Knowledge on rare diseases and orphan drugs

The prevalence in the general population of Europe ranges between 1/256,000-67,000 in the adult population, and the birth prevalence is reported at 1/202,000 in Sweden.

Patients usually present during adolescence or early adulthood with myoclonic epilepsy, sometimes with neurosensory deafness, optic atrophy, short stature or peripheral neuropathy. A few cases have been associated with lipomatosis, cardiomyopathy, pigmentary retinopathy, ophthalmoparesis and/or pyramidal signs. The disease is progressive with worsening of the epilepsy and onset of additional symptoms including ataxia, deafness, muscle weakness, and dementia. Magnetic resonance imaging of the brain may show cortical atrophy, cerebellar atrophy, basal ganglia calcifications and leucodystrophy. Clinical manifestations may vary greatly between patients from the same family and between families.

MERRF syndrome is caused by mutations in the mitochondrial DNA. Over 80% of individuals with MERRF syndrome carry the m.8344A>G mutation in the lysine transfer RNA (tRNA Lys) gene (MTTK). Other mutations have been found in other transfer RNA genes or in the MTND5 gene. They may be associated with MERRF/MELAS overlap syndrome, in which affected individuals also suffer from stroke-like episodes.

The diagnosis of MERRF syndrome relies on the demonstration of abnormal lactate accumulation in blood or, more often, in the cerebrospinal fluid or MRI brain spectroscopy, and on the muscle biopsy, which reveals the presence of cytochrome c oxidase negative muscle fibers and ragged red fibers. Biochemical analysis of muscle often shows cytochrome c oxidase deficiency or combined respiratory chain defect. Genetic testing usually shows heteroplasmic (coexistence of the mutant form with a residual population of wild type mitochondrial DNA) variant in the mitochondrial DNA. The proportion of the mutation may differ considerably between tissues. However, in MERRF syndrome, this proportion is most often very high (above 90%) in every tissue and the mutation may therefore be easily investigated in blood.

The differential diagnosis comprises other syndromes characterized by progressive myoclonic epilepsy and ataxia including Unverricht-Lundborg disease, Lafora disease, neuronal ceroid lipofuscinosis, and sialidosis.

The possibility of heterogeneous proportions of the mutation between tissues theoretically hampers prenatal diagnosis.

The heteroplasmy makes genetic counseling very arduous in MERRF syndrome. Mitochondrial DNA mutations are transmitted through maternal inheritance. An affected man cannot transmit the disease. The mutation will be transmitted along the maternal lineage but its proportion is unpredictable. Although higher proportions of the mutation in the blood of the mother result in a higher risk of having a child with severe phenotype, there are many examples of extreme segregation of the mutation from mother to child, which prevent efficient genetic counseling at an individual level.

As with other mitochondrial encephalomyopathies, there is no specific treatment for MERRF syndrome. Seizures can be treated with conventional anticonvulsant therapies but valporic acid should be avoided (mainly if the cause of the mitochondrial epilepsy is a patnogenic variant in POLG gene) or administered with care. In the absence of proper clinical trials, it is difficult to evaluate the effect of proposed supportive treatment such as coenzyme Q10 and its analogue idebenone, carnitine, etc.

The prognosis for patients with MERRF syndrome is globally poor because of the progressive nature of the disease. However, the severity varies greatly and some patients, mainly those with non-cerebral presenting symptoms, may have a prolonged survival with relatively little handicap.

Last update: January 2023 - Expert reviewer(s): Pr Michelangelo MANCUSO | EURO-NMD*

* European Reference Network