Suggestive Findings
MERRF (myoclonic epilepsy with ragged red fibers) should be suspected in individuals with the following features.
Clinical features
Less common clinical signs (seen in <50% of affected individuals) include the following:
Cardiomyopathy
Pigmentary retinopathy
Pyramidal signs
Ophthalmoparesis
Multiple lipomas
Laboratory features
Lactic acidosis both in blood and in the CSF. In individuals with MERRF, the concentrations of lactate and pyruvate are commonly elevated at rest and increase excessively after moderate activity.
Note: Other situations (unrelated to the diagnosis of MERRF or other mitochondrial diseases) in which lactate and pyruvate can be elevated are acute neurologic events such as seizure or stroke.
Elevated CSF protein concentration. The concentration of CSF protein may be increased but rarely surpasses 100 mg/dL.
Respiratory chain studies. Biochemical analysis of respiratory chain enzymes in muscle extracts usually shows decreased activity of respiratory chain complexes containing mtDNA-encoded subunits, especially COX deficiency. However, biochemical studies may also be normal.
Histopathologic features on muscle biopsy. Ragged red fibers (RRF) are seen with the modified Gomori trichrome stain and hyperactive fibers with the succinate dehydrogenase stain. Both RRF and some non-RRF fail to stain with the histochemical reaction for cytochrome c oxidase. Occasionally, RRF may not be observed [Mancuso et al 2007].
Electrophysiologic features
Electroencephalogram usually shows generalized spike and wave discharges with background slowing, but focal epileptiform discharges may also be seen.
Electrocardiogram often shows pre-excitation; heart block has not been described.
Electromyogram and nerve conduction velocity studies are consistent with a myopathy, but neuropathy may coexist.
Brain imaging. Brain MRI often shows brain atrophy and basal ganglia lesions. Bilateral putaminal necrosis and atrophy of the brain stem and cerebellum have been reported [Orcesi et al 2006, Ito et al 2008].
Establishing the Diagnosis
The clinical diagnosis of MERRF (myoclonic epilepsy with ragged red fibers) can be
established in a proband based on clinical diagnostic criteria [Finsterer et al 2018] or the molecular diagnosis can be established in a proband with suggestive findings and a pathogenic variant in one of the genes listed in Table 1, identified by molecular genetic testing.
Clinical diagnosis. The clinical diagnosis is based on the following four "canonic" features:
Molecular diagnosis. The diagnosis of MERRF is established in a proband with suggestive findings and a pathogenic variant in one of the genes listed in Table 1.
Note: Pathogenic variants can usually be detected in mtDNA from leukocytes in individuals with typical MERRF; however, the occurrence of "heteroplasmy" in disorders of mtDNA can result in varying tissue distribution of mutated mtDNA. Hence, the pathogenic variant may be undetectable in mtDNA from leukocytes and may be detected only in other tissues, such as buccal mucosa, cultured skin fibroblasts, hair follicles, urinary sediment, or (most reliably) skeletal muscle.
Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing, concurrent or serial single-gene testing, multigene panel) and comprehensive genomic testing (exome sequencing, exome array, genome sequencing) depending on the phenotype.
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those with a phenotype indistinguishable from many other inherited disorders with seizures and weakness are more likely to be diagnosed using genomic testing (see Option 2).
Option 1
Serial single-gene
testing can be considered if (1) mutation of a particular gene accounts for a large proportion of the condition or (2) clinical findings, laboratory findings, ancestry, or other factors indicate that mutation of a particular gene is most likely.
Targeted analysis. Typically, blood leukocyte DNA is initially screened for pathogenic variants in MT-TK using targeted analysis for the m.8344A>G pathogenic variant, which is present in more than 80% of individuals with typical clinical findings. Note: If no pathogenic variant is found, consider targeted analysis for this pathogenic variant on DNA from buccal mucosa, muscle, or urine sediment.
Entire mitochondrial
genome sequencing that includes the genes in Table 1 and other mtDNA genes of interest (Differential Diagnosis) is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype.
A
multigene panel that includes the genes in Table 1 and other genes of interest (see Differential Diagnosis) may also be considered. Note: (1) The genes included and the sensitivity of multigene panels vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
Option 2
When the phenotype is indistinguishable from many other inherited disorders characterized by seizures and weakness, comprehensive
genomic
testing, which does not require the clinician to determine which gene is likely involved, is the best option. Exome sequencing is most commonly used; genome sequencing is also possible. Many laboratories require that the clinician specify if the mitochondrial genome should be included as part of the comprehensive genomic testing.
For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.
Table 1.
Molecular Genetic Testing Used in MERRF
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Gene 1, 2 | % of MERRF Attributed to Pathogenic Variants in Gene | Proportion of Pathogenic Variants 3 Detectable by Sequence Analysis 4 |
---|
MT-TK
| >90% 5 | 100% |
MT-TF
| <5% | 100% |
MT-TH
|
MT-TI
|
MT-TL1
|
MT-TP
|
MT-TS1
|
MT-TS2
|
Unknown 6 | NA | |
- 1.
Genes are listed from most frequent to least frequent genetic cause of MERRF.
- 2.
- 3.
- 4.
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, partial-, whole-, or multigene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.
- 5.
- 6.
One child with MERRF was found to have two mtDNA deletions in a buccal swab, suggesting an autosomal disorder with multiple mtDNA deletions; however, the causative nuclear gene was not identified [Yorns et al 2012].