The N-methyl-D-aspartate receptors (NMDARs; GluNRS) are glutamate receptors, commonly located at excitatory synapses. Mutations affecting receptor function often lead to devastating ...neurodevelopmental disorders. We have identified two toddlers with different heterozygous missense mutations of the same, and highly conserved, glycine residue located in the ligand-binding-domain of
GRIN2B
: G689C and G689S. Structure simulations suggest severely impaired glutamate binding, which we confirm by functional analysis. Both variants show three orders of magnitude reductions in glutamate EC
50
, with G689S exhibiting the largest reductions observed for
GRIN2B
(~2000-fold). Moreover, variants multimerize with, and upregulate, GluN2B
wt
-subunits, thus engendering a strong dominant-negative effect on mixed channels. In neurons, overexpression of the variants instigates suppression of synaptic GluNRs. Lastly, while exploring spermine potentiation as a potential treatment, we discovered that the variants fail to respond due to G689’s novel role in proton-sensing. Together, we describe two unique variants with extreme effects on channel function. We employ protein-stability measures to explain why current (and future) LBD mutations in GluN2B primarily instigate Loss-of-Function.
Summary
The first mutations identified in SLC2A1, encoding the glucose transporter type 1 (GLUT1) protein of the blood–brain barrier, were associated with severe epileptic encephalopathy. Recently, ...dominant SLC2A1 mutations were found in rare autosomal dominant families with various forms of epilepsy including early onset absence epilepsy (EOAE), myoclonic astatic epilepsy (MAE), and genetic generalized epilepsy (GGE). Our study aimed to investigate the possible role of SLC2A1 in various forms of epilepsy including MAE and absence epilepsy with early onset. We also aimed to estimate the frequency of GLUT1 deficiency syndrome in the Danish population. One hundred twenty patients with MAE, 50 patients with absence epilepsy, and 37 patients with unselected epilepsies, intellectual disability (ID), and/or various movement disorders were screened for mutations in SLC2A1. Mutations in SLC2A1 were detected in 5 (10%) of 50 patients with absence epilepsy, and in one (2.7%) of 37 patient with unselected epilepsies, ID, and/or various movement disorders. None of the 120 MAE patients harbored SLC2A1 mutations. We estimated the frequency of SLC2A1 mutations in the Danish population to be approximately 1:83,000. Our study confirmed the role of SLC2A1 mutations in absence epilepsy with early onset. However, our study failed to support the notion that SLC2A1 aberrations are a cause of MAE without associated features such as movement disorders.
Glycosylphosphatidylinositol anchoring disorders (GPI‐ADs) are a subgroup of congenital disorders of glycosylation. GPI biosynthesis requires proteins encoded by over 30 genes of which 24 genes are ...linked to neurodevelopmental disorders. Patients, especially those with PIGA‐encephalopathy, have a high risk of premature mortality which sometimes is attributed to cardiomyopathy. We aimed to explore the occurrence of cardiomyopathy among patients with GPI‐ADs and to raise awareness about this potentially lethal feature. Unpublished patients with genetically proven GPI‐ADs and cardiomyopathy were identified through an international collaboration and recruited through the respective clinicians. We also reviewed the literature for published patients with cardiomyopathy and GPI‐AD and contacted the corresponding authors for additional information. We identified four novel and unrelated patients with GPI‐AD and cardiomyopathy. Cardiomyopathy was diagnosed before adulthood and was the cause of early demise in two patients. Only one patients underwent cardiac workup after being diagnosed with a GPI‐AD. All were diagnosed with PIGA‐encephalopathy and three had a disease‐causing variant at the same residue. The literature reports five additional children with GPI‐AD related cardiomyopathy, three of which died before adulthood. We have shown that patients with GPI‐ADs are at risk of developing cardiomyopathy and that regular cardiac workup with echocardiography is necessary.
Glycosylphosphatidylinositol anchoring disorders (GPI‐ADs) are complex neurodevelopmental syndromes with a high risk of premature mortality. We have shown that patients with GPI‐ADs are at risk of developing childhood‐onset cardiomyopathy; an overlooked and potentially fatal feature. We recommend regular cardiac workup with echocardiography once a genetic diagnosis of GPI‐AD is established.
•One in two parents are at risk of developing concerning symptoms of psychopathology.•Seizure-related traumatic episodes are highly influential for parental distress.•Caregiver resources and the ...child's behavioral difficulties are consequential.
To assess the prevalence of psychopathology and the level of stress in parents of children with severe epilepsy to gain a better understanding of parental support needs.
Questionnaires were completed by parents of children with severe epilepsy during the hospitalization of their child at the Danish Epilepsy Center. The questions targeted symptoms of post-traumatic stress disorder (PTSD), complex PTSD (CPTSD), depression, and anxiety, and the level of perceived stress.
A total of 162 caregivers of 140 children with epilepsy participated in the survey. Mothers were more often unemployed than fathers (38% vs. 11%, p < 0.01), and nearly half of the children (47%) attended special needs classes. Psychopathology symptoms were found in 43.5% of parents, fulfilling criteria for one or more diagnoses, and an additional 11% showed symptoms of sub-clinical PTSD. Parent-rated child difficulties were significantly associated with PTSD (Mdiff = 5.51, p = 0.001), depression (Mdiff = 4.50, p < 0.000), and anxiety (Mdiff = 4.61, p = 0.01), and with higher levels of perceived stress (p < 0.001).
Caring for a child with severe epilepsy has a significant psychopathological impact on caregivers. Caregivers’ resources and the degree of behavioral difficulties in the child, rather than epilepsy-related factors, are highly correlated with distress and psychopathological symptoms in caregivers.
Although the classic phenotype of episodic ataxia type 1 (EA1) caused by variants in KCNA1 includes episodic ataxia and myokymia, further genotype‐phenotype correlations are difficult to establish ...due to highly heterogeneous clinical presentations associated with KCNA1 pathogenic variants. De novo variants in the paralogous Pro‐Val‐Pro motif (PVP) of KCNA2, an essential region for channel gating, have been reported to be associated with severe epilepsy phenotypes, including developmental and epileptic encephalopathies (DEE). Here, we describe the first patient with a DEE who developed an encephalopathy related to status epilepticus during sleep (ESES) and cerebellar signs, harbouring a variant in the Kv‐specific PVP motif of the KCNA1 gene. Interestingly, he showed a remarkable long‐term electroclinical response to IM ACTH therapy. This report extends the range of phenotypes associated with KCNA1 variants to include that of ESES, and suggests that ACTH therapy is likely to have a positive effect in patients with these variants.
Neurodevelopmental disorder with dysmorphic facies and distal limb anomalies (NEDDFL), defined primarily by developmental delay/intellectual disability, speech delay, postnatal microcephaly, and ...dysmorphic features, is a syndrome resulting from heterozygous variants in the dosage‐sensitive bromodomain PHD finger chromatin remodeler transcription factor BPTF gene. To date, only 11 individuals with NEDDFL due to de novo BPTF variants have been described. To expand the NEDDFL phenotypic spectrum, we describe the clinical features in 25 novel individuals with 20 distinct, clinically relevant variants in BPTF, including four individuals with inherited changes in BPTF. In addition to the previously described features, individuals in this cohort exhibited mild brain abnormalities, seizures, scoliosis, and a variety of ophthalmologic complications. These results further support the broad and multi‐faceted complications due to haploinsufficiency of BPTF.
Aicardi syndrome (AS) is a well-characterized neurodevelopmental disorder with an unknown etiology. In this study, we performed whole-exome sequencing in 11 female patients with the diagnosis of AS, ...in order to identify the disease-causing gene. In particular, we focused on detecting variants in the X chromosome, including the analysis of variants with a low number of sequencing reads, in case of somatic mosaicism. For 2 of the patients, we also sequenced the exome of the parents to search for de novo mutations. We did not identify any genetic variants likely to be damaging. Only one single missense variant was identified by the de novo analyses of the 2 trios, and this was considered benign. The failure to identify a disease gene in this study may be due to technical limitations of our study design, including the possibility that the genetic aberration leading to AS is situated in a non-exonic region or that the mutation is somatic and not detectable by our approach. Alternatively, it is possible that AS is genetically heterogeneous and that 11 patients are not sufficient to reveal the causative genes. Future studies of AS should consider designs where also non-exonic regions are explored and apply a sequencing depth so that also low-grade somatic mosaicism can be detected.
Summary Early Onset Absence Epilepsy constitutes an Idiopathic Generalized Epilepsy with absences starting before the age of four years. Mutations in SLC2A1 , encoding the glucose transporter, ...account for approximately 10% of EOAE cases. The role of SLC2A1 mutations in absence epilepsies with a later onset has not been assessed. We found two mutation carriers in 26 EOAE patients, while no mutations were found in 124 probands affected by CAE or JAE.
In this study we performed molecular characterization of a patient with an extra ring chromosome derived from chromosome 14, with severe intellectual disability, epilepsy, cerebral paresis, ...tetraplegia, osteoporosis and severe thoraco-lumbal scoliosis. Array CGH analysis did not show any genomic imbalance but conventional karyotyping and FISH analysis revealed the presence of an interstitial 14q12q24.3 deletion and an extra ring chromosome derived from the deleted material. The deletion and ring chromosome breakpoints were identified at base-pair level by mate-pair and Sanger sequencing. Both breakpoints disrupted putative long non-coding RNA genes (TCONS00022561;RP11-148E17.1) of unknown function. However, the proximal breakpoint was 225 kb downstream of the forkhead box G1 gene (FOXG1), within the known regulatory landscape of FOXG1. The patient represents the first case of a r(14) arising from an interstitial excision where the phenotype is compatible with dysregulation of FOXG1. In turn, the phenotypic overlap between the present case, the FOXG1 syndrome and the r(14) syndrome supports that dysregulation of FOXG1 may contribute to the classical r(14)-syndrome, likely mediated by dynamic mosaicism.
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