**6. Non-syndromic pictures**

Seizures can manifest in many patients with infantile MEs, who were diagnosed on the bases of their biochemical defects but still not classified genetically. Epilepsy may manifest as catastrophic neonatal forms, neonatal myoclonic encephalopathies, infantile spasms, refractory status epilepticus, epilepsia partialis continua, myoclonic epilepsy (El Sabbagh et al , 2010), Landau Kleffner, Lennox-Gastaut syndromes, unclassified generalized epilepsy or partial epilepsy (Canafoglia et al, 2001; Lee et al, 2008). Thus, epilepsy may be either focal or generalized and its severity varies in different case series, though the appearance of drugresistant seizures possibly marks a severe turn in the disease with high risk of neurological deterioration and fatal outcome (El Sabbagh et al , 2010).

Among various biochemical defects, it's worth noting complex I deficiency. Complex I deficiency, due to mutations in mtDNA genes coding for ND subunits, has been described in patients with heterogeneous syndromic (MELAS, Leigh) and non-syndromic MEs, frequently associated with severe epilepsy (Antozzi et al, 1995; Malfatti et al, 2007).

Mitochondrial dysfunctions may be implicated also in sporadic forms of partial epilepsy such is temporal lobe epilepsy, since severe impairment of the respiratory chain activity has been detected *in vitro* on hippocampus samples from patients with drug resistant epilepsy. This observation was also supported by various evidences obtained *in vivo* using neuroimaging techniques (Zsurka and Kunz, 2010).

#### **7. Pyruvate dehydrogenase (PDH) Deficiency (MIM ID #312170)**

Pyruvate dehydrogenase complex (PDHC) is a mitochondrial matrix enzyme complex that catalyzes the oxidative decarboxylation of pyruvate to acetyl CoA, nicotinamide adenine dinucleotide (the reduced form, NADH), and CO2. This reaction constitutes the bridge between anaerobic and aerobic cerebral energy metabolism. The great majority of PDH complex deficiencies results from mutations in the X-linked pyruvate dehydrogenase (E1) alpha subunit gene (PDHA1). Gene map locus: *Xp22.2-p22.1.* 

The clinical severity can vary from early neonatal presentation with severe lactic acidosis to a progressive disease with mental retardation and neurological complications. Some females are only mildly affected or asymptomatic in relation to the pattern of X-inactivation.

Epilepsy has been reported with a high frequency in children with PDH deficiency (Canafoglia et al, 2001; Kang et al, 2007). Epilepsy is frequently severe and may have variable characteristics including some forms of epileptic encephalopathy.

Epilepsy in Mitochondrial Disorders 293

Goto Y, Horai S, Matsuoka T, Koga Y, Nihei K, Kobayashi M, Nonaka I. Mitochondrial

Iizuka T, Sakai F, Suzuki N, Hata T, Tsukahara S, Fukuda M, Takiyama Y. Neuronal

Iizuka T, Sakai F, Kan S, Suzuki N. Slowly progressive spread of the stroke-like lesions in

Kang HC, Kwon JW, Lee YM, Kim HD, Lee HJ, Hahn SH. Nonspecific mitochondrial

Lee YM, Kang HC, Lee JS, Kim SH, Kim EY, Lee SK, Slama A, Kim HD. Mitochondrial

Malfatti E, Bugiani M, Invernizzi F, de Souza CF, Farina L, Carrara F, Lamantea E, Antozzi

Mancuso M, Filosto M, Mootha VK, Rocchi A, Pistolesi S, Murri L, DiMauro S, Siciliano GA.

Melone MAB, Tessa A, Petrini S, Lus G, Sampaolo S, di Fede G, Santorelli FM, Cotrufo R.

Nakamura M, Nakano S, Gato Y-i, Ozawa M, Nagahama Y, Fukuyama H, Akiguchi I, Kaji

Roger J, Pellissier JF, Dravet C, Bureau-Paillas M, Arnoux M, Larrieu JL. Spinocerebellar

Shoffner JM, Wallace DC. Mitochondrial genetics: principles and practice. Am J Hum Genet

Spinazzola A, Zeviani M. Disorders of nuclear-mitochondrial intergenomic signaling. Gene.

Tiranti V, Hoertnagel K, Carrozzo R, Galimberti C, Munaro M, Granatiero M, Zelante L,

Neurol Sci 1980;47:117-33

Neurology 1992;42: 545-550.

MELAS. Neurology 2003;61:1238–44.

encephalopathy. Brain. 2007;130:1894-904.

phenotype. Arch Neurol 2004;61: 269-272.

case report. Rev Neurol (Paris) 1982;138:187-200.

Res Commun 1995;214: 86-93.

2005 Jul 18;354:162-8. Review.

Childs Nerv Syst. 2007;23:1301-7.

Epilepsia. 2008;49(4):685-90.

2004;62:2119-2121.

1992;51:1179-1186.

1998;63:1609-21.

2002;59:816–24.

Light-and electron-microscopic studies of two cases and review of literature. J

myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS): a correlative study of the clinical features and mitochondrial DNA mutation.

hyperexcitability in stroke-like episodes of MELAS syndrome.Neurology

disease with epilepsy in children: diagnostic approaches and epileptic phenotypes.

respiratory chain defects: underlying etiology in various epileptic conditions.

C, Confalonieri P, Sanseverino MT, Giugliani R, Uziel G, Zeviani M. Novel mutations of ND genes in complex I deficiency associated with mitochondrial

novel mitochondrial tRNA-phe mutation causes MERRF syndrome. Neurology

Revelation of a new mitochondrial DNA mutation (G12147A) in a MELAS/MERFF

R, Kimura, J. A novel point mutation in the mitochondrial tRNA (ser(UCN)) gene detected in a family with MERRF/MELAS overlap syndrome. Biochem Biophys

degeneration, optic atrophy, epilepsy, myoclonus and mitochondrial myopathy: a

Gasparini P, Marzella R, Rocchi M, Bayona-Bafaluy MP, Enriquez JA, Uziel G, Bertini E, Dionisi-Vici C, Franco B, Meitinger T, Zeviani M. Mutations of SURF-1 in Leigh disease associated with cytochrome c oxidase deficiency. Am J Hum Genet.
