A typical case of myoclonic epilepsy with ragged red fibers (MERRF) and the lessons learned.

Mitochondrial diseases have a special predilection to involve the brain in view of its high metabolic demand and the tendency for the formation of excitatory neurotransmitters when there is deficiency of intracellular ATP. These diseases have a great phenotypic variation and need a high degree of suspicion. However, some specific syndromes are well defined, both genotypically and phenotypically. Some of the drugs are potentially fatal mitochondrial poisons and an insight into that may be lifesaving as well as prevent serious morbidities.We report a typical case of myoclonic epilepsy with ragged red fibers (MERRF) with classical phenotype and genotype. There was rapid multiaxial deterioration with the introduction of sodium valproate which partly reversed on introducing mitochondrial cocktail and withdrawal of the offending drug.Sodium valproate, phenobarbitone, chloramphenicol and many anti-viral agents are mitochondrial poisons that increase the morbidity and mortality in patients with mitochondrial disease. More harm to the patient can be avoided with insight into this information.

Introduction

The oxidative phosphorylation system (OXPHOS) system is an important functional unit of the mitochondria and comprises four respiratory chain complexes, I to IV and ATPase. These are responsible for muscle and brain function. The central nervous system is a high-energy demanding organ and becomes symptomatic more often due to decreased intracellular ATP and increased glutamate. This occurs when the OXPHOS system is less efficient.[1] Complex I deficiency status and myoclonic epilepsy with ragged red fibers (MERRF) result from several tRNA mutations in the gene for lysine which includes m8344A>G, m8356T>C and then m8361G>A.[23] MERRF is characterized by ataxia, deafness, optic atrophy, ophthalmoplegia, dementia, stimulus-sensitive myoclonus, seizures, growth retardation and midline and paramedian lipomas. There is also change in the cerebral vessel histology which shows succinyl dehydrogenase (SDH) reactivity. The prevalence of mitochondrial disease is 1 in 10,000 and seizures and status epilepticus are very common.[2]

Sodium valproate is a very commonly used anticonvulsant in myoclonic seizures. It induces cytochrome P-450 enzyme system forming toxic valproate metabolites and delta 4 valproate inhibits key enzymes in beta oxidation.[45] This can cause rapid death in DNA polymerase gamma (POLG) mutations and is potentially fatal in all mitochondrial cytopathies. Thus sodium valproate and phenytoin and phenobarbitone are to be avoided in these patients with the remaining antiepileptic drugs being safe.[67] We present in this paper a case of myoclonic epilepsy with red ragged fibers.

Case Report

A 13-year-old female born of consanguineous parentage and one of binovular twin was normal until the age of ten. Following a systemic infection she developed repeated myoclonic jerks 3-4 times a day lasting for about 4 seconds which was treated with sodium valproate (500 mg twice daily) and zonisamide (50 mg twice daily). While on treatment, she developed progressive difficulty in reading over a year, resulting in only finger counting vision at 1 m distance. She also complained of progressive hearing loss of 3 months duration. In addition, there was decreased scholastic performance, mild unsteadiness and pulsatile quality headache. The girl's mother and maternal aunt had a history of similar illnesses at age 17 and were on treatment. At ages of 36 and 40 years, the mother and maternal aunt continue to be on Valproate (1200mg/day).

Both mother and maternal aunt had large midline lipomas in the neck [Figure 1] and the latter underwent surgical removal which was followed by recurrence. The mother had bad obstetric history with triplets abortion at 3 months and the other twin of the index case had neonatal death [Figure 2-Family tree].

Figure 1

Large midline lipoma in the mother

Figure 2

Family tree showing bad obstetric history and maternal inheritance

On examination, our patient was short statured with large ears, bilateral primary optic atrophy, sensorineural deafness and mild unsteadiness of gait. The above features suggested the possibility of MERRF which was confirmed by genetic testing. Brainstem auditory evoked responses (BAER) were absent and visual evoked responses showed prolonged latencies. MRI brain was normal but for mild prominence of the cerebellar folia. Other investigations showed normal metabolic workup in urine and blood, serum lactate was53.3mg/dl (4.5-20 mg/dl) and ammonia was 52 μmol/L(<52 μmol/L). Forearm exercise test was non-contributory. EEG showed 2-3 Hz spike and wave discharges. Creatine kinase was 61IU and thyroid profile was normal. A muscle biopsy showed ragged red COX deficient fibers and her blood test was positive for A8344G mutation thereby confirming the diagnosis of MERRF [Figure 3a–c]. The AEDS of both mother and child were changed over to leviteracetam and mitochondrial cocktail consisting of co-enzyme Q10, levo carnitine, vitamin B1, vitamin E, vitamin C, alpha lipoic acid, vitamin B6, vitamin K and benzodiazepines added.[8] At follow up after 4 months, the patient reported significant improvement in vision, cognition and there was nomyoclonus. The diagnosis of MERRF seen phenotypically was confirmed on genotyping. This case is being reported to recognizing the importance of avoiding drugs like sodium valproate which apart from speeding up the degenerative process can also be fatal.

Figure 3

(a)Gomorri'strichrome staining showing ragged red fibers. (b) SDH-COX staining showing COX- deficient fibers. (c) SDH staining - showing ragged blue fibers

Discussion

Large midline lipomas, short stature and minor dysmorphisms are clues to mitochondrial disease and it is important to remember this clue and avoid valproate in such situations.

Conclusion

Our patient is a classical case of MERRF phenotypically and genotypically. This case is being reported to insist on recognizing the importance of avoiding mitochondrial poisons like sodium valproate which apart from speeding up the degenerative process can also be fatal.