dx.doi.org/10.1016/j.jns.2009.01.025
https://doi.org/10.1016/j.jns.2009.01.02...
,2626 . Boulet L, Karpati G, Shoubridge EA. Distribution and threshold expression of the tRNA-lys mutation in skeletal muscle of patients with myoclonic epilepsy and ragged-red fibers (MERRF). Am J Hum Genet. 1992;51(6):1187-200.. This observation allows the mtDNA used for the molecular study of patients with MERRF to be extracted from peripheral blood leukocytes, achieving results similar to those of patients with mtDNA extracted from muscle and making it easier to identify MERRF patients.

What are the clinical features?

Clinical symptoms are highly variable among patients with mitochondrial diseases4. DiMauro S, Hirano M, Kaufmann P, Tanji K, Sano M, Shungu DC et al. Clinical features and genetics of myoclonic epilepsy with ragged red fibers. Adv Neurol. 2002;89:217-29. http://dx.doi.org/10.1016/b978-0-12-374105-9.00349-x
https://doi.org/10.1016/b978-0-12-374105...
,2222 . Fukuhara N. Clinicopathological features of MERRF. Muscle Nerve. 1995;18(Suppl 14):S90-4. http://dx.doi.org/10.1002/mus.880181419
https://doi.org/10.1002/mus.880181419...
. Some of these clinical findings may be absent in the early stage of the disease, while in advanced disease patients usually have more uniform clinical manifestations2222 . Fukuhara N. Clinicopathological features of MERRF. Muscle Nerve. 1995;18(Suppl 14):S90-4. http://dx.doi.org/10.1002/mus.880181419
https://doi.org/10.1002/mus.880181419...
,2424 . Zeviani M, Amati P, Bresolin N, Antozzi C, Piccolo G, Toscano A et al. Rapid detection of the A-to-G(8344) mutation of mtDNA in Italian families with myoclonus epilepsy and ragged-red fibers (MERRF). Am J Hum Genet. 1991;48(2):203-11.,2727 . Ozawa M, Goto Y, Sakuta R, Tanno Y, Tsuji S, Nonaka I. The 8,344 mutation in mitochondrial DNA: a comparison between the proportion of mutant DNA and clinico-pathologic findings. Neuromuscul Disord. 1995;5(6):483-8. http://dx.doi.org/10.1016/0960-8966(95)00009-c
https://doi.org/10.1016/0960-8966(95)000...
,2828 . Mancuso M, Orsucci D, Angelini C, Bertini E, Carelli V, Comi GP et al. Phenotypic heterogeneity of the 8344A>G mtDNA "MERRF" mutation. Neurology. 2013;80(22):2049-54. http://dx.doi.org/10.1212/WNL.0b013e318294b44c
https://doi.org/10.1212/WNL.0b013e318294...
.

A clinical follow-up scheme was recently reported by Mancuso et al for patients with the A8344G mutation (Table 2)2828 . Mancuso M, Orsucci D, Angelini C, Bertini E, Carelli V, Comi GP et al. Phenotypic heterogeneity of the 8344A>G mtDNA "MERRF" mutation. Neurology. 2013;80(22):2049-54. http://dx.doi.org/10.1212/WNL.0b013e318294b44c
https://doi.org/10.1212/WNL.0b013e318294...
. We believe that this scheme could be used with MERRF patients, even though larger prospective studies are needed to obtain a complete picture of the natural history of this disease and clinical symptoms may occur with a different frequency in patients with MERRF, depending upon the type of mtDNA point mutation4. DiMauro S, Hirano M, Kaufmann P, Tanji K, Sano M, Shungu DC et al. Clinical features and genetics of myoclonic epilepsy with ragged red fibers. Adv Neurol. 2002;89:217-29. http://dx.doi.org/10.1016/b978-0-12-374105-9.00349-x
https://doi.org/10.1016/b978-0-12-374105...
,2828 . Mancuso M, Orsucci D, Angelini C, Bertini E, Carelli V, Comi GP et al. Phenotypic heterogeneity of the 8344A>G mtDNA "MERRF" mutation. Neurology. 2013;80(22):2049-54. http://dx.doi.org/10.1212/WNL.0b013e318294b44c
https://doi.org/10.1212/WNL.0b013e318294...
,2929 . Goto Y, Nonaka I, Horai S. A new mtDNA mutation associated with mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS). Biochim Biophys Acta. 1991;1097(3):238-40. http://dx.doi.org/10.1016/0925-4439(91)90042-8
https://doi.org/10.1016/0925-4439(91)900...
. Similar manifestations occur in patients with the T8356C mutation, who have some overlap of symptoms such as stroke-like with MELAS, as well as in patients with the G8363A mutation who have cardiomyopathy4. DiMauro S, Hirano M, Kaufmann P, Tanji K, Sano M, Shungu DC et al. Clinical features and genetics of myoclonic epilepsy with ragged red fibers. Adv Neurol. 2002;89:217-29. http://dx.doi.org/10.1016/b978-0-12-374105-9.00349-x
https://doi.org/10.1016/b978-0-12-374105...
,2828 . Mancuso M, Orsucci D, Angelini C, Bertini E, Carelli V, Comi GP et al. Phenotypic heterogeneity of the 8344A>G mtDNA "MERRF" mutation. Neurology. 2013;80(22):2049-54. http://dx.doi.org/10.1212/WNL.0b013e318294b44c
https://doi.org/10.1212/WNL.0b013e318294...
,2929 . Goto Y, Nonaka I, Horai S. A new mtDNA mutation associated with mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS). Biochim Biophys Acta. 1991;1097(3):238-40. http://dx.doi.org/10.1016/0925-4439(91)90042-8
https://doi.org/10.1016/0925-4439(91)900...
.

Table 2
Follow-up scheme for A8344G patients suggested by Mancuso et al. in 2013.

Although the onset of clinical manifestation often occurs in childhood and early adulthood, a late onset in adults is not uncommon in patients with MERRF4. DiMauro S, Hirano M, Kaufmann P, Tanji K, Sano M, Shungu DC et al. Clinical features and genetics of myoclonic epilepsy with ragged red fibers. Adv Neurol. 2002;89:217-29. http://dx.doi.org/10.1016/b978-0-12-374105-9.00349-x
https://doi.org/10.1016/b978-0-12-374105...
,3030 . Finsterer J. Mitochondriopathies. Eur J Neurol. 2004;11(3):163-86. http://dx.doi.org/10.1046/j.1351-5101.2003.00728.x
https://doi.org/10.1046/j.1351-5101.2003...
. Moreover, the age of onset may be different among affected members of the same family2222 . Fukuhara N. Clinicopathological features of MERRF. Muscle Nerve. 1995;18(Suppl 14):S90-4. http://dx.doi.org/10.1002/mus.880181419
https://doi.org/10.1002/mus.880181419...
. Psychomotor development in children is usually normal in almost all patients with MERRF4. DiMauro S, Hirano M, Kaufmann P, Tanji K, Sano M, Shungu DC et al. Clinical features and genetics of myoclonic epilepsy with ragged red fibers. Adv Neurol. 2002;89:217-29. http://dx.doi.org/10.1016/b978-0-12-374105-9.00349-x
https://doi.org/10.1016/b978-0-12-374105...
. Affected parents of MERRF patients can be found and family history may be positive in up to 50% of cases when muscle biopsy or genetic studies are performed in asymptomatic or mildly symptomatic family members4. DiMauro S, Hirano M, Kaufmann P, Tanji K, Sano M, Shungu DC et al. Clinical features and genetics of myoclonic epilepsy with ragged red fibers. Adv Neurol. 2002;89:217-29. http://dx.doi.org/10.1016/b978-0-12-374105-9.00349-x
https://doi.org/10.1016/b978-0-12-374105...
,2222 . Fukuhara N. Clinicopathological features of MERRF. Muscle Nerve. 1995;18(Suppl 14):S90-4. http://dx.doi.org/10.1002/mus.880181419
https://doi.org/10.1002/mus.880181419...
,2424 . Zeviani M, Amati P, Bresolin N, Antozzi C, Piccolo G, Toscano A et al. Rapid detection of the A-to-G(8344) mutation of mtDNA in Italian families with myoclonus epilepsy and ragged-red fibers (MERRF). Am J Hum Genet. 1991;48(2):203-11.,3131 . Marotta R, Chin J, Quigley A, Katsababus S, Kapsa R, Byrne E et al. Diagnostic screening of mitochondrial DNA mutations in Australian adults 1990-2001. Intern Med J. 2004;34(1-2):10-9. http://dx.doi.org/10.1111/j.1444-0903.2004.t01-3-.x
https://doi.org/10.1111/j.1444-0903.2004...
,3232 . Tanno Y, Yoneda M, Nonaka I, Tanaka K, Miyatake T, Tsuji S. Quantitation of mitochondrial DNA carrying tRNA-lys mutation in MERRF patients. Biochem Biophys Res Commun. 1991;179(2):880-5. http://dx.doi.org/10.1016/0006-291x(91)91900-w
https://doi.org/10.1016/0006-291x(91)919...
.

However, as the presence of myoclonus and epilepsy are diagnostic criteria for MERRF, it is expected that all patients have both clinical manifestations4. DiMauro S, Hirano M, Kaufmann P, Tanji K, Sano M, Shungu DC et al. Clinical features and genetics of myoclonic epilepsy with ragged red fibers. Adv Neurol. 2002;89:217-29. http://dx.doi.org/10.1016/b978-0-12-374105-9.00349-x
https://doi.org/10.1016/b978-0-12-374105...
,2222 . Fukuhara N. Clinicopathological features of MERRF. Muscle Nerve. 1995;18(Suppl 14):S90-4. http://dx.doi.org/10.1002/mus.880181419
https://doi.org/10.1002/mus.880181419...
. The myoclonus may occur alone or in association with generalized seizures4. DiMauro S, Hirano M, Kaufmann P, Tanji K, Sano M, Shungu DC et al. Clinical features and genetics of myoclonic epilepsy with ragged red fibers. Adv Neurol. 2002;89:217-29. http://dx.doi.org/10.1016/b978-0-12-374105-9.00349-x
https://doi.org/10.1016/b978-0-12-374105...
,3030 . Finsterer J. Mitochondriopathies. Eur J Neurol. 2004;11(3):163-86. http://dx.doi.org/10.1046/j.1351-5101.2003.00728.x
https://doi.org/10.1046/j.1351-5101.2003...
.

The presence of clonic or myoclonic seizures, with electroencephalographic correlation, is greater in the chronic than in the initial phase of the disease3333 . Canafoglia L, Franceschetti S, Antozzi C, Carrara F, Farina L, Granata T et al. Epileptic phenotypes associated with mitochondrial disorders. Neurology. 2001;56(10):1340-6. http://dx.doi.org/10.1212/wnl.56.10.1340
https://doi.org/10.1212/wnl.56.10.1340...
. Generalized seizures are frequently observed in different forms of myoclonic epilepsy, mainly associated with mutations in the tRNALys and tRNASer genes of mtDNA. Partial seizures are most commonly found in mitochondrial encephalopathies, such as MELAS associated with mutations in the tRNALeu gene8. Shoffner JM, Lott MT, Lezza A, Seibel P, Ballinger SW, Wallace DC. Myoclonic epilepsy and ragged-red fiber disease (MERRF) is associated with a mitochondrial DNA tRNALys mutation. Cell. 1990;61(6):931-7. http://dx.doi.org/10.1016/0092-8674(90)90059-n
https://doi.org/10.1016/0092-8674(90)900...
,9. Yoneda M, Tanno Y, Horai S, Ozawa T, Miyatake T, Tsuji S. A common mitochondrial DNA mutation in the tRNA-lys of patients with myoclonus epilepsy associated with ragged-red fibers. Biochem Int. 1990;21:789-96.,3333 . Canafoglia L, Franceschetti S, Antozzi C, Carrara F, Farina L, Granata T et al. Epileptic phenotypes associated with mitochondrial disorders. Neurology. 2001;56(10):1340-6. http://dx.doi.org/10.1212/wnl.56.10.1340
https://doi.org/10.1212/wnl.56.10.1340...
,3434 . Berkovic SF, Carpenter S, Evans A, Karpati G, Shoubridge EA, Andermann F et al. Myoclonus epilepsy and ragged-red fibres (MERRF). 1. A clinical, pathological, biochemical, magnetic resonance spectrographic and positron emission tomographic study. Brain. 1989;112(5):1231-60. http://dx.doi.org/10.1093/brain/112.5.1231
https://doi.org/10.1093/brain/112.5.1231...
.

In MERRF, myoclonus are clinically indistinguishable from those presented by patients with other myoclonic diseases (irregular rhythm, which may increase with movement or stimuli), but their pathogenesis has not been fully elucidated, most likely because, like most of the diseases that cause myoclonus, there are multiple affected structures in the CNS. Regarding the type of myoclonus and its origin in the central nervous system, there is substantial evidence indicating the occurrence of more cortical myoclonus than subcortical type, although both may occur in patients with MERRF3434 . Berkovic SF, Carpenter S, Evans A, Karpati G, Shoubridge EA, Andermann F et al. Myoclonus epilepsy and ragged-red fibres (MERRF). 1. A clinical, pathological, biochemical, magnetic resonance spectrographic and positron emission tomographic study. Brain. 1989;112(5):1231-60. http://dx.doi.org/10.1093/brain/112.5.1231
https://doi.org/10.1093/brain/112.5.1231...
.

Cerebellar ataxia is one of the most common clinical manifestations of MERRF and is supportive of the diagnostic criteria of MERRF, occurring in up to 83% of cases6. Lorenzoni PJ, Scola RH, Kay CS, Arndt RC, Silvado CE, Werneck LC. MERRF: clinical features, muscle biopsy and molecular genetics in Brazilian patients. Mitochondrion. 2011;11(3):528-32. http://dx.doi.org/10.1016/j.mito.2011.01.003
https://doi.org/10.1016/j.mito.2011.01.0...
,3535 . Chinnery PF, Howell N, Lightowlers RN, Turnbull DM. Molecular pathology of MELAS and MERRF. The relationship between mutation load and clinical phenotypes. Brain. 1997;120(10):1713-21. http://dx.doi.org/10.1093/brain/120.10.1713
https://doi.org/10.1093/brain/120.10.171...
. The presence of manifestation cerebellar ataxia is an important indicator in patients with MERRF, although it may not be present in the early phase of the disease2727 . Ozawa M, Goto Y, Sakuta R, Tanno Y, Tsuji S, Nonaka I. The 8,344 mutation in mitochondrial DNA: a comparison between the proportion of mutant DNA and clinico-pathologic findings. Neuromuscul Disord. 1995;5(6):483-8. http://dx.doi.org/10.1016/0960-8966(95)00009-c
https://doi.org/10.1016/0960-8966(95)000...
,3434 . Berkovic SF, Carpenter S, Evans A, Karpati G, Shoubridge EA, Andermann F et al. Myoclonus epilepsy and ragged-red fibres (MERRF). 1. A clinical, pathological, biochemical, magnetic resonance spectrographic and positron emission tomographic study. Brain. 1989;112(5):1231-60. http://dx.doi.org/10.1093/brain/112.5.1231
https://doi.org/10.1093/brain/112.5.1231...
. However, clinical and radiological findings in patients with MERRF vary and may suggest spinocerebellar degeneration, especially in early phase of the disease3636 . Ito S, Shirai W, Asahina M, Hattori T. 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):392-5. http://dx.doi.org/10.3174/ajnr.a0865
https://doi.org/10.3174/ajnr.a0865 ...
. Similarly, atrophy of the superior cerebellar peduncle and cerebellum, in addition to changes in the brain and basal ganglia, suggest MERRF, especially in patients with a dissociation between clinical manifestation with severe cerebellar symptoms and radiological manifestation with mild abnormalities3636 . Ito S, Shirai W, Asahina M, Hattori T. 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):392-5. http://dx.doi.org/10.3174/ajnr.a0865
https://doi.org/10.3174/ajnr.a0865 ...
.

What are the imaging features?

MERRF preferentially involves the inferior olivary nucleus, cerebellar dentate nucleus, red nucleus and pons of the brainstem, as well as the gray matter2222 . Fukuhara N. Clinicopathological features of MERRF. Muscle Nerve. 1995;18(Suppl 14):S90-4. http://dx.doi.org/10.1002/mus.880181419
https://doi.org/10.1002/mus.880181419...
,3434 . Berkovic SF, Carpenter S, Evans A, Karpati G, Shoubridge EA, Andermann F et al. Myoclonus epilepsy and ragged-red fibres (MERRF). 1. A clinical, pathological, biochemical, magnetic resonance spectrographic and positron emission tomographic study. Brain. 1989;112(5):1231-60. http://dx.doi.org/10.1093/brain/112.5.1231
https://doi.org/10.1093/brain/112.5.1231...
,3737 . DiMauro S, Kulikova R, Tanji K, Bonilla E, Hirano M. Mitochondrial genes for generalized epilepsies. Adv Neurol. 1999;79:411-9.. Conventional imaging studies of the brain, such as computed tomography or magnetic resonance imaging, have confirmed that the gray matter is altered early on in patients with MERRF, while changes in the white matter can be seen more often in the later stages of the disease and are never an isolated finding3737 . DiMauro S, Kulikova R, Tanji K, Bonilla E, Hirano M. Mitochondrial genes for generalized epilepsies. Adv Neurol. 1999;79:411-9.,3838 . Barkovich AJ, Good WV, Koch TK, Berg BO. Mitochondrial disorders: analysis of their clinical and imaging characteristics. AJNR Am J Neuroradiol. 1993;14(5):1119-37.. Cerebral, cerebellar and brainstem atrophy occurs as a result of progressive neuronal loss4. DiMauro S, Hirano M, Kaufmann P, Tanji K, Sano M, Shungu DC et al. Clinical features and genetics of myoclonic epilepsy with ragged red fibers. Adv Neurol. 2002;89:217-29. http://dx.doi.org/10.1016/b978-0-12-374105-9.00349-x
https://doi.org/10.1016/b978-0-12-374105...
,3636 . Ito S, Shirai W, Asahina M, Hattori T. 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):392-5. http://dx.doi.org/10.3174/ajnr.a0865
https://doi.org/10.3174/ajnr.a0865 ...
,3939 . Orcesi S, Gorni K, Termine C, Uggetti C, Veffiotti P, Carrara F 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(1):79-82. http://dx.doi.org/10.1177/08830738060210010901
https://doi.org/10.1177/0883073806021001...
. Thus, one expects to find in patients with MERRF frequent cortical atrophy, predominantly in the brain and cerebellum, and discrete changes in the inferior olivary nucleus, cerebellar dentate nucleus, red nucleus and pons of the brainstem.

What are the laboratory and biochemical features?

The lactic acid level in the blood and cerebrospinal fluid (CSF) is elevated at rest in patients with MERFF and can increase moderately after physical activity4. DiMauro S, Hirano M, Kaufmann P, Tanji K, Sano M, Shungu DC et al. Clinical features and genetics of myoclonic epilepsy with ragged red fibers. Adv Neurol. 2002;89:217-29. http://dx.doi.org/10.1016/b978-0-12-374105-9.00349-x
https://doi.org/10.1016/b978-0-12-374105...
,2727 . Ozawa M, Goto Y, Sakuta R, Tanno Y, Tsuji S, Nonaka I. The 8,344 mutation in mitochondrial DNA: a comparison between the proportion of mutant DNA and clinico-pathologic findings. Neuromuscul Disord. 1995;5(6):483-8. http://dx.doi.org/10.1016/0960-8966(95)00009-c
https://doi.org/10.1016/0960-8966(95)000...
. These high lactic acid serum levels can also be found in the asymptomatic family members of patients with MERRF2424 . Zeviani M, Amati P, Bresolin N, Antozzi C, Piccolo G, Toscano A et al. Rapid detection of the A-to-G(8344) mutation of mtDNA in Italian families with myoclonus epilepsy and ragged-red fibers (MERRF). Am J Hum Genet. 1991;48(2):203-11.. The level of ventricle lactic acid, measured by spectroscopy, is usually increased in most patients with MERRF and in their families, but these levels are lower overall than those found in patients with MELAS4. DiMauro S, Hirano M, Kaufmann P, Tanji K, Sano M, Shungu DC et al. Clinical features and genetics of myoclonic epilepsy with ragged red fibers. Adv Neurol. 2002;89:217-29. http://dx.doi.org/10.1016/b978-0-12-374105-9.00349-x
https://doi.org/10.1016/b978-0-12-374105...
. Other tests may be used in initial investigation, such as dosages of creatine kinase (CK), but their results are not specific for MERRF, mainly helping to differentiate the diagnosis from other diseases. Thus, although nonspecific to demonstrate mitochondrial myopathy, serum CK may be slightly increased in some patients and may demonstrate muscle involvement in these patients4040 . Goto Y, Horai S, Matsuoka T, Koga Y, Nihei K, Kobayashi M et al. Mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS): a correlative study of the clinical features and mitochondrial DNA mutation. Neurology. 1992;42(3):545-50. http://dx.doi.org/10.1212/wnl.42.3.545
https://doi.org/10.1212/wnl.42.3.545 ...
,4141 . Finsterer J. Mitochondrial ataxias. Can J Neurol Sci. 2009;36(5):543-53.. The CSF protein level is also high in 1.6-8% of patients, but it generally does not exceed 100mg/dl4. DiMauro S, Hirano M, Kaufmann P, Tanji K, Sano M, Shungu DC et al. Clinical features and genetics of myoclonic epilepsy with ragged red fibers. Adv Neurol. 2002;89:217-29. http://dx.doi.org/10.1016/b978-0-12-374105-9.00349-x
https://doi.org/10.1016/b978-0-12-374105...
,3131 . Marotta R, Chin J, Quigley A, Katsababus S, Kapsa R, Byrne E et al. Diagnostic screening of mitochondrial DNA mutations in Australian adults 1990-2001. Intern Med J. 2004;34(1-2):10-9. http://dx.doi.org/10.1111/j.1444-0903.2004.t01-3-.x
https://doi.org/10.1111/j.1444-0903.2004...
. A laboratory scheme suggested by Mancuso et al could also help in the follow-up of the patients with the A8344G mutation (Table 2)2828 . Mancuso M, Orsucci D, Angelini C, Bertini E, Carelli V, Comi GP et al. Phenotypic heterogeneity of the 8344A>G mtDNA "MERRF" mutation. Neurology. 2013;80(22):2049-54. http://dx.doi.org/10.1212/WNL.0b013e318294b44c
https://doi.org/10.1212/WNL.0b013e318294...
.

Biochemical studies have shown that several complexes of respiratory chains can be disabled either in isolation or in combination. Complexes I and IV seem to be more involved in the respiratory chain in patients with MERRF, and they are usually associated with changes in other respiratory chain complexes, whereas complex II seems to be the least affected8. Shoffner JM, Lott MT, Lezza A, Seibel P, Ballinger SW, Wallace DC. Myoclonic epilepsy and ragged-red fiber disease (MERRF) is associated with a mitochondrial DNA tRNALys mutation. Cell. 1990;61(6):931-7. http://dx.doi.org/10.1016/0092-8674(90)90059-n
https://doi.org/10.1016/0092-8674(90)900...
,2323 . Shoffner JM, Wallace DC. Mitochondrial genetics: principles and practice. Am J Hum Genet. 1992;51(6):1179-86.,2727 . Ozawa M, Goto Y, Sakuta R, Tanno Y, Tsuji S, Nonaka I. The 8,344 mutation in mitochondrial DNA: a comparison between the proportion of mutant DNA and clinico-pathologic findings. Neuromuscul Disord. 1995;5(6):483-8. http://dx.doi.org/10.1016/0960-8966(95)00009-c
https://doi.org/10.1016/0960-8966(95)000...
,3434 . Berkovic SF, Carpenter S, Evans A, Karpati G, Shoubridge EA, Andermann F et al. Myoclonus epilepsy and ragged-red fibres (MERRF). 1. A clinical, pathological, biochemical, magnetic resonance spectrographic and positron emission tomographic study. Brain. 1989;112(5):1231-60. http://dx.doi.org/10.1093/brain/112.5.1231
https://doi.org/10.1093/brain/112.5.1231...
,4242 . Bindoff LA, Desnuelle C, Birch-Machin MA, et al. Multiple defects of the mitochondrial respiratory chain in a mitochondrial encephalopathy (MERRF): a clinical, biochemical and molecular study. J Neurol Sci. 1991;102(1):17-24. http://dx.doi.org/10.1016/0022-510x(91)90088-o
https://doi.org/10.1016/0022-510x(91)900...
,4343 . Coquet M, Degoul F, Vital A, Malgat M, Mazat JP, Louvet-Giendai C et al. Merrf family with 8344 mutation in tRNA (lys). Evidence of a mitochondrial vasculopathy in muscle biopsies. Neuromuscul Disord. 1993;3(5-6):593-7. http://dx.doi.org/10.1016/0960-8966(93)90122-z
https://doi.org/10.1016/0960-8966(93)901...
,4444 . Wallace DC, Zheng XX, Lott MT, Shoffner JM, Hodge JA, Kelley RI et al. Familial mitochondrial encephalomyopathy (MERRF): genetic, pathophysiological and biochemical characterization of a mitochondrial DNA disease. Cell. 1988;55(4):601-10. http://dx.doi.org/10.1016/0092-8674(88)90218-8
https://doi.org/10.1016/0092-8674(88)902...
. The number of muscle fibers with deficient activity of COX observed upon muscle biopsy suggests that respiratory chain complex IV could be one of the complexes that are most affected in MERRF patients4545 . Bourgeois JM, Tarnopolsky MA. Pathology of the skeletal muscle in mitochondrial disorders. Mitochondrion. 2004;4(5-6):441-52. http://dx.doi.org/10.1016/j.mito.2004.07.036
https://doi.org/10.1016/j.mito.2004.07.0...
,4646 . Mancuso M, Petrozzi L, Filosto M, Nesti C, Rocchi A, Choub A et al. MERRF syndrome without ragged-red fibers: the need for molecular diagnosis. Biochem Biophys Res Commun. 2007;354(4):1058-60. http://dx.doi.org/10.1016/j.bbrc.2007.01.099
https://doi.org/10.1016/j.bbrc.2007.01.0...
,4747 . De Paepe B, Smet J, Lammens M, Seneca S, Martin JJ, De Bkeecjer J et al. Immunohistochemical analysis of the oxidative phosphorylation complexes in skeletal muscle from patients with mitochondrial DNA encoded tRNA gene defects. J Clin Pathol. 2009;62(2):172-6. http://dx.doi.org/10.1136/jcp.2008.061267
https://doi.org/10.1136/jcp.2008.061267 ...
,4848 . Lorenzoni PJ, Scola RH, Kay CS, Arndt RC, Freund AA, Bruck I et al MELAS: clinical features, muscle biopsy and molecular genetics. Arq Neuropsiquiatr. 2009;67(3A):668-76. http://dx.doi.org/10.1590/s0004-282x2009000400018
https://doi.org/10.1590/s0004-282x200900...
,4949 . Shahwan A, Farrel M, Delanty N. Progressive myoclonic epilepsies: a review of genetic and therapeutic aspects. Lancet Neurol. 2005;4(4):239-48. http://dx.doi.org/10.1016/s1474-4422(05)70043-0
https://doi.org/10.1016/s1474-4422(05)70...
,5050 . Sinha S, Satishchandra P, Gayathri N, Yasha TC, Shankar SK. Progressive mioclonic epilepsy: a clinical, electrophysiological and pathological study from South India. J Neurol Sci. 2007;252(1):16-23. http://dx.doi.org/10.1016/j.jns.2006.09.021
https://doi.org/10.1016/j.jns.2006.09.02...
,5151 . So N, Berkovic S, Andermann F, Kuzniecky R, Gendron D, Quesney LF. Myoclonus epilepsy and ragged-red fibres (MERRF). 2. Electrophysiological studies and comparison with other progressive myoclonus epilepsies. Brain. 1989;112(Pt 5):1261-76. http://dx.doi.org/10.1093/brain/112.5.1261
https://doi.org/10.1093/brain/112.5.1261...
,5252 . Goto Y. Clinical features of MELAS and mitochondrial DNA mutations. Muscle Nerve. 1995;18(Suppl 14):S107-12. http://dx.doi.org/10.1002/mus.880181422
https://doi.org/10.1002/mus.880181422...
,5353 . Mita S, Tokunaga M, Uyama E, Kumamoto T, Uekawa K, Uchino M. Single muscle fiber analysis of myoclonus epilepsy with ragged-red fibers. Muscle Nerve. 1998;21(4):490-7. http://dx.doi.org/10.1002/(SICI)1097-4598(199804)21:4?ENT(lt)?490::AID-MUS7?ENT(gt)?3.0.CO;2-4
https://doi.org/10.1002/(SICI)1097-4598(...
,5454 . Matsuoka T, Goto Y, Yoneda M, Nonaka I. Muscle histopathology in myoclonus epilepsy with ragged-red fibers (MERRF). J Neurol Sci. 1991;106(2):193-8. http://dx.doi.org/10.1016/0022-510x(91)90257-8
https://doi.org/10.1016/0022-510x(91)902...
,5555 . Zeviani M, Di Donato S. Mitochondrial disorders. Brain. 2004;127(10):2153-72. http://dx.doi.org/10.1093/brain/awh259
https://doi.org/10.1093/brain/awh259...
,5656 . Hasegawa H, Matsuoka T, Goto Y, Nonaka I. Strongly succinate dehydrogenase-reactive blood vessels in muscle from patients with mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes. Ann Neurol. 1991;29(6):601-5. http://dx.doi.org/10.1002/ana.410290606
https://doi.org/10.1002/ana.410290606 ...
,5757 . Hasegawa H, Matsuoka T, Goto Y, Nonaka I. Cytochrome c oxidase activity is deficient in blood vessels of patients with myoclonus epilepsy with ragged-red fibers. Acta Neuropathol. 1993;85(3):280-4. http://dx.doi.org/10.1007/bf00227723
https://doi.org/10.1007/bf00227723...
. This reasoning can also be supported by the fact that patients with MERRF who have the A8344G point mutation also exhibit a high frequency of muscle fibers (RRF and no-RRF) with deficient COX activity upon muscle biopsy2626 . Boulet L, Karpati G, Shoubridge EA. Distribution and threshold expression of the tRNA-lys mutation in skeletal muscle of patients with myoclonic epilepsy and ragged-red fibers (MERRF). Am J Hum Genet. 1992;51(6):1187-200.,4545 . Bourgeois JM, Tarnopolsky MA. Pathology of the skeletal muscle in mitochondrial disorders. Mitochondrion. 2004;4(5-6):441-52. http://dx.doi.org/10.1016/j.mito.2004.07.036
https://doi.org/10.1016/j.mito.2004.07.0...
,4848 . Lorenzoni PJ, Scola RH, Kay CS, Arndt RC, Freund AA, Bruck I et al MELAS: clinical features, muscle biopsy and molecular genetics. Arq Neuropsiquiatr. 2009;67(3A):668-76. http://dx.doi.org/10.1590/s0004-282x2009000400018
https://doi.org/10.1590/s0004-282x200900...
. In contrast to patients with MELAS, patients with point mutations of A3243G show a high incidence of RRF fibers with a normal COX histochemical reaction2626 . Boulet L, Karpati G, Shoubridge EA. Distribution and threshold expression of the tRNA-lys mutation in skeletal muscle of patients with myoclonic epilepsy and ragged-red fibers (MERRF). Am J Hum Genet. 1992;51(6):1187-200.,4545 . Bourgeois JM, Tarnopolsky MA. Pathology of the skeletal muscle in mitochondrial disorders. Mitochondrion. 2004;4(5-6):441-52. http://dx.doi.org/10.1016/j.mito.2004.07.036
https://doi.org/10.1016/j.mito.2004.07.0...
,4848 . Lorenzoni PJ, Scola RH, Kay CS, Arndt RC, Freund AA, Bruck I et al MELAS: clinical features, muscle biopsy and molecular genetics. Arq Neuropsiquiatr. 2009;67(3A):668-76. http://dx.doi.org/10.1590/s0004-282x2009000400018
https://doi.org/10.1590/s0004-282x200900...
. The biochemical analysis of respiratory chain complexes may be normal in some cases2727 . Ozawa M, Goto Y, Sakuta R, Tanno Y, Tsuji S, Nonaka I. The 8,344 mutation in mitochondrial DNA: a comparison between the proportion of mutant DNA and clinico-pathologic findings. Neuromuscul Disord. 1995;5(6):483-8. http://dx.doi.org/10.1016/0960-8966(95)00009-c
https://doi.org/10.1016/0960-8966(95)000...
,3434 . Berkovic SF, Carpenter S, Evans A, Karpati G, Shoubridge EA, Andermann F et al. Myoclonus epilepsy and ragged-red fibres (MERRF). 1. A clinical, pathological, biochemical, magnetic resonance spectrographic and positron emission tomographic study. Brain. 1989;112(5):1231-60. http://dx.doi.org/10.1093/brain/112.5.1231
https://doi.org/10.1093/brain/112.5.1231...
.

What are the electrophysiological features?

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 . Ozawa M, Goto Y, Sakuta R, Tanno Y, Tsuji S, Nonaka I. The 8,344 mutation in mitochondrial DNA: a comparison between the proportion of mutant DNA and clinico-pathologic findings. Neuromuscul Disord. 1995;5(6):483-8. http://dx.doi.org/10.1016/0960-8966(95)00009-c
https://doi.org/10.1016/0960-8966(95)000...
,3333 . Canafoglia L, Franceschetti S, Antozzi C, Carrara F, Farina L, Granata T et al. Epileptic phenotypes associated with mitochondrial disorders. Neurology. 2001;56(10):1340-6. http://dx.doi.org/10.1212/wnl.56.10.1340
https://doi.org/10.1212/wnl.56.10.1340...
,4949 . Shahwan A, Farrel M, Delanty N. Progressive myoclonic epilepsies: a review of genetic and therapeutic aspects. Lancet Neurol. 2005;4(4):239-48. http://dx.doi.org/10.1016/s1474-4422(05)70043-0
https://doi.org/10.1016/s1474-4422(05)70...
,5050 . Sinha S, Satishchandra P, Gayathri N, Yasha TC, Shankar SK. Progressive mioclonic epilepsy: a clinical, electrophysiological and pathological study from South India. J Neurol Sci. 2007;252(1):16-23. http://dx.doi.org/10.1016/j.jns.2006.09.021
https://doi.org/10.1016/j.jns.2006.09.02...
,5151 . So N, Berkovic S, Andermann F, Kuzniecky R, Gendron D, Quesney LF. Myoclonus epilepsy and ragged-red fibres (MERRF). 2. Electrophysiological studies and comparison with other progressive myoclonus epilepsies. Brain. 1989;112(Pt 5):1261-76. http://dx.doi.org/10.1093/brain/112.5.1261
https://doi.org/10.1093/brain/112.5.1261...
. Epilepsy can be observed in other mitochondrial disorders, and, hence, patients with other mitochondrial diseases may exhibit changes in EEG similar to those of patients with MERRF3333 . Canafoglia L, Franceschetti S, Antozzi C, Carrara F, Farina L, Granata T et al. Epileptic phenotypes associated with mitochondrial disorders. Neurology. 2001;56(10):1340-6. http://dx.doi.org/10.1212/wnl.56.10.1340
https://doi.org/10.1212/wnl.56.10.1340...
. However, patients with MERRF show fewer focal EEG signs than patients with MELAS or Leigh syndrome3333 . Canafoglia L, Franceschetti S, Antozzi C, Carrara F, Farina L, Granata T et al. Epileptic phenotypes associated with mitochondrial disorders. Neurology. 2001;56(10):1340-6. http://dx.doi.org/10.1212/wnl.56.10.1340
https://doi.org/10.1212/wnl.56.10.1340...
,5151 . So N, Berkovic S, Andermann F, Kuzniecky R, Gendron D, Quesney LF. Myoclonus epilepsy and ragged-red fibres (MERRF). 2. Electrophysiological studies and comparison with other progressive myoclonus epilepsies. Brain. 1989;112(Pt 5):1261-76. http://dx.doi.org/10.1093/brain/112.5.1261
https://doi.org/10.1093/brain/112.5.1261...
. Moreover, EEG reveals abnormalities in patients with MERRF that closely resemble those found in other progressive myoclonic epilepsies4949 . Shahwan A, Farrel M, Delanty N. Progressive myoclonic epilepsies: a review of genetic and therapeutic aspects. Lancet Neurol. 2005;4(4):239-48. http://dx.doi.org/10.1016/s1474-4422(05)70043-0
https://doi.org/10.1016/s1474-4422(05)70...
,5050 . Sinha S, Satishchandra P, Gayathri N, Yasha TC, Shankar SK. Progressive mioclonic epilepsy: a clinical, electrophysiological and pathological study from South India. J Neurol Sci. 2007;252(1):16-23. http://dx.doi.org/10.1016/j.jns.2006.09.021
https://doi.org/10.1016/j.jns.2006.09.02...
,5151 . So N, Berkovic S, Andermann F, Kuzniecky R, Gendron D, Quesney LF. Myoclonus epilepsy and ragged-red fibres (MERRF). 2. Electrophysiological studies and comparison with other progressive myoclonus epilepsies. Brain. 1989;112(Pt 5):1261-76. http://dx.doi.org/10.1093/brain/112.5.1261
https://doi.org/10.1093/brain/112.5.1261...
. Additionally, photoparoxysmal response to EEG can be observed both in patients with MERRF and in patients with other mitochondrial myopathies such as MELAS or Leigh syndrome or other overlapping syndromes3333 . Canafoglia L, Franceschetti S, Antozzi C, Carrara F, Farina L, Granata T et al. Epileptic phenotypes associated with mitochondrial disorders. Neurology. 2001;56(10):1340-6. http://dx.doi.org/10.1212/wnl.56.10.1340
https://doi.org/10.1212/wnl.56.10.1340...
,5050 . Sinha S, Satishchandra P, Gayathri N, Yasha TC, Shankar SK. Progressive mioclonic epilepsy: a clinical, electrophysiological and pathological study from South India. J Neurol Sci. 2007;252(1):16-23. http://dx.doi.org/10.1016/j.jns.2006.09.021
https://doi.org/10.1016/j.jns.2006.09.02...
. Intermittent photic stimulation is occasionally described to trigger seizures in patients with MERRF5151 . So N, Berkovic S, Andermann F, Kuzniecky R, Gendron D, Quesney LF. Myoclonus epilepsy and ragged-red fibres (MERRF). 2. Electrophysiological studies and comparison with other progressive myoclonus epilepsies. Brain. 1989;112(Pt 5):1261-76. http://dx.doi.org/10.1093/brain/112.5.1261
https://doi.org/10.1093/brain/112.5.1261...
.

Needle electromyography and nerve conduction studies are consistent with the myopathic process in patients with MERRF, but neuropathy can coexist in some patients. The presence of alterations in the needle electromyography shows that changes in muscle fibers occur in approximately 50% of patients with MERRF2727 . Ozawa M, Goto Y, Sakuta R, Tanno Y, Tsuji S, Nonaka I. The 8,344 mutation in mitochondrial DNA: a comparison between the proportion of mutant DNA and clinico-pathologic findings. Neuromuscul Disord. 1995;5(6):483-8. http://dx.doi.org/10.1016/0960-8966(95)00009-c
https://doi.org/10.1016/0960-8966(95)000...
. However, these changes in needle EMG can vary depending upon when the test is performed and the severity of the disease, presenting with a myopathic, neurogenic or mixed (myopathic and neurogenic) pattern2727 . Ozawa M, Goto Y, Sakuta R, Tanno Y, Tsuji S, Nonaka I. The 8,344 mutation in mitochondrial DNA: a comparison between the proportion of mutant DNA and clinico-pathologic findings. Neuromuscul Disord. 1995;5(6):483-8. http://dx.doi.org/10.1016/0960-8966(95)00009-c
https://doi.org/10.1016/0960-8966(95)000...
. Because neuropathy may occur in patients with MERRF, nerve conduction studies also have utility for the evaluation of these patients, showing the presence of motor and sensory axonal neuropathy in most cases4. DiMauro S, Hirano M, Kaufmann P, Tanji K, Sano M, Shungu DC et al. Clinical features and genetics of myoclonic epilepsy with ragged red fibers. Adv Neurol. 2002;89:217-29. http://dx.doi.org/10.1016/b978-0-12-374105-9.00349-x
https://doi.org/10.1016/b978-0-12-374105...
,5050 . Sinha S, Satishchandra P, Gayathri N, Yasha TC, Shankar SK. Progressive mioclonic epilepsy: a clinical, electrophysiological and pathological study from South India. J Neurol Sci. 2007;252(1):16-23. http://dx.doi.org/10.1016/j.jns.2006.09.021
https://doi.org/10.1016/j.jns.2006.09.02...
,5151 . So N, Berkovic S, Andermann F, Kuzniecky R, Gendron D, Quesney LF. Myoclonus epilepsy and ragged-red fibres (MERRF). 2. Electrophysiological studies and comparison with other progressive myoclonus epilepsies. Brain. 1989;112(Pt 5):1261-76. http://dx.doi.org/10.1093/brain/112.5.1261
https://doi.org/10.1093/brain/112.5.1261...
.

What are the histological features?

The muscle biopsy is an important diagnostic tool for MERRF because RRF are found in over 92% of patients with this disease (Figure 3)4. DiMauro S, Hirano M, Kaufmann P, Tanji K, Sano M, Shungu DC et al. Clinical features and genetics of myoclonic epilepsy with ragged red fibers. Adv Neurol. 2002;89:217-29. http://dx.doi.org/10.1016/b978-0-12-374105-9.00349-x
https://doi.org/10.1016/b978-0-12-374105...
,2222 . Fukuhara N. Clinicopathological features of MERRF. Muscle Nerve. 1995;18(Suppl 14):S90-4. http://dx.doi.org/10.1002/mus.880181419
https://doi.org/10.1002/mus.880181419...
,2727 . Ozawa M, Goto Y, Sakuta R, Tanno Y, Tsuji S, Nonaka I. The 8,344 mutation in mitochondrial DNA: a comparison between the proportion of mutant DNA and clinico-pathologic findings. Neuromuscul Disord. 1995;5(6):483-8. http://dx.doi.org/10.1016/0960-8966(95)00009-c
https://doi.org/10.1016/0960-8966(95)000...
. Initially, the muscle biopsy may show only muscle fibers with subsarcolemmal accumulation of mitochondria without forming typical RRF, but virtually all patients with MERRF present RRF during the evolution of the disease4040 . Goto Y, Horai S, Matsuoka T, Koga Y, Nihei K, Kobayashi M et al. Mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS): a correlative study of the clinical features and mitochondrial DNA mutation. Neurology. 1992;42(3):545-50. http://dx.doi.org/10.1212/wnl.42.3.545
https://doi.org/10.1212/wnl.42.3.545 ...
,4545 . Bourgeois JM, Tarnopolsky MA. Pathology of the skeletal muscle in mitochondrial disorders. Mitochondrion. 2004;4(5-6):441-52. http://dx.doi.org/10.1016/j.mito.2004.07.036
https://doi.org/10.1016/j.mito.2004.07.0...
,5252 . Goto Y. Clinical features of MELAS and mitochondrial DNA mutations. Muscle Nerve. 1995;18(Suppl 14):S107-12. http://dx.doi.org/10.1002/mus.880181422
https://doi.org/10.1002/mus.880181422...
. RRF frequency is usually greater in the histochemical reaction for succinate dehydrogenase (SDH) than in staining by modified Trichrome Gomori (TGM), as is the case in other mitochondrial diseases4040 . Goto Y, Horai S, Matsuoka T, Koga Y, Nihei K, Kobayashi M et al. Mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS): a correlative study of the clinical features and mitochondrial DNA mutation. Neurology. 1992;42(3):545-50. http://dx.doi.org/10.1212/wnl.42.3.545
https://doi.org/10.1212/wnl.42.3.545 ...
,4545 . Bourgeois JM, Tarnopolsky MA. Pathology of the skeletal muscle in mitochondrial disorders. Mitochondrion. 2004;4(5-6):441-52. http://dx.doi.org/10.1016/j.mito.2004.07.036
https://doi.org/10.1016/j.mito.2004.07.0...
,5252 . Goto Y. Clinical features of MELAS and mitochondrial DNA mutations. Muscle Nerve. 1995;18(Suppl 14):S107-12. http://dx.doi.org/10.1002/mus.880181422
https://doi.org/10.1002/mus.880181422...
. The absence of RRF is rarely be observed in muscle biopsies from patients with MERRF1818 . Ozawa M, Nishino I, Horai S, Nonaka I, Goto YI. Myoclonus epilepsy associated with ragged-red fibers: a G-to-A mutation at nucleotide pair 8363 in mitochondrial tRNA(Lys) in two families. Muscle Nerve. 1997:20(3):271-8. http://dx.doi.org/10.1002/(SICI)1097-4598(199703)20:3?ENT(lt)?271::AID-MUS2?ENT(gt)?3.0.CO;2-8
https://doi.org/10.1002/(SICI)1097-4598(...
,2222 . Fukuhara N. Clinicopathological features of MERRF. Muscle Nerve. 1995;18(Suppl 14):S90-4. http://dx.doi.org/10.1002/mus.880181419
https://doi.org/10.1002/mus.880181419...
,3434 . Berkovic SF, Carpenter S, Evans A, Karpati G, Shoubridge EA, Andermann F et al. Myoclonus epilepsy and ragged-red fibres (MERRF). 1. A clinical, pathological, biochemical, magnetic resonance spectrographic and positron emission tomographic study. Brain. 1989;112(5):1231-60. http://dx.doi.org/10.1093/brain/112.5.1231
https://doi.org/10.1093/brain/112.5.1231...
,4646 . Mancuso M, Petrozzi L, Filosto M, Nesti C, Rocchi A, Choub A et al. MERRF syndrome without ragged-red fibers: the need for molecular diagnosis. Biochem Biophys Res Commun. 2007;354(4):1058-60. http://dx.doi.org/10.1016/j.bbrc.2007.01.099
https://doi.org/10.1016/j.bbrc.2007.01.0...
. The degree of heteroplasmy (proportion of normal and mutant mtDNA in each tissue) is also an important factor influencing the variability of muscle biopsy findings1818 . Ozawa M, Nishino I, Horai S, Nonaka I, Goto YI. Myoclonus epilepsy associated with ragged-red fibers: a G-to-A mutation at nucleotide pair 8363 in mitochondrial tRNA(Lys) in two families. Muscle Nerve. 1997:20(3):271-8. http://dx.doi.org/10.1002/(SICI)1097-4598(199703)20:3?ENT(lt)?271::AID-MUS2?ENT(gt)?3.0.CO;2-8
https://doi.org/10.1002/(SICI)1097-4598(...
,2727 . Ozawa M, Goto Y, Sakuta R, Tanno Y, Tsuji S, Nonaka I. The 8,344 mutation in mitochondrial DNA: a comparison between the proportion of mutant DNA and clinico-pathologic findings. Neuromuscul Disord. 1995;5(6):483-8. http://dx.doi.org/10.1016/0960-8966(95)00009-c
https://doi.org/10.1016/0960-8966(95)000...
. A quantitative analysis shows that 80 to 90% of muscle fibers have a higher amount of mtDNA (normal and mutant), and the proportion of mutant mtDNA is extremely high in RRF when compared with fibers that do not form RRF1818 . Ozawa M, Nishino I, Horai S, Nonaka I, Goto YI. Myoclonus epilepsy associated with ragged-red fibers: a G-to-A mutation at nucleotide pair 8363 in mitochondrial tRNA(Lys) in two families. Muscle Nerve. 1997:20(3):271-8. http://dx.doi.org/10.1002/(SICI)1097-4598(199703)20:3?ENT(lt)?271::AID-MUS2?ENT(gt)?3.0.CO;2-8
https://doi.org/10.1002/(SICI)1097-4598(...
,2727 . Ozawa M, Goto Y, Sakuta R, Tanno Y, Tsuji S, Nonaka I. The 8,344 mutation in mitochondrial DNA: a comparison between the proportion of mutant DNA and clinico-pathologic findings. Neuromuscul Disord. 1995;5(6):483-8. http://dx.doi.org/10.1016/0960-8966(95)00009-c
https://doi.org/10.1016/0960-8966(95)000...
,5353 . Mita S, Tokunaga M, Uyama E, Kumamoto T, Uekawa K, Uchino M. Single muscle fiber analysis of myoclonus epilepsy with ragged-red fibers. Muscle Nerve. 1998;21(4):490-7. http://dx.doi.org/10.1002/(SICI)1097-4598(199804)21:4?ENT(lt)?490::AID-MUS7?ENT(gt)?3.0.CO;2-4
https://doi.org/10.1002/(SICI)1097-4598(...
.

Figure 3
Classic muscle biopsy features of MERRF: (A) ragged-red fibers (RRF) stained with modified Gomori-trichrome; (B) RRF stained with succinate dehydrogenase (SDH); and (C) deficient muscle fiber activity using a cytochrome c oxidase (COX) stain. Bar=50 µm.

The morphological changes observed in muscle biopsies that can help distinguish MERRF from other mitochondrial diseases are as follows: (1) a large proportion of muscle fibers (RRF and no-RRF) that have deficient activity of cytochrome c oxidase (COX), and (2) the presence of COX deficient vessels with a strong reaction for SDH4545 . Bourgeois JM, Tarnopolsky MA. Pathology of the skeletal muscle in mitochondrial disorders. Mitochondrion. 2004;4(5-6):441-52. http://dx.doi.org/10.1016/j.mito.2004.07.036
https://doi.org/10.1016/j.mito.2004.07.0...
,4646 . Mancuso M, Petrozzi L, Filosto M, Nesti C, Rocchi A, Choub A et al. MERRF syndrome without ragged-red fibers: the need for molecular diagnosis. Biochem Biophys Res Commun. 2007;354(4):1058-60. http://dx.doi.org/10.1016/j.bbrc.2007.01.099
https://doi.org/10.1016/j.bbrc.2007.01.0...
,4747 . De Paepe B, Smet J, Lammens M, Seneca S, Martin JJ, De Bkeecjer J et al. Immunohistochemical analysis of the oxidative phosphorylation complexes in skeletal muscle from patients with mitochondrial DNA encoded tRNA gene defects. J Clin Pathol. 2009;62(2):172-6. http://dx.doi.org/10.1136/jcp.2008.061267
https://doi.org/10.1136/jcp.2008.061267 ...
.

COX activity in muscle fibers is decreased or absent in most patients with MERRF (Figure 3)4. DiMauro S, Hirano M, Kaufmann P, Tanji K, Sano M, Shungu DC et al. Clinical features and genetics of myoclonic epilepsy with ragged red fibers. Adv Neurol. 2002;89:217-29. http://dx.doi.org/10.1016/b978-0-12-374105-9.00349-x
https://doi.org/10.1016/b978-0-12-374105...
,2727 . Ozawa M, Goto Y, Sakuta R, Tanno Y, Tsuji S, Nonaka I. The 8,344 mutation in mitochondrial DNA: a comparison between the proportion of mutant DNA and clinico-pathologic findings. Neuromuscul Disord. 1995;5(6):483-8. http://dx.doi.org/10.1016/0960-8966(95)00009-c
https://doi.org/10.1016/0960-8966(95)000...
,4545 . Bourgeois JM, Tarnopolsky MA. Pathology of the skeletal muscle in mitochondrial disorders. Mitochondrion. 2004;4(5-6):441-52. http://dx.doi.org/10.1016/j.mito.2004.07.036
https://doi.org/10.1016/j.mito.2004.07.0...
,5454 . Matsuoka T, Goto Y, Yoneda M, Nonaka I. Muscle histopathology in myoclonus epilepsy with ragged-red fibers (MERRF). J Neurol Sci. 1991;106(2):193-8. http://dx.doi.org/10.1016/0022-510x(91)90257-8
https://doi.org/10.1016/0022-510x(91)902...
,5555 . Zeviani M, Di Donato S. Mitochondrial disorders. Brain. 2004;127(10):2153-72. http://dx.doi.org/10.1093/brain/awh259
https://doi.org/10.1093/brain/awh259...
. As mentioned previously, the presence of COX- fibers in patients with MERRF is greater than that found in other mitochondrial diseases, such as MELAS, demonstrating that different mutations of mtDNA may influence the histological findings in different mitochondrial disorders4040 . Goto Y, Horai S, Matsuoka T, Koga Y, Nihei K, Kobayashi M et al. Mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS): a correlative study of the clinical features and mitochondrial DNA mutation. Neurology. 1992;42(3):545-50. http://dx.doi.org/10.1212/wnl.42.3.545
https://doi.org/10.1212/wnl.42.3.545 ...
,4545 . Bourgeois JM, Tarnopolsky MA. Pathology of the skeletal muscle in mitochondrial disorders. Mitochondrion. 2004;4(5-6):441-52. http://dx.doi.org/10.1016/j.mito.2004.07.036
https://doi.org/10.1016/j.mito.2004.07.0...
,4646 . Mancuso M, Petrozzi L, Filosto M, Nesti C, Rocchi A, Choub A et al. MERRF syndrome without ragged-red fibers: the need for molecular diagnosis. Biochem Biophys Res Commun. 2007;354(4):1058-60. http://dx.doi.org/10.1016/j.bbrc.2007.01.099
https://doi.org/10.1016/j.bbrc.2007.01.0...
,4747 . De Paepe B, Smet J, Lammens M, Seneca S, Martin JJ, De Bkeecjer J et al. Immunohistochemical analysis of the oxidative phosphorylation complexes in skeletal muscle from patients with mitochondrial DNA encoded tRNA gene defects. J Clin Pathol. 2009;62(2):172-6. http://dx.doi.org/10.1136/jcp.2008.061267
https://doi.org/10.1136/jcp.2008.061267 ...
,4848 . Lorenzoni PJ, Scola RH, Kay CS, Arndt RC, Freund AA, Bruck I et al MELAS: clinical features, muscle biopsy and molecular genetics. Arq Neuropsiquiatr. 2009;67(3A):668-76. http://dx.doi.org/10.1590/s0004-282x2009000400018
https://doi.org/10.1590/s0004-282x200900...
,5252 . Goto Y. Clinical features of MELAS and mitochondrial DNA mutations. Muscle Nerve. 1995;18(Suppl 14):S107-12. http://dx.doi.org/10.1002/mus.880181422
https://doi.org/10.1002/mus.880181422...
.

The presence of vessels in the muscle biopsy, usually arterioles, with a strong reaction to SDH (SDH+) can be found more often in patients with MELAS or MERRF than in PEO patients4040 . Goto Y, Horai S, Matsuoka T, Koga Y, Nihei K, Kobayashi M et al. Mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS): a correlative study of the clinical features and mitochondrial DNA mutation. Neurology. 1992;42(3):545-50. http://dx.doi.org/10.1212/wnl.42.3.545
https://doi.org/10.1212/wnl.42.3.545 ...
,5252 . Goto Y. Clinical features of MELAS and mitochondrial DNA mutations. Muscle Nerve. 1995;18(Suppl 14):S107-12. http://dx.doi.org/10.1002/mus.880181422
https://doi.org/10.1002/mus.880181422...
,5656 . Hasegawa H, Matsuoka T, Goto Y, Nonaka I. Strongly succinate dehydrogenase-reactive blood vessels in muscle from patients with mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes. Ann Neurol. 1991;29(6):601-5. http://dx.doi.org/10.1002/ana.410290606
https://doi.org/10.1002/ana.410290606 ...
,5757 . Hasegawa H, Matsuoka T, Goto Y, Nonaka I. Cytochrome c oxidase activity is deficient in blood vessels of patients with myoclonus epilepsy with ragged-red fibers. Acta Neuropathol. 1993;85(3):280-4. http://dx.doi.org/10.1007/bf00227723
https://doi.org/10.1007/bf00227723...
. Histological studies of MERRF patients, regardless of the type of point mutation, have shown that the incidence of vessels with a strong reaction to SDH (SDH+) is below 8%4. DiMauro S, Hirano M, Kaufmann P, Tanji K, Sano M, Shungu DC et al. Clinical features and genetics of myoclonic epilepsy with ragged red fibers. Adv Neurol. 2002;89:217-29. http://dx.doi.org/10.1016/b978-0-12-374105-9.00349-x
https://doi.org/10.1016/b978-0-12-374105...
. However, these vessels can be found in up to 50% of arterioles intramuscularly in patients with the A8344G mutation, showing that the incidence of this change may also be related to the type of mutation in the mtDNA of the patient2727 . Ozawa M, Goto Y, Sakuta R, Tanno Y, Tsuji S, Nonaka I. The 8,344 mutation in mitochondrial DNA: a comparison between the proportion of mutant DNA and clinico-pathologic findings. Neuromuscul Disord. 1995;5(6):483-8. http://dx.doi.org/10.1016/0960-8966(95)00009-c
https://doi.org/10.1016/0960-8966(95)000...
,5757 . Hasegawa H, Matsuoka T, Goto Y, Nonaka I. Cytochrome c oxidase activity is deficient in blood vessels of patients with myoclonus epilepsy with ragged-red fibers. Acta Neuropathol. 1993;85(3):280-4. http://dx.doi.org/10.1007/bf00227723
https://doi.org/10.1007/bf00227723...
. The SDH+ vessels found in patients with MERRF are also deficient in COX, unlike in MELAS, suggesting that, in these patients, the COX deficiency has greater relevance to the pathophysiology of the disease4343 . Coquet M, Degoul F, Vital A, Malgat M, Mazat JP, Louvet-Giendai C et al. Merrf family with 8344 mutation in tRNA (lys). Evidence of a mitochondrial vasculopathy in muscle biopsies. Neuromuscul Disord. 1993;3(5-6):593-7. http://dx.doi.org/10.1016/0960-8966(93)90122-z
https://doi.org/10.1016/0960-8966(93)901...
,5757 . Hasegawa H, Matsuoka T, Goto Y, Nonaka I. Cytochrome c oxidase activity is deficient in blood vessels of patients with myoclonus epilepsy with ragged-red fibers. Acta Neuropathol. 1993;85(3):280-4. http://dx.doi.org/10.1007/bf00227723
https://doi.org/10.1007/bf00227723...
.

What are the main differential diagnoses?

MERRF should be considered in the differential diagnosis of all progressive myoclonic epilepsies, including Lafora disease, neurolipofuscinose and Unverricht-Lundborg disease4949 . Shahwan A, Farrel M, Delanty N. Progressive myoclonic epilepsies: a review of genetic and therapeutic aspects. Lancet Neurol. 2005;4(4):239-48. http://dx.doi.org/10.1016/s1474-4422(05)70043-0
https://doi.org/10.1016/s1474-4422(05)70...
,5050 . Sinha S, Satishchandra P, Gayathri N, Yasha TC, Shankar SK. Progressive mioclonic epilepsy: a clinical, electrophysiological and pathological study from South India. J Neurol Sci. 2007;252(1):16-23. http://dx.doi.org/10.1016/j.jns.2006.09.021
https://doi.org/10.1016/j.jns.2006.09.02...
,5151 . So N, Berkovic S, Andermann F, Kuzniecky R, Gendron D, Quesney LF. Myoclonus epilepsy and ragged-red fibres (MERRF). 2. Electrophysiological studies and comparison with other progressive myoclonus epilepsies. Brain. 1989;112(Pt 5):1261-76. http://dx.doi.org/10.1093/brain/112.5.1261
https://doi.org/10.1093/brain/112.5.1261...
.

In other diseases with epilepsy, myoclonus and ataxia, the affected structures of the CNS have similar locations, but different types of lesion. Thus, in a review of some of the cases previously diagnosed as Friedreich's ataxia, atrophy dentate palido-red-luisiana or Ramsay-Hunt syndrome, a diagnosis of MERRF has been found2222 . Fukuhara N. Clinicopathological features of MERRF. Muscle Nerve. 1995;18(Suppl 14):S90-4. http://dx.doi.org/10.1002/mus.880181419
https://doi.org/10.1002/mus.880181419...
,3434 . Berkovic SF, Carpenter S, Evans A, Karpati G, Shoubridge EA, Andermann F et al. Myoclonus epilepsy and ragged-red fibres (MERRF). 1. A clinical, pathological, biochemical, magnetic resonance spectrographic and positron emission tomographic study. Brain. 1989;112(5):1231-60. http://dx.doi.org/10.1093/brain/112.5.1231
https://doi.org/10.1093/brain/112.5.1231...
,5151 . So N, Berkovic S, Andermann F, Kuzniecky R, Gendron D, Quesney LF. Myoclonus epilepsy and ragged-red fibres (MERRF). 2. Electrophysiological studies and comparison with other progressive myoclonus epilepsies. Brain. 1989;112(Pt 5):1261-76. http://dx.doi.org/10.1093/brain/112.5.1261
https://doi.org/10.1093/brain/112.5.1261...
. Additionally, patients with cerebellar ataxia, myoclonus and lipomas, initially described by Ekbom in 1975, have the same mtDNA mutation as found in patients with MERRF, suggesting that these patients have MERRF3434 . Berkovic SF, Carpenter S, Evans A, Karpati G, Shoubridge EA, Andermann F et al. Myoclonus epilepsy and ragged-red fibres (MERRF). 1. A clinical, pathological, biochemical, magnetic resonance spectrographic and positron emission tomographic study. Brain. 1989;112(5):1231-60. http://dx.doi.org/10.1093/brain/112.5.1231
https://doi.org/10.1093/brain/112.5.1231...
,5858 . So N, Berkovic S, Andermann F, Kuzniecky R, Gendron D, Quesney LF. Myoclonus epilepsy and ragged-red fibres (MERRF). 2. Electrophysiological studies and comparison with other progressive myoclonus epilepsies. Brain. 1989;112(5):1261-76. http://dx.doi.org/10.1093/brain/112.5.1261
https://doi.org/10.1093/brain/112.5.1261...
,5959 . Ekbom K. Hereditary ataxia, photomyoclonus, skeletal deformities and lipoma. Acta Neurol Scand. 1975;51(5):393-404. http://dx.doi.org/10.1111/j.1600-0404.1975.tb01379.x
https://doi.org/10.1111/j.1600-0404.1975...
.

These findings strengthen the hypothesis that neuronal loss plays an important role in the pathophysiology of these diseases. In addition, this clinical, and sometimes pathological, similarity also suggests these alternative diseases as candidates in the differential diagnosis of patients with MERRF.

What is the treatment?

As with other mitochondrial diseases, there is no specific treatment for MERRF4. DiMauro S, Hirano M, Kaufmann P, Tanji K, Sano M, Shungu DC et al. Clinical features and genetics of myoclonic epilepsy with ragged red fibers. Adv Neurol. 2002;89:217-29. http://dx.doi.org/10.1016/b978-0-12-374105-9.00349-x
https://doi.org/10.1016/b978-0-12-374105...
,4949 . Shahwan A, Farrel M, Delanty N. Progressive myoclonic epilepsies: a review of genetic and therapeutic aspects. Lancet Neurol. 2005;4(4):239-48. http://dx.doi.org/10.1016/s1474-4422(05)70043-0
https://doi.org/10.1016/s1474-4422(05)70...
. Therapeutic compounds may ameliorate symptoms in individual cases; however, the available therapeutic interventions are not able to affect the essential progression of this disease.

Many of the extant therapeutic strategies have been adopted based upon the results of isolated case reports or limited clinical studies that have included a heterogeneous population of patients with MERRF or other mitochondrial disorders. The therapeutic compounds that have been used in treatment are mainly meant to improve respiratory chain function or to reduce the levels of reactive oxygen species arising from disrupted mitochondrial metabolism. Some of the most frequently prescribed agents include ubidecarenone (coenzyme Q10, CoQ), B complex vitamins and levocarnitine (L-carnitine). The concomitant administration of these different drugs can be useful in some MERRF patients. Medications with potential to increase mitochondrial toxicity should be recognized and avoided.

In addition, MERRF management includes additional therapy for complications, for example, cardiac disease, diabetes mellitus, deafness, myoclonus or epilepsy. The main symptomatic treatments include drugs used to control myoclonus and epilepsy4. DiMauro S, Hirano M, Kaufmann P, Tanji K, Sano M, Shungu DC et al. Clinical features and genetics of myoclonic epilepsy with ragged red fibers. Adv Neurol. 2002;89:217-29. http://dx.doi.org/10.1016/b978-0-12-374105-9.00349-x
https://doi.org/10.1016/b978-0-12-374105...
,4949 . Shahwan A, Farrel M, Delanty N. Progressive myoclonic epilepsies: a review of genetic and therapeutic aspects. Lancet Neurol. 2005;4(4):239-48. http://dx.doi.org/10.1016/s1474-4422(05)70043-0
https://doi.org/10.1016/s1474-4422(05)70...
. The myoclonus is often refractory to conventional treatment, but clonazepam and zonisamide can be used in these patients4. DiMauro S, Hirano M, Kaufmann P, Tanji K, Sano M, Shungu DC et al. Clinical features and genetics of myoclonic epilepsy with ragged red fibers. Adv Neurol. 2002;89:217-29. http://dx.doi.org/10.1016/b978-0-12-374105-9.00349-x
https://doi.org/10.1016/b978-0-12-374105...
. Treatment of epilepsy in mitochondrial disorders is generally not at variance from treatment of epilepsy due to other causes. The management of epilepsy in MERRF includes antiepileptic drugs, as phenobarbital, phenytoin, carbamazepine, gabapentin, lamotrigine, benzodiazepines and zonisamide6. Lorenzoni PJ, Scola RH, Kay CS, Arndt RC, Silvado CE, Werneck LC. MERRF: clinical features, muscle biopsy and molecular genetics in Brazilian patients. Mitochondrion. 2011;11(3):528-32. http://dx.doi.org/10.1016/j.mito.2011.01.003
https://doi.org/10.1016/j.mito.2011.01.0...
. We are not aware of any controlled studies comparing the efficacy of different antiepileptic drugs in MERRF. Valproate is the first-line antiepileptic drug for generalized seizures and myoclonic epileptiform abnormalities4949 . Shahwan A, Farrel M, Delanty N. Progressive myoclonic epilepsies: a review of genetic and therapeutic aspects. Lancet Neurol. 2005;4(4):239-48. http://dx.doi.org/10.1016/s1474-4422(05)70043-0
https://doi.org/10.1016/s1474-4422(05)70...
. Valproic acid is considered to be one of the drugs of first choice in progressive myoclonic epilepsy, but in the treatment of patients with MERRF, its use is usually empirical6. Lorenzoni PJ, Scola RH, Kay CS, Arndt RC, Silvado CE, Werneck LC. MERRF: clinical features, muscle biopsy and molecular genetics in Brazilian patients. Mitochondrion. 2011;11(3):528-32. http://dx.doi.org/10.1016/j.mito.2011.01.003
https://doi.org/10.1016/j.mito.2011.01.0...
,4949 . Shahwan A, Farrel M, Delanty N. Progressive myoclonic epilepsies: a review of genetic and therapeutic aspects. Lancet Neurol. 2005;4(4):239-48. http://dx.doi.org/10.1016/s1474-4422(05)70043-0
https://doi.org/10.1016/s1474-4422(05)70...
. In addition, valproic acid causes inhibition of carnitine uptake and should be used with caution when treating patients with MERRF, and whenever possible, it should be combined with L-carnitine to prevent the worsening of the mitochondrial dysfunction4. DiMauro S, Hirano M, Kaufmann P, Tanji K, Sano M, Shungu DC et al. Clinical features and genetics of myoclonic epilepsy with ragged red fibers. Adv Neurol. 2002;89:217-29. http://dx.doi.org/10.1016/b978-0-12-374105-9.00349-x
https://doi.org/10.1016/b978-0-12-374105...
,4949 . Shahwan A, Farrel M, Delanty N. Progressive myoclonic epilepsies: a review of genetic and therapeutic aspects. Lancet Neurol. 2005;4(4):239-48. http://dx.doi.org/10.1016/s1474-4422(05)70043-0
https://doi.org/10.1016/s1474-4422(05)70...
.

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    Shahwan A, Farrel M, Delanty N. Progressive myoclonic epilepsies: a review of genetic and therapeutic aspects. Lancet Neurol. 2005;4(4):239-48. http://dx.doi.org/10.1016/s1474-4422(05)70043-0
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Publication Dates

  • Publication in this collection
    Oct 2014

History

  • Received
    13 June 2014
  • Reviewed
    02 July 2014
  • Accepted
    22 July 2014
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