MERRF is a multisystem mitochondrial disease which typically presents with myoclonus (brief, involuntary twitching of a muscle or a group of muscles), followed by generalized epilepsy, ataxia (lack of coordination of muscle movements), weakness, and dementia.  Ragged red fibers (RRF) are identified on muscle biopsy pathology.  Other common findings include hearing loss, short stature, optic atrophy, and cardiomyopathy with Wolff-Parkinson-White syndrome (a syndrome in which there is extra electrical connection in the heart at birth causing rapid heartbeat).  Occasionally pigmentary retinopathy and lipomatosis are observed.  Most cases present in childhood after normal early development.

MERRF is caused by mutations in the mitochondrial DNA (mtDNA) and follows maternal inheritance. This means that a female who carries the mtDNA point mutation will pass it on to all of her children. A male who carries the mtDNA mutation cannot pass it on to his children.

Management is usually palliative. Certain antiepileptic drugs, such as valproic acid, should be avoided as they may cause secondary carnitine deficiency or can be used with L-carnitine supplementation.

Guidelines and Evidence

• No specific evidence-based U.S. testing guidelines were identified.
• Case reports and a limited number of case series are the primary evidence base available for the diagnosis of mitochondrial disease.4-6
• The Mitochondrial Medicine Society developed consensus recommendations using the Delphi method and published them in 2015.
  • Recommendations for DNA testing:
    • “Massively parallel sequencing/NGS of the mtDNA genome is the preferred methodology when testing mtDNA and should be performed in cases of suspected mitochondrial disease instead of testing for a limited number of pathogenic point mutations.”
    • “Patients with a strong likelihood of mitochondrial disease because of a mtDNA mutation and negative testing in blood, should have mtDNA assessed in another tissue to avoid the possibility of missing tissue-specific mutations or low levels of heteroplasmy in blood; tissue-based testing also helps assess the risk of other organ involvement and heterogeneity in family members and to guide genetic counseling.”
    • “Heteroplasmy analysis in urine can selectively be more informative and accurate than testing in blood alone, especially in cases of MELAS due to the common m.3243 A>G mutation.”
    • “When considering nuclear gene testing in patients with likely primary mitochondrial disease, NGS methodologies providing complete coverage of known mitochondrial disease gene is preferred.  Single-gene testing should usually be avoided because mutations in different genes can produce the same phenotype. If no mutation is identified via known NGS panels, then whole exome sequencing should be considered.
• The European Federation of Neurological Sciences (2009) provided molecular diagnostic consensus-based guidelines based on literature reviews: "If the phenotype suggests syndromic mitochondrial disease due to mtDNA point mutations (MELAS, MERRF, NARP, LHON) DNA-microarrays using allele-specific oligonucleotide hybridisation, real-time-PCR or single-gene sequencing are indicated."
• The clinical utility of genetic testing for MERRF was described by a workshop of the National Institute of Neurological Disorders and Stroke (2008):
  • "The diagnosis of mitochondrial diseases is complicated by their heterogeneous presentations and by the lack of screening procedures or diagnostic biomarkers that are both sensitive and specific.  The workshop panelists explained that diagnosis is often a lengthy process beginning with a general clinical evaluation followed by metabolic screening and imaging and finally by genetic tests and more invasive biochemical and histological analyses.  The identification of known mitochondrial mutations in tissue has greatly aided diagnosis.  However, even when clinical features and family history strongly suggest mitochondrial disease, the underlying genetic mutation can elude detection, and there is no current screening procedure that would be practical for all cases of suspected mitochondrial disease.
  • Initial screening includes testing lactate and CSF protein levels, muscle biopsy, EEG, ECG, and MRI. "It is important to note that biochemical abnormalities may not be present during periods when the mitochondrial disease is quiescent/ dormant.
• The Clinical Molecular Genetics Society of UK (2008) provided practice-based guidelines for the molecular diagnosis of mitochondrial disease: "In cases with strong clinical evidence, testing should begin with checking for the common mutation, m.8344A>G. Subsequent testing for other mutations, such as m.8356T>C, may be indicated in cases with a strong clinical indication of MERRF."