Outcomes and hidden subgroups in WDR45-related disorders

BPAN. WDR45-related disorders are one of the most common X-linked neurodevelopmental disorders. While initially conceptualized within the framework of rare conditions with neurodegeneration with brain iron accumulation, WDR45-related disorders challenge the traditional concept of neurodegenerative conditions. Most individuals are diagnosed in childhood with neurodevelopmental features. However, the full spectrum of the pediatric presentation of WDR45-disorders has not been fully delineated yet. In a recent publication, we delineate the pediatric presentation of WDR45-disorders. We find that typical outcome measures often fail to capture the full range of features in WDR45-related disorders and that there might be two distinct previously not appreciated subgroups. Continue reading

DDX3X, WDR45 and the ongoing mystery of X-linked disorders

X-linked. Almost a decade ago, the former EuroEPINOMICS team was asked to perform a difficult task. We reviewed inherited variants in X-linked genes, trying to understand whether inherited variants are causative of neurodevelopmental disorders for one of our research studies. In most cases, we decided that we did not have enough evidence. How could we tell whether variants in genes such as HUWE1 or CNKSR2 that were transmitted from unaffected females to affected sons were disease-causing or not? I remembered my frustration when I came across a publication on the contribution of X-linked variants to neurodevelopmental disorders that was published last year. Continue reading

This was epilepsy genetics in 2021 – five things to remember

Looking back. Admittedly, I have not written an end-of-the-year review for a quite some time. However, there were a few notable moments in epilepsy genetics in 2021 that I think were worth remembering. The second year of the COVID-19 pandemic started out as a year of recovery and readjustment, only to run into unanticipated supply chain issues and novel COVID variants hanging over our transition into 2022. The scientific community was affected by these developments in different ways that made progress of science somewhat unpredictable and uneven. 2021 was the year when the phrase “unprecedented times” became stale and overused. Here are five things to remember from 2021, which will be remembered as part of a transitional phase in epilepsy genetics. Continue reading

WDR45 – this is what you need to know in 2015

BPAN. We have selected WDR45 to be our Epilepsiome gene of the week. WDR45 was initially identified as the causative gene for a rare phenotype referred to as static encephalopathy with neurodegeneration in adulthood (SENDA), which belongs to a group of neurodegenerative disorders that have accumulation of iron in the CNS as the common feature. In contrast to the narrow and very specific phenotype in most other disorders in this group, the phenotypic spectrum of WDR45 has expanded significantly since the initial discovery in 2013. Mutation in WDR45 can be identified in patients with a broad range of neurodevelopmental phenotypes including epileptic encephalopathies. Continue reading

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