Exomes. Massive parallel sequencing technologies are ideally suited to identify the genetic basis of monogenic disorders, particularly recessive diseases. In a recent publication in the Orphanet Journal of Rare Disease, Abdel-Salam and collaborators identify a homozygous mutation in WWOX in a family with epileptic encephalopathy and neurodegeneration. Their study highlights the issues of how to interpret recessive gene findings spanning different phenotypes identified in the era of exome sequencing. Continue reading
Tag Archives: neurodegeneration
Twisting DNA and seizures: TDP2 mutations in neurodegeneration with epilepsy
Torsional stress. The DNA double helix has one major problem that we know from telephone cords: it is difficult to untangle. However, our DNA is constantly twisted and untangled for gene transcription. This constant twisting and untwisting produces torsional stress that is relieved by topoisomerases. A recent publication in Nature Genetics now identified a human neurological phenotype that is caused by faulty activity of this mechanism: neurodegeneration with epileptic encephalopathy. However, there are some features of the phenotype that are not easily explained by erroneous DNA twisting. Continue reading
What neuronal membranes are made of – CERS1 in progressive myoclonus epilepsy
Ceramide. Sphingolipids are a major component of neuronal membranes and help neurons in intracellular signaling and trafficking. Ceramide is one of the basic building blocks of sphingolipids. In a recent publication in Annals of Neurology, mutations in CERS1, coding for ceramide synthetase, are identified in a family with progressive myoclonus epilepsy – and provides an unexpected linked between a group of storage disorders such as Niemann-Pick disease and Tay-Sachs disease and progressive myoclonus epilepsies. Continue reading
QARS mutations, tRNA, and neurodegeneration with migrating seizures
Q for glutamine. Transfer RNAs (tRNAs) are small adaptor molecules that match a nucleotide sequence to a given amino acid during protein translation. After unloading their amino acid payload, tRNAs are recharged with new amino acids through specific tRNA synthetases. Q is the official letter for the amino acid glutamine, and its respective tRNA synthetase is glutaminyl-tRNA synthetase (QARS). In a recent publication in the American Journal of Human Genetics, Zhang and colleagues identify compound heterozygous mutations in the QARS gene in two families with progressive microcephaly, neurodegeneration, and intractable, early-onset epilepsy. Interestingly, in at least two probands, the seizures are described as migrating partial seizures reminiscent of Malignant Migrating Partial Seizures of Infancy (MMPSI) due to mutations in KCNT1. The disease mechanism, however, appears to be entirely different. Continue reading
