Merrf

Clinical characteristics.

MERRF (myoclonic epilepsy with ragged red fibers) is a multisystem disorder characterized by myoclonus (often the first symptom) followed by generalized epilepsy, ataxia, weakness, exercise intolerance, and dementia. Onset can occur from childhood to adulthood, occurring after normal early development. Common findings are ptosis, hearing loss, short stature, optic atrophy, cardiomyopathy, cardiac dysrhythmias such as Wolff-Parkinson-White syndrome, and peripheral neuropathy. Pigmentary retinopathy, optic neuropathy, diabetes mellitus, and lipomatosis have been observed.

Diagnosis/testing.

A clinical diagnosis of MERRF can be established in a proband with the following four "canonic" features: myoclonus, generalized epilepsy, ataxia, and ragged red fibers (RRF) in the muscle biopsy. A molecular diagnosis is established in a proband with suggestive findings and a pathogenic variant in one of the genes associated with MERRF. The m.8344A>G pathogenic variant in the mitochondrial gene MT-TK is present in more than 80% of affected individuals with typical findings. Pathogenic variants in MT-TF, MT-TH, MT-TI, MT-TL1, MT-TP, MT-TS1, and MT-TS2 have also been described in a subset of individuals with MERRF.

Management.

Treatment of manifestations: Ubiquinol, carnitine, alpha lipoic acid, vitamin E, vitamin B complex, and creatine may be of benefit to some individuals; traditional anticonvulsant therapy per neurologist for seizures; levetiracetam or clonazepam for myoclonus; physical therapy to improve any impaired motor function; aerobic exercise; standard pharmacologic therapy for cardiac symptoms; hearing aids or cochlear implants for hearing loss; diabetes mellitus treatment per endocrinologist.

Prevention of primary manifestations: Coenzyme Q₁₀ (50-200 mg 2-3x/day), L-carnitine (1000 mg 2-3x/day), alpha lipoic acid, vitamin E, vitamin B supplements, and creatine, often used to improve mitochondrial function, have been of modest benefit in some individuals. Doses for children should be adjusted appropriately.

Surveillance: Routine evaluations every six to 12 months initially; annual neurologic, ophthalmologic, cardiology (electrocardiogram and echocardiogram), and endocrinologic evaluations (fasting blood sugar and TSH); audiology evaluations every two to three years.

Agents/circumstances to avoid: Mitochondrial toxins (e.g., aminoglycoside antibiotics, linezolid, cigarettes, alcohol); valproic acid should be avoided in the treatment of seizures.

Pregnancy management: During pregnancy, affected or at-risk women should be monitored for diabetes mellitus and respiratory insufficiency, which may require therapeutic interventions.

Genetic counseling.

MERRF is caused by pathogenic variants in mtDNA and is transmitted by maternal inheritance. The father of a proband is not at risk of having the mtDNA pathogenic variant. The mother of a proband usually has the mtDNA pathogenic variant and may or may not have symptoms. A male with a mtDNA pathogenic variant cannot transmit the pathogenic variant to any of his offspring. A female with a mtDNA pathogenic variant (whether symptomatic or asymptomatic) transmits the pathogenic variant to all of her offspring. Prenatal testing and preimplantation genetic testing for MERRF are possible if a mtDNA pathogenic variant has been detected in the mother. However, because the mutational load in embryonic and fetal tissues sampled (i.e., amniocytes and chorionic villi) may not correspond to that of all fetal tissues and because the mutational load in tissues sampled prenatally may shift in utero or after birth as a result of random mitotic segregation, prediction of the phenotype from prenatal studies is not possible.

Suggestive Findings

MERRF (myoclonic epilepsy with ragged red fibers) should be suspected in individuals with the following features.

Clinical features

• Myoclonus
• Generalized epilepsy
• Ataxia
• Myopathy
• Exercise intolerance
• Dementia
• Ptosis
• Sensorineural hearing loss
• Short stature
• Optic atrophy
• Peripheral neuropathy

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:

• Myoclonus
• Generalized epilepsy
• Ataxia
• Ragged red fibers (RRF) in the muscle biopsy

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).

Clinical Description

MERRF (myoclonic epilepsy with ragged red fibers) is a multisystem disorder characterized by myoclonus, which is often the first symptom, followed by generalized epilepsy, ataxia, weakness, exercise intolerance, and dementia. Onset can occur from childhood to adulthood, after normal early development. Table 2 lists the most frequent signs and symptoms reported [Hirano & DiMauro 1996, Mancuso et al 2013].

Neurologic manifestations

• Myopathy. The most common features are exercise intolerance, muscle weakness, and elevated blood creatine kinase level.
• Epilepsy. Generalized myoclonic seizures are the most frequent seizure type in individuals with MERRF. Other reported types of seizures include focal myoclonic, focal atonic, focal clonic, generalized tonic-clonic, generalized atonic, generalized myoclonic-atonic, typical absences, myoclonic absences, or tonic-clonic seizures of unknown onset [Finsterer & Zarrouk-Mahjoubb 2017].
• Migrainous headaches. Migraines are common in individuals with MERRF and can be present at the onset of symptoms. Vollono et al [2018] reported seven individuals with MERRF and migraines and found that migraines can present with or without aura. The frequency of migraine episodes in most individuals was every two months.
• Hearing impairment. Hearing loss is typically sensorineural and occurs in 35%-91% of individuals.
• Peripheral neuropathy. It has been reported that either sensory axonal neuropathy or sensory motor axonal neuropathy can be present.
• Early psychomotor development. Early development is typically normal in individuals with MERRF.
• Psychiatric illnesses. Although psychiatric illness is not a prominent feature in this disorder, several individuals with depressive mood disorders have been reported.

Cardiac involvement. Cardiomyopathy can be observed. Both hypertrophic and dilated cardiomyopathy have been described. Arrhythmias are common in individuals with MERRF and can accompany the cardiomyopathy or be an isolated cardiac finding.

Lipomatosis can be seen in adulthood in individuals with MERRF, with an average age of onset of 45.2 years [Chong et al 2003]. Lipomas can be infiltrative, progressive, and massive in size [Gilson & Osswald 2018]. The most common location of lipomas is the cervical region.

Phenotype Correlations by Gene

No phenotype correlations by gene have been identified.

Genotype-Phenotype Correlations

No genotype-phenotype correlations have been identified.

For all mtDNA pathogenic variants, clinical expression depends on three factors:

• Heteroplasmy. The relative abundance of mutated mtDNAs
• Tissue distribution of mutated mtDNAs
• Threshold effect. The vulnerability of each tissue to impaired oxidative metabolism

The tissue vulnerability threshold probably does not vary substantially among individuals, but variable mutational load and tissue distribution may account for the clinical diversity of individuals with MERRF.

Penetrance

See Genotype-Phenotype Correlations.

Nomenclature

Ramsay Hunt [1921] described six individuals with a disorder characterized by ataxia, myoclonus, and epilepsy, which he called "dyssynergia cerebellaris myoclonica." Individuals with the diagnosis of Ramsay Hunt syndrome should be investigated for MERRF.

Prevalence

Four epidemiologic studies of mtDNA-related diseases in northern Europe gave concordantly low estimates for the prevalence of the m.8344A>G pathogenic variant:

• 0-1.5:100,000 in the adult population of northern Finland [Remes et al 2005]
• 0.39:100,000 in the adult population of northern England [Schaefer et al 2008]
• 0-0.25:100,000 in a pediatric population of western Sweden [Darin et al 2001]
• 0.7:100,000 in a large population-based study in northeast England [Gorman et al 2015]

See Mitochondrial Disorders Overview for general prevalence information.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with MERRF (myoclonic epilepsy with ragged red fibers), the evaluations summarized in Table 5 (if not performed as part of the evaluation that led to the diagnosis) are recommended.