Treatable causes of intellectual disability and epilepsy that you don’t want to miss

Think metabolic. We have discussed de novo mutations as a cause of epileptic encephalopathies repeatedly on our blog. While there is emerging evidence that de novo mutations in established genes such as SCN1A or CDKL5 or novel genes including GNAO1 or CHD2 are a major cause of genetic morbidity in patients with epileptic encephalopathies, investigations for de novo mutations are not the immediate knee-jerk reaction in clinical practice. In fact, if a child presents with an epileptic encephalopathy, excluding inborn errors of metabolism (IEM) takes priority. While metabolic causes of epileptic encephalopathies are rare, they need to be excluded as some of these conditions are treatable. In a recent review in Molecular Genetics and Metabolism, van Karnebeek and colleagues review the 89 causes of intellectual disability that are potentially treatable. Many of these conditions also present with epilepsy. They present an updated diagnostic algorithm and provide an online resource for these conditions – in a nutshell, there is an app for that.  Continue reading

Recessive mutations in autism – the return of hidden metabolic disorders

My wrong guesses of 2012. Two weeks ago during a presentation, I had to admit that there is little evidence for a large contribution of recessive or compound heterozygous mutations in epileptic encephalopathies. At the beginning of 2012, I had initially suggested that recessive or compound heterozygous mutation of known neurometabolic disorders could be identified through exome sequencing in sporadic epileptic encephalopathies. However, as of 2013, there is little evidence for this in our data or the data from other consortia. Now, two papers in Cell suggest a significant contribution of recessive mutations in autism including a revival of the “hidden neurometabolic hypothesis”. Continue reading