scholarly journals UNC13B variants associated with partial epilepsy with favourable outcome

Brain ◽  
2021 ◽  
Author(s):  
Jie Wang ◽  
Jing-Da Qiao ◽  
Xiao-Rong Liu ◽  
De-Tian Liu ◽  
Yan-Hui Chen ◽  
...  
Keyword(s):  
Neuronal Excitability ◽  
Brain Mri ◽  
Missense Variant ◽  
Febrile Seizures ◽  
Favourable Outcome ◽  
Partial Epilepsy ◽  
Favorable Outcome ◽  
Compound Heterozygous ◽  
Developmental Abnormalities ◽  
Seizure Rate

Abstract The unc-13 homolog B (UNC13B) gene encodes a presynaptic protein, mammalian uncoordinated 13–2 (Munc13-2), that is highly expressed in the brain—predominantly in the cerebral cortex—and plays an essential role in synaptic vesicle priming and fusion, potentially affecting neuronal excitability. However, the functional significance of UNC13B mutation in human disease is not known. In this study we screened for novel genetic variants in a cohort of 446 unrelated cases (families) with partial epilepsy without acquired causes by trio-based whole-exome sequencing. UNC13B variants were identified in 12 individuals affected by partial epilepsy and/or febrile seizures from eight unrelated families. The eight probands all had focal seizures and focal discharges in EEG recordings, including two patients who experienced frequent daily seizures and one who showed abnormalities in the hippocampus by brain MRI; however, all of the patients showed favorable outcome without intellectual or developmental abnormalities. The identified UNC13B variants included one nonsense variant, two variants at or around a splice site, one compound heterozygous missense variant, and four missense variants that cosegregated in the families. The frequency of UNC13B variants identified in the present study was significantly higher than that in a control cohort of Han Chinese and controls of the East Asian and all populations in the Genome Aggregation Database. Computational modeling, including hydrogen bond and docking analyses, suggested that the variants lead to functional impairment. In Drosophila, seizure rate and duration were increased by Unc13b knockdown compared to wild-type flies, but these effects were less pronounced than in sodium voltage-gated channel alpha subunit 1 (Scn1a) knockdown Drosophila. Electrophysiologic recordings showed that excitatory neurons in Unc13b-deficient flies exhibited increased excitability. These results suggest that UNC13B is potentially associated with epilepsy. The frequent daily seizures and hippocampal abnormalities but ultimately favorable outcome under antiepileptic therapy in our patients indicate that partial epilepsy caused by UNC13B variant is a clinically manageable condition.

scholarly journals NUBPL mitochondrial disease: new patients and review of the genetic and clinical spectrum

2020 ◽  
pp. jmedgenet-2020-106846
Author(s):  
Virginia Kimonis ◽  
Rehab al Dubaisi ◽  
Andrew E Maclean ◽  
Kathy Hall ◽  
Lan Weiss ◽  
...  
Keyword(s):  
Complex I ◽  
Phenotypic Variability ◽  
Brain Mri ◽  
Mitochondrial Disorder ◽  
Cerebellar Atrophy ◽  
Missense Variant ◽  
Global Developmental Delay ◽  
Compound Heterozygous ◽  
Site Mutation ◽  
Yeast Model

BackgroundThe nucleotide binding protein-like (NUBPL) gene was first reported as a cause of mitochondrial complex I deficiency (MIM 613621, 618242) in 2010. To date, only eight patients have been reported with this mitochondrial disorder. Five other patients were recently reported to have NUBPL disease but their clinical picture was different from the first eight patients. Here, we report clinical and genetic findings in five additional patients (four families).MethodsWhole exome sequencing was used to identify patients with compound heterozygous NUBPL variants. Functional studies included RNA-Seq transcript analyses, missense variant biochemical analyses in a yeast model (Yarrowia lipolytica) and mitochondrial respiration experiments on patient fibroblasts.ResultsThe previously reported c.815-27T>C branch-site mutation was found in all four families. In prior patients, c.166G>A [p.G56R] was always found in cis with c.815-27T>C, but only two of four families had both variants. The second variant found in trans with c.815-27T>C in each family was: c.311T>C [p.L104P] in three patients, c.693+1G>A in one patient and c.545T>C [p.V182A] in one patient. Complex I function in the yeast model was impacted by p.L104P but not p.V182A. Clinical features include onset of neurological symptoms at 3–18 months, global developmental delay, cerebellar dysfunction (including ataxia, dysarthria, nystagmus and tremor) and spasticity. Brain MRI showed cerebellar atrophy. Mitochondrial function studies on patient fibroblasts showed significantly reduced spare respiratory capacity.ConclusionWe report on five new patients with NUBPL disease, adding to the number and phenotypic variability of patients diagnosed worldwide, and review prior reported patients with pathogenic NUBPL variants.

Magnetic resonance imaging findings and its association to electroencephalogram in children with partial epilepsy (Preprint)

2020 ◽  
Author(s):  
Huynh Quang Huy
Keyword(s):  
Magnetic Resonance Imaging ◽  
Preschool Children ◽  
Magnetic Resonance ◽  
Brain Mri ◽  
Partial Epilepsy ◽  
Small Sample ◽  
Normal Brain ◽  
Resonance Imaging ◽  
Normal Children ◽  
Eeg Abnormalities

BACKGROUND It is important to identify the neuroimaging features that are associated with partial epilepsy in preschool children. Advances in technology recently to localize focal epileptogenic lesions, especially that of high-resolution structural imaging with magnetic resonance imaging (MRI). The recommendation that electroencephalography (EEG) should be gold criteria and that M.R.I should be optional has been questioned. OBJECTIVE The present study aims to to explore the brain lesions on MRI and its association to electroencephalogram in children with partial epilepsy. METHODS The present study was conducted among 112 preschool children with history of partial seizures. All patients underwent EEG and brain MRI. The epileptogenic lesions were identified on the basis of the signal intensities and morphological abnormalities seen on MRI. The correlation between MRI and EEG abnormalities was explored using a chi-square test. RESULTS Abnormal MRI were found in 34.8% (n = 39) of the sample. The EEG and MRI agreed with respect to classify into abnormal or normal in 48.2% (n = 54). Of the 27 patients with a normal EEG, six (22.2%) were seen to have an abnormal MRI. CONCLUSIONS A number of MRI abnormalities was found in our study of otherwise normal children, although the correlation between these results was not clear. Follow-up of these children will help us identify the important abnormalities. Despite of small sample, our results showed that a normal E.E.G findings does not predict a normal brain MRI in children with partial epilepsy.

Molecular basis of ciliary defects caused by compound heterozygous IFT144/WDR19 mutations found in cranioectodermal dysplasia

2021 ◽  
Author(s):  
Yamato Ishida ◽  
Takuya Kobayashi ◽  
Shuhei Chiba ◽  
Yohei Katoh ◽  
Kazuhisa Nakayama
Keyword(s):  
Protein Trafficking ◽  
Primary Cilia ◽  
Intraflagellar Transport ◽  
Missense Variant ◽  
Cellular Level ◽  
Compound Heterozygous ◽  
Hypomorphic Allele ◽  
Genes Encoding ◽  
Specific Proteins ◽  
Compound Heterozygous Mutations

Abstract Primary cilia contain specific proteins to achieve their functions as cellular antennae. Ciliary protein trafficking is mediated by the intraflagellar transport (IFT) machinery containing the IFT-A and IFT-B complexes. Mutations in genes encoding the IFT-A subunits (IFT43, IFT121/WDR35, IFT122, IFT139/TTC21B, IFT140, and IFT144/WDR19) often result in skeletal ciliopathies, including cranioectodermal dysplasia (CED). We here characterized the molecular and cellular defects of CED caused by compound heterozygous mutations in IFT144 [the missense variant IFT144(L710S) and the nonsense variant IFT144(R1103*)]. These two variants were distinct with regard to their interactions with other IFT-A subunits and with the IFT-B complex. When exogenously expressed in IFT144-knockout (KO) cells, IFT144(L710S) as well as IFT144(WT) rescued both moderately compromised ciliogenesis and the abnormal localization of ciliary proteins. As the homozygous IFT144(L710S) mutation was found to cause autosomal recessive retinitis pigmentosa, IFT144(L710S) is likely to be hypomorphic at the cellular level. In striking contrast, the exogenous expression of IFT144(R1103*) in IFT144-KO cells exacerbated the ciliogenesis defects. The expression of IFT144(R1103*) together with IFT144(WT) restored the abnormal phenotypes of IFT144-KO cells. However, the coexpression of IFT144(R1103*) with the hypomorphic IFT144(L710S) variant in IFT144-KO cells, which mimics the genotype of compound heterozygous CED patients, resulted in severe ciliogenesis defects. Taken together, these observations demonstrate that compound heterozygous mutations in IFT144 cause severe ciliary defects via a complicated mechanism, where one allele can cause severe ciliary defects when combined with a hypomorphic allele.

scholarly journals Unusual phenotypes in patients with a pathogenic germline variant in DICER1

2021 ◽  
Author(s):  
Kateryna Venger ◽  
Miriam Elbracht ◽  
Julia Carlens ◽  
Peter Deutz ◽  
Felix Zeppernick ◽  
...  
Keyword(s):  
Wilms Tumor ◽  
Pleuropulmonary Blastoma ◽  
Global Developmental Delay ◽  
Facial Dysmorphism ◽  
Compound Heterozygous ◽  
Incomplete Penetrance ◽  
Developmental Abnormalities ◽  
Lung Cysts ◽  
Developmental Features ◽  
Skeletal Findings

AbstractPathogenic germline DICER1 variants are associated with pleuropulmonary blastoma, multinodular goiter, embryonal rhabdomyosarcoma and other tumour types, while mosaic missense DICER1 variants in the RNase IIIb domain are linked to cause GLOW (global developmental delay, lung cysts, overgrowth, and Wilms’ tumor) syndrome. Here, we report four families with germline DICER1 pathogenic variants in which one member in each family had a more complex phenotype, including skeletal findings, facial dysmorphism and developmental abnormalities. The developmental features occur with a variable expressivity and incomplete penetrance as also described for the neoplastic and dysplastic lesions associated with DICER1 variants. Whole exome sequencing (WES) was performed on all four cases and revealed no further pathogenic or likely pathogenic dominant, homozygous or compound heterozygous variants in three of them. Notably, a frameshift variant in ARID1B was detected in one patient explaining part of her phenotype. This series of patients shows that pathogenic DICER1 variants may be associated with a broader phenotypic spectrum than initially assumed, including predisposition to different tumours, skeletal findings, dysmorphism and developmental abnormalities, but genetic work up in syndromic patients should be comprehensive in order not to miss additional underlying /modifying causes.

scholarly journals Intrauterine death following intraamniotic triiodothyronine and thyroxine therapy for fetal goitrous hypothyroidism associated with polyhydramnios and caused by a thyroglobulin mutation

2017 ◽  
Vol 2017 ◽  
Author(s):  
Pradeep Vasudevan ◽  
Corrina Powell ◽  
Adeline K Nicholas ◽  
Ian Scudamore ◽  
James Greening ◽  
...  
Keyword(s):  
Prenatal Diagnosis ◽  
Hormone Replacement ◽  
Favourable Outcome ◽  
Compound Heterozygous ◽  
Intrauterine Death ◽  
List Type ◽  
Loss Of Function ◽  
Respiratory Compromise ◽  
Mechanical Complications ◽  
Elective Delivery

Summary In the absence of maternal thyroid disease or iodine deficiency, fetal goitre is rare and usually attributable to dyshormonogenesis, for which genetic ascertainment is not always undertaken in the UK. Mechanical complications include tracheal and oesophageal compression with resultant polyhydramnios, malpresentation at delivery and neonatal respiratory distress. We report an Indian kindred in which the proband (first-born son) had congenital hypothyroidism (CH) without obvious neonatal goitre. His mother’s second pregnancy was complicated by fetal hypothyroid goitre and polyhydramnios, prompting amniotic fluid drainage and intraamniotic therapy (with liothyronine, T3 and levothyroxine, T4). Sadly, intrauterine death occurred at 31 weeks. Genetic studies in the proband demonstrated compound heterozygous novel (c.5178delT, p.A1727Hfs*26) and previously described (c.7123G > A, p.G2375R) thyroglobulin (TG) mutations which are the likely cause of fetal goitre in the deceased sibling. TG mutations rarely cause fetal goitre, and management remains controversial due to the potential complications of intrauterine therapy however an amelioration in goitre size may be achieved with intraamniotic T4, and intraamniotic T3/T4 combination has achieved a favourable outcome in one case. A conservative approach, with surveillance, elective delivery and commencement of levothyroxine neonatally may also be justified, although intubation may be required post delivery for respiratory obstruction. Our observations highlight the lethality which may be associated with fetal goitre. Additionally, although this complication may recur in successive pregnancies, our case highlights the possibility of discordance for fetal goitre in siblings harbouring the same dyshormonogenesis-associated genetic mutations. Genetic ascertainment may facilitate prenatal diagnosis and assist management in familial cases. Learning points: CH due to biallelic, loss-of-function TG mutations is well-described and readily treatable in childhood however mechanical complications from associated fetal goitre may include polyhydramnios, neonatal respiratory compromise and neck hyperextension with dystocia complicating delivery. CH due to TG mutations may manifest with variable phenotypes, even within the same kindred. Treatment options for hypothyroid dyshormogenic fetal goitre in a euthyroid mother include intraamniotic thyroid hormone replacement in cases with polyhydramnios or significant tracheal obstruction. Alternatively, cases may be managed conservatively with radiological surveillance, elective delivery and neonatal levothyroxine treatment, although intubation and ventilation may be required to support neonatal respiratory compromise. Genetic ascertainment in such kindreds may enable prenatal diagnosis and anticipatory planning for antenatal management of further affected offspring.

scholarly journals Health Education based on 10 Steps at Mother Knowledge Level in Handling Febrile Seizure on Toddler

2018 ◽  
Vol 1 (3) ◽  
Author(s):  
Ernawaty Siagian ◽  
Vera Manalu
Keyword(s):  
Health Education ◽  
Febrile Seizure ◽  
Sampling Technique ◽  
Knowledge Score ◽  
Febrile Seizures ◽  
P Value ◽  
Before And After ◽  
Post Test ◽  
Seizure Rate ◽  
The Right

Febrile seizure rate on toddler was quite high and tended to increase every year. This was because as toddler experiencing febrile seizures they were not properly handled by the parents. Febrile seizure in toddler if not treated quickly can affect the increasing in seizure frequency and can cause death. The capability of mother in handling febrile seizure must be based on the right knowledge of febrile seizure. The purpose of this study was to determine the level of knowledge of the mother before and after health education based on 10 steps in handling febrile seizure on toddler in Bandar Lampung Adventist Hospital. Experimental research method with one group pretest-posttest designed with random sampling technique approach involving 80 mothers with 0 to 5 year old who had fever being hospitalized. The researchers prepared 10 images of steps in handling febrile seizures randomly and asked the respondents to arrange the pictures according to their knowledge. The results were observed to determine their knowledge rearranging as pretest data. Afterward, health education was given about 10 correct steps. Thereafter, reobserved was made and the knowledge in arranging 10 images was obtained as post test data. The knowledge score before health education was 20.75% and after was 83.75%. While the analytical test used paired t test. The results showed a significant relationship between knowledge before and after health education. p value = 0.00 < 0.05. The results showed that the value of tcount (14.26) > t table (2.26). Increased knowledge in mothers reduced the risk of recurrence of febrile seizures in toddler and the nurse who had not tought these steps needed to run regularly to the mothers whose child was being hospitalized.

scholarly journals Mechanisms of Congenital Myasthenia Caused by Three Mutations in the COLQ Gene

2021 ◽  
Vol 9 ◽  
Author(s):  
Xiaona Luo ◽  
Chunmei Wang ◽  
Longlong Lin ◽  
Fang Yuan ◽  
Simei Wang ◽  
...  
Keyword(s):  
Missense Mutation ◽  
Neuromuscular Junctions ◽  
Three Dimensional ◽  
Missense Variant ◽  
Homozygous Deletion ◽  
Dimensional Structure ◽  
Compound Heterozygous ◽  
Splicing Mutation ◽  
Gene Encoding ◽  
Congenital Myasthenia

The gene encoding collagen like tail subunit of asymmetric acetylcholinesterase (COLQ) is responsible for the transcription of three strands of collagen of acetylcholinesterase, which is attached to the endplate of neuromuscular junctions. Mutations in the COLQ gene are inherited in an autosomal-recessive manner and can lead to type V congenital myasthenia syndrome (CMS), which manifests as decreased muscle strength at birth or shortly after birth, respiratory failure, restricted eye movements, drooping of eyelids, and difficulty swallowing. Here we reported three variants within COLQ in two unrelated children with CMS. An intronic variant (c.393+1G&gt;A) and a novel missense variant (p.Q381P) were identified as compound heterozygous in a 13-month-old boy, with the parents being carriers of each. An intragenic deletion including exons 14 and 15 was found in a homozygous state in a 12-year-old boy. We studied the relative expression of the COLQ and AChE gene in the probands' families, performed three-dimensional protein structural analysis, and analyzed the conservation of the missense mutation c.1142A&gt;C (p.Q381P). The splicing mutation c.393+1G&gt;A was found to affect the normal splicing of COLQ exon 5, resulting in a 27-bp deletion. The missense mutation c.1142A&gt;C (p.Q381P) was located in a conserved position in different species. We found that homozygous deletion of COLQ exons 14–15 resulted in a 241-bp deletion, which decreased the number of amino acids and caused a frameshift translation. COLQ expression was significantly lower in the probands than in the probands' parents and siblings, while AChE expression was significantly higher. Moreover, the mutations were found to cause significant differences in the predicted three-dimensional structure of the protein. The splicing mutation c.393+1G&gt;A, missense mutation c.1A&gt;C (p.Q381P), and COLQ exon 14–15 deletion could cause CMS.

scholarly journals Effects of White Matter Hyperintensities on 90-Day Functional Outcome after Large Vessel and Non-Large Vessel Stroke

2020 ◽  
Vol 49 (4) ◽  
pp. 419-426
Author(s):  
Christoph Johannes Griessenauer ◽  
David McPherson ◽  
Andrea Berger ◽  
Ping Cuiper ◽  
Nelson Sofoluke ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
White Matter ◽  
Acute Ischemic Stroke ◽  
Functional Outcome ◽  
Brain Mri ◽  
Large Vessel ◽  
Favorable Outcome ◽  
White Matter Hyperintensity ◽  
Vessel Occlusion ◽  
Brain Extraction

Introduction: White matter hyperintensity (WMH) burden is a critically important cerebrovascular phenotype related to the diagnosis and prognosis of acute ischemic stroke. The effect of WMH burden on functional outcome in large vessel occlusion (LVO) stroke has only been sparsely assessed, and direct LVO and non-LVO comparisons are currently lacking. Material and Methods: We reviewed acute ischemic stroke patients admitted between 2009 and 2017 at a large healthcare system in the USA. Patients with LVO were identified and clinical characteristics, including 90-day functional outcomes, were assessed. Clinical brain MRIs obtained at the time of the stroke underwent quantification of WMH using a fully automated algorithm. The pipeline incorporated automated brain extraction, intensity normalization, and WMH segmentation. Results: A total of 1,601 acute ischemic strokes with documented 90-day mRS were identified, including 353 (22%) with LVO. Among those strokes, WMH volume was available in 1,285 (80.3%) who had a brain MRI suitable for WMH quantification. Increasing WMH volume from 0 to 4 mL, age, female gender, a number of stroke risk factors, presence of LVO, and higher NIHSS at presentation all decreased the odds for a favorable outcome. Increasing WMH above 4 mL, however, was not associated with decreasing odds of favorable outcome. While WMH volume was associated with functional outcome in non-LVO stroke (p = 0.0009), this association between WMH and functional status was not statistically significant in the complete case multivariable model of LVO stroke (p = 0.0637). Conclusion: The burden of WMH has effects on 90-day functional outcome after LVO and non-LVO strokes. Particularly, increases from no measurable WMH to 4 mL of WMH correlate strongly with the outcome. Whether this relationship of increasing WMH to worse outcome is more pronounced in non-LVO than LVO strokes deserves additional investigation.

PRUNE1 Deficiency: Expanding the Clinical and Genetic Spectrum

2018 ◽  
Vol 49 (05) ◽  
pp. 330-338 ◽  
Author(s):  
Anna Schossig ◽  
Tobias Haack ◽  
Reka Kovács-Nagy ◽  
Matthias Braunisch ◽  
Christine Makowski ◽  
...  
Keyword(s):  
Developmental Delay ◽  
Early Onset ◽  
Brain Mri ◽  
Missense Variant ◽  
Global Developmental Delay ◽  
Multiplex Family ◽  
Consistent Finding ◽  
Whole Exome ◽  
Severe Developmental Disabilities ◽  
Stem Lesions

Background Primary microcephaly and profound global developmental delay have been considered the core clinical phenotype in patients with bi-allelic PRUNE1 mutations. Methods Linkage analysis and whole-exome sequencing (WES) in a multiplex family and extraction of further cases from a WES repository containing 571 children with severe developmental disabilities and neurologic symptoms. Results We identified bi-allelic PRUNE1 mutations in twelve children from six unrelated families. All patients who survived beyond the first 6 months of life had early-onset global developmental delay, bilateral spastic paresis, dysphagia and difficult-to-treat seizures, while congenital or later-evolving microcephaly was not a consistent finding. Brain MRI showed variable anomalies with progressive cerebral and cerebellar atrophies and T2-hyperintense brain stem lesions. Peripheral neuropathy was documented in five cases. Disease course was progressive in all patients and eight children died in the first or early second decade of life. In addition to the previously reported missense mutation p.(Asp106Asn), we observed a novel homozygous missense variant p.(Leu172Pro) and a homozygous contiguous gene deletion encompassing most of the PRUNE1 gene and part of the neighboring BNIPL gene. Conclusions PRUNE1 deficiency causes severe early-onset disease affecting the central and peripheral nervous systems. Microcephaly is probably not a universal feature.

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