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MERRF Syndrome

MERRF syndrome (or Myoclonic Epilepsy with Ragged Red Fibers) is a mitochondrial disease. It is extremely rare, with an estimated prevalence of 1/400,000 in Northern Europe, and has varying degrees of expressivity owing to heteroplasmy.^[1]

Presentation

It involves the following characteristics:

• progressive myoclonic epilepsy
• "Ragged Red Fibers" - clumps of diseased mitochondria accumulate in the subsarcolemmal region of the muscle fiber and appear as "Ragged Red Fibers" when muscle is stained with modified Gömöri trichrome stain
• short stature
• hearing loss
• lactic acidosis
• exercise intolerance
• poor night vision

Causes

The MERRF syndrome is caused by a maternally-inherited mutation at position 8344 in the mitochondrial genome in over 80% of cases. This point mutation disrupts the mitochondrial gene for tRNA-Lys and so disrupts synthesis of proteins essential for oxidative phosphorylation.

Many genes are involved.^[2] These include:

• MT-TK^[3]

• MT-TL1

• MT-TH^[4]

• MT-TS1^[5]

• MT-TS2

• MT-TF^[6]

The Mitochondria is an organelle responsible for generating energy for the cells to use, mainly in the form of ATP. ATP is made through oxidative phosphorylation in the mitochondria, which is composed of 5 (I to V) enzyme complexes. MERRF arises from a mutation in a gene encoding tRNAlys, resulting a reduced amount of charged tRNAlys in the mitochondria by up to 60%. The point mutation disrupting the tRNAlys encoding gene results in increased chance of termination when translating mRNA that contain lysine, as there are a reduced number of tRNAlys in the mitochondria. This affects the enzyme complexes I and IV the most since they have the most components synthesized in the mitochondria, and so their enzyme activity decreases. Due to each mitochondrion containing varying amounts of normal and diseased mtDNA, the expression and severity of MERRF depends on the overall reduction in the oxidative phosphorylation process. There is a threshold for expression of MERRF however, and that is reached once there is more abnormal (mtDNA containing the tRNAlys mutation in this case) than normal mtDNA. This threshold is determined by age and each individuals’ organ system and tissues, and can be reached more quickly due to mtDNA having a high (10x more than nuclear DNA) mutation rate, which can be explained by the fact that mutations in mtDNA usually affect coding sequences since mtDNA don't have introns, nor do they have effective DNA repair. Accumulation of mutation increases with age, hence the likelihood of MERRF expression increased in adults. The threshold can be reached quicker if the patient initially inherited a lot of abnormal mtDNA from the heteroplasmic (containing both normal and abnormal mtDNA) mother. 

Inheritance Pattern

Since MERRF is a mitochondrial disease and the mitochondria is inherited from mother to child, it is inherited maternally.(also known as Mitochondrial Inheritance). This means that an affected father can’t pass this on to his children (provided the mother doesn't have MERRF).  MERRF can be passed down to both daughters and sons, as the affected genes are in the mtDNA . The mitochondria have numerous copies of mtDNA, consisting of copies of mutant mtDNA, in this case yielding to MERRF syndrome, and normal mtDNA. The mother can look phenotypically normal if she has a large percentage of normal mtDNA but by bottleneck effect can pass all of her mutant mtDNA to her offspring, who will then have MERRF.

MERRF can also occur from a spontaneous mutation in a mitochondrial gene, meaning that even people that have had no prior family history of MERRF can suddenly develop the disease.

Diagnosis and Treatment

To be diagnosed with MERRF, the patient must be presenting the following symptoms:

• myoclonus- involuntary twitching of muscles.
• generalized epilepsy- general seizures.
• ataxia- lack of voluntary coordination between muscle movements.
• The muscle biopsy must also show ragged red fibers (RRF).

The myoclonus and epilepsy can occur alone or with other seizures, and get worse as the disease develops, while cerebellar ataxia is one of the most common symptom, showing in up to 83% of cases, but may not show until the later stages of the disease .

There are also tests that can be done to confirm the diagnosis :

• Patients with MERRF will have higher concentrations of lactate and pyruvate during rest, which will increase even more after activity. 
• Brain MRI will show brain atrophy, as well as calcification of the basal ganglia. 
• Electromyogram (EMG) and nerve conduction velocity (NVC) studies show results pointing to myopathy.

The disease genotype of the mutant genes are usually present in the mtDNA of leukocytes, but in asymptomatic individuals the pathogenic variant may be present in other tissues such as skeletal muscle, saliva, and urine.

Like many mitochondrial diseases, there is no cure for MERRF and treatment is primarily symptomatic. High doses of Coenzyme Q10 and L-Carnitine have been tried with little success as therapies in hopes of improving mitochondrial function.^[7] There are also management treatments, which are mostly used to treat any complications that arise from MERRF (ie cardiac disease, diabetes mellitus) and its symptoms. One of the main symptoms, myoclonic epilepsy, is controlled by anti epileptic drugs.