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The mitochondrial epilepsies
Journal Pre-proof The mitochondrial epilepsies Albert Lim, Rhys H. Thomas PII:
S1090-3798(19)30441-6
DOI:
https://doi.org/10.1016/j.ejpn.2019.12.021
Reference:
YEJPN 2623
To appear in:
European Journal of Paediatric Neurology
Received Date: 6 December 2019 Revised Date:
17 December 2019
Accepted Date: 18 December 2019
Please cite this article as: Lim A, Thomas RH, The mitochondrial epilepsies, European Journal of Paediatric Neurology, https://doi.org/10.1016/j.ejpn.2019.12.021. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.
ERUK – Mitochondrial Epilepsy – Lim, Thomas
The mitochondrial epilepsies Albert Lim1,2, Rhys H Thomas2,3,4 1. Department of Paediatrics, Great Northern Children’s Hospital, Queen Victoria Rd, Newcastle-Upon-Tyne, NE1 4LP, United Kingdom 2. Wellcome Centre for Mitochondrial Research, Institute of Neuroscience, Newcastle University, Newcastle-Upon-Tyne, NE2 4HH, United Kingdom 3. Department of Neurology, Royal Victoria Infirmary, Queen Victoria Rd, Newcastle-UponTyne, NE1 4LP, United Kingdom 4. Institute of Neuroscience, Henry Wellcome Building, Framlington Place, Newcastle University, Newcastle-Upon-Tyne, NE2 4HH, United Kingdom
Address for Correspondence: Rhys H Thomas Institute of Neuroscience, Henry Wellcome Building, Framlington Place, Newcastle University, Newcastle-Upon-Tyne, NE2 4HH, United Kingdom [email protected]
Word and character counts:
Abstract: 196 words Manuscript: 2662 words References: 81
Keywords
Mitochondrial disease, POLG, MELAS, MERRF, Leigh syndrome, epilepsy
Author disclosures R Thomas has received honoraria from Eisai, GW Pharma, Sanofi, UCB Pharma, Zogenix and meeting support from LivaNova, Novartis and Bial.
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Abstract Mitochondria are vital organelles within cells that undertake many important metabolic roles, the most significant of which is to generate energy to support organ function. Dysfunction of the mitochondrion can lead to a wide range of clinical features, predominantly affecting organs with a high metabolic demand such as the brain. One of the main neurological manifestations of mitochondrial disease is metabolic epilepsies. These epileptic seizures are more frequently of posterior quadrant and occipital lobe onset, more likely to present with non-convulsive status epilepticus which may last months and be more resistant to treatment from the onset. The onset of can be of any age. Childhood onset epilepsy is a major phenotypic feature in mitochondrial disorders such as Alpers-Huttenlocher syndrome, pyruvate dehydrogenase complex deficiencies, and Leigh syndrome. Meanwhile, adults with classical mitochondrial disease syndrome such as MELAS, MERFF or POLG-related disorders could present with either focal or generalised seizures. There are no specific curative treatments for mitochondrial epilepsy. Generally, the epileptic seizures should be managed by specialist neurologist with appropriate use of anticonvulsants. As a general rule, especially in disorders associated with mutation in POLG, sodium valproate is best avoided because hepato-toxicity can be fulminant and fatal.
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Introduction Mitochondrial disorders are genetically determined metabolic diseases arising from mitochondrial DNA (mtDNA) and nuclear DNA (nDNA) mutations. The minimum prevalence in the UK is 1 in 5,0001. With the advancement in molecular genetic diagnostic technologies, and better clinical acumen, it has become readily apparent that the majority of mitochondrial disorders in children are precipitated by nuclear DNA mutations2,3. Although there are no curable mitochondrial disorders, many comorbidities are treatable – it can be argued that the most important of which is epileptic seizures, as they are a significant predictor of outcome.4-6 Mitochondrial diabetes can be more challenging to treat than classic Type 1 or Type 2 diabetes mellitus; cardiomyopathy and arrhythmias are essential to identify and monitor; as are constipation, and gastro-intestinal dysmotility. However the epileptic seizures leading to ‘stroke-like episodes’ and atrophy are a potent cause of dementia and decline. In keeping with other metabolic disorders, seizures include both spontaneous epileptic seizures and provoked seizures. The epileptic seizures in mitochondrial disorders differ from seizures in other contexts with respect 1) more frequently of posterior quadrant and occipital lobe onset; 2) more likely to present with non-convulsive status epilepticus which may last months; 3) multi-drug resistant from the onset; 4) may have only a minimal EEG correlate. The underlying pathophysiological process associated with these ‘metabolic’ seizures has been proposed to be initiated by interneuron mitochondrial respiratory chain deficiency consequently altering the balance of excitation and inhibition in neural networks, promoting neuronal hyperexcitability7. The dramatic downregulation of OXPHOS subunits of complexes I and IV within the GABAergic interneurons of these patients makes these interneurons particularly vulnerable to the propagation of neuronal hyperexcitability8. This acute process leads to rapid neuronal damage that have been demonstrated by histopathological findings of micro-vacuolation, neuronal cell dropout, eosinophilia, astrogliosis and secondary myelin loss in patients8,9. Epileptic seizure may be the first and, not uncommonly the only sign of mitochondrial dysfunction and it warrants an aggressive management from the outset. There are currently no established treatments with proven efficacy. The existing clinical drug studies to explore definitive disease-modifying treatment have been limited by small sample size and the lack of natural history data. The tendency for variable degrees of spontaneous recovery means that the true effect of acute therapies is difficult to prove without large clinical randomised placebo-controlled trials. At present, these seizures should be managed by specialist neurologists with appropriate use of anticonvulsant medication, ketogenic diet and on occasion epilepsy surgery (vagal nerve stimulator). Page 3
ERUK – Mitochondrial Epilepsy – Lim, Thomas In our experience, intravenous loading with Levetiracetam or/and Phenytoin is the first line AED of choice, with the addition of Clobazam to new or existing regime. L-arginine has been reported to provide benefit, but the non-randomised, open label study design employed excluded this study from the recent Cochrane review of treatments for mitochondrial disorders10,11. Supplements such as ubiquinone, riboflavin, or creatine have been assessed in small trials but have not been proven to provide benefit in general or in relation to focal refractory seizures11. Given the recurrent and protracted nature of these seizures, clinicians will inevitably face the ultimate dilemma when escalating medical treatment of having to admit their patient to intensive care for a general anaesthetic, with the increased morbidity and mortality this entails. Unfortunately, the prognosis for refractory seizure disorders in mitochondrial disease is very poor and frequently associated with a neurodegenerative process12,13. The precise role of seizure activity in hastening neurodegeneration is unclear, but the associated abnormal electrical activity is highly energy dependent and occurs in a cellular network that is already energetically compromised. As a general rule (and certainly in disorders associated with mutation in POLG) sodium valproate is best avoided because hepato-toxicity can be fulminant and fatal. There are theoretical concerns about the use of valproic acid outside of POLG disorders. It is thought to cause complex-I and complex-IV dysfunction triggering a cascade that can produce a secondary carnitine-deficiency. It is worth noting that the adverse effects of sodium valproate have not been ubiquitously demonstrated in mitochondrial disease and it has proved an effective anticonvulsant in some patients14,15. Nonetheless, this removes an important weapon from our armamentarium. Clearly in a rare disease the evidence base for treatment is weak and predominantly anecdotal or extrapolated from adults without this multisystem disease. Comparisons of outcome in a disorder which can be slowly progressive or decline in a step-wise fashion means that it can be a challenge to know if medication is tolerated, and harder still to gather an evidence base for non-pharmacological adjuncts such as vagus nerve stimulator treatment. Many people with focal seizures will need treating with polytherapy and anecdotally older medications are more commonly used in this group – than say patients with an epileptic encephalopathy. The common use of phenytoin, phenobarbitone, clobazam or carbamazepine means that there is a perpetual balance between seizures and side-effects, between the risk of neuronal damage from a preventable stroke-like episode versus quality of life in between seizures. At later stages of disease there is a loss of cortical reserve meaning that drug side effects (particularly sedation) and the consequences of frequent seizures – such as delirium – are common.
Paediatrics Page 4
ERUK – Mitochondrial Epilepsy – Lim, Thomas The current prevalence of childhood-onset mitochondrial disorders has been predicted to range from 5 to 15 cases per 10,00016-22. Although the exact prevalence of mitochondrial epilepsy in children is unknown, seizures are commonly reported in 20- 60% of individuals with biochemically or genetically-confirmed diseases.5,18,20,23-29 In most cases, the other features of mitochondrial disease, such as developmental delay, hearing loss, visual impairment, muscle weakness, hypotonia or ataxia precede the onset of first epileptic seizure. The presentation of the epilepsy in children can be highly varied from infantile spasms, generalised seizures, focal seizures, myoclonic epilepsy to refractory status epilepticus. Multi-gene panel testing has traditionally been a popular means of investigating genetic epilepsy syndromes including mitochondrial causes, but panels can quickly become obsolete with newer gene discoveries and whole exome or genome sequencing is now increasingly employed in the diagnostic algorithm30,31. Several nuclear genes have been linked to mitochondrial epilepsy presenting before adulthood. These nuclear genes affect various mitochondrial pathways and components including oxidative OXPHOS assembly (e.g. NDUFAF233, NDUFAF334, NDUFA434, COX1035, FASTKD236, SDHA37) , OXPHOS subunits (e.g. NDUFV138, NDUFS439, NDUFS840), mitochondrial DNA maintenance (e.g. POLG41, RRM2B42, SUCLA243), mitochondrial aminoacyl-tRNA synthetases (e.g. RARS244), membrane solute carriers (e.g. SLC25A2245) and coenzyme Q10 biosynthesis (e.g. PDSS246, COQ947, ADCK3 (CABC1)48).Several hypotheses32 had linked how these affected mitochondrial pathways generate seizures - changes in calcium homoeostasis49, ROS-induced oxidation of ion channels and neurotransmitter transporters50, increased excitability by a decrease in plasma membrane potential51, and reduced network inhibition by inhibitory interneuron dysfunction52. Epilepsy is a major phenotypic feature in several key groups of childhood onset mitochondrial disease, namely Alpers-Huttenlocher syndrome, pyruvate dehydrogenase complex deficiencies and Leigh syndrome. Alpers-Huttenlocher syndrome Alpers-Huttenlocher syndrome (AHS), characterised by progressive neurodegeneration, refractory seizures, movement disorder, neuropathy and hepatic failure, is the most commonly reported phenotypes of POLG-related disease in children.53 Prevalence of AHS is approximately 1 in 51,000 but the sum frequency of the five most common autosomal recessive pathogenic variants can be estimated to affect 1 in 10,000 people.18,54 Carriers of POLG mutations are usually healthy until disease onset, most commonly between age 2 to 4 years55,56 and a second peak onset between 17 to 24 years.12,57 Sadly, death usually occurs within four years of onset12,13. Homozygous variants located Page 5
ERUK – Mitochondrial Epilepsy – Lim, Thomas in the linker domain of the POLG gene correlated with later age of onset and longer survival compared to compound heterozygous variants.58,59 Focal-onset seizures in the POLG-related disorders predominate, but seizure may also be focal leading to bilateral tonic, clinic or myoclonic; occipital seizures are common at the outset and are usually refractory to antiepileptic drugs58. Although some may present with status epilepticus, the more recognisable seizure type is epilepsia partialis continua, a constant and repetitive myoclonic jerking of only one part of the body with or without altered consciousness. The phenotypic spectrum of AHS has expanded beyond the classical triad of intractable seizures, developmental regression and hepatopathy13 to include ataxia, myoclonus hypotonia, myopathy, migraines, ophthalmoparesis and optic atrophy.60 The seizure management in POLG-related disorders is challenging, and often unsuccessful with some succumbing to liver failure. Sodium valproate is avoided because of the risk of precipitating and accelerating liver dysfunction in this POLG-related disorder.61,62
Liver
dysfunction might be one of triad syndromic features of AHS but it is rarely the presenting symptom and it is often associated with pre-terminal disease stage.58,63 Pyruvate dehydrogenase deficiency The pyruvate dehydrogenase complex (PDHc) is a multi-enzyme platform located on the inner mitochondrial membrane that catalyses the conversion of pyruvate to acetyl CoA and carbon dioxide. PDH-deficiency, a progressive neuro-muscular degeneration disorder, typically presents in infancy with dysgenesis of the corpus callosum, epilepsy and an elevated serum lactate:pyruvate ratio > 20. 64 Autosomal recessive PDH deficiencies can be subdivided into several main categories: 1) Lipoic acid synthesis defects (LIAS and LIPT1); 65,66 2) PDHc subunit E3 defects (DLD and PDHX)67,68 and 3) absence of thiamine pyrophosphate activity (PDHA1, SLC25A19, SLC19A3 and TPK1).69 Epilepsy in pyruvate dehydrogenase deficiency typically begins in infancy with infantile spasms, clonic seizures or refractory focal epilepsy.70,71 Ketogenic diet which encourages hepatic conversion of fat into ketone bodies which then replace glucose as the main energy source for the brain, is used under specialist supervision to treat epileptic seizures in these infants or young children. Ketones have been reported to reduce mitochondrial DNA deletion load in cybrid models72 and appeared to slow the rate of progression of myopathy and hepatopathy in some mouse models.73,74 Another possible therapeutic avenue is the use of an active component in the ketogenic diet known as decanoic acid75 but the current evidence of its clinical efficacy in mitochondrial disease is limited. Leigh syndrome Page 6
ERUK – Mitochondrial Epilepsy – Lim, Thomas One of the commonest syndromic presentation of mitochondrial disease in children is Leigh syndrome. This early-onset neurodegenerative disorder is caused by more than 80 pathogenic gene mutations76,77 and is typically characterised as a triad of (1) stepwise developmental regression or developmental delay, (2) specific basal ganglia/brain stem changes bilaterally and (3) abnormal mitochondrial energy metabolism.76,78,79 The onset of Leigh syndrome is often triggered by metabolic challenges followed by a loss of acquired neuro-developmental skills.79 Central nervous system features such as encephalopathy, hypotonia, dystonia and spasticity predominate early in the course of the disease. Epileptic seizures are also common, with both generalised onset and focal onset convulsive seizures witnessed in many patients.4,76,80,81 A history of epileptic seizures and early age of onset are clinical indicators for poor survival.4,76 Treatment of these seizures, which are almost always drug-refractory is a major clinical problem. However, there are a small number Leigh or Leigh-like syndromes that could be treated with varying degrees of response expected depending on the underlying genetic mutations. Biotinidase deficiency secondary to BTD gene mutations have shown improvement in ataxia and seizures with the treatment of biotin.82 Meanwhile, thiamine transporter 2 deficiency caused by SLC19A3 gene defect, presenting with episodic encephalopathy and basal ganglia changes, responds to biotin and high-dose thiamine.83 Variable degree of improvement have been reported in Leigh syndrome caused by PDSS2,82,84 ETHE1,85,86 PDHA187 and TPK188 mutations with specific treatments.
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Adults We would differentiate adults with mitochondrial disorders in to at least four different groups: 1) the myoclonic epilepsy of MERRF; 2) focal seizures and status epilepticus associated with POLG; 3) focal seizures and status epilepticus associated with m.3243A>G; 4) the other mitochondrial disorders.
1) Generalised epilepsy of MERRF Myoclonic epilepsy with ragged-red fibres (MERRF) is most commonly caused by the m.8344A > G mutation in MTTK, but can be caused by any one of 13 mDNA-located genes and one nDNA-located gene. Mean age of onset is in the 30s but a third present in childhood.89 CNS manifestations are common (56%) most commonly including generalised tonic clonic seizures (35%). Not all the myoclonus that presents is epileptic myoclonus and myoclonus co-occurs more commonly with cerebellar ataxia, than with other generalised seizures; dementia is a late sign.89 Myoclonus in MERRF may be intermittent or induced by photosensitivity or action. Focal onset seizures are not a feature. Status epilepticus is seen and can even be a presenting feature and stroke-like episodes are rare but recognised. Interictal EEG abnormalities include non-specific slowing of background rhythms, and generalised epileptiform discharges such as spikes, polyspike, and irregular and slow wave complexes. Myoclonic seizures may correlate with these EEG features and this may be suppressed by eye opening. Control of GTCS may be achieved with the first choice of AED, but pharmacological control of myoclonus is more challenging- perhaps in part – because some myoclonus may be cortical reflex myoclonus. A number of drugs have been reported to exacerbate myoclonus including carbamazepine, oxcarbazepine, phenytoin, lamotrigine, gabapentin, pregabalin and topiramate. Benzodiazepines, valproate and levetiracetam, piracetam are more commonly reported to produce a symptomatic benefit.90-92
2) Focal seizures and status epilepticus associated with POLG Recessive POLG is associated with a variety of phenotypic gestalts: mitochondrial recessive ataxia syndrome (MIRAS); myoclonic epilepsy myopathy sensory ataxia (MEMSA); spinocerebellar ataxia with epilepsy (SCAE); sensory ataxia with neuropathy, dysarthria, and ophthalmoplegia (SANDO); as
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ERUK – Mitochondrial Epilepsy – Lim, Thomas well as AHS, described earlier. It is notable that there are a plethora of unclassifiable patients and overlap syndrome also. Seizures predominate and are seen in 40% of adult-onset cases, but twice as many that present before the age of 5 years.93 Seizures are predominantly focal motor and epilepsia partialis continua is common as is nonconvulsive status epilepticus – with and without visual features. These features, which localise to the occipital lobe may not be obvious as seizures to the patient or their family as they consist of coloured lights, scotoma, or visual blurring.
3) Focal seizures and status epilepticus associated with m.3243A>G MELAS (mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes) is predominantly caused by a single mutation in MTTL1, m.3243A>G. Approximately a quarter of people with m.3243A>G disorders have seizures, and at least half of people with MELAS. People with MELAS may have a number of different seizures – these include provoked metabolic seizures exacerbated by hypoglycaemia, hyponatraemia or bowel stasis. People may also have focal-onset seizures in part caused by the sequalae of prior stroke-like episodes. However the most pathognomonic ‘seizure’ in MELAS is the stroke-like episode. This is conceptualised as a form of focal status epilepticus with a secondary encephalopathy. In fact some individuals will only have seizures in the context of strokelike episodes. Like POLG (above) epilepsia partialis continua can persist for weeks or months and may be overlooked by the patient and their physician as it may be as subtle as persistent flashing lights. Anecdotal reports of the benefits of non-invasive transcranial direct current stimulation in people with drug-refractory epilepsia partialis continua are promising as the clinical progression is ubiquitously poor.94
4) The other mitochondrial disorders Epileptic seizures are a rare feature of other mitochiondrial disorders including NARP (Neuropathy, ataxia, retinitis pigmentosa), KSS (Kearns–Sayre syndrome), LHON (Leber's hereditary optic neuropathy) and non syndromic mitocohondrial disorders. In these cases seizure control is similar to that of adults without mitochondrial disease in that ~70% have good seizure control.95
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Conclusions There are currently no specific curative treatments for other causes of paediatric mitochondrial epilepsy except from the rare primary coenzyme Q10 deficiencies, which can be successfully treated by coenzyme Q10 supplementation. Generally, the epileptic seizures should be managed by a paediatric neurologist with appropriate use of anticonvulsant medication, ketogenic diet and on occasion epilepsy surgery (vagus nerve stimulator). The management of other symptoms associated with mitochondrial disease (e.g. spasticity and dystonia) is important, as is prevention, recognition and prompt treatment of exacerbating factors such as fever, dehydration and poor nutrition. Monikers and acronyms are useful but may also create intellectual silos that can impair patient care: the myoclonus in MERRF may not be from ‘myoclonic epilepsy’ and the ‘stroke like episodes’ in MELAS are not conventional stroke: however we are far from re-coining the terms to be myoclonic ataxia with red ragged fibres and mitochondrial encephalopathy, lactic acidosis, and seizures. Similarly the delineation of individuals with m.3243A>G in to MIDD, CPEO or MELAS is often indistinct, or varies over time and many overlap disorders are recognised.
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References 1. 2.
3. 4. 5. 6.
7. 8.
9. 10. 11. 12. 13.
14.
15.
16. 17. 18.
19.
20.
Gorman GS, Schaefer AM, Ng Y, et al. Prevalence of nuclear and mitochondrial DNA mutations related to adult mitochondrial disease. Ann Neurol. 2015;77(5):753-759. Ng YS, Gorman G, Nesbitt V, et al. Phenotypes and Genotypes of Mitochondrial DiseaseFindings from A National Mitochondrial Disease Cohort (P2.061). Neurology. 2015;84(14 Supplement). Thompson K, Collier JJ, Glasgow RIC, et al. Recent advances in understanding the molecular genetic basis of mitochondrial disease. J Inherit Metab Dis. 2019. Sofou K, De Coo IF, Isohanni P, et al. A multicenter study on Leigh syndrome: disease course and predictors of survival. Orphanet J Rare Dis. 2014;9:52. El Sabbagh S, Lebre A-S, Bahi-Buisson N, et al. Epileptic phenotypes in children with respiratory chain disorders. Epilepsia. 2010;51(7):1225-1235. Lee HN, Eom S, Kim SH, et al. Epilepsy Characteristics and Clinical Outcome in Patients With Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-Like Episodes (MELAS). Pediatric neurology. 2016;64:59-65. Iizuka T, Sakai F, Suzuki N, et al. Neuronal hyperexcitability in stroke-like episodes of MELAS syndrome. Neurology. 2002;59(6):816-824. Lax NZ, Grady J, Laude A, et al. Extensive respiratory chain defects in inhibitory interneurones in patients with mitochondrial disease. Neuropathol Appl Neurobiol. 2016;42(2):180-193. Alston CL, Rocha MC, Lax NZ, Turnbull DM, Taylor RW. The genetics and pathology of mitochondrial disease. J Pathol. 2017;241(2):236-250. Koga Y, Akita Y, Nishioka J, et al. L-arginine improves the symptoms of strokelike episodes in MELAS. Neurology. 2005;64(4):710-712. Pfeffer G, Majamaa K, Turnbull DM, Thorburn D, Chinnery PF. Treatment for mitochondrial disorders. Cochrane Database Syst Rev. 2012(4):CD004426. Wiltshire E, Davidzon G, DiMauro S, et al. Juvenile Alpers disease. Arch Neurol. 2008;65(1):121-124. Harding BN, Alsanjari N, Smith SJ, et al. Progressive neuronal degeneration of childhood with liver disease (Alpers' disease) presenting in young adults. J Neurol Neurosurg Psychiatry. 1995;58(3):320-325. Anderson CM, Norquist BA, Vesce S, et al. Barbiturates induce mitochondrial depolarization and potentiate excitotoxic neuronal death. The Journal of neuroscience : the official journal of the Society for Neuroscience. 2002;22(21):9203-9209. Melegh B, Trombitas K. Valproate treatment induces lipid globule accumulation with ultrastructural abnormalities of mitochondria in skeletal muscle. Neuropediatrics. 1997;28(5):257-261. Skladal D, Halliday J, Thorburn DR. Minimum birth prevalence of mitochondrial respiratory chain disorders in children. Brain. 2003;126(Pt 8):1905-1912. Diogo L, Grazina M, Garcia P, et al. Pediatric mitochondrial respiratory chain disorders in the Centro region of Portugal. Pediatr Neurol. 2009;40(5):351-356. Darin N, Oldfors A, Moslemi AR, Holme E, Tulinius M. The incidence of mitochondrial encephalomyopathies in childhood: clinical features and morphological, biochemical, and DNA abnormalities. Ann Neurol. 2001;49(3):377-383. Castro-Gago M, Blanco-Barca MO, Campos-Gonzalez Y, Arenas-Barbero J, Pintos-Martinez E, Eiris-Punal J. Epidemiology of pediatric mitochondrial respiratory chain disorders in northwest Spain. Pediatr Neurol. 2006;34(3):204-211. Uusimaa J, Remes AM, Rantala H, et al. Childhood encephalopathies and myopathies: a prospective study in a defined population to assess the frequency of mitochondrial disorders. Pediatrics. 2000;105(3 Pt 1):598-603. Page 11
ERUK – Mitochondrial Epilepsy – Lim, Thomas 21.
22. 23.
24. 25.
26. 27. 28. 29. 30.
31. 32. 33. 34.
35.
36.
37.
38. 39.
40.
Yamazaki T, Murayama K, Compton AG, et al. Molecular diagnosis of mitochondrial respiratory chain disorders in Japan: focusing on mitochondrial DNA depletion syndrome. Pediatrics international : official journal of the Japan Pediatric Society. 2014;56(2):180-187. Ryan E, King MD, Rustin P, et al. Mitochondrial cytopathies, phenotypic heterogeneity and a high incidence. Irish medical journal. 2006;99(9):262-264. Verity CM, Winstone AM, Stellitano L, Krishnakumar D, Will R, McFarland R. The clinical presentation of mitochondrial diseases in children with progressive intellectual and neurological deterioration: a national, prospective, population-based study. Developmental medicine and child neurology. 2010;52(5):434-440. Munnich A, Rotig A, Chretien D, et al. Clinical presentation of mitochondrial disorders in childhood. J Inherit Metab Dis. 1996;19(4):521-527. Kisler JE, Whittaker RG, McFarland R. Mitochondrial diseases in childhood: a clinical approach to investigation and management. Developmental medicine and child neurology. 2010;52(5):422-433. Khurana D, Salganicoff L, Melvin J, et al. Epilepsy and Respiratory Chain Defects in Children with Mitochondrial Encephalopathies. Neuropediatrics. 2008;39(1):8-13. Debray FG, Lambert M, Chevalier I, et al. Long-term Outcome and Clinical Spectrum of 73 Pediatric Patients With Mitochondrial Diseases. PEDIATRICS. 2007;119(4):722-733. Scaglia F, Towbin JA, Craigen WJ, et al. Clinical spectrum, morbidity, and mortality in 113 pediatric patients with mitochondrial disease. Pediatrics. 2004;114(4):925-931. Skladal D, Sudmeier C, Konstantopoulou V, et al. The clinical spectrum of mitochondrial disease in 75 pediatric patients. Clinical pediatrics. 2003;42(8):703-710. Calvo SE, Compton AG, Hershman SG, et al. Molecular Diagnosis of Infantile Mitochondrial Disease with Targeted Next-Generation Sequencing. Science Translational Medicine. 2012;4(118):118ra110-118ra110. Carroll CJ, Brilhante V, Suomalainen A. Next-generation sequencing for mitochondrial disorders. British Journal of Pharmacology. 2014;171(8):1837-1853. Zsurka G, Kunz WS. Mitochondrial dysfunction and seizures: the neuronal energy crisis. The Lancet Neurology. 2015;14(9):956-966. Barghuti F, Elian K, Gomori JM, et al. The unique neuroradiology of complex I deficiency due to NDUFA12L defect. Molecular genetics and metabolism. 2008;94(1):78-82. Saada A, Vogel RO, Hoefs SJ, et al. Mutations in NDUFAF3 (C3ORF60), Encoding an NDUFAF4 (C6ORF66)-Interacting Complex I Assembly Protein, Cause Fatal Neonatal Mitochondrial Disease. The American Journal of Human Genetics. 2009;84(6):718-727. Valnot I, von Kleist-Retzow JC, Barrientos A, et al. A mutation in the human heme A:farnesyltransferase gene (COX10 ) causes cytochrome c oxidase deficiency. Hum Mol Genet. 2000;9(8):1245-1249. Ghezzi D, Saada A, D'Adamo P, et al. FASTKD2 Nonsense Mutation in an Infantile Mitochondrial Encephalomyopathy Associated with Cytochrome C Oxidase Deficiency. The American Journal of Human Genetics. 2008;83(3):415-423. Horvath R, Abicht A, Holinski-Feder E, et al. Leigh syndrome caused by mutations in the flavoprotein (Fp) subunit of succinate dehydrogenase (SDHA). J Neurol Neurosurg Psychiatry. 2006;77(1):74-76. Schuelke M, Smeitink J, Mariman E, et al. Mutant NDUFV1 subunit of mitochondrial complex I causes leukodystrophy and myoclonic epilepsy. Nature Genetics. 1999;21(3):260-261. van den Heuvel L, Ruitenbeek W, Smeets R, et al. Demonstration of a New Pathogenic Mutation in Human Complex I Deficiency: A 5-bp Duplication in the Nuclear Gene Encoding the 18-kD (AQDQ) Subunit. The American Journal of Human Genetics. 1998;62(2):262-268. Loeffen J, Smeitink J, Triepels R, et al. The first nuclear-encoded complex I mutation in a patient with Leigh syndrome. Am J Hum Genet. 1998;63(6):1598-1608.
Page 12
ERUK – Mitochondrial Epilepsy – Lim, Thomas 41. 42. 43.
44.
45.
46.
47.
48.
49.
50.
51. 52. 53. 54. 55. 56. 57.
58.
59.
Wolf NI, Rahman S, Schmitt B, et al. Status epilepticus in children with Alpers’ disease caused byPOLG1mutations: EEG and MRI features. Epilepsia. 2009;50(6):1596-1607. Kollberg G, Darin N, Benan K, et al. A novel homozygous RRM2B missense mutation in association with severe mtDNA depletion. Neuromuscular Disorders. 2009;19(2):147-150. Elpeleg O, Miller C, Hershkovitz E, et al. Deficiency of the ADP-Forming Succinyl-CoA Synthase Activity Is Associated with Encephalomyopathy and Mitochondrial DNA Depletion. The American Journal of Human Genetics. 2005;76(6):1081-1086. Glamuzina E, Brown R, Hogarth K, et al. Further delineation of pontocerebellar hypoplasia type 6 due to mutations in the gene encoding mitochondrial arginyl-tRNA synthetase, RARS2. Journal of inherited metabolic disease. 2011;35(3):459-467. Molinari F, Kaminska A, Fiermonte G, et al. Mutations in the mitochondrial glutamate carrierSLC25A22in neonatal epileptic encephalopathy with suppression bursts. Clinical Genetics. 2009;76(2):188-194. López LC, Schuelke M, Quinzii CM, et al. Leigh syndrome with nephropathy and CoQ10 deficiency due to decaprenyl diphosphate synthase subunit 2 (PDSS2) mutations. The American Journal of Human Genetics. 2006;79(6):1125-1129. Duncan AJ, Bitner-Glindzicz M, Meunier B, et al. A nonsense mutation in COQ9 causes autosomal-recessive neonatal-onset primary coenzyme Q10 deficiency: a potentially treatable form of mitochondrial disease. The American Journal of Human Genetics. 2009;84(5):558-566. Mollet J, Delahodde A, Serre V, et al. CABC1 gene mutations cause ubiquinone deficiency with cerebellar ataxia and seizures. The American Journal of Human Genetics. 2008;82(3):623-630. Sanganahalli BG, Herman P, Hyder F, Kannurpatti SS. Mitochondrial calcium uptake capacity modulates neocortical excitability. Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism. 2013;33(7):1115-1126. Trotti D, Danbolt NC, Volterra A. Glutamate transporters are oxidant-vulnerable: a molecular link between oxidative and excitotoxic neurodegeneration? Trends in pharmacological sciences. 1998;19(8):328-334. Hardie DG, Ross FA, Hawley SA. AMPK: a nutrient and energy sensor that maintains energy homeostasis. Nature reviews Molecular cell biology. 2012;13(4):251-262. Kudin AP, Zsurka G, Elger CE, Kunz WS. Mitochondrial involvement in temporal lobe epilepsy. Experimental neurology. 2009;218(2):326-332. Nguyen KV, Sharief FS, Chan SS, Copeland WC, Naviaux RK. Molecular diagnosis of Alpers syndrome. J Hepatol. 2006;45(1):108-116. Cohen BH, Chinnery PF, Copeland WC. POLG-Related Disorders. In: Adam MP, Ardinger HH, Pagon RA, et al., eds. GeneReviews((R)). Seattle (WA)1993. Harding BN. Progressive neuronal degeneration of childhood with liver disease (AlpersHuttenlocher syndrome): a personal review. Journal of child neurology. 1990;5(4):273-287. Horvath R, Hudson G, Ferrari G, et al. Phenotypic spectrum associated with mutations of the mitochondrial polymerase gamma gene. Brain. 2006;129(Pt 7):1674-1684. Uusimaa J, Hinttala R, Rantala H, et al. Homozygous W748S mutation in the POLG1 gene in patients with juvenile-onset Alpers syndrome and status epilepticus. Epilepsia. 2008;49(6):1038-1045. Anagnostou ME, Ng YS, Taylor RW, McFarland R. Epilepsy due to mutations in the mitochondrial polymerase gamma (POLG) gene: A clinical and molecular genetic review. Epilepsia. 2016;57(10):1531-1545. Farnum GA, Nurminen A, Kaguni LS. Mapping 136 pathogenic mutations into functional modules in human DNA polymerase gamma establishes predictive genotype-phenotype
Page 13
ERUK – Mitochondrial Epilepsy – Lim, Thomas
60. 61.
62. 63. 64.
65.
66.
67. 68. 69.
70. 71.
72. 73. 74. 75.
76. 77. 78. 79.
correlations for the complete spectrum of POLG syndromes. Biochim Biophys Acta. 2014;1837(7):1113-1121. Saneto RP, Cohen BH, Copeland WC, Naviaux RK. Alpers-Huttenlocher syndrome. Pediatr Neurol. 2013;48(3):167-178. Pronicka E, Weglewska-Jurkiewicz A, Pronicki M, et al. Drug-resistant epilepsia and fulminant valproate liver toxicity. Alpers-Huttenlocher syndrome in two children confirmed post mortem by identification of p.W748S mutation in POLG gene. Medical science monitor : international medical journal of experimental and clinical research. 2011;17(4):Cr203-209. Schwabe MJ, Dobyns WB, Burke B, Armstrong DL. Valproate-induced liver failure in one of two siblings with Alpers disease. Pediatr Neurol. 1997;16(4):337-343. Nguyen KV, Ostergaard E, Ravn SH, et al. POLG mutations in Alpers syndrome. Neurology. 2005;65(9):1493-1495. Patel KP, O'Brien TW, Subramony SH, Shuster J, Stacpoole PW. The spectrum of pyruvate dehydrogenase complex deficiency: clinical, biochemical and genetic features in 371 patients. Mol Genet Metab. 2012;106(3):385-394. Soreze Y, Boutron A, Habarou F, et al. Mutations in human lipoyltransferase gene LIPT1 cause a Leigh disease with secondary deficiency for pyruvate and alpha-ketoglutarate dehydrogenase. Orphanet J Rare Dis. 2013;8:192. Baker PR, 2nd, Friederich MW, Swanson MA, et al. Variant non ketotic hyperglycinemia is caused by mutations in LIAS, BOLA3 and the novel gene GLRX5. Brain. 2014;137(Pt 2):366379. Schiff M, Mine M, Brivet M, et al. Leigh's disease due to a new mutation in the PDHX gene. Ann Neurol. 2006;59(4):709-714. Quinonez SC, Leber SM, Martin DM, Thoene JG, Bedoyan JK. Leigh syndrome in a girl with a novel DLD mutation causing E3 deficiency. Pediatr Neurol. 2013;48(1):67-72. Mayr JA, Freisinger P, Schlachter K, et al. Thiamine pyrophosphokinase deficiency in encephalopathic children with defects in the pyruvate oxidation pathway. Am J Hum Genet. 2011;89(6):806-812. Prasad C, Rupar T, Prasad AN. Pyruvate dehydrogenase deficiency and epilepsy. Brain and Development. 2011;33(10):856-865. BARNERIAS C, SAUDUBRAY J-M, TOUATI G, et al. Pyruvate dehydrogenase complex deficiency: four neurological phenotypes with differing pathogenesis. Developmental Medicine & Child Neurology. 2010;52(2):e1-e9. Santra S, Gilkerson RW, Davidson M, Schon EA. Ketogenic treatment reduces deleted mitochondrial DNAs in cultured human cells. Annals of neurology. 2004;56(5):662-669. Ahola-Erkkila S, Carroll CJ, Peltola-Mjosund K, et al. Ketogenic diet slows down mitochondrial myopathy progression in mice. Hum Mol Genet. 2010;19(10):1974-1984. Purhonen J, Rajendran J. Ketogenic diet attenuates hepatopathy in mouse model of respiratory chain complex III deficiency caused by a Bcs1l mutation. 2017;7(1):957. Kanabus M, Fassone E, Hughes SD, et al. The pleiotropic effects of decanoic acid treatment on mitochondrial function in fibroblasts from patients with complex I deficient Leigh syndrome. J Inherit Metab Dis. 2016;39(3):415-426. Lake NJ, Compton AG, Rahman S, Thorburn DR. Leigh syndrome: One disorder, more than 75 monogenic causes. Ann Neurol. 2016;79(2):190-203. Rahman J, Noronha A, Thiele I, Rahman S. Leigh map: A novel computational diagnostic resource for mitochondrial disease. Ann Neurol. 2017;81(1):9-16. Rahman S, Blok RB, Dahl HH, et al. Leigh syndrome: clinical features and biochemical and DNA abnormalities. Ann Neurol. 1996;39(3):343-351. Baertling F, Rodenburg RJ, Schaper J, et al. A guide to diagnosis and treatment of Leigh syndrome. J Neurol Neurosurg Psychiatry. 2014;85(3):257-265.
Page 14
ERUK – Mitochondrial Epilepsy – Lim, Thomas 80. 81. 82.
83. 84. 85.
86. 87.
88.
89. 90.
91. 92. 93. 94.
95.
Ruhoy IS, Saneto RP. The genetics of Leigh syndrome and its implications for clinical practice and risk management. Appl Clin Genet. 2014;7:221-234. Zhang Y, Yang YL, Sun F, et al. Clinical and molecular survey in 124 Chinese patients with Leigh or Leigh-like syndrome. Journal of inherited metabolic disease. 2007;30(2):265-265. Jay AM, Conway RL, Feldman GL, Nahhas F, Spencer L, Wolf B. Outcomes of individuals with profound and partial biotinidase deficiency ascertained by newborn screening in Michigan over 25 years. Genetics in medicine : official journal of the American College of Medical Genetics. 2015;17(3):205-209. Haack TB, Klee D, Strom TM, et al. Infantile Leigh-like syndrome caused by SLC19A3 mutations is a treatable disease. Brain. 2014;137(Pt 9):e295. Hargreaves IP. Coenzyme Q10 as a therapy for mitochondrial disease. Int J Biochem Cell Biol. 2014;49:105-111. Viscomi C, Burlina AB, Dweikat I, et al. Combined treatment with oral metronidazole and Nacetylcysteine is effective in ethylmalonic encephalopathy. Nature medicine. 2010;16(8):869-871. Dionisi-Vici C, Diodato D, Torre G, et al. Liver transplant in ethylmalonic encephalopathy: a new treatment for an otherwise fatal disease. Brain. 2016;139(Pt 4):1045-1051. van Dongen S, Brown RM, Brown GK, Thorburn DR, Boneh A. Thiamine-Responsive and Nonresponsive Patients with PDHC-E1 Deficiency: A Retrospective Assessment. JIMD reports. 2015;15:13-27. Banka S, de Goede C, Yue WW, et al. Expanding the clinical and molecular spectrum of thiamine pyrophosphokinase deficiency: a treatable neurological disorder caused by TPK1 mutations. Mol Genet Metab. 2014;113(4):301-306. Mancuso M, Orsucci D, Angelini C, et al. Phenotypic heterogeneity of the 8344A>G mtDNA "MERRF" mutation. Neurology. 2013;80(22):2049-2054. Michelucci R, Pasini E, Riguzzi P, Andermann E, Kälviäinen R, Genton P. Myoclonus and seizures in progressive myoclonus epilepsies: pharmacology and therapeutic trials. Epileptic Disorders. 2016;18(s2):S145-S153. Whittaker RG, Devine HE, Gorman GS, et al. Epilepsy in adults with mitochondrial disease: a cohort study. Annals of neurology. 2015;78(6):949-957. Steele HE, Chinnery PF. Mitochondrial causes of epilepsy: evaluation, diagnosis, and treatment. Paper presented at: Seminars in neurology2015. Tang S, Wang J, Lee NC, et al. Mitochondrial DNA polymerase gamma mutations: an ever expanding molecular and clinical spectrum. J Med Genet. 2011;48(10):669-681. Ng YS, van Ruiten H, Lai HM, et al. The adjunctive application of transcranial direct current stimulation in the management of de novo refractory epilepsia partialis continua in adolescent-onset POLG-related mitochondrial disease. Epilepsia open. 2018;3(1):103-108. Chevallier JA, Von Allmen GK, Koenig MK. Seizure semiology and EEG findings in mitochondrial diseases. Epilepsia. 2014;55(5):707-712.
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Highlights The presentation of seizures in children and adults differs greatly but drug resistance is the norm Half of patients with POLG mitochondrial disorders first present with epileptic seizures The epileptic seizures leading to ‘stroke-like episodes’ and atrophy are a potent cause of dementia and decline in MELAS There are rare examples of paediatric onset mitochondrial disorders that specific treatments, such as high-dose thiamine
Author disclosures R Thomas has received honoraria from Eisai, GW Pharma, Sanofi, UCB Pharma, Zogenix and meeting support from LivaNova and Bilal.
S1090-3798(19)30441-6
DOI:
https://doi.org/10.1016/j.ejpn.2019.12.021
Reference:
YEJPN 2623
To appear in:
European Journal of Paediatric Neurology
Received Date: 6 December 2019 Revised Date:
17 December 2019
Accepted Date: 18 December 2019
Please cite this article as: Lim A, Thomas RH, The mitochondrial epilepsies, European Journal of Paediatric Neurology, https://doi.org/10.1016/j.ejpn.2019.12.021. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.
ERUK – Mitochondrial Epilepsy – Lim, Thomas
The mitochondrial epilepsies Albert Lim1,2, Rhys H Thomas2,3,4 1. Department of Paediatrics, Great Northern Children’s Hospital, Queen Victoria Rd, Newcastle-Upon-Tyne, NE1 4LP, United Kingdom 2. Wellcome Centre for Mitochondrial Research, Institute of Neuroscience, Newcastle University, Newcastle-Upon-Tyne, NE2 4HH, United Kingdom 3. Department of Neurology, Royal Victoria Infirmary, Queen Victoria Rd, Newcastle-UponTyne, NE1 4LP, United Kingdom 4. Institute of Neuroscience, Henry Wellcome Building, Framlington Place, Newcastle University, Newcastle-Upon-Tyne, NE2 4HH, United Kingdom
Address for Correspondence: Rhys H Thomas Institute of Neuroscience, Henry Wellcome Building, Framlington Place, Newcastle University, Newcastle-Upon-Tyne, NE2 4HH, United Kingdom [email protected]
Word and character counts:
Abstract: 196 words Manuscript: 2662 words References: 81
Keywords
Mitochondrial disease, POLG, MELAS, MERRF, Leigh syndrome, epilepsy
Author disclosures R Thomas has received honoraria from Eisai, GW Pharma, Sanofi, UCB Pharma, Zogenix and meeting support from LivaNova, Novartis and Bial.
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Abstract Mitochondria are vital organelles within cells that undertake many important metabolic roles, the most significant of which is to generate energy to support organ function. Dysfunction of the mitochondrion can lead to a wide range of clinical features, predominantly affecting organs with a high metabolic demand such as the brain. One of the main neurological manifestations of mitochondrial disease is metabolic epilepsies. These epileptic seizures are more frequently of posterior quadrant and occipital lobe onset, more likely to present with non-convulsive status epilepticus which may last months and be more resistant to treatment from the onset. The onset of can be of any age. Childhood onset epilepsy is a major phenotypic feature in mitochondrial disorders such as Alpers-Huttenlocher syndrome, pyruvate dehydrogenase complex deficiencies, and Leigh syndrome. Meanwhile, adults with classical mitochondrial disease syndrome such as MELAS, MERFF or POLG-related disorders could present with either focal or generalised seizures. There are no specific curative treatments for mitochondrial epilepsy. Generally, the epileptic seizures should be managed by specialist neurologist with appropriate use of anticonvulsants. As a general rule, especially in disorders associated with mutation in POLG, sodium valproate is best avoided because hepato-toxicity can be fulminant and fatal.
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Introduction Mitochondrial disorders are genetically determined metabolic diseases arising from mitochondrial DNA (mtDNA) and nuclear DNA (nDNA) mutations. The minimum prevalence in the UK is 1 in 5,0001. With the advancement in molecular genetic diagnostic technologies, and better clinical acumen, it has become readily apparent that the majority of mitochondrial disorders in children are precipitated by nuclear DNA mutations2,3. Although there are no curable mitochondrial disorders, many comorbidities are treatable – it can be argued that the most important of which is epileptic seizures, as they are a significant predictor of outcome.4-6 Mitochondrial diabetes can be more challenging to treat than classic Type 1 or Type 2 diabetes mellitus; cardiomyopathy and arrhythmias are essential to identify and monitor; as are constipation, and gastro-intestinal dysmotility. However the epileptic seizures leading to ‘stroke-like episodes’ and atrophy are a potent cause of dementia and decline. In keeping with other metabolic disorders, seizures include both spontaneous epileptic seizures and provoked seizures. The epileptic seizures in mitochondrial disorders differ from seizures in other contexts with respect 1) more frequently of posterior quadrant and occipital lobe onset; 2) more likely to present with non-convulsive status epilepticus which may last months; 3) multi-drug resistant from the onset; 4) may have only a minimal EEG correlate. The underlying pathophysiological process associated with these ‘metabolic’ seizures has been proposed to be initiated by interneuron mitochondrial respiratory chain deficiency consequently altering the balance of excitation and inhibition in neural networks, promoting neuronal hyperexcitability7. The dramatic downregulation of OXPHOS subunits of complexes I and IV within the GABAergic interneurons of these patients makes these interneurons particularly vulnerable to the propagation of neuronal hyperexcitability8. This acute process leads to rapid neuronal damage that have been demonstrated by histopathological findings of micro-vacuolation, neuronal cell dropout, eosinophilia, astrogliosis and secondary myelin loss in patients8,9. Epileptic seizure may be the first and, not uncommonly the only sign of mitochondrial dysfunction and it warrants an aggressive management from the outset. There are currently no established treatments with proven efficacy. The existing clinical drug studies to explore definitive disease-modifying treatment have been limited by small sample size and the lack of natural history data. The tendency for variable degrees of spontaneous recovery means that the true effect of acute therapies is difficult to prove without large clinical randomised placebo-controlled trials. At present, these seizures should be managed by specialist neurologists with appropriate use of anticonvulsant medication, ketogenic diet and on occasion epilepsy surgery (vagal nerve stimulator). Page 3
ERUK – Mitochondrial Epilepsy – Lim, Thomas In our experience, intravenous loading with Levetiracetam or/and Phenytoin is the first line AED of choice, with the addition of Clobazam to new or existing regime. L-arginine has been reported to provide benefit, but the non-randomised, open label study design employed excluded this study from the recent Cochrane review of treatments for mitochondrial disorders10,11. Supplements such as ubiquinone, riboflavin, or creatine have been assessed in small trials but have not been proven to provide benefit in general or in relation to focal refractory seizures11. Given the recurrent and protracted nature of these seizures, clinicians will inevitably face the ultimate dilemma when escalating medical treatment of having to admit their patient to intensive care for a general anaesthetic, with the increased morbidity and mortality this entails. Unfortunately, the prognosis for refractory seizure disorders in mitochondrial disease is very poor and frequently associated with a neurodegenerative process12,13. The precise role of seizure activity in hastening neurodegeneration is unclear, but the associated abnormal electrical activity is highly energy dependent and occurs in a cellular network that is already energetically compromised. As a general rule (and certainly in disorders associated with mutation in POLG) sodium valproate is best avoided because hepato-toxicity can be fulminant and fatal. There are theoretical concerns about the use of valproic acid outside of POLG disorders. It is thought to cause complex-I and complex-IV dysfunction triggering a cascade that can produce a secondary carnitine-deficiency. It is worth noting that the adverse effects of sodium valproate have not been ubiquitously demonstrated in mitochondrial disease and it has proved an effective anticonvulsant in some patients14,15. Nonetheless, this removes an important weapon from our armamentarium. Clearly in a rare disease the evidence base for treatment is weak and predominantly anecdotal or extrapolated from adults without this multisystem disease. Comparisons of outcome in a disorder which can be slowly progressive or decline in a step-wise fashion means that it can be a challenge to know if medication is tolerated, and harder still to gather an evidence base for non-pharmacological adjuncts such as vagus nerve stimulator treatment. Many people with focal seizures will need treating with polytherapy and anecdotally older medications are more commonly used in this group – than say patients with an epileptic encephalopathy. The common use of phenytoin, phenobarbitone, clobazam or carbamazepine means that there is a perpetual balance between seizures and side-effects, between the risk of neuronal damage from a preventable stroke-like episode versus quality of life in between seizures. At later stages of disease there is a loss of cortical reserve meaning that drug side effects (particularly sedation) and the consequences of frequent seizures – such as delirium – are common.
Paediatrics Page 4
ERUK – Mitochondrial Epilepsy – Lim, Thomas The current prevalence of childhood-onset mitochondrial disorders has been predicted to range from 5 to 15 cases per 10,00016-22. Although the exact prevalence of mitochondrial epilepsy in children is unknown, seizures are commonly reported in 20- 60% of individuals with biochemically or genetically-confirmed diseases.5,18,20,23-29 In most cases, the other features of mitochondrial disease, such as developmental delay, hearing loss, visual impairment, muscle weakness, hypotonia or ataxia precede the onset of first epileptic seizure. The presentation of the epilepsy in children can be highly varied from infantile spasms, generalised seizures, focal seizures, myoclonic epilepsy to refractory status epilepticus. Multi-gene panel testing has traditionally been a popular means of investigating genetic epilepsy syndromes including mitochondrial causes, but panels can quickly become obsolete with newer gene discoveries and whole exome or genome sequencing is now increasingly employed in the diagnostic algorithm30,31. Several nuclear genes have been linked to mitochondrial epilepsy presenting before adulthood. These nuclear genes affect various mitochondrial pathways and components including oxidative OXPHOS assembly (e.g. NDUFAF233, NDUFAF334, NDUFA434, COX1035, FASTKD236, SDHA37) , OXPHOS subunits (e.g. NDUFV138, NDUFS439, NDUFS840), mitochondrial DNA maintenance (e.g. POLG41, RRM2B42, SUCLA243), mitochondrial aminoacyl-tRNA synthetases (e.g. RARS244), membrane solute carriers (e.g. SLC25A2245) and coenzyme Q10 biosynthesis (e.g. PDSS246, COQ947, ADCK3 (CABC1)48).Several hypotheses32 had linked how these affected mitochondrial pathways generate seizures - changes in calcium homoeostasis49, ROS-induced oxidation of ion channels and neurotransmitter transporters50, increased excitability by a decrease in plasma membrane potential51, and reduced network inhibition by inhibitory interneuron dysfunction52. Epilepsy is a major phenotypic feature in several key groups of childhood onset mitochondrial disease, namely Alpers-Huttenlocher syndrome, pyruvate dehydrogenase complex deficiencies and Leigh syndrome. Alpers-Huttenlocher syndrome Alpers-Huttenlocher syndrome (AHS), characterised by progressive neurodegeneration, refractory seizures, movement disorder, neuropathy and hepatic failure, is the most commonly reported phenotypes of POLG-related disease in children.53 Prevalence of AHS is approximately 1 in 51,000 but the sum frequency of the five most common autosomal recessive pathogenic variants can be estimated to affect 1 in 10,000 people.18,54 Carriers of POLG mutations are usually healthy until disease onset, most commonly between age 2 to 4 years55,56 and a second peak onset between 17 to 24 years.12,57 Sadly, death usually occurs within four years of onset12,13. Homozygous variants located Page 5
ERUK – Mitochondrial Epilepsy – Lim, Thomas in the linker domain of the POLG gene correlated with later age of onset and longer survival compared to compound heterozygous variants.58,59 Focal-onset seizures in the POLG-related disorders predominate, but seizure may also be focal leading to bilateral tonic, clinic or myoclonic; occipital seizures are common at the outset and are usually refractory to antiepileptic drugs58. Although some may present with status epilepticus, the more recognisable seizure type is epilepsia partialis continua, a constant and repetitive myoclonic jerking of only one part of the body with or without altered consciousness. The phenotypic spectrum of AHS has expanded beyond the classical triad of intractable seizures, developmental regression and hepatopathy13 to include ataxia, myoclonus hypotonia, myopathy, migraines, ophthalmoparesis and optic atrophy.60 The seizure management in POLG-related disorders is challenging, and often unsuccessful with some succumbing to liver failure. Sodium valproate is avoided because of the risk of precipitating and accelerating liver dysfunction in this POLG-related disorder.61,62
Liver
dysfunction might be one of triad syndromic features of AHS but it is rarely the presenting symptom and it is often associated with pre-terminal disease stage.58,63 Pyruvate dehydrogenase deficiency The pyruvate dehydrogenase complex (PDHc) is a multi-enzyme platform located on the inner mitochondrial membrane that catalyses the conversion of pyruvate to acetyl CoA and carbon dioxide. PDH-deficiency, a progressive neuro-muscular degeneration disorder, typically presents in infancy with dysgenesis of the corpus callosum, epilepsy and an elevated serum lactate:pyruvate ratio > 20. 64 Autosomal recessive PDH deficiencies can be subdivided into several main categories: 1) Lipoic acid synthesis defects (LIAS and LIPT1); 65,66 2) PDHc subunit E3 defects (DLD and PDHX)67,68 and 3) absence of thiamine pyrophosphate activity (PDHA1, SLC25A19, SLC19A3 and TPK1).69 Epilepsy in pyruvate dehydrogenase deficiency typically begins in infancy with infantile spasms, clonic seizures or refractory focal epilepsy.70,71 Ketogenic diet which encourages hepatic conversion of fat into ketone bodies which then replace glucose as the main energy source for the brain, is used under specialist supervision to treat epileptic seizures in these infants or young children. Ketones have been reported to reduce mitochondrial DNA deletion load in cybrid models72 and appeared to slow the rate of progression of myopathy and hepatopathy in some mouse models.73,74 Another possible therapeutic avenue is the use of an active component in the ketogenic diet known as decanoic acid75 but the current evidence of its clinical efficacy in mitochondrial disease is limited. Leigh syndrome Page 6
ERUK – Mitochondrial Epilepsy – Lim, Thomas One of the commonest syndromic presentation of mitochondrial disease in children is Leigh syndrome. This early-onset neurodegenerative disorder is caused by more than 80 pathogenic gene mutations76,77 and is typically characterised as a triad of (1) stepwise developmental regression or developmental delay, (2) specific basal ganglia/brain stem changes bilaterally and (3) abnormal mitochondrial energy metabolism.76,78,79 The onset of Leigh syndrome is often triggered by metabolic challenges followed by a loss of acquired neuro-developmental skills.79 Central nervous system features such as encephalopathy, hypotonia, dystonia and spasticity predominate early in the course of the disease. Epileptic seizures are also common, with both generalised onset and focal onset convulsive seizures witnessed in many patients.4,76,80,81 A history of epileptic seizures and early age of onset are clinical indicators for poor survival.4,76 Treatment of these seizures, which are almost always drug-refractory is a major clinical problem. However, there are a small number Leigh or Leigh-like syndromes that could be treated with varying degrees of response expected depending on the underlying genetic mutations. Biotinidase deficiency secondary to BTD gene mutations have shown improvement in ataxia and seizures with the treatment of biotin.82 Meanwhile, thiamine transporter 2 deficiency caused by SLC19A3 gene defect, presenting with episodic encephalopathy and basal ganglia changes, responds to biotin and high-dose thiamine.83 Variable degree of improvement have been reported in Leigh syndrome caused by PDSS2,82,84 ETHE1,85,86 PDHA187 and TPK188 mutations with specific treatments.
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Adults We would differentiate adults with mitochondrial disorders in to at least four different groups: 1) the myoclonic epilepsy of MERRF; 2) focal seizures and status epilepticus associated with POLG; 3) focal seizures and status epilepticus associated with m.3243A>G; 4) the other mitochondrial disorders.
1) Generalised epilepsy of MERRF Myoclonic epilepsy with ragged-red fibres (MERRF) is most commonly caused by the m.8344A > G mutation in MTTK, but can be caused by any one of 13 mDNA-located genes and one nDNA-located gene. Mean age of onset is in the 30s but a third present in childhood.89 CNS manifestations are common (56%) most commonly including generalised tonic clonic seizures (35%). Not all the myoclonus that presents is epileptic myoclonus and myoclonus co-occurs more commonly with cerebellar ataxia, than with other generalised seizures; dementia is a late sign.89 Myoclonus in MERRF may be intermittent or induced by photosensitivity or action. Focal onset seizures are not a feature. Status epilepticus is seen and can even be a presenting feature and stroke-like episodes are rare but recognised. Interictal EEG abnormalities include non-specific slowing of background rhythms, and generalised epileptiform discharges such as spikes, polyspike, and irregular and slow wave complexes. Myoclonic seizures may correlate with these EEG features and this may be suppressed by eye opening. Control of GTCS may be achieved with the first choice of AED, but pharmacological control of myoclonus is more challenging- perhaps in part – because some myoclonus may be cortical reflex myoclonus. A number of drugs have been reported to exacerbate myoclonus including carbamazepine, oxcarbazepine, phenytoin, lamotrigine, gabapentin, pregabalin and topiramate. Benzodiazepines, valproate and levetiracetam, piracetam are more commonly reported to produce a symptomatic benefit.90-92
2) Focal seizures and status epilepticus associated with POLG Recessive POLG is associated with a variety of phenotypic gestalts: mitochondrial recessive ataxia syndrome (MIRAS); myoclonic epilepsy myopathy sensory ataxia (MEMSA); spinocerebellar ataxia with epilepsy (SCAE); sensory ataxia with neuropathy, dysarthria, and ophthalmoplegia (SANDO); as
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ERUK – Mitochondrial Epilepsy – Lim, Thomas well as AHS, described earlier. It is notable that there are a plethora of unclassifiable patients and overlap syndrome also. Seizures predominate and are seen in 40% of adult-onset cases, but twice as many that present before the age of 5 years.93 Seizures are predominantly focal motor and epilepsia partialis continua is common as is nonconvulsive status epilepticus – with and without visual features. These features, which localise to the occipital lobe may not be obvious as seizures to the patient or their family as they consist of coloured lights, scotoma, or visual blurring.
3) Focal seizures and status epilepticus associated with m.3243A>G MELAS (mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes) is predominantly caused by a single mutation in MTTL1, m.3243A>G. Approximately a quarter of people with m.3243A>G disorders have seizures, and at least half of people with MELAS. People with MELAS may have a number of different seizures – these include provoked metabolic seizures exacerbated by hypoglycaemia, hyponatraemia or bowel stasis. People may also have focal-onset seizures in part caused by the sequalae of prior stroke-like episodes. However the most pathognomonic ‘seizure’ in MELAS is the stroke-like episode. This is conceptualised as a form of focal status epilepticus with a secondary encephalopathy. In fact some individuals will only have seizures in the context of strokelike episodes. Like POLG (above) epilepsia partialis continua can persist for weeks or months and may be overlooked by the patient and their physician as it may be as subtle as persistent flashing lights. Anecdotal reports of the benefits of non-invasive transcranial direct current stimulation in people with drug-refractory epilepsia partialis continua are promising as the clinical progression is ubiquitously poor.94
4) The other mitochondrial disorders Epileptic seizures are a rare feature of other mitochiondrial disorders including NARP (Neuropathy, ataxia, retinitis pigmentosa), KSS (Kearns–Sayre syndrome), LHON (Leber's hereditary optic neuropathy) and non syndromic mitocohondrial disorders. In these cases seizure control is similar to that of adults without mitochondrial disease in that ~70% have good seizure control.95
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Conclusions There are currently no specific curative treatments for other causes of paediatric mitochondrial epilepsy except from the rare primary coenzyme Q10 deficiencies, which can be successfully treated by coenzyme Q10 supplementation. Generally, the epileptic seizures should be managed by a paediatric neurologist with appropriate use of anticonvulsant medication, ketogenic diet and on occasion epilepsy surgery (vagus nerve stimulator). The management of other symptoms associated with mitochondrial disease (e.g. spasticity and dystonia) is important, as is prevention, recognition and prompt treatment of exacerbating factors such as fever, dehydration and poor nutrition. Monikers and acronyms are useful but may also create intellectual silos that can impair patient care: the myoclonus in MERRF may not be from ‘myoclonic epilepsy’ and the ‘stroke like episodes’ in MELAS are not conventional stroke: however we are far from re-coining the terms to be myoclonic ataxia with red ragged fibres and mitochondrial encephalopathy, lactic acidosis, and seizures. Similarly the delineation of individuals with m.3243A>G in to MIDD, CPEO or MELAS is often indistinct, or varies over time and many overlap disorders are recognised.
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References 1. 2.
3. 4. 5. 6.
7. 8.
9. 10. 11. 12. 13.
14.
15.
16. 17. 18.
19.
20.
Gorman GS, Schaefer AM, Ng Y, et al. Prevalence of nuclear and mitochondrial DNA mutations related to adult mitochondrial disease. Ann Neurol. 2015;77(5):753-759. Ng YS, Gorman G, Nesbitt V, et al. Phenotypes and Genotypes of Mitochondrial DiseaseFindings from A National Mitochondrial Disease Cohort (P2.061). Neurology. 2015;84(14 Supplement). Thompson K, Collier JJ, Glasgow RIC, et al. Recent advances in understanding the molecular genetic basis of mitochondrial disease. J Inherit Metab Dis. 2019. Sofou K, De Coo IF, Isohanni P, et al. A multicenter study on Leigh syndrome: disease course and predictors of survival. Orphanet J Rare Dis. 2014;9:52. El Sabbagh S, Lebre A-S, Bahi-Buisson N, et al. Epileptic phenotypes in children with respiratory chain disorders. Epilepsia. 2010;51(7):1225-1235. Lee HN, Eom S, Kim SH, et al. Epilepsy Characteristics and Clinical Outcome in Patients With Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-Like Episodes (MELAS). Pediatric neurology. 2016;64:59-65. Iizuka T, Sakai F, Suzuki N, et al. Neuronal hyperexcitability in stroke-like episodes of MELAS syndrome. Neurology. 2002;59(6):816-824. Lax NZ, Grady J, Laude A, et al. Extensive respiratory chain defects in inhibitory interneurones in patients with mitochondrial disease. Neuropathol Appl Neurobiol. 2016;42(2):180-193. Alston CL, Rocha MC, Lax NZ, Turnbull DM, Taylor RW. The genetics and pathology of mitochondrial disease. J Pathol. 2017;241(2):236-250. Koga Y, Akita Y, Nishioka J, et al. L-arginine improves the symptoms of strokelike episodes in MELAS. Neurology. 2005;64(4):710-712. Pfeffer G, Majamaa K, Turnbull DM, Thorburn D, Chinnery PF. Treatment for mitochondrial disorders. Cochrane Database Syst Rev. 2012(4):CD004426. Wiltshire E, Davidzon G, DiMauro S, et al. Juvenile Alpers disease. Arch Neurol. 2008;65(1):121-124. Harding BN, Alsanjari N, Smith SJ, et al. Progressive neuronal degeneration of childhood with liver disease (Alpers' disease) presenting in young adults. J Neurol Neurosurg Psychiatry. 1995;58(3):320-325. Anderson CM, Norquist BA, Vesce S, et al. Barbiturates induce mitochondrial depolarization and potentiate excitotoxic neuronal death. The Journal of neuroscience : the official journal of the Society for Neuroscience. 2002;22(21):9203-9209. Melegh B, Trombitas K. Valproate treatment induces lipid globule accumulation with ultrastructural abnormalities of mitochondria in skeletal muscle. Neuropediatrics. 1997;28(5):257-261. Skladal D, Halliday J, Thorburn DR. Minimum birth prevalence of mitochondrial respiratory chain disorders in children. Brain. 2003;126(Pt 8):1905-1912. Diogo L, Grazina M, Garcia P, et al. Pediatric mitochondrial respiratory chain disorders in the Centro region of Portugal. Pediatr Neurol. 2009;40(5):351-356. Darin N, Oldfors A, Moslemi AR, Holme E, Tulinius M. The incidence of mitochondrial encephalomyopathies in childhood: clinical features and morphological, biochemical, and DNA abnormalities. Ann Neurol. 2001;49(3):377-383. Castro-Gago M, Blanco-Barca MO, Campos-Gonzalez Y, Arenas-Barbero J, Pintos-Martinez E, Eiris-Punal J. Epidemiology of pediatric mitochondrial respiratory chain disorders in northwest Spain. Pediatr Neurol. 2006;34(3):204-211. Uusimaa J, Remes AM, Rantala H, et al. Childhood encephalopathies and myopathies: a prospective study in a defined population to assess the frequency of mitochondrial disorders. Pediatrics. 2000;105(3 Pt 1):598-603. Page 11
ERUK – Mitochondrial Epilepsy – Lim, Thomas 21.
22. 23.
24. 25.
26. 27. 28. 29. 30.
31. 32. 33. 34.
35.
36.
37.
38. 39.
40.
Yamazaki T, Murayama K, Compton AG, et al. Molecular diagnosis of mitochondrial respiratory chain disorders in Japan: focusing on mitochondrial DNA depletion syndrome. Pediatrics international : official journal of the Japan Pediatric Society. 2014;56(2):180-187. Ryan E, King MD, Rustin P, et al. Mitochondrial cytopathies, phenotypic heterogeneity and a high incidence. Irish medical journal. 2006;99(9):262-264. Verity CM, Winstone AM, Stellitano L, Krishnakumar D, Will R, McFarland R. The clinical presentation of mitochondrial diseases in children with progressive intellectual and neurological deterioration: a national, prospective, population-based study. Developmental medicine and child neurology. 2010;52(5):434-440. Munnich A, Rotig A, Chretien D, et al. Clinical presentation of mitochondrial disorders in childhood. J Inherit Metab Dis. 1996;19(4):521-527. Kisler JE, Whittaker RG, McFarland R. Mitochondrial diseases in childhood: a clinical approach to investigation and management. Developmental medicine and child neurology. 2010;52(5):422-433. Khurana D, Salganicoff L, Melvin J, et al. Epilepsy and Respiratory Chain Defects in Children with Mitochondrial Encephalopathies. Neuropediatrics. 2008;39(1):8-13. Debray FG, Lambert M, Chevalier I, et al. Long-term Outcome and Clinical Spectrum of 73 Pediatric Patients With Mitochondrial Diseases. PEDIATRICS. 2007;119(4):722-733. Scaglia F, Towbin JA, Craigen WJ, et al. Clinical spectrum, morbidity, and mortality in 113 pediatric patients with mitochondrial disease. Pediatrics. 2004;114(4):925-931. Skladal D, Sudmeier C, Konstantopoulou V, et al. The clinical spectrum of mitochondrial disease in 75 pediatric patients. Clinical pediatrics. 2003;42(8):703-710. Calvo SE, Compton AG, Hershman SG, et al. Molecular Diagnosis of Infantile Mitochondrial Disease with Targeted Next-Generation Sequencing. Science Translational Medicine. 2012;4(118):118ra110-118ra110. Carroll CJ, Brilhante V, Suomalainen A. Next-generation sequencing for mitochondrial disorders. British Journal of Pharmacology. 2014;171(8):1837-1853. Zsurka G, Kunz WS. Mitochondrial dysfunction and seizures: the neuronal energy crisis. The Lancet Neurology. 2015;14(9):956-966. Barghuti F, Elian K, Gomori JM, et al. The unique neuroradiology of complex I deficiency due to NDUFA12L defect. Molecular genetics and metabolism. 2008;94(1):78-82. Saada A, Vogel RO, Hoefs SJ, et al. Mutations in NDUFAF3 (C3ORF60), Encoding an NDUFAF4 (C6ORF66)-Interacting Complex I Assembly Protein, Cause Fatal Neonatal Mitochondrial Disease. The American Journal of Human Genetics. 2009;84(6):718-727. Valnot I, von Kleist-Retzow JC, Barrientos A, et al. A mutation in the human heme A:farnesyltransferase gene (COX10 ) causes cytochrome c oxidase deficiency. Hum Mol Genet. 2000;9(8):1245-1249. Ghezzi D, Saada A, D'Adamo P, et al. FASTKD2 Nonsense Mutation in an Infantile Mitochondrial Encephalomyopathy Associated with Cytochrome C Oxidase Deficiency. The American Journal of Human Genetics. 2008;83(3):415-423. Horvath R, Abicht A, Holinski-Feder E, et al. Leigh syndrome caused by mutations in the flavoprotein (Fp) subunit of succinate dehydrogenase (SDHA). J Neurol Neurosurg Psychiatry. 2006;77(1):74-76. Schuelke M, Smeitink J, Mariman E, et al. Mutant NDUFV1 subunit of mitochondrial complex I causes leukodystrophy and myoclonic epilepsy. Nature Genetics. 1999;21(3):260-261. van den Heuvel L, Ruitenbeek W, Smeets R, et al. Demonstration of a New Pathogenic Mutation in Human Complex I Deficiency: A 5-bp Duplication in the Nuclear Gene Encoding the 18-kD (AQDQ) Subunit. The American Journal of Human Genetics. 1998;62(2):262-268. Loeffen J, Smeitink J, Triepels R, et al. The first nuclear-encoded complex I mutation in a patient with Leigh syndrome. Am J Hum Genet. 1998;63(6):1598-1608.
Page 12
ERUK – Mitochondrial Epilepsy – Lim, Thomas 41. 42. 43.
44.
45.
46.
47.
48.
49.
50.
51. 52. 53. 54. 55. 56. 57.
58.
59.
Wolf NI, Rahman S, Schmitt B, et al. Status epilepticus in children with Alpers’ disease caused byPOLG1mutations: EEG and MRI features. Epilepsia. 2009;50(6):1596-1607. Kollberg G, Darin N, Benan K, et al. A novel homozygous RRM2B missense mutation in association with severe mtDNA depletion. Neuromuscular Disorders. 2009;19(2):147-150. Elpeleg O, Miller C, Hershkovitz E, et al. Deficiency of the ADP-Forming Succinyl-CoA Synthase Activity Is Associated with Encephalomyopathy and Mitochondrial DNA Depletion. The American Journal of Human Genetics. 2005;76(6):1081-1086. Glamuzina E, Brown R, Hogarth K, et al. Further delineation of pontocerebellar hypoplasia type 6 due to mutations in the gene encoding mitochondrial arginyl-tRNA synthetase, RARS2. Journal of inherited metabolic disease. 2011;35(3):459-467. Molinari F, Kaminska A, Fiermonte G, et al. Mutations in the mitochondrial glutamate carrierSLC25A22in neonatal epileptic encephalopathy with suppression bursts. Clinical Genetics. 2009;76(2):188-194. López LC, Schuelke M, Quinzii CM, et al. Leigh syndrome with nephropathy and CoQ10 deficiency due to decaprenyl diphosphate synthase subunit 2 (PDSS2) mutations. The American Journal of Human Genetics. 2006;79(6):1125-1129. Duncan AJ, Bitner-Glindzicz M, Meunier B, et al. A nonsense mutation in COQ9 causes autosomal-recessive neonatal-onset primary coenzyme Q10 deficiency: a potentially treatable form of mitochondrial disease. The American Journal of Human Genetics. 2009;84(5):558-566. Mollet J, Delahodde A, Serre V, et al. CABC1 gene mutations cause ubiquinone deficiency with cerebellar ataxia and seizures. The American Journal of Human Genetics. 2008;82(3):623-630. Sanganahalli BG, Herman P, Hyder F, Kannurpatti SS. Mitochondrial calcium uptake capacity modulates neocortical excitability. Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism. 2013;33(7):1115-1126. Trotti D, Danbolt NC, Volterra A. Glutamate transporters are oxidant-vulnerable: a molecular link between oxidative and excitotoxic neurodegeneration? Trends in pharmacological sciences. 1998;19(8):328-334. Hardie DG, Ross FA, Hawley SA. AMPK: a nutrient and energy sensor that maintains energy homeostasis. Nature reviews Molecular cell biology. 2012;13(4):251-262. Kudin AP, Zsurka G, Elger CE, Kunz WS. Mitochondrial involvement in temporal lobe epilepsy. Experimental neurology. 2009;218(2):326-332. Nguyen KV, Sharief FS, Chan SS, Copeland WC, Naviaux RK. Molecular diagnosis of Alpers syndrome. J Hepatol. 2006;45(1):108-116. Cohen BH, Chinnery PF, Copeland WC. POLG-Related Disorders. In: Adam MP, Ardinger HH, Pagon RA, et al., eds. GeneReviews((R)). Seattle (WA)1993. Harding BN. Progressive neuronal degeneration of childhood with liver disease (AlpersHuttenlocher syndrome): a personal review. Journal of child neurology. 1990;5(4):273-287. Horvath R, Hudson G, Ferrari G, et al. Phenotypic spectrum associated with mutations of the mitochondrial polymerase gamma gene. Brain. 2006;129(Pt 7):1674-1684. Uusimaa J, Hinttala R, Rantala H, et al. Homozygous W748S mutation in the POLG1 gene in patients with juvenile-onset Alpers syndrome and status epilepticus. Epilepsia. 2008;49(6):1038-1045. Anagnostou ME, Ng YS, Taylor RW, McFarland R. Epilepsy due to mutations in the mitochondrial polymerase gamma (POLG) gene: A clinical and molecular genetic review. Epilepsia. 2016;57(10):1531-1545. Farnum GA, Nurminen A, Kaguni LS. Mapping 136 pathogenic mutations into functional modules in human DNA polymerase gamma establishes predictive genotype-phenotype
Page 13
ERUK – Mitochondrial Epilepsy – Lim, Thomas
60. 61.
62. 63. 64.
65.
66.
67. 68. 69.
70. 71.
72. 73. 74. 75.
76. 77. 78. 79.
correlations for the complete spectrum of POLG syndromes. Biochim Biophys Acta. 2014;1837(7):1113-1121. Saneto RP, Cohen BH, Copeland WC, Naviaux RK. Alpers-Huttenlocher syndrome. Pediatr Neurol. 2013;48(3):167-178. Pronicka E, Weglewska-Jurkiewicz A, Pronicki M, et al. Drug-resistant epilepsia and fulminant valproate liver toxicity. Alpers-Huttenlocher syndrome in two children confirmed post mortem by identification of p.W748S mutation in POLG gene. Medical science monitor : international medical journal of experimental and clinical research. 2011;17(4):Cr203-209. Schwabe MJ, Dobyns WB, Burke B, Armstrong DL. Valproate-induced liver failure in one of two siblings with Alpers disease. Pediatr Neurol. 1997;16(4):337-343. Nguyen KV, Ostergaard E, Ravn SH, et al. POLG mutations in Alpers syndrome. Neurology. 2005;65(9):1493-1495. Patel KP, O'Brien TW, Subramony SH, Shuster J, Stacpoole PW. The spectrum of pyruvate dehydrogenase complex deficiency: clinical, biochemical and genetic features in 371 patients. Mol Genet Metab. 2012;106(3):385-394. Soreze Y, Boutron A, Habarou F, et al. Mutations in human lipoyltransferase gene LIPT1 cause a Leigh disease with secondary deficiency for pyruvate and alpha-ketoglutarate dehydrogenase. Orphanet J Rare Dis. 2013;8:192. Baker PR, 2nd, Friederich MW, Swanson MA, et al. Variant non ketotic hyperglycinemia is caused by mutations in LIAS, BOLA3 and the novel gene GLRX5. Brain. 2014;137(Pt 2):366379. Schiff M, Mine M, Brivet M, et al. Leigh's disease due to a new mutation in the PDHX gene. Ann Neurol. 2006;59(4):709-714. Quinonez SC, Leber SM, Martin DM, Thoene JG, Bedoyan JK. Leigh syndrome in a girl with a novel DLD mutation causing E3 deficiency. Pediatr Neurol. 2013;48(1):67-72. Mayr JA, Freisinger P, Schlachter K, et al. Thiamine pyrophosphokinase deficiency in encephalopathic children with defects in the pyruvate oxidation pathway. Am J Hum Genet. 2011;89(6):806-812. Prasad C, Rupar T, Prasad AN. Pyruvate dehydrogenase deficiency and epilepsy. Brain and Development. 2011;33(10):856-865. BARNERIAS C, SAUDUBRAY J-M, TOUATI G, et al. Pyruvate dehydrogenase complex deficiency: four neurological phenotypes with differing pathogenesis. Developmental Medicine & Child Neurology. 2010;52(2):e1-e9. Santra S, Gilkerson RW, Davidson M, Schon EA. Ketogenic treatment reduces deleted mitochondrial DNAs in cultured human cells. Annals of neurology. 2004;56(5):662-669. Ahola-Erkkila S, Carroll CJ, Peltola-Mjosund K, et al. Ketogenic diet slows down mitochondrial myopathy progression in mice. Hum Mol Genet. 2010;19(10):1974-1984. Purhonen J, Rajendran J. Ketogenic diet attenuates hepatopathy in mouse model of respiratory chain complex III deficiency caused by a Bcs1l mutation. 2017;7(1):957. Kanabus M, Fassone E, Hughes SD, et al. The pleiotropic effects of decanoic acid treatment on mitochondrial function in fibroblasts from patients with complex I deficient Leigh syndrome. J Inherit Metab Dis. 2016;39(3):415-426. Lake NJ, Compton AG, Rahman S, Thorburn DR. Leigh syndrome: One disorder, more than 75 monogenic causes. Ann Neurol. 2016;79(2):190-203. Rahman J, Noronha A, Thiele I, Rahman S. Leigh map: A novel computational diagnostic resource for mitochondrial disease. Ann Neurol. 2017;81(1):9-16. Rahman S, Blok RB, Dahl HH, et al. Leigh syndrome: clinical features and biochemical and DNA abnormalities. Ann Neurol. 1996;39(3):343-351. Baertling F, Rodenburg RJ, Schaper J, et al. A guide to diagnosis and treatment of Leigh syndrome. J Neurol Neurosurg Psychiatry. 2014;85(3):257-265.
Page 14
ERUK – Mitochondrial Epilepsy – Lim, Thomas 80. 81. 82.
83. 84. 85.
86. 87.
88.
89. 90.
91. 92. 93. 94.
95.
Ruhoy IS, Saneto RP. The genetics of Leigh syndrome and its implications for clinical practice and risk management. Appl Clin Genet. 2014;7:221-234. Zhang Y, Yang YL, Sun F, et al. Clinical and molecular survey in 124 Chinese patients with Leigh or Leigh-like syndrome. Journal of inherited metabolic disease. 2007;30(2):265-265. Jay AM, Conway RL, Feldman GL, Nahhas F, Spencer L, Wolf B. Outcomes of individuals with profound and partial biotinidase deficiency ascertained by newborn screening in Michigan over 25 years. Genetics in medicine : official journal of the American College of Medical Genetics. 2015;17(3):205-209. Haack TB, Klee D, Strom TM, et al. Infantile Leigh-like syndrome caused by SLC19A3 mutations is a treatable disease. Brain. 2014;137(Pt 9):e295. Hargreaves IP. Coenzyme Q10 as a therapy for mitochondrial disease. Int J Biochem Cell Biol. 2014;49:105-111. Viscomi C, Burlina AB, Dweikat I, et al. Combined treatment with oral metronidazole and Nacetylcysteine is effective in ethylmalonic encephalopathy. Nature medicine. 2010;16(8):869-871. Dionisi-Vici C, Diodato D, Torre G, et al. Liver transplant in ethylmalonic encephalopathy: a new treatment for an otherwise fatal disease. Brain. 2016;139(Pt 4):1045-1051. van Dongen S, Brown RM, Brown GK, Thorburn DR, Boneh A. Thiamine-Responsive and Nonresponsive Patients with PDHC-E1 Deficiency: A Retrospective Assessment. JIMD reports. 2015;15:13-27. Banka S, de Goede C, Yue WW, et al. Expanding the clinical and molecular spectrum of thiamine pyrophosphokinase deficiency: a treatable neurological disorder caused by TPK1 mutations. Mol Genet Metab. 2014;113(4):301-306. Mancuso M, Orsucci D, Angelini C, et al. Phenotypic heterogeneity of the 8344A>G mtDNA "MERRF" mutation. Neurology. 2013;80(22):2049-2054. Michelucci R, Pasini E, Riguzzi P, Andermann E, Kälviäinen R, Genton P. Myoclonus and seizures in progressive myoclonus epilepsies: pharmacology and therapeutic trials. Epileptic Disorders. 2016;18(s2):S145-S153. Whittaker RG, Devine HE, Gorman GS, et al. Epilepsy in adults with mitochondrial disease: a cohort study. Annals of neurology. 2015;78(6):949-957. Steele HE, Chinnery PF. Mitochondrial causes of epilepsy: evaluation, diagnosis, and treatment. Paper presented at: Seminars in neurology2015. Tang S, Wang J, Lee NC, et al. Mitochondrial DNA polymerase gamma mutations: an ever expanding molecular and clinical spectrum. J Med Genet. 2011;48(10):669-681. Ng YS, van Ruiten H, Lai HM, et al. The adjunctive application of transcranial direct current stimulation in the management of de novo refractory epilepsia partialis continua in adolescent-onset POLG-related mitochondrial disease. Epilepsia open. 2018;3(1):103-108. Chevallier JA, Von Allmen GK, Koenig MK. Seizure semiology and EEG findings in mitochondrial diseases. Epilepsia. 2014;55(5):707-712.
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Highlights The presentation of seizures in children and adults differs greatly but drug resistance is the norm Half of patients with POLG mitochondrial disorders first present with epileptic seizures The epileptic seizures leading to ‘stroke-like episodes’ and atrophy are a potent cause of dementia and decline in MELAS There are rare examples of paediatric onset mitochondrial disorders that specific treatments, such as high-dose thiamine
Author disclosures R Thomas has received honoraria from Eisai, GW Pharma, Sanofi, UCB Pharma, Zogenix and meeting support from LivaNova and Bilal.