Myoclonus epilepsy with ragged-red fibres (MERRF)

MERRF (myoclonic epilepsy with ragged-red fibres) is a progressive mitochondrial multisystem disorder. Onset ranges from childhood to adulthood, typically after normal early development. Myoclonus is frequently the first manifestation and is followed by generalised epilepsy, cerebellar ataxia, proximal muscle weakness, exercise intolerance and cognitive decline progressing to dementia.

Additional features include sensorineural hearing loss (reported in 35-91% of affected individuals), optic atrophy, peripheral neuropathy, short stature and endocrine involvement (notably diabetes mellitus). Cardiac involvement encompasses hypertrophic and dilated cardiomyopathy as well as arrhythmias, which may occur in isolation or accompany the cardiomyopathy. Multiple, often cervical, lipomas may develop in adulthood, with an average age of onset of 45.2 years and occasional infiltrative and massive growth. Clinical symptoms are highly variable both within and between affected families, reflecting heteroplasmy levels, tissue distribution of mutated mitochondrial DNA and tissue-specific vulnerability thresholds.

The estimated prevalence is approximately 1/140,000. This figure derives from a population-based study of the m.8344A>G variant in the adult population of northeast England; concordantly low estimates of 0 to 1.5 per 100,000 have been reported across multiple northern European cohorts.

MERRF is caused by germline pathogenic variants in mitochondrial DNA-encoded transfer-RNA genes. Across the eight known causative genes, MT-TK accounts for ~90% of cases, with MT-TF, MT-TH, MT-TI, MT-TL1, MT-TP, MT-TS1 and MT-TS2 each contributing less than 5%. Four recurrent MT-TK variants (m.8344A>G, m.8356T>C, m.8363G>A and m.8361G>A) together account for approximately 90% of identified pathogenic variants, with m.8344A>G alone present in more than 80% of typical cases. High heteroplasmic mutational loads impair mitochondrial protein synthesis, reduce oxygen consumption and produce cytochrome c oxidase deficiency, with disproportionate effects on polypeptides rich in lysine residues.

MERRF follows mitochondrial (maternal) inheritance: the pathogenic mtDNA variant is transmitted from an affected mother to all her children, while affected fathers do not transmit the variant. Clinical expression in siblings depends on the proportion of mutated mitochondria (mutational load) and on the organs and tissues in which they are concentrated; siblings frequently inherit different heteroplasmy levels and show a wide range of manifestations. Apparently simplex cases may reflect an incomplete family history or, rarely, a de novo mtDNA pathogenic variant in the proband. Prenatal molecular testing is technically possible once the familial pathogenic variant has been identified, although heteroplasmy levels in prenatal samples may not reliably predict postnatal clinical expression.

The crucial point concerning pathogenic mtDNA variants is that the clinical relevance of a variant is dependent not only on the pathogenicity of the variant but also on the heteroplasmic state of this variant in the affected tissue. Therefore, it is important to know that heteroplasmy in nucleated blood cells may be not the relevant heteroplasmy for diagnosis.

The clinical diagnosis in pre-WES times rested on the four canonic features defined by Finsterer and colleagues: myoclonus, generalised epilepsy, cerebellar ataxia and ragged-red fibres on muscle biopsy. Meeting these canonic criteria constituted the clinical diagnosis. Lactic acidosis in blood and cerebrospinal fluid is typical, with lactate and pyruvate concentrations frequently elevated at rest and rising excessively after moderate activity. Muscle histology shows ragged-red fibres on modified Gomori trichrome stain, hyperactive fibres on succinate-dehydrogenase stain and cytochrome c oxidase (COX)-negative fibres. Respiratory-chain enzyme analysis usually demonstrates reduced activity of complexes containing mtDNA-encoded subunits, particularly COX. Brain MRI may reveal cerebral atrophy and basal-ganglia lesions, including bilateral putaminal necrosis and brainstem or cerebellar atrophy.

In times any suspicion in MERRF syndrome should be tested first by sequencing complete mtDNA (see below), only if this sequencing does not reveal an explanation for the clinical symptoms WES sequencing and – if necessary – muscly biopsy and histology should be done.

Main differential diagnoses include:

• POLG-related disorders: myoclonus, epilepsy, ataxia and peripheral neuropathy with autosomal recessive inheritance and absence of ragged-red fibres on muscle biopsy; POLG
• MERRF/MELAS overlap syndrome: may initially resemble MERRF but additional stroke-like episodes distinguish the overlap phenotype; MT-ND5, MT-TC
• Combined oxidative phosphorylation deficiency 27 (CARS2-related): juvenile-onset MERRF-like severe myoclonus epilepsy with ataxia, spastic tetraparesis, vision loss, hearing loss and cognitive decline; autosomal recessive inheritance; CARS2

• Molecular genetic testing establishes the diagnosis at the molecular level and clarifies the underlying genetic cause.
• A confirmed molecular diagnosis enables specific and individualised surveillance and clinical management; in MERRF, affected individuals and their at-risk relatives are followed at regular intervals to monitor disease progression and the emergence of new symptoms, with the precise measures determined by the treating physicians in consultation with the affected individual.
• Once the familial pathogenic variant is known, predictive testing of at-risk maternal relatives becomes technically possible and supports informed family planning within human-genetic counselling.

• Velez-Bartolomei F, Lee C, Enns G. MERRF. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews^® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024. PMID: .
• Gorman GS, Schaefer AM, Ng Y, Gomez N, Blakely EL, Alston CL, et al. Prevalence of nuclear and mitochondrial DNA mutations related to adult mitochondrial disease. Ann Neurol. 2015;77(5):753-759. PMID: .
• 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):2049-2054. PMID: .
• Finsterer J, Zarrouk-Mahjoub S, Shoffner JM. MERRF classification: implications for diagnosis and clinical trials. Pediatr Neurol. 2018;80:8-23. PMID: .