Hidden neurometabolic disorders – the expanding spectrum of PNPO deficiency

Pyridoxal 5’-phosphate (PLP). PNPO deficiency is a rare neurometabolic disease that presents with severe neonatal epilepsy responsive to pyridoxal phosphate. While the classical clinical presentation is well described, there might be milder versions of this potentially treatable neurometabolic disease that have not been recognized so far. In a recent publication in Brain, the phenotypic spectrum of PNPO deficiency is revisited. In addition to the classical neonatal phenotype, the authors identify patients with later onset and atypical response to pyridoxal phosphate. In addition, they identify a rare, potentially causative PNPO variant that probably gets stuck in most exome filtering pipelines. Continue reading

GPHN deletions in IGE and mutation-dependent recessive inheritance

Bild1Living in Cologne is a little tough at the moment. Currently, we are in the middle of the Cologne Carnival, the world’s oldest carnival, which started in 1829. Until the upcoming Wednesday the entire city is one big festival. In addition to the 1 million Cologne citizens probably another million tourists will join. Due to this (positive) distraction I will write less than usual. However, I still consider this week’s publications noteworthy. Continue reading

Navigating the epilepsiome – live from Tübingen

2D. I am writing this post during our EuroEPINOMICS meeting in Tübingen listening to presentation from CoGIE, the EuroEPINOMICS project working on IGE/GGE and Rolandic Epilepsies and RES, the project on rare epilepsies. At some point during the afternoon, I made my selection for the best graph during the presentations today – an overview of the conservation space of epilepsy genes. Continue reading

A metabolic disorder masquerading as adult-onset focal epilepsy

Bella Italia. What a strange day. I am on “emergency duty” for the first day of kindergarten for our daughter. Since the kindergarten is a few meters down the road, I decided to stay home. However, as our windows are currently being replaced, I had nowhere to go. I ended up in a small cafe nearby that I hadn’t noticed before, which turned out to be authentically Italian. Between cornetto e cappuccino, I tried to catch up with some of my blogging duties. For quite some time, I had carried around a case report in the Orphanet Journal of Rare Diseases that I eventually managed to read. In this paper, the authors report on a sib pair with alpha-methylacyl-coA-racemase deficiency (AMACRD). Alpha what?? Exactly. I hadn’t heard of this before, either. However, what raised my interest was the phenotype of one of the patients – adult-onset focal epilepsy. Continue reading

PGAP2 mutations and intellectual disability with elevated alkaline phosphatase

Red flags. Despite the availability of a large panel of metabolic and genetic tests as well as high-resolution neuroimaging, the cause of disease in the vast majority of patients remains unknown. This situation also applies for intellectual disability, where there is little to offer in terms of diagnostic procedures once patients are negative for array comparative genomic hybridization (array CGH). In clinical practice, we often hope that some minor clinical or biochemical features may lead us to the correct diagnosis, but in the majority of cases, these investigations lead nowhere. Now, in two back-to-back publications in the American Journal of Human Genetics, two papers describe PGAP2 mutations in patients with non-syndromal intellectual disability with elevated alkaline phosphatase.  Continue reading

One in four – the carrier rate of recessive diseases

How frequent? With all the genetic information around, we are often wondering how much genetic morbidity is really hidden in our genomes. Yes, everybody is a knock-out for 1-3 genes, but in most cases, these variants do not cause disease. However, what happens if you apply genomics to estimate the burden of known disease variants? Now in a recent paper in Genetics in Medicine by Lazarin and colleagues, the carrier frequency for ~400 variants known to cause ~100 recessive disorders is investigated. 24% of all individuals are carriers for at least one recessive disorder. Continue reading

Rare Epilepsy Syndromes and the Congenital Disorders of Glycosylation

Rare Epilepsy Syndromes. Motivated by a recent paper in JIMD Reports, I wanted to use this post to present a very rare group of disorders, in which glycosylation of a variety of tissue proteins and/or lipids is deficient. These so-called congenital disorders of glycosylation (CDG) are a highly heterogeneous group of recessive disorders that you might be confronted with. As CDG may masquerade as otherwise non-specific epileptic encephalopathies, you might encounter them clinically or by browsing through exomes of patients with RES. Imtiaz and colleagues now report on two brothers in a large Saudi family with 18 affected siblings. They identified a mutation in DPAGT1, which is known to cause CDG Ij.   Continue reading

The return of TBC1D24

First of its kind. In 2010, a virtually unknown gene became the first epilepsy gene to be discovered through massive parallel sequencing techniques. This gene, TBC1D24, was found in two recessive families with different types of epilepsy. Afterwards, it became silent around this gene with no further findings. Now, a recent paper reports on a third family with a mutation in this gene with a complex phenotype of epileptic encephalopathy and movement disorders. As the mutation is located in an alternative exon of this gene, this raises important issues on how we identify and interpret mutations. 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

A new twist on an old gene: EFHC1 in epileptic encephalopathy

A peculiar gene. There is one gene in the small world of epilepsy genetics that has always troubled me. A gene that has an unknown function and is not expressed in the postnatal brain, but is well established as one of the few genes for autosomal dominant Juvenile Myoclonic Epilepsy (JME). This gene is EFHC1. Now, a recent paper in Epilepsia reports EFHC1 as a possible candidate gene in autosomal recessive epileptic encephalopathy with neonatal onset. The mystery surrounding this gene continues. Continue reading