PNKP Mutations Identified by Whole-Exome Sequencing in a Norwegian Patient with Sporadic Ataxia and Edema.

We identified PNKP mutations in a Norwegian woman with AOA. This patient had the typical findings with cognitive dysfunction, peripheral neuropathy, cerebellar dysarthria, horizontal nystagmus, oculomotor apraxia, and severe truncal and appendicular ataxia. In addition, she had hypoalbuminemia and massive lower limb edema which showed some improvement with treatment. Exome sequencing identified two heterozygous mutations, one in exon 14 (c.1196T>C, p.Leu399Pro) and one in exon 16 (c.1393_1396del, p.Glu465*). This is the first non-Portuguese patient with AOA due to PNKP mutations and provides independent verification that PNKP mutations cause AOA.

ADCK3 mutations with epilepsy, stroke-like episodes and ataxia: a POLG mimic?

BACKGROUND AND PURPOSE: Defects of coenzyme Q10 (CoQ10) metabolism cause a variety of disorders ranging from isolated myopathy to multisystem involvement. ADCK3 is one of several genes associated with CoQ10 deficiency that presents with progressive cerebellar ataxia, epilepsy, migraine and psychiatric disorders. Diagnosis is challenging due to the wide clinical spectrum and overlap with other mitochondrial disorders. METHODS: A detailed description of three new patients and one previously reported patient from three Norwegian families with novel and known ADCK3 mutations is provided focusing on the epileptic semiology and response to treatment. Mutations were identified by whole exome sequencing and in two measurement of skeletal muscle CoQ10 was performed. RESULTS: All four patients presented with childhood-onset epilepsy and progressive cerebellar ataxia. Three patients had epilepsia partialis continua and stroke-like episodes affecting the posterior brain. Electroencephalography showed focal epileptic activity in the occipital and temporal lobes. Genetic investigation revealed ADCK3 mutations in all patients including a novel change in exon 15: c.T1732G, p.F578V. There was no apparent genotype-phenotype correlation. CONCLUSION: ADCK3 mutations can cause a combination of progressive ataxia and acute epileptic encephalopathy with stroke-like episodes. The clinical, radiological and electrophysiological features of this disorder mimic the phenotype of polymerase gamma (POLG) related encephalopathy and it is therefore suggested that ADCK3 mutations be considered in the differential diagnosis of mitochondrial encephalopathy with POLG-like features.

Management of dystonia in Europe: a survey of the European network for the study of the dystonia syndromes.

BACKGROUND AND PURPOSE: Dystonia is difficult to recognize due to its large phenomenological complexity. Thus, the use of experts in dystonia is essential for better recognition and management of dystonia syndromes (DS). Our aim was to document managing strategies, facilities and expertise available in various European countries in order to identify which measures should be implemented to improve the management of DS. METHODS: A survey was conducted, funded by the Cooperation in Science and Technology, via the management committee of the European network for the study of DS, which is formed from representatives of the 24 countries involved. RESULTS: Lack of specific training in dystonia by general neurologists, general practitioners as well as other allied health professionals was universal in all countries surveyed. Genetic testing for rare dystonia mutations is not readily available in a significant number of countries and neurophysiological studies are difficult to perform due to a lack of experts in this field of movement disorders. Tetrabenazine is only readily available for treatment of dystonia in half of the surveyed countries. Deep brain stimulation is available in three-quarters of the countries, but other surgical procedures are only available in one-quarter of countries. CONCLUSIONS: Internationally, collaboration in training, advanced diagnosis, treatment and research of DS and, locally, in each country the creation of multidisciplinary teams for the management of dystonia patients could provide the basis for improving all aspects of dystonia management across Europe.

Mitochondrial DNA depletion in progressive external ophthalmoplegia caused by POLG1 mutations.

OBJECTIVES: To investigate two patients with late onset, progressive external ophthalmoplegia (PEO) and sensory peripheral neuropathy. MATERIALS & METHODS: The patients aged 86 and 50 years were investigated clinically including magnetic resonance imaging of the brain, electrophysiological studies and, in one, skeletal muscle biopsy. Molecular studies included sequencing of the whole coding region of the POLG1 gene and mitochondrial DNA (mtDNA) analysis for deletions and depletion. RESULTS: Both patients were compound heterozygous for gene encoding the catalytic subunit of the DNA-polymerase gamma (POLG1) mutations. One had the p.737R and p.W748S mutations while the other carried the p.T251I, p.P587L and p.W748S mutations. While these mutations have been previously described, these combinations are novel. mtDNA studies in skeletal muscle showed evidence of multiple deletions and approximately 64% depletion of the mitochondrial genome. CONCLUSION: Our findings broaden the genotypic spectrum of POLG-associated PEO and show that in addition to multiple deletions, mtDNA depletion occurs and may contribute to the pathogenesis of this disorder.