Mild head trauma: Acute encephalopathy trigger in children with RHOBTB2 de novo mutation

ObjectiveDe novo missense mutations in the RHOBTB2 gene have been described as causative for developmental and epileptic encephalopathy.MethodsThe clinical phenotype of this disorder includes early-onset epilepsy, severe intellectual disability, postnatal microcephaly, and movement disorder. Three RHOBTB2 patients have been described with acute encephalopathy and febrile epileptic status. All showed severe EEG abnormalities during this episode and abnormal MRI with hemisphere swelling or reduced diffusion in various brain regions.ResultsWe describe the episode of acute encephalopathy after head trauma in a 5-year-old RHOBTB2 patient. At admission, Glasgow coma scale score was E4M4V1. EEG was severely abnormal showing a noncontinuous pattern with slow activity without epileptic activity indicating severe encephalopathy. A second EEG on day 8 was still severely slowed and showed focal delta activity frontotemporal in both hemispheres. Gradually, he recovered, and on day 11, he had regained his normal reactivity, behavior, and mood. Two months after discharge, EEG showed further decrease in slow activity and increase in normal electroencephalographic activity. After discharge, parents noted that he showed more hyperkinetic movements compared to before this period of encephalopathy. Follow-up MRI showed an increment of hippocampal atrophy. In addition, we summarize the clinical characteristics of a second RHOBTB2 patient with increase of focal periventricular atrophy and development of hemiparesis after epileptic status.ConclusionsAcute encephalopathy in RHOBTB2 patients can also be triggered by head trauma.

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Direct Transmission of Within-Host Mycobacterium Tuberculosis Diversity to Secondary Cases Can Lead to Variable Between-Host Heterogeneity Without De Novo Mutation: A Genomic Investigation

SSRN Electronic Journal ◽

10.2139/ssrn.3384856 ◽

2019 ◽

Author(s):

Marie Séraphin ◽

Anders Norman ◽

Erik Michael Rasmussen ◽

Alexandra M. Gerace ◽

Calin Chiribau ◽

...

Keyword(s):

Mycobacterium Tuberculosis ◽

De Novo ◽

De Novo Mutation ◽

Direct Transmission ◽

Host Heterogeneity

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R1352Q CACNA1A Variant in a Patient with Sporadic Hemiplegic Migraine, Ataxia, Seizures and Cerebral Oedema: A Case Report

Case Reports in Neurology ◽

10.1159/000512275 ◽

2021 ◽

pp. 123-130

Author(s):

Anker Stubberud ◽

Emer O’Connor ◽

Erling Tronvik ◽

Henry Houlden ◽

Manjit Matharu

Keyword(s):

Mental Retardation ◽

Case Report ◽

Genetic Testing ◽

Head Trauma ◽

Cerebral Oedema ◽

De Novo ◽

Minor Head Trauma ◽

Hemiplegic Migraine ◽

Wide Range ◽

History Of

Mutations in the CACNA1A gene show a wide range of neurological phenotypes including hemiplegic migraine, ataxia, mental retardation and epilepsy. In some cases, hemiplegic migraine attacks can be triggered by minor head trauma and culminate in encephalopathy and cerebral oedema. A 37-year-old male without a family history of complex migraine experienced hemiplegic migraine attacks from childhood. The attacks were usually triggered by minor head trauma, and on several occasions complicated with encephalopathy and cerebral oedema. Genetic testing of the proband and unaffected parents revealed a de novo heterozygous nucleotide missense mutation in exon 25 of the CACNA1A gene (c.4055G>A, p.R1352Q). The R1352Q CACNA1A variant shares the phenotype with other described CACNA1A mutations and highlights the interesting association of trauma as a precipitant for hemiplegic migraine. Subjects with early-onset sporadic hemiplegic migraine triggered by minor head injury or associated with seizures, ataxia or episodes of encephalopathy should be screened for mutations. These patients should also be advised to avoid activities that may result in head trauma, and anticonvulsants should be considered as prophylactic migraine therapy.

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Intranasal oxytocin administration ameliorates social behavioral deficits in a POGZWT/Q1038R mouse model of autism spectrum disorder

Molecular Brain ◽

10.1186/s13041-021-00769-8 ◽

2021 ◽

Vol 14 (1) ◽

Author(s):

Kohei Kitagawa ◽

Kensuke Matsumura ◽

Masayuki Baba ◽

Momoka Kondo ◽

Tomoya Takemoto ◽

...

Keyword(s):

Autism Spectrum Disorder ◽

Social Behavior ◽

Mouse Model ◽

Mouse Models ◽

De Novo ◽

Neurodevelopmental Disorder ◽

Autism Spectrum ◽

Spectrum Disorder ◽

De Novo Mutation ◽

Behavioral Deficits

AbstractAutism spectrum disorder (ASD) is a highly prevalent neurodevelopmental disorder characterized by core symptoms of impaired social behavior and communication. Recent studies have suggested that the oxytocin system, which regulates social behavior in mammals, is potentially involved in ASD. Mouse models of ASD provide a useful system for understanding the associations between an impaired oxytocin system and social behavior deficits. However, limited studies have shown the involvement of the oxytocin system in the behavioral phenotypes in mouse models of ASD. We have previously demonstrated that a mouse model that carries the ASD patient-derived de novo mutation in the pogo transposable element derived with zinc finger domain (POGZWT/Q1038R mice), showed ASD-like social behavioral deficits. Here, we have explored whether oxytocin (OXT) administration improves impaired social behavior in POGZWT/Q1038R mice and found that intranasal oxytocin administration effectively restored the impaired social behavior in POGZWT/Q1038R mice. We also found that the expression level of the oxytocin receptor gene (OXTR) was low in POGZWT/Q1038R mice. However, we did not detect significant changes in the number of OXT-expressing neurons between the paraventricular nucleus of POGZWT/Q1038R mice and that of WT mice. A chromatin immunoprecipitation assay revealed that POGZ binds to the promoter region of OXTR and is involved in the transcriptional regulation of OXTR. In summary, our study demonstrate that the pathogenic mutation in the POGZ, a high-confidence ASD gene, impairs the oxytocin system and social behavior in mice, providing insights into the development of oxytocin-based therapeutics for ASD.

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The L1-dependant and Pol III transcribed Alu retrotransposon, from its discovery to innate immunity

Molecular Biology Reports ◽

10.1007/s11033-021-06258-4 ◽

2021 ◽

Vol 48 (3) ◽

pp. 2775-2789

Author(s):

Ludwig Stenz

Keyword(s):

Human Genome ◽

Viral Infections ◽

De Novo ◽

Current Knowledge ◽

Innate Immune ◽

De Novo Mutation ◽

Neuronal Diversity ◽

Alu Sequences ◽

Pol Iii ◽

The Brain

AbstractThe 300 bp dimeric repeats digestible by AluI were discovered in 1979. Since then, Alu were involved in the most fundamental epigenetic mechanisms, namely reprogramming, pluripotency, imprinting and mosaicism. These Alu encode a family of retrotransposons transcribed by the RNA Pol III machinery, notably when the cytosines that constitute their sequences are de-methylated. Then, Alu hijack the functions of ORF2 encoded by another transposons named L1 during reverse transcription and integration into new sites. That mechanism functions as a complex genetic parasite able to copy-paste Alu sequences. Doing that, Alu have modified even the size of the human genome, as well as of other primate genomes, during 65 million years of co-evolution. Actually, one germline retro-transposition still occurs each 20 births. Thus, Alu continue to modify our human genome nowadays and were implicated in de novo mutation causing diseases including deletions, duplications and rearrangements. Most recently, retrotransposons were found to trigger neuronal diversity by inducing mosaicism in the brain. Finally, boosted during viral infections, Alu clearly interact with the innate immune system. The purpose of that review is to give a condensed overview of all these major findings that concern the fascinating physiology of Alu from their discovery up to the current knowledge.

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Publisher Correction: Germline de novo mutation clusters arise during oocyte aging in genomic regions with high double-strand-break incidence

Nature Genetics ◽

10.1038/s41588-021-00905-z ◽

2021 ◽

Author(s):

Jakob M. Goldmann ◽

Vladimir B. Seplyarskiy ◽

Wendy S. W. Wong ◽

Thierry Vilboux ◽

Pieter B. Neerincx ◽

...

Keyword(s):

De Novo ◽

Strand Break ◽

Double Strand Break ◽

De Novo Mutation ◽

Oocyte Aging ◽

Genomic Regions

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Sleep Exacerbations and Facial Twitching: Diagnostic Clues for ADCY5-Related Dyskinesias

Neuropediatrics ◽

10.1055/s-0040-1721685 ◽

2020 ◽

Author(s):

Margherita Nosadini ◽

Gianluca D'Onofrio ◽

Maria Federica Pelizza ◽

Concetta Luisi ◽

Davide Padrin ◽

...

Keyword(s):

Movement Disorder ◽

Developmental Delay ◽

De Novo ◽

Brain Magnetic Resonance Imaging ◽

Neurological Impairment ◽

De Novo Mutation ◽

Oligoclonal Bands ◽

Emotional Stimuli ◽

Childhood Onset ◽

Ataxic Gait

Abstract Background Mutations in the adenylate cyclase 5 (ADCY5) gene are associated with childhood-onset paroxysmal dyskinesia. Methods We report a new video-documented case of pediatric ADCY5-related dyskinesia with de novo ADCY5 mutation. Results A boy born to nonconsanguineous parents after an uneventful pregnancy had developmental delay and hypotonia. At the age of 7 months, he presented with paroxysmal jerky–choreic–dystonic involuntary movements in wakefulness involving limbs, trunk, and face, exacerbated by emotional stimuli. These episodes gradually worsened in duration and frequency: at the age of 2.5 years, they occurred up to six times per day, and appeared also during sleep in prolonged bouts; the boy also had basal choreoathetoid–dystonic movements, hyperactivity, paraparetic–ataxic gait, generalized hypotonia with brisk tendon reflexes, drooling, and language delay with intellectual disability. Brain magnetic resonance imaging, electroencephalogram, electromyogram, eye review, metabolic investigations, oligoclonal bands, and autoantibodies were normal. Extensive genetic testing had not let to a diagnosis, until a heterozygous de novo mutation c.1252C > T (p.Arg418Trp) was identified in the ADCY5 gene. Clonazepam had partial effectiveness. The boy walked at the age of 3.5 years. At the age of 5 years, the paroxysmal movement disorder has slightly improved. Conclusion ADCY5 mutations should be considered among the differential diagnoses of early-onset paroxysmal choreic–athetosic–myoclonic–dystonic movement disorder involving limbs, trunk, and face, in patients with global neurological impairment with hypotonia and developmental delay. Facial dyskinesias and exacerbation by drowsiness/sleep and emotional stimuli are important clues that may allow a timely recognition of the disorder and avoidance of unnecessary diagnostic investigations.

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Neugeborenes mit Nasenagenesie: Neonatologische Herausforderungen bei der Versorgung eines Neugeborenen mit Bosma-Arhinie-Mikrophthalmie-Syndrom (BAMS)

Laryngo-Rhino-Otologie ◽

10.1055/a-1307-3374 ◽

2021 ◽

Vol 100 (04) ◽

pp. 294-296

Author(s):

Helen Stromiedel ◽

Chantal Van Quekelberghe ◽

Gökhan Yigit ◽

Ammar Al Naimi ◽

Franz Bahlmann ◽

...

Keyword(s):

De Novo ◽

De Novo Mutation ◽

Intrauterine Wachstumsrestriktion

ZusammenfassungAnhand eines weiblichen Neugeborenen soll das seltene Krankheitsbild der konnatalen Nasenagenesie vorgestellt werden. In der Schwangerschaft fielen eine intrauterine Wachstumsrestriktion mit Polyhydramnion und eine Mittelgesichtshypoplasie auf. Das Atemwegsmanagement nach primärer Sectio in der 38 + 4 SSW gelang mittels Schienung durch einen Güdel- bzw. im Verlauf Rachentubus ohne Zeichen einer respiratorischen Insuffizienz. Neben der vollständigen Nasenagenesie zeigten sich bei unauffälligen zerebralen Strukturen ein Hypertelorismus, ein gotischer Gaumen, ein beidseitiger Mikrophthalmus und Iriskolobom. Die Nahrungsaufnahme wurde mit einer orogastralen Sonde sichergestellt, durch Trinktraining und einen speziellen Schnuller konnten eine bessere Koordination und Trinkleistung erzielt werden. Der sich bei assoziierten Fehlbildungen ergebende Verdacht auf ein Bosma-Arhinie-Mikrophthalmie-Syndrom (BAMS) wurde humangenetisch durch den Nachweis einer heterozygoten de novo Mutation im SMCHD1-Gen, welches eine Schlüsselfunktion in der Embryogenese der menschlichen Nase spielt, bestätigt (c.1043A > G; pHis348Arg). Aus neonatologischer Sicht ist oftmals die initiale Kreißsaal-Versorgung eine Herausforderung: Patienten mit Nasenagenesie werden häufig postpartal intubiert und elektiv tracheotomiert. Bei fehlender respiratorischer Problematik und Nahrungsaufnahme mit perzentilengerechtem Wachstum besteht jedoch keine dringliche Indikation zur frühzeitigen plastisch-chirurgischen Versorgung, insbesondere da diese mit Gefahren wie Sepsis und Wachstumsstörungen im Mittelgesicht behaftet ist.

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Enhanced specificity of clinical high-sensitivity tumor mutation profiling in cell-free DNA via paired normal sequencing using MSK-ACCESS

Nature Communications ◽

10.1038/s41467-021-24109-5 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

A. Rose Brannon ◽

Gowtham Jayakumaran ◽

Monica Diosdado ◽

Juber Patel ◽

Anna Razumova ◽

...

Keyword(s):

Cancer Patients ◽

De Novo ◽

Low Frequency ◽

High Sensitivity ◽

Clinical Analysis ◽

De Novo Mutation ◽

Cell Free Dna ◽

Free Dna ◽

Somatic Alterations ◽

Mutation Profiling

AbstractCirculating cell-free DNA from blood plasma of cancer patients can be used to non-invasively interrogate somatic tumor alterations. Here we develop MSK-ACCESS (Memorial Sloan Kettering - Analysis of Circulating cfDNA to Examine Somatic Status), an NGS assay for detection of very low frequency somatic alterations in 129 genes. Analytical validation demonstrated 92% sensitivity in de-novo mutation calling down to 0.5% allele frequency and 99% for a priori mutation profiling. To evaluate the performance of MSK-ACCESS, we report results from 681 prospective blood samples that underwent clinical analysis to guide patient management. Somatic alterations are detected in 73% of the samples, 56% of which have clinically actionable alterations. The utilization of matched normal sequencing allows retention of somatic alterations while removing over 10,000 germline and clonal hematopoiesis variants. Our experience illustrates the importance of analyzing matched normal samples when interpreting cfDNA results and highlights the importance of cfDNA as a genomic profiling source for cancer patients.

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