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

Microcephaly, WDR62, and how to analyze recessive epilepsy families

Success rate. What is in an exome? There are lots of rare and unknown variants that are hard to make sense of unless we can ask a specific question or have further data to limit the number of genes that we look at. Genetic studies in recessive diseases with limited candidate genes to consider might represent one of the most straightforward cases. In a recent paper in BMC Neurology, the genetic cause of a recessive epilepsy/intellectual disability syndrome in a consanguineous family presenting with primary microcephaly was solved using a single exome of an affected individual. Was this just lucky or can this strategy be applied to any recessive family with a reasonable chance? Continue reading