Recessive twinkle mutations cause severe epileptic encephalopathy

Division of Child Neurology, Helsinki University Central Hospital, Helsinki, Finland.
Brain (Impact Factor: 9.2). 04/2009; 132(Pt 6):1553-62. DOI: 10.1093/brain/awp045
Source: PubMed


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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    • "Also twinkle mutations were associated adult-onset MDS.5 Exercise intolerance has been reported as a phenotypic feature of DGUOK mutations and migraine or migrainelike headache as a feature of PEO1 mutations. 12,13 Hypersomnia or other sleep disorders and myalgias have not been reported in association with MDS. It must be admitted, however, that the phenotype of the presented patient fitted to none of those previously described in MDS. "
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    ABSTRACT: Mitochondrial DNA depletion syndrome (MDS) is usually a severe disorder of infancy or childhood, due to a reduced copy number of mtDNA molecules. MDS with only mild, nonspecific clinical manifestations and onset in adulthood has not been reported. A 47-year-old Caucasian female with short stature and a history of migraine, endometriosis, Crohn's disease, C-cell carcinoma of the thyroid gland, and a family history positive for mitochondrial disorder (2 sisters, aunt, niece), developed day-time sleepiness, exercise intolerance, and myalgias in the lower-limb muscles since age 46y. She slept 9-10 hours during the night and 2 hours after lunch daily. Clinical exam revealed sore neck muscles, bilateral ptosis, and reduced Achilles tendon reflexes exclusively. Blood tests revealed hyperlipidemia exclusively. Nerve conduction studies, needle electromyography, and cerebral and spinal magnetic resonance imaging were noninformative. Muscle biopsy revealed detached lobulated fibers with subsarcolemmal accentuation of the NADH and SDH staining. Realtime polymerase chain reaction revealed depletion of the mtDNA down to 9% of normal. MDS may be associated with a mild phenotype in adults and may not significantly progress during the first year after onset. In an adult with hypersomnia, severe tiredness, exercise intolerance, and a family history positive for mitochondrial disorder, a MDS should be considered.
    Neurology International 06/2013; 5(2):28-30. DOI:10.4081/ni.2013.e9
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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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    ABSTRACT: Mitochondrial dysfunction and disease may arise as a result of mutations in either the mitochondrial genome itself or nuclear encoded genes involved in mitochondrial homeostasis and function. Irrespective of which genome is affected, mitochondrial encephalopathies share clinical and biochemical features suggesting common pathophysiological pathways. Two common paradigms of mitochondrial encephalopathy are mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes caused by maternally transmitted mutations of mitochondrial DNA and mitochondrial spinocerebellar ataxia and epilepsy caused by recessively inherited mutations of the nuclear-encoded DNA polymerase gamma, which replicates and repairs the mitochondrial genome. We studied and compared the disease mechanisms involved in these two syndromes. Despite having different genetic origins, their pathophysiological pathways converge on one critical event, damage to the respiratory chain leading to insufficient energy to maintain cellular homeostasis. In the central nervous system, this appears to cause selective neuronal damage leading to the development of lesions that mimic ischaemic damage, but which lack evidence of decreased tissue perfusion. Although these stroke-like lesions may expand or regress dynamically, the critical factor that dictates prognosis is the presence of epilepsy. Epileptic seizures increase the energy requirements of the metabolically already compromised neurons establishing a vicious cycle resulting in worsening energy failure and neuronal death. We believe that it is this cycle of events that determines outcome and which provides us with a mechanistic structure to understand the pathophysiology of acute mitochondrial encephalopathies and plan future treatments.
    Brain 10/2012; 135(12). DOI:10.1093/brain/aws223 · 9.20 Impact Factor
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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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    ABSTRACT: Recessive mutations in genes encoding mitochondrial DNA replication machinery lead to mitochondrial DNA depletion syndromes. This genetically and phenotypically heterogeneous group includes infantile onset spinocerebellar ataxia (OMIM# 271245) a neurodegenerative disease caused by mutations in the mtDNA helicase gene, c10orf2, with an increased frequency in the Finnish population due to a founder mutation. We describe a child of English descent who presented with a severe phenotype of IOSCA as a result of two-novel mutations in the c10orf2 gene. This paper expands the phenotypic spectrum of IOSCA and adds further evidence for the presence of a genotype-phenotype correlation among patients with recessive mutations in this gene.
    08/2012; 2012:303096. DOI:10.1155/2012/303096
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