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List of references:
Infantile onset spinocerebellar ataxia with sensory neuropathy: a new inherited disease.
T Koskinen, P Santavuori, K Sainio, M Lappi, A K Kallio, H Pihko,
We report the clinical findings in 19 Finnish patients, including six pairs of siblings, with a new, early onset spinocerebellar ataxia. The slowly progressive clinical symptoms manifested between one and two years of age in previously healthy infants. The first manifestation of children at that age was clumsiness and loss of ability to walk. Ataxia, athetosis and muscle hypotonia with loss of deep tendon reflexes were discovered on clinical examination. By school age ophthalmoplegia and hearing loss were diagnosed, while sensory neuropathy developed by adolescence. In addition, an acute crisis with status epilepticus was a late manifestation. We found a marked decrease in sensory nerve condition velocities, a progressive loss of myelinated fibers in sural nerve specimen, and abnormal background activity in EEG with advancing age. The main finding in neuroradiological investigations was cerebellar atrophy. The occurrence of the disease in siblings and lack of manifestations in parents indicate recessive inheritance.
Journal of the neurological sciences - Jan 1994
Recessive twinkle mutations cause severe epileptic encephalopathy.
Tuula Lönnqvist, Anders Paetau, Leena Valanne, Helena Pihko,
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.
Brain : a journal of neurology - Jun 2009