Novel WWOX deleterious variants cause early infantile epileptic encephalopathy, severe developmental delay and dysmorphism among Yemenite Jews

2019 ◽  
Vol 23 (3) ◽  
pp. 418-426 ◽  
Author(s):  
M. Weisz-Hubshman ◽  
H. Meirson ◽  
R. Michaelson-Cohen ◽  
R. Beeri ◽  
S. Tzur ◽  
...  
Keyword(s):  
Developmental Delay ◽  
Epileptic Encephalopathy ◽  
Yemenite Jews

scholarly journals Mr. Potato Head

2019 ◽  
pp. 468-487
Author(s):  
Nancy Foldvary-Schaefer ◽  
Thapanee Somboon ◽  
Zahreddin Alsheikhtaha
Keyword(s):  
Sleep Apnea ◽  
Sleep Disorders ◽  
Developmental Delay ◽  
Epileptic Encephalopathy ◽  
Electrode Placement ◽  
Age Related ◽  
Generalized Epilepsy ◽  
Patients With Epilepsy ◽  
Spike Wave

This case illustrates diagnostic challenges in patients with epilepsy and suspected sleep disorders. Specifically, the symptomatic generalized epilepsy Lennox-Gastaut syndrome is an age-related epileptic encephalopathy characterized by developmental delay; multiple seizure types, including tonic seizures in drowsiness and sleep; and generalized slow spike-wave complexes on electroencephalography (EEG). Tonic seizures in sleep can be unrecognized or can be confused with sleep disorders such as sleep apnea. The case demonstrates how to identify generalized epileptic abnormalities and seizures on the limited EEG montage used in routine polysomnography and expanded EEG using the 10-20 system of electrode placement.

Recurrent GNAO1 Mutations Associated With Developmental Delay and a Movement Disorder

2016 ◽  
Vol 31 (14) ◽  
pp. 1598-1601 ◽  
Author(s):  
Leonie A. Menke ◽  
Marc Engelen ◽  
Mariel Alders ◽  
Vincent J. J. Odekerken ◽  
Frank Baas ◽  
...  
Keyword(s):  
Movement Disorder ◽  
Missense Mutation ◽  
Developmental Delay ◽  
Recurrence Risk ◽  
Epileptic Encephalopathy ◽  
Missense Mutations ◽  
Phenotype Correlation ◽  
Affected Child ◽  
Sibling Pairs ◽  
Hyperkinetic Movement Disorder

In 2 unrelated patients with axial hypotonia, developmental delay and a hyperkinetic movement disorder, a missense mutation was found in codon 209 of the GNAO1 gene. From the still scarce literature on GNAO1 mutations, a clear genotype-phenotype correlation emerged. From the 26 patients reported thus far, 12 patients had epileptic encephalopathy, and 14 had a developmental delay and a hyperkinetic movement disorder. All but 1 of the latter patients had missense mutations in GNAO1 codon 209 or 246, which thus appear to be mutation hotspots. At least 2 sibling pairs showed that the recurrence risk after 1 affected child with a GNAO1 mutation might be relatively high (5-15%), due to apparent gonadal mosaicism in the parents.

scholarly journals KCNQ2 mutations: genotype-phenotype association beyond epilepsy

2015 ◽  
Vol 42 (S1) ◽  
pp. S8-S8
Author(s):  
SE Buerki ◽  
GA Horwath ◽  
MI Van Allen ◽  
A Datta ◽  
C Boelman ◽  
...  
Keyword(s):  
Developmental Delay ◽  
Autonomic Dysfunction ◽  
De Novo ◽  
Focal Epilepsy ◽  
Missense Variant ◽  
Epileptic Encephalopathy ◽  
Global Developmental Delay ◽  
High Signal ◽  
Brain Volume Loss ◽  
Hyperkinetic Movement Disorder

Background: KCNQ2 abnormalities were described in infants with benign familial neonatal seizures (BFNS) and epileptic encephalopathy (EE). Associated features possibly include abnormal neuroimaging findings such as hypomyelination and/or T2 high signal of basal ganglia. Methods: This report describes 4 infants carrying different heterozygous KCNQ2 variants and 2 infants with 20q13.33 deletions encompassing KCNQ2 gene. Results: The different KCNQ2 mutations led to EE in 3 patients and included a novel de novo missense variant, p.Arg201Cys/c.601C>T, in an infant with severe EE and global developmental delay, hyperkinetic movement disorder, autonomic dysfunction with chronic hypoventilation, apnea, low GABA levels in CSF, and hypomyelination. She died at age 3 years of respiratory failure. One patient with BFNS and normal MRI has a previously reported c.508delG frame shift mutation in KCNQ2. Of the two de novo 22q13.33 deletions (1.2Mb versus 254.1 Kb) the larger caused a more severe phenotype, including focal epilepsy from infancy until 4 years, moderate developmental delay and diffuse brain volume loss. Conclusions: Along with varied epilepsy phenotypes and neuroimaging findings KCNQ abnormalities were associated with severe autonomic dysfunction and reduced CSF GABA levels. This might have further treatment implications, besides that the altered potassium channel function itself presents a therapeutic target.

scholarly journals Early-onset epileptic encephalopathy and severe developmental delay in an association with de novo double mutations in NF1 and MAGEL2

2017 ◽  
Vol 3 (1) ◽  
pp. 81-85 ◽  
Author(s):  
Satoshi Akamine ◽  
Noriaki Sagata ◽  
Yasunari Sakai ◽  
Takahiro A. Kato ◽  
Takeshi Nakahara ◽  
...  
Keyword(s):  
Developmental Delay ◽  
Early Onset ◽  
De Novo ◽  
Epileptic Encephalopathy

scholarly journals X-linked neonatal-onset epileptic encephalopathy associated with a gain-of-function variant p.R660T in GRIA3

PLoS Genetics ◽  
2021 ◽  
Vol 17 (6) ◽  
pp. e1009608
Author(s):  
Jia-Hui Sun ◽  
Jiang Chen ◽  
Fernando Eduardo Ayala Valenzuela ◽  
Carolyn Brown ◽  
Diane Masser-Frye ◽  
...  
Keyword(s):  
Developmental Delay ◽  
Prolonged Exposure ◽  
De Novo ◽  
Missense Variant ◽  
Epileptic Encephalopathy ◽  
Global Developmental Delay ◽  
Decay Kinetics ◽  
Gain Of Function ◽  
Ca1 Neurons ◽  
Pathogenic Variants

The X-linked GRIA3 gene encodes the GLUA3 subunit of AMPA-type glutamate receptors. Pathogenic variants in this gene were previously reported in neurodevelopmental diseases, mostly in male patients but rarely in females. Here we report a de novo pathogenic missense variant in GRIA3 (c.1979G>C; p. R660T) identified in a 1-year-old female patient with severe epilepsy and global developmental delay. When exogenously expressed in human embryonic kidney (HEK) cells, GLUA3_R660T showed slower desensitization and deactivation kinetics compared to wildtype (wt) GLUA3 receptors. Substantial non-desensitized currents were observed with the mutant but not for wt GLUA3 with prolonged exposure to glutamate. When co-expressed with GLUA2, the decay kinetics were similarly slowed in GLUA2/A3_R660T with non-desensitized steady state currents. In cultured cerebellar granule neurons, miniature excitatory postsynaptic currents (mEPSCs) were significantly slower in R660T transfected cells than those expressing wt GLUA3. When overexpressed in hippocampal CA1 neurons by in utero electroporation, the evoked EPSCs and mEPSCs were slower in neurons expressing R660T mutant compared to those expressing wt GLUA3. Therefore our study provides functional evidence that a gain of function (GoF) variant in GRIA3 may cause epileptic encephalopathy and global developmental delay in a female subject by enhancing synaptic transmission.

PPP2R5D-Related Neurodevelopmental Disorder or Developmental and Epileptic Encephalopathy?: A Novel Phenotypic Description and Review of Published Cases

2021 ◽  
Author(s):  
Priyanka Madaan ◽  
Amrit Kaur ◽  
Lokesh Saini ◽  
Pradip Paria ◽  
Sameer Vyas ◽  
...  
Keyword(s):  
Developmental Delay ◽  
Case Reports ◽  
Neurodevelopmental Disorder ◽  
Epileptic Encephalopathy ◽  
Regulatory Subunit ◽  
History Of ◽  
The Common ◽  
Diagnostic Clue ◽  
Protein Phosphatase 2 ◽  
Subunit B

Abstract Background Protein phosphatase 2 regulatory subunit B′ delta (PPP2R5D)-related neurodevelopmental disorder is caused by pathogenic variations in the PPP2R5D gene, product of which is involved in dephosphorylation. This is a rare disorder with description limited to case reports. Its phenotypic spectrum has expanded over the last decade. Methods We report a child with a developmental and epileptic encephalopathy phenotype with a pathogenic PPP2R5D variant. This phenotype has not been previously reported. We also reviewed the previously published reports of patients with this disorder. Results Including the index child, 28 cases (15 girls) were identified from nine relevant research items for analysis. All patients had developmental delay. History of seizures was observed in seven patients while macrocephaly was seen in nearly 80% of patients. Nonneurological manifestations were observed in 13 patients with the most common one being ophthalmological manifestations. The most common genetic variation was c.G592A (p.E198K). The common phenotypic associations of this variation were developmental delay, macrocephaly (11/15), and epilepsy (6/15). Conclusion PPP2R5D gene variations should be suspected in children with developmental delay, autistic features, macrocephaly with or without epilepsy in the absence of any clear etiology. Dysmorphic features might provide a diagnostic clue. DEE phenotype may also be the presenting feature and might be an underreported entity.

A novel missense variant in the SDR domain of the WWOX gene leads to complete loss of WWOX protein with early-onset epileptic encephalopathy and severe developmental delay

Neurogenetics ◽  
2018 ◽  
Vol 19 (3) ◽  
pp. 151-156 ◽  
Author(s):  
Jessika Johannsen ◽  
Fanny Kortüm ◽  
Georg Rosenberger ◽  
Kristin Bokelmann ◽  
Markus A. Schirmer ◽  
...  
Keyword(s):  
Developmental Delay ◽  
Early Onset ◽  
Missense Variant ◽  
Epileptic Encephalopathy ◽  
Complete Loss ◽  
Wwox Gene

scholarly journals Loss of UGP2 in brain leads to a severe epileptic encephalopathy, emphasizing that bi-allelic isoform-specific start-loss mutations of essential genes can cause genetic diseases

2019 ◽  
Vol 139 (3) ◽  
pp. 415-442 ◽  
Author(s):  
Elena Perenthaler ◽  
Anita Nikoncuk ◽  
Soheil Yousefi ◽  
Woutje M. Berdowski ◽  
Maysoon Alsagob ◽  
...  
Keyword(s):  
Developmental Delay ◽  
Genetic Disorders ◽  
Genetic Diseases ◽  
Intractable Epilepsy ◽  
Stem Cell Differentiation ◽  
Visual Disturbance ◽  
Epileptic Encephalopathy ◽  
Start Codon

AbstractDevelopmental and/or epileptic encephalopathies (DEEs) are a group of devastating genetic disorders, resulting in early-onset, therapy-resistant seizures and developmental delay. Here we report on 22 individuals from 15 families presenting with a severe form of intractable epilepsy, severe developmental delay, progressive microcephaly, visual disturbance and similar minor dysmorphisms. Whole exome sequencing identified a recurrent, homozygous variant (chr2:64083454A > G) in the essential UDP-glucose pyrophosphorylase (UGP2) gene in all probands. This rare variant results in a tolerable Met12Val missense change of the longer UGP2 protein isoform but causes a disruption of the start codon of the shorter isoform, which is predominant in brain. We show that the absence of the shorter isoform leads to a reduction of functional UGP2 enzyme in neural stem cells, leading to altered glycogen metabolism, upregulated unfolded protein response and premature neuronal differentiation, as modeled during pluripotent stem cell differentiation in vitro. In contrast, the complete lack of all UGP2 isoforms leads to differentiation defects in multiple lineages in human cells. Reduced expression of Ugp2a/Ugp2b in vivo in zebrafish mimics visual disturbance and mutant animals show a behavioral phenotype. Our study identifies a recurrent start codon mutation in UGP2 as a cause of a novel autosomal recessive DEE syndrome. Importantly, it also shows that isoform-specific start-loss mutations causing expression loss of a tissue-relevant isoform of an essential protein can cause a genetic disease, even when an organism-wide protein absence is incompatible with life. We provide additional examples where a similar disease mechanism applies.

scholarly journals Defining and expanding the phenotype of QARS-associated developmental epileptic encephalopathy

2019 ◽  
Vol 5 (6) ◽  
pp. e373
Author(s):  
Katrine M. Johannesen ◽  
Diana Mitter ◽  
Robert Janowski ◽  
Christian Roth ◽  
Joseph Toulouse ◽  
...  
Keyword(s):  
Developmental Delay ◽  
Early Onset ◽  
Epileptic Encephalopathy ◽  
Small Subset ◽  
Mri Findings ◽  
Pharmacoresistant Epilepsy ◽  
Pathogenic Variants ◽  
Cranial Mri ◽  
Delayed Myelination

ObjectiveThe study is aimed at widening the clinical and genetic spectrum and at assessing genotype-phenotype associations in QARS encephalopathy.MethodsThrough diagnostic gene panel screening in an epilepsy cohort, and recruiting through GeneMatcher and our international network, we collected 10 patients with biallelic QARS variants. In addition, we collected data on 12 patients described in the literature to further delineate the associated phenotype in a total cohort of 22 patients. Computer modeling was used to assess changes on protein folding.ResultsBiallelic pathogenic variants in QARS cause a triad of progressive microcephaly, moderate to severe developmental delay, and early-onset epilepsy. Microcephaly was present at birth in 65%, and in all patients at follow-up. Moderate (14%) or severe (73%) developmental delay was characteristic, with no achievement of sitting (85%), walking (86%), or talking (90%). Additional features included irritability (91%), hypertonia/spasticity (75%), hypotonia (83%), stereotypic movements (75%), and short stature (56%). Seventy-nine percent had pharmacoresistant epilepsy with mainly neonatal onset. Characteristic cranial MRI findings include early-onset progressive atrophy of cerebral cortex (89%) and cerebellum (61%), enlargement of ventricles (95%), and age-dependent delayed myelination (88%). A small subset of patients displayed a less severe phenotype.ConclusionsThese data revealed first genotype-phenotype associations and may serve for improved interpretation of new QARS variants and well-founded genetic counseling.

scholarly journals Spectrum of Movement Disorders in GNAO1 Encephalopathy: in-depth Phenotyping and Literature Review

2020 ◽  
Author(s):  
Soo Yeon Kim ◽  
YoungKyu Shim ◽  
Young Joon Ko ◽  
Soojin Park ◽  
Se Song Jang ◽  
...  
Keyword(s):  
Literature Review ◽  
Exome Sequencing ◽  
Developmental Delay ◽  
Whole Exome Sequencing ◽  
De Novo ◽  
Neurodevelopmental Disorder ◽  
Epileptic Encephalopathy ◽  
Global Developmental Delay ◽  
Pathogenic Variants ◽  
Whole Exome

Abstract Background GNAO1 encephalopathy is a rare neurodevelopmental disorder characterized by distinct movement presentations and early onset epileptic encephalopathy. Here, we report the in-depth phenotyping of genetically confirmed patients with GNAO1 encephalopathy, focusing on movement presentations. Results Six patients who participated in Korean Undiagnosed Disease Program were diagnosed to have pathogenic or likely pathogenic variants in GNAO1 using whole exome sequencing. All medical records and personal video clips were analyzed with a literature review. Three of the 6 patients were male. Mean follow-up duration was 39 months (range, 7–78 months) and age at last examination was 8.0 years (range, 3.3–16.9 years). Initial complaints were hypotonia or developmental delay in 5 and right-hand clumsiness in 1 patient, which were noticed at 20 months of age on average (range, 0–75 months). All patients showed global developmental delay and 4 had severely retarded development. Five patients (5/6, 83.3%) had many different movement symptoms with various onset and progression. The symptoms included stereotyped hands movement, non-epileptic myoclonus, dyskinesia, dystonia and choreoathetosis. Whole exome sequencing identified 6 different variants in GNAO1. Three were novel de novo variants and atypical presentation was noted in a patient. One variant turned out to be inherited from patient’s mother who had mosaic variant. Distinct phenotypes in patients with variant p.Glu246Lys and p.Arg209His were elucidated by in-depth phenotyping and literature review. Conclusions We reported 6 patients with GNAO1 encephalopathy showing an extremely diverse clinical spectrum on video. Some characteristic movement features identified by careful inspection may also provide important diagnostic insight and practice guidelines.

Sign in / Sign up

Export Citation Format

Share Document