Mitochondrial disease-associated seizures (MDAS)

Mitochondria are widely recognized as the energy-producing “powerhouse” of a cell.¹ 

The mitochondrial respiratory chain is responsible for generating adenosine triphosphate (ATP) through oxidative phosphorylation. A mutation in the chain’s genome may compromise its function, resulting in cellular ATP deficiency.² Consequently, the clinical features of mitochondrial disorders are most apparent in tissues with high-energy demands, including the central and peripheral nervous systems.² 

Mitochondrial disease, which can arise at any age,² affects approximately 1 in 5,000,³ with seizures and epilepsy being common features. Seizure rates are higher among people with mitochondrial diseases than in the general population.⁴

According to the Orphanet database, several diseases fall under the umbrella of mitochondrial disease associated with seizures.⁵ These include, but are not limited to: 

• Alpers-Huttenlocher syndrome 
• Coenzyme Q10 deficiency 
• Fumaric aciduria 
• Isolated complex I deficiency 
• Kearns-Sayre syndrome (KSS) 
• Leigh syndrome 
• Lipoic acid synthetase deficiency 
• MEHMO (mental retardation, epileptic seizures, hypogenitalism, microcephaly and obesity) syndrome 
• Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) 
• Myoclonic epilepsy with ragged red fibers (MERRF) 
• Mitochondrial neurogastrointestinal encephalomyopathy 
• Neuropathy, ataxia, and retinitis pigmentosa (NARP) syndrome 
• Oxoglutaric aciduria 
• Pyruvate dehydrogenase deficiency 
• Sensory ataxic neuropathy-dysarthria-ophthalmoparesis syndrome 

For adults with mitochondrial disorders where seizures are a common feature, they may be broadly grouped into four main categories:  

1. MERRF  
2. Recessive DNA polymerase subunit gamma (POLG) (eg, mitochondrial recessive ataxia syndrome [MIRAS])  
3. Focal seizures and status epilepticus associated with m.3243A >G 
4. Other mitochondrial disorders (eg, NARP, KSS, Leber’s hereditary optic neuropathy [LHON], and non-syndromic mitochondrial disorders)⁶ 

Since a primary function of mitochondria is to generate cellular ATP, it has long been assumed that epilepsy in mitochondrial disorders is a consequence of neuronal energy depletion. However, if this were the case, then 100% of patients with mitochondrial disease would be expected to present with seizures.⁷ 

Since this is not the case, there are likely other pathophysiological mechanisms at play, and different mechanisms are likely to predominate in different mitochondrial disorders since mitochondrial function varies between neurons and astrocytes, between different types of neurons, and in different brain regions.⁷ 

Beyond energy deficiency, potential mechanisms causing seizures in mitochondrial disorders found in animal models and in vitro studies include: 

• Oxidative stress (ie, ROS generation, Sod2 gene dysregulation, 3-hydroxyisobutyryl-CoA hydrolase [HIBCH] deficiency)^8–10  
• Calcium homeostasis (ie, aberrant signaling and impaired handling),^11–13 POLG gene mutations¹⁴  
• Cerebral folate deficiency^15,16  
• Defective biosynthesis of coenzyme Q10^17–19  
• Glutamate transporter mutations^20–23  
• Depletion of L-arginine and/or L-citrulline^24–26  
• Nicotinamide adenine dinucleotide (NAD⁺) depletion^28–30 

These causal factors feed into a complex interrelationship, whereby a molecular cascade is triggered, with each component feeding-back to other components of the cascade, leading to a vicious spiral of mitochondrial dysfunction, seizure generation, and cell death.⁷ 

A study of individuals with childhood-onset mitochondrial disease (N=174) found that the average age of their first seizure was 2.86 years.⁴ Individuals with childhood-onset epilepsy who go on to receive a diagnosis of a respiratory chain defect often experience preceding symptoms of failure to thrive, psychomotor delay, ataxia, encephalomyopathy, multi-organ symptomatology, or a fluctuating clinical course.^2,31,32 The presentation of epilepsy in children can be highly varied, from infantile spasms, generalized seizures, focal seizures, and myoclonic epilepsy to refractory status epilepticus.⁶ 

Furthermore, the seizures in mitochondrial disorders differ from seizures in other contexts. Specifically, they are more frequently of posterior quadrant and occipital lobe onset, more likely to present with non-convulsive status epilepticus which may last months, are multi-drug resistant from the onset, and may only minimally correlate with electroencephalogram (EEG).⁶ 

The current prevalence of childhood-onset mitochondrial disorders has been predicted to range from 5 to 15 cases per 100,000.^6,33–39 Although the exact prevalence of mitochondrial disease-associated seizures in children is unknown, seizures are commonly reported in 20–60% of individuals with biochemically or genetically confirmed diseases.^{6,31,35,37,40,41} 

In adults in the Northeast of England, the minimum prevalence rate for mitochondrial mutations has been estimated as 1 in 5,000.⁴² Results based on a group of 182 patients with mitochondrial disease in England found that the prevalence of epilepsy was 23.1%, with a mean age of epilepsy onset of 29.4 years.⁴³ 

Diagnosis of mitochondrial disease is often challenging unless the symptoms are clearly identified as part of a specific mitochondrial mutation (such as in MELAS or MERRF).^2,44 Recognition of mitochondrial disorders in children is particularly challenging, and diagnosis can be even harder. Compared with adults, children are more likely to have a nuclear DNA mutation, where classic syndromic findings tend to be absent.⁴⁴ 

In adults, diagnosis of a mitochondrial disorder is comparatively straightforward. Adults tend to present with well-defined mitochondrial syndromes and generally carry mitochondrial DNA mutations that can be easily identified.⁴⁵ 

Diagnosis often relies on genetic testing, in addition to histochemical and biochemical analysis of tissue biopsies.⁴⁶ Multi-gene panel testing has traditionally been used to determine genetic epilepsy syndromes associated with mitochondrial disorders. However, assessment panels can quickly become obsolete and screening for mutations of the underlying genetic defects in epilepsy is often complicated by the many potential responsible genes. Newer gene discoveries and whole exome or genome sequencing, including next generation sequencing (NGS), are increasingly being used as diagnostic tools. These techniques allow for the identification of pathogenic variants and variable sites implemented in the development of epilepsy.^6,47–49 

EEGs have limited utility for diagnosis, given that there is not a discernable “characteristic mitochondrial EEG”. That said, there are some features potentially suggestive of a mitochondrial disorder, including abnormalities with a posterior predilection, periodic lateralized epileptiform discharges (suggestive of MELAS in children), and focal high-voltage delta waves with polyspikes (may occur in acute stroke-like lesions in MELAS).² 

Likewise, neuroimaging is of limited value given that brain imaging may be normal, especially in nonsyndromic mitochondrial disease or early in the disease course. Nonetheless, features frequently identified in people with respiratory chain defects and seizures include prominent and progressive cerebral atrophy, cortical signal change, stroke-like episodes, and symmetrical extracortical lesions.² 

While the rates of premature death are high among people with mitochondrial disease,^50,51 the added presence of epilepsy may not increase the risk of mortality.⁴³ 

There are currently no specific curative treatments for the causes of pediatric mitochondrial disease-associated seizures, except for the rare primary coenzyme Q10 deficiencies, which can be successfully treated by coenzyme Q10 supplementation.⁶ While mitochondrial disorders are not curable, many of the typical comorbidities can be treated.  

Generally, seizures should be managed by a pediatric neurologist with appropriate use of anticonvulsant medication.⁵ Choice of medication should be guided largely by whether the seizure has a focal or generalized onset.² As a general rule, especially in disorders associated with mutation in DNA polymerase subunit gamma (POLG), sodium valproate should be avoided because hepato-toxicity can be severe, sudden, and fatal.⁶ 

Given that seizures in mitochondrial disorders may be triggered, or exacerbated, by metabolic disturbance, physicians should aim to regulate the biochemical milieu by ensuring appropriate hydration, normalizing blood glucose, managing acidosis, and treating concomitant infections where present.² 

While the prognostic evidence is limited, a ketogenic diet has been shown to reduce seizures, and may be an adjunct to traditional pharmaceutical agents in the acute setting.^2,52–55 

On occasion, vagus nerve stimulation has been used, however there is currently little evidence for its efficacy. Palliative care should also be a consideration for clinical teams.² 

1. Giacomello M, Pyakurel A, Glytsou C, et al. Nat Rev Molec Biol 2020;21:204–224. 
2. Steele HE, Chinnery PF. Semin Neurol 2015;35(3):300–309. 
3. Schaefer AM, McFarland R, Blakely EL, et al. Ann Neurol 2008;63:35–39. 
4. Saneto RP. J Inborn Errors Metab 2017;5:1–12.  
5. Orphanet classification of rare neurological diseases. Available at: https://www.orpha.net/consor/cgi-bin/Disease_Classif.php?lng=EN&data_id=181&PatId=19015&search=Disease_Classif_Simple&new=1. Last accessed July 2022.
6. Lim A, Thomas RH. Eur J Paediatr Neurol 2020;24:47–52.
7. Rahman S. Epilep Behav 2015; 49:71–75. 
8. Jacobson J, Duchen MR, Hothersall J, et al. J Neurochem 2005;95:388–395. 
9. Liang LP, Patel M. Free Radic Biol Med 2004;36:542–554. 
10. Ferdinandusse S, Waterham HR, Heales SJ, et al. Orphanet J Rare Dis 2013;8:188. 
11. Steinlein OK. Cell Tissue Res 2014;357:385–393. 
12. Kann O, Kovacs R. Am J Physiol Cell Physiol 2007;292:C641–657. 
13. Kunz WS. Curr Opin Neurol 2002;15:179–184. 
14. Rahman S. Dev Med Child Neurol 2012;54:397–406. 
15. Hasselmann O, Blau N, Ramaekers VT, et al. Mol Genet Metab 2010;99:58–61. 
16. Pineda M, Ormazabal A, López-Gallardo E, et al. Ann Neurol 2006;59:394–398. 
17. Rahman S, Clarke CF, Hirano M. Neuromuscul Disord 2012;22:76–86. 
18. Brea-Calvo G, Haack TB, Karall D, et al. Am J Hum Genet 2015;96:309–317. 
19. Desbats MA, Lunardi G, Doimo M, et al. J Inherit Metab Dis 2015;38:145–156. 
20. Cohen R, Basel-Vanagaite L, Goldberg-Stern H, et al. Eur J Paediatr Neurol 2014;18:801–805. 
21. Molinari F, Kaminska A, Fiermonte G, et al. Clin Genet 2009;76:188–194. 
22. Molinari F, Raas-Rothschild A, Rio M, et al. Am J Hum Genet 2005;76:334–339. 
23. Poduri A, Heinzen EL, Chitsazzadeh V, et al. Ann Neurol 2013;74:873–882. 
24. Koga Y, Povalko N, Nishioka J, et al. Ann N Y Acad Sci 2010;1201:104–110. 
25. Naini A, Kaufmann P, Shanske S, et al. J Neurol Sci 2005;229–230:187–193. 
26. El-Hattab AW, Hsu JW, Emrick LT, et al. Mol Genet Metab 2012;105:607–614. 
27. Debray FG, Lambert M, Allard P, et al. J Child Neurol 2010;25:1000–1002. 
28. Lightowlers RN, Chrzanowska-Lightowlers ZM. EMBO Mol Med 2014;6:705–707. 
29. Cerutti R, Pirinen E, Lamperti C, et al. Cell Metab 2014;19:1042–1049. 
30. Khan NA, Auranen M, Paetau I, et al. EMBO Mol Med 2014;6:721–731. 
31. El Sabbagh S, Lebre AS, Bahi-Buisson N, et al. Epilepsia 2010;51(7):1225–1235. 
32. Kang HC, Kwon JW, Lee YM, et al. Childs Nerv Syst 2007;23(11):1301–1307. 
33. Skladal D, Halliday J, Thorburn DR. Brain 2003;126:1905–1912. 
34. Diogo L, Grazina M, Garcia P, et al. Pediatr Neurol 2009;40(5):351–356. 
35. Darin N, Oldfors A, Moslemi AR, et al. Ann Neurol 2001;49:377–383. 
36. Castro-Gago M, Blanco-Barca MO, Campos-Gonzalez Y, et al. Pediatr Neurol 2006;34(3):204–211. 
37. Uusimaa J, Remes AM, Rantala H, et al. Pediatrics 2000;105(3):598–603. 
38. Yamazaki T, Murayama K, Compton AG, et al. Pediatr Int 2014;56:180–187. 
39. Ryan E, King MD, Rustin P, et al. Ir Med J 2006:99;262–264. 
40. Verity CM, Winstone AM, Stellitano L, et al. Dev Med Child Neurol 2010;52:434–440. 
41. Skladal D, Sudmeier C, Konstantopoulou V, et al. Clin Pediatr 2003;42:703–710. 
42. Gorman GS, Schaefer AM, Ng Y, et al. Ann Neurol 2015;77:753–759. 
43. Whittaker RG, Devine HE, Gorman GS, et al. Ann Neurol 2015;78(6):949–957.  
44. Chevallier JA, Von Allmen GK, Koenig MK. Epilepsia 2014;55:707–712. 
45. Koenig MK. Pediatr Neurol 2008;38(5):305–313. 
46. Gorman GS, Chinnery PF, DiMauro S, et al. Nat Rev Dis Primers 2016;2:16080. 
47. Calvo SE, Compton AG, Hershman SG, et al. Sci Transl Med 2012;4(118):118ra110. 
48. Carroll CJ, Brilhante V, Suomalainen A. Br J Pharmacol 2014:171(8):1837–1853. 
49. Khamdiyeva OK, Tileulesa ZB, Baratzhanova GS, et al. Int J Biol Chem 2020;13:53–58. 
50. Scaglia F, Towbin JA, Craigen WJ, et al. Pediatrics 2004;114;925–931. 
51. Barends M, et al. JIMD Reports 2016;26:103–113. 
52. Lee YM, Kang HC, Lee JS, et al. Epilepsia 2008;49(4):685–690. 
53. Joshi CN, Greenberg CR, Mhanni AA, et al. Pediatr Neurol 2009;40(4):314–316. 
54. Martikainen MH, Päivärinta M, Jääskeläinen S, et al. Epileptic Disord 2012;14(4):438–441. 
55. Kang HC, Lee YM, Kim HD, et al. Epilepsia 2007;48(1):82–88.