Josef Finsterer, Fulvio A. Scorza, Ana C Fiorini and Carla A. Scorza. Mitochondrial myoclonic epilepsy requires specific treatment . Seizure, in press.
With interest we read the review article by Orsini et al. about myoclonic epilepsy in Unverricht-Lundborg disease, Lafora disease, neuronal ceroid lipofuscinoses, myoclonus epilepsy with ragged-red fibers (MERRF), and sialidoses type 1 and 2. The authors recommend valproic acid (VPA) as first choice for myoclonic epilepsy irrespective of the underlying cause followed by lamotrigine (LTG), primidone (PRM), phenobarbital (PB), and levetiracetam (LEV). Other anti-seizure drugs (ASD) that can be considered for myoclonic epilepsy include topiramate (TPM), zonisamide (ZNS), ethosuximide (ESX), felbamate (FLB), benzodiazepines (BZD), and perampanel (PER). We have the following comments and concerns.
We do not agree that VPA can be recommended as the first line ASD most frequently applied in myoclonic epilepsy for all types of diseases associated with myoclonic epilepsy, including MERRF. MERRF is an ultra-rare mitochondrial disorder (MID) clinically diagnosed if the four canonical features myoclonus, generalised epilepsy, ataxia, and myopathy are present. If additional phenotypic features occur, the term MERRF-plus is applied. From VPA it is well known that it can be mitochondrion-toxic and that it should be avoided in these conditions, since it can be even fatal. Particularly in MIDs due to POLG1 mutations fatal acute liver failure has been reported after application of VPA. Also from PB it is known that it can be mitochondrion-toxic. Thus, therapy of myoclonic epilepsy in MERRF or other MIDs should be at variance from conditions other than MERRF discussed in the review. In recent publications it has been shown that LEV and clonazepam (CLZ) are the ASDs of choice for myoclonic epilepsy in MIDs, particularly MERRF syndrome.
The authors mention that MERRF may be due to mutations in MT-TK, MT-TL1, MT-TH, MT-TS1, MT-TS2, or MT-TF. However, the variant m.8342 G > A in MT-TK has been classified as only possibly pathogenic. Also the variant m.12207 G > A in MT-TS2 has been classified as only possibly pathogenic. [The authors do not mention that MERRF may be also due to mutations in MT-ND3 or MT-TW , and probably due to variants in MT-ND5. There are also indications that MERRF can be caused by mutations in POLG1. Altogether 26 pathogenic variants causing a MERRF phenotype have been identified so far.
The authors mention that the MIDs most frequently associated with epilepsy are MERRF and Alpers Huttenlocher disease (AHD). However, it should be included that also mitochondrial encephalopathy with lactic acidosis and stroke-like episodes (MELAS), myoclonic epilepsy, myopathy, and sensory ataxia (MEMSA) syndrome, and Leigh syndrome frequently manifest with seizures. Occasionally, epilepsy is a phenotypic feature in infantile onset spinocerebellar ataxia (IOSCA) syndrome, Kearns-Sayre syndrome (KSS), Leber’s hereditary optic neuropathy (LHON), leucoencephalopathy with brainstem and spinal cord and lactate elevation (LBSL), or neuropathy ataxia, and retinitis pigmentosa (NARP) syndrome.
In summary, myoclonic epilepsy in MIDs, including MERRF, should be treated differentially to myoclonic epilepsy in other hereditary syndromes. The most appropriate ASDs for myoclonic epilepsy in MIDs are LEV and CLZ. Mitochondrion-toxic ASDs should be strictly avoided as first line ASDs. The genetic background of MERRF is more variegated than anticipated.
Orsini A, Valetto A, Bertini V, et al. The best evidence for progressive myoclonic epilepsy: A pathway to precision therapy. Seizure. 2019;71:247‐257. doi:10.1016/j.seizure.2019.08.012
Progressive Myoclonus Epilepsies (PMEs) are a group of uncommon clinically and genetically heterogeneous disorders characterised by myoclonus, generalized epilepsy, and neurological deterioration, including dementia and ataxia. PMEs may have infancy, childhood, juvenile or adult onset, but usually present in late childhood or adolescence, at variance from epileptic encephalopathies, which start with polymorphic seizures in early infancy. Neurophysiologic recordings are suited to describe faithfully the time course of the shock-like muscle contractions which characterize myoclonus. A combination of positive and negative myoclonus is typical of PMEs. The gene defects for most PMEs (Unverricht-Lundborg disease, Lafora disease, several forms of neuronal ceroid lipofuscinoses, myoclonus epilepsy with ragged-red fibers [MERRF], and type 1 and 2 sialidoses) have been identified. PMEs are uncommon disorders, difficult to diagnose in the absence of extensive experience. Thus, aetiology is undetermined in many patients, despite the advance in molecular medicine. Treatment of PMEs remains essentially symptomaticof seizures and myoclonus, together with palliative, supportive, and rehabilitative measures. The response to therapy may initially be relatively favourable, afterwards however, seizures may become more frequent, and progressive neurologic decline occurs. The prognosis of a PME depends on the specific disease. The history of PMEs revealed that the international collaboration and sharing experience is the right way to proceed. This emerging picture and biological insights will allow us to find ways to provide the patients with meaningful treatment.