Clinical and genetic characteristics of patients with Doose syndrome

Abstract

Objective To elucidate the genetic background and genotype‐phenotype correlations for epilepsy with myoclonic‐atonic seizures, also known as myoclonic‐astatic epilepsy (MAE) or Doose syndrome. Methods We collected clinical information and blood samples from 29 patients with MAE. We performed whole‐exome sequencing for all except one MAE case in whom custom capture sequencing identified a variant. Results We newly identified four variants: SLC6A1 and HNRNPU missense variants and microdeletions at 2q24.2 involving SCN1A and Xp22.31 involving STS. Febrile seizures preceded epileptic or afebrile seizures in four patients, of which two patients had gene variants. Myoclonic‐atonic seizures occurred at onset in four patients, of which two had variants, and during the course of disease in three patients. Variants were more commonly identified in patients with a developmental delay or intellectual disability (DD/ID), but genetic status was not associated with the severity of DD/ID. Attention‐deficit/hyperactivity disorder and autistic spectrum disorder were less frequently observed in patients with variants than in those with unknown etiology. Significance MAE patients had genetic heterogeneity, and HNRNPU and STS emerged as possible candidate causative genes. Febrile seizures prior to epileptic seizures and myoclonic‐atonic seizure at onset indicate a genetic predisposition to MAE. Comorbid conditions were not related to genetic predisposition to MAE.

Further evidence for de novo variants in SYNCRIP as the cause of a neurodevelopmental disorder

“…Interestingly, the first reported child carrying a truncating SYNCRIP variant also presented with MAE underscoring the role of SYNCRIP as another candidate gene for this rare epilepsy syndrome (Rauch et al, 2012). In line with this report, individuals with MAE frequently present with ID and ASD, but so far only a few genes have been associated, including SLC2A1 , SLC6A1 , several ion channels, as well as HNRNPU , another member of the hnRNP family (de Kovel et al, 2016; Hinokuma et al, 2020; Tang et al, 2020).…”

“…In particular, SYNCRIP modulates alternative splicing of the SMN2 transcript postulated to compensate for the loss of SMN1 in spinal muscular atrophy (Chen et al, 2008). Further RNA‐interacting proteins, such as argonaute‐2 as well as the hnRNP family members HNRNPU and HNRNPD , have previously been associated with developmental and epileptic encephalopathies (Epi4K et al, 2013; Hinokuma et al, 2020; Lessel et al, 2020). The involvement of SYNCRIP in RNA‐binding and regulation of multiple pathways suggests its relevance in several important functions including neurodevelopment.…”

“…Similar to SYNCRIP , central RRM domains of other hnRNP family members are spared from variation in the general population supporting the essential role of these motifs. Besides SYNCRIP/hnRNPQ , hnRNPU has previously been associated with developmental and epileptic encephalopathies highlighting the importance of this gene family for physiological neurodevelopment and making genes within this family putative candidates for NDDs (Epi4K et al, 2013; Hinokuma et al, 2020).…”

Genetic Epilepsy Syndromes

“…Even in monogenic cases, the syndrome appears to be highly genetically heterogeneous, with pathogenic variants in many genes reported to be causative. Some of the more commonly reported include SLC6A1 , SCN1A , and SLC2A1 (the gene for GLUT1 deficiency, discussed earlier) 79-82 . Valproic acid and clobazam are the most commonly used first-line antiseizure medications, but the ketogenic diet should be considered early if patients do not respond to initial medical therapy 77,78 .…”

“…Some of the more commonly reported include SLC6A1, SCN1A, and SLC2A1 (the gene for GLUT1 deficiency, discussed earlier). [79][80][81][82] Valproic acid and clobazam are the most commonly used first-line antiseizure medications, but the ketogenic diet should be considered early if patients do not respond to initial medical therapy. 77,78 Seizures remit in at least half of patients, generally within 5 years of onset.…”