Article

Recessive twinkle mutations cause severe epileptic encephalopathy

Division of Child Neurology, Helsinki University Central Hospital, Helsinki, Finland.
Brain (Impact Factor: 10.23). 04/2009; 132(Pt 6):1553-62. DOI: 10.1093/brain/awp045
Source: PubMed

ABSTRACT The C10orf2 gene encodes the mitochondrial DNA helicase Twinkle, which is one of the proteins important for mitochondrial DNA maintenance. Dominant mutations cause multiple mitochondrial DNA deletions and progressive external ophthalmoplegia, but recent findings associate recessive mutations with mitochondrial DNA depletion and encephalopathy or hepatoencephalopathy. The latter clinical phenotypes resemble those associated with recessive POLG1 mutations. We have previously described patients with infantile onset spinocerebellar ataxia (MIM271245) caused either by homozygous (Y508C) or compound heterozygous (Y508C and A318T) Twinkle mutations. Our earlier reports focused on the spinocerebellar degeneration, but the 20-year follow-up of 23 patients has shown that refractory status epilepticus, migraine-like headaches and severe psychiatric symptoms are also pathognomonic for the disease. All adolescent patients have experienced phases of severe migraine, and seven patients had antipsychotic medication. Epilepsia partialis continua occurred in 15 patients leading to generalized epileptic statuses in 13 of them. Eight of these patients have died. Valproate treatment was initiated on two patients, but had to be discontinued because of a severe elevation of liver enzymes. The patients recovered, and we have not used valproate in infantile onset spinocerebellar ataxia since. The first status epilepticus manifested between 15 and 34 years of age in the homozygotes, and at 2 and 4 years in the compound heterozygotes. The epileptic statuses lasted from several days to weeks. Focal, stroke-like lesions were seen in magnetic resonance imaging, but in infantile onset spinocerebellar ataxia these lesions showed no predilection. They varied from resolving small cortical to large hemispheric oedematous lesions, which reached from cerebral cortex to basal ganglia and thalamus and caused permanent necrotic damage and brain atrophy. Brain atrophy with focal laminar cortical necrosis and hippocampal damage was confirmed on neuropathological examination. The objective of our study was to describe the development and progression of encephalopathy in infantile onset spinocerebellar ataxia syndrome, and compare the pathognomonic features with those in other mitochondrial encephalopathies.

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    • "None Short stature Alpers-Huttenlocher, MTDPS6, MELAS, MERFF, NARP, Coenzyme Q10 deficiency, MLASA2, ACADSD (Hammans et al., 1995; Holt et al., 1990; Karadimas et al., 2006; Kurt et al., 2010; Riley et al., 2010; Rosing et al., 1985; Rotig et al., 2007; Tein et al., 2008) Weight loss MNGIE, MLASA2 (Nishino et al., 2000; Riley et al., 2010) Cerebral atrophy Alpers-Huttenlocher, MERFF, NARP, MTDPS5, Coenzyme Q10 deficiency (Carrozzo et al., 2007; de Vries et al., 2007; Gelfand et al., 2011; Lorenzoni et al., 2011; Rotig et al., 2007) Contractures MTDPS5 (Elpeleg et al., 2005) Lactic acidosis in the CNS MTDPS8A, MTDPS5, MELAS, MTDPS9, Leigh syndrome, MTDPS6 (Bourdon et al., 2007; Carrozzo et al., 2007; Lorenzoni et al., 2009; Ostergaard et al., 2010; Rahman et al., 1996; Spinazzola et al., 2008) Cerebellar atrophy MERFF, NARP, MTDPS5, Coenzyme Q10 deficiency, IOSCA (Carrozzo et al., 2007; Gelfand et al., 2011; Koskinen et al., 1994; Lorenzoni et al., 2011; Rotig et al., 2007) Peripheral neuropathy ADOA, Friedreich ataxia, Leigh syndrome, MTDPS6, Leber optic atrophy, MERFF, NARP, MNGIE, MTDPS5, Coenzyme Q10 deficiency, SANDO, PEO autosomal dominant, IOSCA, LCHAD (Carrozzo et al., 2007; Gelfand et al., 2011; Koskinen et al., 1994; Lorenzoni et al., 2011; Nishino et al., 2000; Schulte et al., 2009; Yu-Wai-Man et al., 2010) Basal ganglia pathology Leigh syndrome, NARP, MTDPS5 (Carrozzo et al., 2007; Gelfand et al., 2011; Lee et al., 2009) Leukodystrophy MTDPS6, MNGIE (Karadimas et al., 2006; Nishino et al., 2000) Dental caries Friedreich ataxia (Camm and Carpenter, 1987) Sensorineural hearing loss ADOA, Alpers-Huttenlocher, Friedreich ataxia, DGUOK deficiency, MIDD, MELAS, MERFF, MNGIE, MTPS5, Coenzyme Q10 deficiency, SANDO, PEO autosomal dominant, Combined complex deficiency, IOSCA (Carrozzo et al., 2007; Di et al., 2009; Durr et al., 1996; Fratter et al., 2010; Freisinger et al., 2006; Guillausseau et al., 2001; Hammans et al., 1995; Koskinen et al., 1994; Kurt et al., 2010; Mancuso et al., 2004; Nishino et al., 2000; Rosing et al., 1985; Rotig et al., 2007; Yu-Wai-Man et al., 2010) Xerophthalmus ME (Zelnik et al., 1996) Kyphosis LHON (Huoponen, 2001) Retinitis pigmentosa Leigh syndrome, MIDD, MELAS, NARP, MNGIE, Coenzyme Q10 deficiency, LCHAD (Hammans et al., 1995; Holt et al., 1990; Lee et al., 2009; Massin et al., 2008; Nishino et al., 2000; Rotig et al., 2007; Tyni et al., 1997) Vomiting DGUOK deficiency, Leigh syndrome, MELAS, MERFF, MNGIE, Coenzyme Q10 deficiency, ACADM, HADHSC, LCHAD (Bennett et al., 1996; Freisinger et al., 2006; Iafolla et al., 1994; Lee et al., 2009; Lorenzoni et al., 2009, 2011; Nishino et al., 2000; Rotig et al., 2007) Ataxia ADOA, Friedreich ataxia, Leigh syndrome, MTDPS6, MELAS, MERFF, NARP, Pearson syndrome, Coenzyme Q10 deficiency, SANDO, PDH deficiency, ACADSD, IOSCA (Durr et al., 1996; Hammans et al., 1995; Holt et al., 1990; Ito et al., 1992; Karadimas et al., 2006; Koskinen et al., 1994; Lee et al., 2007; Lorenzoni et al., 2011; Mancuso et al., 2004; Rahman et al., 1996; Rotig et al., 2007; Tein et al., 2008; Yu-Wai-Man et al., 2010) Hypertension MIDD (Guillausseau et al., 2001) Tremor LHON, NARP, Pearson syndrome, PEO autosomal dominant (Baloh et al., 2007; Gelfand et al., 2011; Huoponen, 2001; Lee et al., 2007) Pruritus None Cataracts Sengers syndrome, Coenzyme Q10 deficiency, PEO autosomal dominant, Combined complex deficiency (Di et al., 2009; Fratter et al., 2010; Morava et al., 2004; Rotig et al., 2007) Developmental delay Alpers-Huttenlocher, DGUOK deficiency, Leigh syndrome, MTDPS6, MELAS, Pearson syndrome, MTDPS5, Coenzyme Q10 deficiency, PDH deficiency, Combined complex deficiency, MLASA2, ACADVL, ACADSD, MADD, LCHAD (Angle and Burton, 2008; Aoyama et al., 1995; Di et al., 2009; Elpeleg et al., 2005; Freisinger et al., 2006; Karadimas et al., 2006; Kurt et al., 2010; Lee et al., 2007, 2009; Lorenzoni et al., 2009; Maj et al., 2005; Riley et al., 2010; Rotig et al., 2007; Tein et al., 2008; Tyni et al., 1997) Optic atrophy ADOA, Alpers-Huttenlocher, Leigh syndrome, LHON, NARP, CoenzymeQ10 deficiency, IOSCA (Holt et al., 1990; Koskinen et al., 1994; Kurt et al., 2010; Lodi et al., 2011; Nikoskelainen et al., 1985; Rahman et al., 1996; Rotig et al., 2007) Nystagmus Friedreich ataxia, DGUOK deficiency, Leigh syndrome, MTDPS6, NARP, Coenzyme Q10 deficiency, Combined complex deficiency, ACADVL (Aoyama et al., 1995; Di et al., 2009; Durr et al., 1996; Gelfand et al., 2011; Rahman et al., 1996; Rotig et al., 2007; Spinazzola et al., 2008; Taanman et al., 2002) Hyperactive reflexes Leigh syndrome, MERFF (Rahman et al., 1996; Rosing et al., 1985) Seizures Alpers-Huttenlocher, Leigh syndrome, MTDPS6, LHON, MELAS, MERFF, MTDPS5, Coenzyme Q10 deficiency, SANDO, PDH deficiency, TK2, deficiency, ACADM, MADD, IOSCA, LCHAD (Angle and Burton, 2008; Diomedi-Camassei et al., 2007; Elpeleg et al., 2005; Gotz et al., 2008; Huoponen, 2001; Iafolla et al., 1994; Ito et al., 1992; Karadimas et al., 2006; Kurt et al., 2010; Lee et al., 2009; Lonnqvist et al., 2009; Lorenzoni et al., 2009, 2011; Tyni et al., 1997; Winterthun et al., 2005) Areflexia Friedreich ataxia, MTDPS6, NARP, MNGIE, TK2 deficiency, Combined complex deficiency, IOSCA, LCHAD (Di et al., 2009; Durr et al., 1996; Gotz et al., 2008; Holt et al., 1990; Karadimas et al., 2006; Koskinen et al., 1994; Nishino et al., 2000; Tyni et al., 1997) ROS production in agreement with our findings. Further they investigated the oxygen consumption rate of the cells after culturing them in media where glucose has been exchanged for galactose. "
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    • "In the mitochondrial genome, this includes mutations in complex I subunits (Horvath et al., 2008) and in other mitochondrial transfer RNA genes (de Coo et al., 1998; Hanna et al., 1998; Bataillard et al., 2001; Jaksch et al., 2001) and large-scale mitochondrial DNA deletions (Yamashita et al., 2008). Mutations in other nuclear-encoded genes causing stroke-like episode include Twinkle (now known as C10orf2) (Lonnqvist et al., 2009) and LRPPRC (Debray et al., 2011). It appears therefore, that acute encephalopathy with stroke-like lesions may result from different genetic causes. "
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    • "Mitochondrial recessive ataxia syndromes caused by mutations in c10orf2, which encodes mitochondrial DNA (mtDNA) helicase, and in POLG1, which encodes mitochondrial DNA polymerase, can result in abnormal mtDNA replication leading to depletion in copy number. Mitochondrial DNA depletion results in a neurodegenerative course in infantile-onset spinocerebellar ataxia (IOSCA) (OMIM# 271245) caused by mutations in c10orf2, and in mitochondrial spinocerebellar ataxia epilepsy syndrome (MSCAE) (OMIM# 607459) and Alpers-Huttenlocher syndrome (OMIM# 203700) both caused by mutations in POLG1 [1]. IOSCA is characterized by a period of normal development for approximately the first year of life followed by development of ataxia, hypotonia, loss of deep-tendon reflexes, and athetosis. "
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