Neuro-Ophthalmologic Manifestations of Myoclonic Epilepsy with Ragged Red Fibers (MERRF)

From EyeWiki


Myoclonic Epilepsy with Ragged Red Fibers (MERRF) is recognized by the following International Center for Diseases (ICD) codes:

ICD-10: E88.4

Summary

Myoclonic Epilepsy with Ragged Red Fibers (MERRF) is a mitochondrial disorder associated with a mitochondrial gene mutation for the gene encoding the tRNA for lysine.1,2 This mutation is usually an A to G point mutation at np 8344. 2–4 MERRF usually presents in early childhood with myoclonic epileptic (ME) episodes and the muscle biopsy confirms the ragged red fibers (RRF).1 It can later progress to include other neurological features, including cerebellar ataxia, sensorineural hearing loss, peripheral neuropathy, mental retardation, dementia, optic atrophy, and myopathy with ragged red fibers on biopsy due to lactic acidosis and mitochondrial proliferation.1,3,5,6  

Ophthalmological Manifestations

Ophthalmological manifestations include optic neuropathy6,7, ophthalmoplegia, 3,6–8, pigmentary retinopathy6,7,9, ptosis3,6,7, low visual acuity6, and nystagmus.6

Author Title N Ophthalmological Manifestations
Cheng-Cheng Zhu et al.


Ophthalmological findings in 74 patients with mitochondrial disease 2 2/2 Decreased extraocular movement
Raymond P. Najjar et al. Retinal Neuronal Loss in Visually Asymptomatic Patients With Myoclonic Epilepsy With Ragged-Red Fibers 3 3/3 visually asymptomatic

3/3 had thinning of retinal nerve fiber layers and macular ganglion cell complexes

M A Grönlund et al. Ophthalmological findings in children and young adults with genetically verified mitochondrial disease 7 1/7 ptosis

3/7 reduced eye motility

1/7 nystagmus

2/7 low visual acuity

6/7 optic nerve atrophy

1/7 retinal dystrophy

Mancuso, Michelangelo MD et al. Phenotypic heterogeneity of the 8344A>G mtDNA "MERRF" mutation


34 10/34 ptosis

2/34 ophthalmoparesis

Mancuso, Michelangelo MD et al. Myoclonus in mitochondrial disorders


24 2/24 optic neuropathy

4/24 retinopathy

6/24 ptosis/ophthalmoparesis

Prevalence

Mitochondrial disorders are relatively uncommon but  may have a prevalence of up to 1 in 5000.10 The epidemiological data for MERRF is largely unknown, but the prevalence is estimated to be around 1 in 100,000 or less.11


In summary, MERRF is a mitochondrial disorder characterized by myoclonic epilepsy and ragged red fibers on muscle biopsy. The neuro-ophthalmic findings include optic atrophy, ophthalmoplegia, ptosis, or pigmentary retinopathy. There is no cure, but supportive measures are recommended.

Diagnosis

MERRF has four clinical features that can be used in diagnosis: myoclonus, generalized epilepsy, ataxia, and ragged-red fibers in a muscle biopsy.12 Molecular genetic testing can also be used to confirm the diagnosis, with most patients having the 8344 A>G point mutation (present in 80% of MERRF patients). 2–4,12

Treatment

As with treatment of many mitochondrial disorders, drugs like ubiquinol, carnitine, alpha lipoic acid, vitamin E, vitamin B complex, or creatine can be considered.12 These drugs do not provide benefit in all patient populations and can be discontinued if they are ineffective.12 Seizures can be treated with any traditional anticonvulsant except valproic acid, due to its interaction with mitochondrial respiration.12 MERRF myoclonus is usually treated with levetiracetam or clonazepam.12,13 Any impaired motor ability can be improved with physical therapy or aerobic exercise.12,14

References

1.         Turner C, Pitceathly RDS, Schapira AHV. Mitochondrial Disorders. In: Bradley and Daroff’s Neurology in Clinical Practice. Eighth. Elservier; 2022.

2.         Isashiki Y, Nakagawa M, Ohba N, et al. Retinal manifestations in mitochondrial diseases associated with mitochondrial DNA mutation. Acta Ophthalmol Scand. 1998;76(1):6-13. doi:https://doi.org/10.1034/j.1600-0420.1998.760103.x

3.         Mancuso M, Orsucci D, Angelini C, et al. Phenotypic heterogeneity of the 8344A>G mtDNA “MERRF” mutation. Neurology. 2013;80(22):2049-2054. doi:10.1212/WNL.0b013e318294b44c

4.         Shoffner JM, Lott MT, Lezza AMS, 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):931-937. doi:10.1016/0092-8674(90)90059-N

5.         Al-Enezi M, Al-Saleh H, Nasser M. Mitochondrial Disorders with Significant Ophthalmic Manifestations. Middle East Afr J Ophthalmol. 2008;15(2):81-86. doi:10.4103/0974-9233.51998

6.         Grönlund MA, Honarvar AKS, Andersson S, et al. Ophthalmological findings in children and young adults with genetically verified mitochondrial disease. Br J Ophthalmol. 2010;94(1):121-127. doi:10.1136/bjo.2008.154187

7.         Mancuso M, Orsucci D, Angelini C, et al. Myoclonus in mitochondrial disorders. Mov Disord. 2014;29(6):722-728. doi:https://doi.org/10.1002/mds.25839

8.         Zhu C-C, Traboulsi EI, Parikh S. Ophthalmological findings in 74 patients with mitochondrial disease. Ophthalmic Genet. 2015;38(1):67-69.

9.         Najjar RP, Reynier P, Caignard A, et al. Retinal Neuronal Loss in Visually Asymptomatic Patients With Myoclonic Epilepsy With Ragged-Red Fibers. J Neuroophthalmol. 2019;39(1):18-22. doi:10.1097/WNO.0000000000000690

10.       Schaefer AM, Taylor RW, Turnbull DM, Chinnery PF. The epidemiology of mitochondrial disorders—past, present and future. Biochim Biophys Acta BBA - Bioenerg. 2004;1659(2):115-120. doi:10.1016/j.bbabio.2004.09.005

11.       Hameed S, Tadi P. Myoclonic Epilepsy and Ragged Red Fibers. In: StatPearls. StatPearls Publishing; 2021. Accessed March 31, 2021. http://www.ncbi.nlm.nih.gov/books/NBK555923/

12.       Velez-Bartolomei F, Lee C, Enns G. MERRF. In: Adam MP, Ardinger HH, Pagon RA, et al., eds. GeneReviews®. University of Washington, Seattle; 1993. Accessed April 2, 2021. http://www.ncbi.nlm.nih.gov/books/NBK1520/

13.       Mancuso M, Petrozzi L, Filosto M, et al. MERRF syndrome without ragged-red fibers: The need for molecular diagnosis. Biochem Biophys Res Commun. 2007;354(4):1058-1060. doi:10.1016/j.bbrc.2007.01.099

14.       Taivassalo T, Haller RG. Implications of exercise training in mtDNA defects—use it or lose it? Biochim Biophys Acta BBA - Bioenerg. 2004;1659(2):221-231. doi:10.1016/j.bbabio.2004.09.007{{Article

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