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 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.

STXBP1 encephalopathy

Neurology ◽  
2019 ◽  
Vol 93 (3) ◽  
pp. 114-123 ◽  
Author(s):  
Vanessa Lanoue ◽  
Ye Jin Chai ◽  
Julie Z. Brouillet ◽  
Sarah Weckhuysen ◽  
Elizabeth E. Palmer ◽  
...  
Keyword(s):  
Neurodegenerative Diseases ◽  
Neural Development ◽  
Early Onset ◽  
De Novo ◽  
Basic Research ◽  
Autism Spectrum ◽  
Epileptic Encephalopathy ◽  
Severe Form ◽  
Pathogenic Variants ◽  
Extrapyramidal Features

De novo pathogenic variants in STXBP1 encoding syntaxin1-binding protein (STXBP1, also known as Munc18-1) lead to a range of early-onset neurocognitive conditions, most commonly early infantile epileptic encephalopathy type 4 (EIEE4, also called STXBP1 encephalopathy), a severe form of epilepsy associated with developmental delay/intellectual disability. Other neurologic features include autism spectrum disorder and movement disorders. The progression of neurologic symptoms has been reported in a few older affected individuals, with the appearance of extrapyramidal features, reminiscent of early onset parkinsonism. Understanding the pathologic process is critical to improving therapies, as currently available antiepileptic drugs have shown limited success in controlling seizures in EIEE4 and there is no precision medication approach for the other neurologic features of the disorder. Basic research shows that genetic knockout of STXBP1 or other presynaptic proteins of the exocytic machinery leads to widespread perinatal neurodegeneration. The mechanism that regulates this effect is under scrutiny but shares intriguing hallmarks with classical neurodegenerative diseases, albeit appearing early during brain development. Most critically, recent evidence has revealed that STXBP1 controls the self-replicating aggregation of α-synuclein, a presynaptic protein involved in various neurodegenerative diseases that are collectively known as synucleinopathies, including Parkinson disease. In this review, we examine the tantalizing link among STXBP1 function, EIEE, and the neurodegenerative synucleinopathies, and suggest that neural development in EIEE could be further affected by concurrent synucleinopathic mechanisms.

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 Asymptomatic Brain Edema after Hemodialysis Initiation in a Patient with Severe Uremia

2017 ◽  
Vol 2017 ◽  
pp. 1-6
Author(s):  
Kiichiro Fujisaki ◽  
Kaneyasu Nakagawa ◽  
Hiroshi Nagae ◽  
Toshiaki Nakano ◽  
Masatomo Taniguchi ◽  
...  
Keyword(s):  
Cerebral Edema ◽  
Occipital Lobe ◽  
Neurological Deficits ◽  
Mri Findings ◽  
Severe Renal Insufficiency ◽  
Cranial Mri ◽  
Dialysis Disequilibrium Syndrome ◽  
Magnetic Resonance Imaging Mri ◽  
Mri Changes

A 66-year-old man with severe renal insufficiency presented with mild confusion associated with uremia. Cranial magnetic resonance imaging (MRI) showed no remarkable changes. The patient was placed on short-duration hemodialysis (2 hours) with smaller surface area and low blood flow (100 mL/min) to avoid dialysis disequilibrium syndrome (DDS). His consciousness gradually improved and he did not develop apparent DDS symptoms. However, T2-weighted FLAIR MRI showed increased signal intensities bilaterally in the cortical and subcortical areas of the occipital lobe on day 15. In other words, cranial MRI showed cerebral edema, indicating asymptomatic DDS. On day 29, cranial MRI showed a return to findings on admission. In this case, because the patient did not have apparent DDS symptoms despite MRI changes, we diagnosed asymptomatic cerebral edema. The patient was discharged on regular intermittent HD without any neurological deficits. No further neurological disturbances were noted during 1-year follow-up. MRI findings in ESKD patients without DDS symptoms help to clarify the diagnosis of cerebral edema. In this case, the patient did not have apparent DDS symptoms and was therefore diagnosed with asymptomatic cerebral edema.

scholarly journals Clinical and Genetic Characteristics and Prenatal Diagnosis of Rare Monogenic Global Developmental Delay and Intellectual Disability.

2020 ◽  
Author(s):  
Liling Lin ◽  
Ying Zhang ◽  
Hong Pan ◽  
Jingmin Wang ◽  
Yu Qi ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Prenatal Diagnosis ◽  
Developmental Delay ◽  
Hot Spot ◽  
Disease Onset ◽  
Genetic Diagnosis ◽  
Global Developmental Delay ◽  
Genetic Characteristics ◽  
Pathogenic Variants

Abstract Background: The estimated worldwide prevalence of global developmental delay (GDD) and intellectual disability (ID) is 1-3%. Rare monogenic GDD/ID is poorly characterized because its low prevalence limits research. In this study, we aimed to describe the diagnostic courses and clinical and genetic characteristics of a cohort with rare monogenic GDD/ID.Method:We retrospectively analyzed the diagnostic courses, clinical characteristics, and genetic spectra of rare monogenic GDD/ID patients. We also conducted a follow-up study on prenatal diagnosis in these families. Mutation pathogenicity was interpreted by molecular geneticists and clinicians according to the guidelines of the American College of Medical Genetics and Genomics. Results:Among 108 patients with rare monogenic GDD/ID, it often took 0.5-4 years and 3-5 referrals to obtain a genetic diagnosis after disease onset. Onset typically occurred before 6 years of age, and patients usually presented moderate to severe GDD/ID. The most common coexisting conditions were epilepsy (68%), facial dysmorphism (14%) and microcephaly (13%). In total, 149 different pathogenic variants were found in 81 different genes among the 108 pedigrees, and 71 variants were novel. The most common inheritance patterns in this outbred Chinese population were autosomal recessive (AR; 46.3%), autosomal dominant (AD; 37%), and X-linked (XL; 16.7%). GLB1, PLA2G6, SCN2A, SHANK3 and STXBP1 were important causal genes. Hot-spot mutations were rarely found. By the follow-up, 43 families, including 24 ARID, 13 ADID and 6 XLID families, had undergone prenatal diagnosis. The offspring of 6 ARID, 2 ADID and 2 XLID families had the same pathogenic variants as the probands.Conclusion:Rare monogenic GDD/ID is characterized by early onset, relatively severe symptoms, great clinical variability and genetic heterogeneity. Moreover, timely referrals to genetic counseling and prenatal diagnostic laboratories are important for affected families planning to have additional children.

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.

scholarly journals Spectrum of Movement Disorders in GNAO1 Encephalopathy: In-Depth Phenotyping and Case-by-Case Analysis

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. Median follow-up duration was 41 months (range, 7–78 months) and age at last examination was 7.4 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 median age of 3 months (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 and characteristics movement 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.

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