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

The familial risk of epilepsy – revisited

Missing heritability. The concept of missing heritability is often invoked to demonstrate that existing genetic techniques only identify a fraction of the overall genetic risk for human diseases including the epilepsies. This statement implicitly assumes that we have a good and solid understanding of what the magnitude of genetic risk actually is. However, when looking at the epidemiological studies that have investigated familial risk of epilepsy, some of these studies have inherent problems, including small sample sizes, different phenotype definitions, recruitment bias, and lack of controls. A recent study in Brain now reassesses the familial risk of epilepsy in a population-based cohort of the Rochester Epidemiology Project. There are few instant classics in the field of epilepsy genetics – this study is one of them. Continue reading

Copy number variations and the forgotten epilepsy phenotypes

Complexity. Structural genomic variants or copy number variations (CNV) are known genetic risk factors for various epilepsy syndromes. In fact, CNVs might represent the single most studied type of genetic alterations across a very broad range of epilepsy syndromes. There is, however, a group of patients that is usually not investigated in genetic studies: patients with presumable lesional epilepsies or questionable findings on Magnetic Resonance Imaging (MRI). Many of these epilepsies are usually thought to be secondary to the identified lesion, and genetic risk factors are not considered.  In a recent study in the European Journal of Human Genetics last week, we investigated the role of CNVs in a cohort of patients with complex epilepsy phenotypes that were not easily classified into existing categories. Many of patients included had definite or questionable findings on MRI.  The results of our study made us wonder whether the boundary between lesional and genetic epilepsies needs to redrawn. Continue reading

Papers of the week – Copy Number Variations

Dennis' paper of the weekVariations on Copy Numbers. In the third issue of our series on the papers of the week I will focus on the detection and annotation of the most common form of structural variation encountered in genomes. Deletions, duplications and inversions are frequent events, which are surprisingly hard to deal with using sequencing-based tools. Hence, this is an area of active development.

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Pharmacogenomics for epilepsy

The treatment options for epilepsy must undoubtedly be improved. More than 20 antiepileptic drugs are licensed but in 30% of patients seizures are not controlled, despite treatment with a number of anti epileptic drugs and the response to medication is difficult to predict. Antiepileptic medications can cause severe adverse reactions and increase the risk of fetal malformations in women taking them during pregnancy. The differences in drug response and the occurrence of rare adverse reactions are believed to be caused by variants in the genetic makeup of individuals. Knowledge of these variants would help us to predict drug response and adverse drug reactions. This personalized treatment would help us to select medications for each individual.

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An inconvenient truth – segregation of monogenic variants in small families

Climate change. In the era of exome and genome sequencing, it might be worthwhile revisiting the merit of family studies in epilepsy research. Seizure disorders are known to have a highly diverse genetic architecture. When singleton studies identify a single, unique gene finding, this discovery usually does not provide much information about the potential causal role of the variant given the high degree of genomic noise. In contrast, family studies are usually considered more robust, as segregation of variants can be traced. Here is the inconvenient truth: unless the family is very large, segregation of possibly monogenic variants adds little information given the vast amount of variants present in our genomes. Continue reading

The mosaic brain – single neuron copy number variations in humans

Variability. It has been rumored for quite some time, but only now is solid evidence present to show this phenomenon: the high degree of genomic diversity of human neurons. In a recent paper in Science, the genomic diversity among frontal brain neurons is explored on a cell-by-cell basis. The results are breathtaking: up to 40% of frontal cortex neurons have altered genomic material affected by large deletions or duplications. This study provides the linchpin for a plethora of new investigations aiming to understand the impact of this phenomenon in health and disease. Continue reading

Identifying core phenotypes – epilepsy, ID and recurrent microdeletions

Triad. There are three microdeletions in particular that increase the risk for the Idiopathic/Genetic Generalized Epilepsies (IGE/GGE). This triad includes microdeletions at 15q13.3, 16p13.11 and 15q11.2, which are hotspot deletions arising from the particular architecture of the human genome. While the association of these microdeletions with epilepsy and other neurodevelopmental disorders including autism, intellectual disability and schizophrenia is well established, the core phenotype of these variants remains elusive, including the question whether such a core phenotype actually exists. In a recent paper in Neurology, Mullen and collaborators zoom in on a possible core phenotype of these microdeletions. The authors investigate a phenotype in which these microdeletions are particularly enriched: generalized epilepsy with intellectual disability. Continue reading

Guilt by association: SCN1A in Temporal Lobe Epilepsy

GWAS. Genome-wide association studies investigate the association of common genetic variants with disease in large patient samples. While this approach has been very successful in many other diseases, the results in epilepsy research have been less convincing. Given the complexity of epilepsy phenotypes, selection of the right epilepsy phenotype has been an ongoing debate. Now, a recent study in Brain finds an intronic variant of the SCN1A gene that is associated with Temporal Lobe Epilepsy (TLE), the most common epilepsy in man. Interestingly, the association with SCN1A seems to be specific for only a particular subtype of focal epilepsies. Continue reading