scholarly journals Migrating Focal Seizures and Myoclonic Status in ARV1-Related Encephalopathy

2021 ◽  
Vol 7 (3) ◽  
pp. e593
Author(s):  
Francesca Darra ◽  
Tommaso Lo Barco ◽  
Roberta Opri ◽  
Elena Parrini ◽  
Claudia Bianchini ◽  
...  
Keyword(s):  
Respiratory Infections ◽  
Brain Mri ◽  
High Amplitude ◽  
Epileptic Encephalopathy ◽  
Severe Form ◽  
Compound Heterozygous ◽  
Mri Findings ◽  
Eeg Activity ◽  
Focal Seizures ◽  
Visual Inattention

ObjectiveTo report longitudinal clinical, EEG, and MRI findings in 2 sisters carrying compound heterozygous ARV1 mutations and exhibiting a peculiar form of developmental and epileptic encephalopathy (DEE). Neuropathologic features are also described in one of the sisters.MethodsClinical course description, video-EEG polygraphic recordings, brain MRI, skin and muscle biopsies, whole-exome sequencing (WES), and brain neuropathology.ResultsSince their first months of life, both girls exhibited severe axial hypotonia, visual inattention, dyskinetic movements, severe developmental delay, and slow background EEG activity. Intractable nonmotor seizures started in both at the eighth month of life, exhibiting the electroclinical characteristics of epilepsy of infancy with migrating focal seizures (EIMFS). In the second year of life, continuous epileptiform EEG activity of extremely high amplitude appeared in association with myoclonic status, leading to severely impaired alertness and responsiveness. Repeated brain MRI revealed progressive atrophic changes and severe hypomyelination. WES identified a compound heterozygous in the ARV1 gene [(p.Ser122Glnfs*7) and (p.Trp163*)] in one patient and was subsequently confirmed in the other. Both sisters died prematurely during respiratory infections. Postmortem neuropathologic examination of the brain, performed in one, revealed atrophic brain changes, mainly involving the cerebellum.ConclusionsThis report confirms that biallelic ARV1 mutations cause a severe form of DEE and adds epilepsy with migrating focal seizures and myoclonic status to the spectrum of epilepsy phenotypes. Considering the potential role of human ARV1 in glycosylphosphatidylinositol (GPI) anchor biosynthesis, this severe syndrome can be assigned to the group of inherited GPI deficiency disorders, with which it shares remarkably similar clinical and neuroimaging features. ARV1 should be considered in the genetic screening of individuals with EIMFS.

scholarly journals VPS41 recessive mutation causes ataxia and dystonia with retinal dystrophy and mental retardation by inhibiting HOPS function and mTORC1 signaling

2019 ◽  
Author(s):  
R.E.N. van der Welle ◽  
R. Jobling ◽  
C. Burns ◽  
P. Sanza ◽  
C. ten Brink ◽  
...  
Keyword(s):  
Neuroprotective Effect ◽  
Protein Sorting ◽  
Brain Mri ◽  
Retinal Dystrophy ◽  
Cerebellar Atrophy ◽  
Recessive Mutation ◽  
Compound Heterozygous ◽  
Mri Findings ◽  
Mtorc1 Signaling ◽  
Vacuolar Protein

AbstractThe vacuolar protein sorting protein 41 (VPS41) is a neuroprotective protein in models of Parkinson’s disease (PD). As part of the HOPS (Homotypic fusion and Protein Sorting) complex, VPS41 regulates fusion of lysosomes with late endosomes and autophagosomes. Independent of HOPS, VPS41 regulates transport of newly synthesized lysosomal membrane proteins and secretory proteins. Here we report two brothers with compound heterozygous mutations in VPS41 (VPS41R662* and VPS41S285P), born to healthy and non-consanguineous parents. Both patients displayed transient retinal dystrophy, ataxia and dystonia, with brain MRI findings of cerebellar atrophy and a thin saber-shape corpus callosum. Patient-derived fibroblasts contained enzymatically active lysosomes that were poorly reached by endocytic cargo and failed to attract the mTORC1 complex. Consequently, transcription factor TFE3, a driver of autophagy and lysosomal genes, showed continuous nuclear localization which resulted in elevated LC3-II levels and an impaired response to nutrient starvation. CRISPR/CAS VPS41 HeLa knockout cells showed a similar phenotype that could be rescued by wildtype VPS41 but not by VPS41S285P or VPS41R662*. mTORC1 inhibition was also seen after knockout of HOPS subunits VPS11 or VPS18. Regulated neuropeptide secretion in PC12 VPS41 knockout cells was rescued by VPS41S285P expression, indicating that this HOPS-independent function was preserved. Co-expression of the VPS41S285P and VPS41R662* variants in a C. elegans model of PD abolished the protective effect of VPS41 against α-synuclein-induced neurodegeneration. We conclude that both disease-associated VPS41 variants specifically abrogate HOPS function, which leads to a delay in endocytic cargo delivery to lysosomes, mTORC1 inhibition and irresponsiveness to autophagic clues. Our studies signify a link between HOPS function and mTORC1 signaling and imply that HOPS function is required for the neuroprotective effect of VPS41 in PD.

Magnetic Resonance Brain Imaging in Regularly Transfused Beta Thalassemia Major and Intermedia Subjects and Prevalence of Thrombophilia Mutations

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 5175-5175 ◽  
Author(s):  
Patricia Jane Giardina ◽  
Dorothy A. Kleinert ◽  
Suzanne O. Salamon ◽  
Linda A. Heier
Keyword(s):  
White Matter ◽  
Magnetic Resonance ◽  
Brain Mri ◽  
Thalassemia Major ◽  
Cerebral White Matter ◽  
Compound Heterozygous ◽  
White Matter Disease ◽  
Mri Findings ◽  
Brain Infarcts ◽  
Pai 1

Abstract Abstract 5175 Introduction/Background: Recent reports of magnetic resonance (MRI) brain imaging have emerged detecting covert cerebral infarcts in thalassemia subjects. The thalassemia phenotype, and splenectomy and hypercoagulation are suggested mechanisms. Methods: We conducted a retrospective review of all brain MRIs performed in thalassemia subjects at the Weill Cornell/New York Presbyterian Hospital Thalassemia Center over the past 15 years (yrs). Blood counts, platelet counts and ferritin levels at the time of MRI as well as genotype and phenotype diagnoses, splenectomy status and thrombophilia mutational analysis historically performed were reviewed. Results: 16 thalassemia subjects: 7M:9F, mean age = 29. 9 yrs (range: 11 to 45 yrs) were identified who underwent brain MRI studies from 1998 to 2012. Brain MRIs were performed for evaluation of various symptoms including: headaches (6), dizziness (2), growth hormone efficiency (2), unilateral hearing loss (1), optic neuritis (1), cerebral hypoxia (1), acquired human immunodeficiency syndrome (1), s/p craniopharyngioma excision (1), and paresis (1). MRI findings included 3 chronic infarcts, 2 cerebral white matter disease images consistent with chronic ischemia, 1 acute infarct, 2 opacified maxillary sinuses, 1 sphenoid sinusitis, 1 acute hemorrhage, 1 recurrent hemorrhage, 1 cerebellopontine angle schwannoma and 4 unremarkable studies. Clinical diagnosis included: 12 Thalassemia Major (TM) subjects who were on regular red blood cell (RBC) hypertransfusion regimens since infancy to maintain pre-transfusion hemoglobin (Hgb) levels greater than 10 gm/dl and 4 Thalassemia Intermedia (TI) subjects (3M/1F) were periodically transfused until adolescence or early adulthood when they were placed on regular RBC hypertransfusion support owing to complications including extramedullary hematopoiesis causing spinal cord compression, progressive anemia with fatigue and thrombosis. All but 2 subjects were splenectomized; all but 6 subjects had platelet counts greater than 500 (mean platelet count = 567; range 175 to 1101). All were on iron chelation therapy including 2 Deferoxamine (DFO), 1 on DFO and Deferiprone (DFP) and 13 on Deferasirox (DFX). Prothrombotic genetic mutations were identified in 10 subjects including: (2) homozygous PAI-1, (5) heterozygous PAI-1, (2) homozygous MTHFR and (4) heterozygous for MTHFR; those 3 TM subjects with lacunar infarcts were heterozygous PAI-1 or negative for other thrombophilia mutations however 1 TM also had a patent foramen ovale. In addition, the 2 TI subjects with cerebral white matter disease had compound heterozygous MTHFR or PAI-1 in association with homozygous PAI-1 or homozygous MTHFR respectively. Conclusion: Chronic brain infarcts and cerebral white matter disease consistent with ischemia were detected on MRI in 5/16 adolescent and adult thalassemia subjects (31%): TM = 3/16 (19%) and TI = 2/16 (10%) thalassemia subjects. Headache, pain and dizziness were the predominant symptoms in those subjects with brain MRI findings of chronic infarcts and white matter disease. Thrombocytosis was common in all splenectomized subjects Homozygous and compound heterozygous co-inheritance of thrombophilia mutations PAI-1 and MTHFR were relatively more common in subjects with chronic infarcts and white matter disease. Further brain MRI studies need to be performed to address the prevalence, pathogenesis, risk factors, neurological and cognitive outcomes of brain infarcts in at risk adolescent and adult thalassemia subjects for the prevention and development of therapeutic strategies. Disclosures: No relevant conflicts of interest to declare.

Use of Perampanel and a Ketogenic Diet in Nonketotic Hyperglycinemia: A Case Report

2020 ◽  
Vol 51 (06) ◽  
pp. 417-420
Author(s):  
Atsuro Daida ◽  
Shin-ichiro Hamano ◽  
Satoru Ikemoto ◽  
Yuko Hirata ◽  
Ryuki Matsuura ◽  
...  
Keyword(s):  
Ketogenic Diet ◽  
Adrenocorticotropic Hormone ◽  
Seizure Control ◽  
Epileptic Encephalopathy ◽  
Severe Form ◽  
Focal Seizures ◽  
Aspartate Receptor ◽  
Epileptic Spasms ◽  
Glycine Cleavage ◽  
Nonketotic Hyperglycinemia

Abstract Background Nonketotic hyperglycinemia is a severe form of early onset epileptic encephalopathy caused by disturbances in the glycine cleavage system; the neurological damage is mainly attributed to overstimulation of the N-methyl-D-aspartate receptor. Case The patient presented with a severe form of nonketotic hyperglycinemia and experienced frequent epileptic spasms and focal seizures, which were resistant to vigabatrin, adrenocorticotropic hormone therapy, and combined dextromethorphan and sodium benzoate treatments. By 9 months of age, perampanel reduced epileptic spasms by >50%. At 14 months of age, the ketogenic diet markedly reduced focal seizures and glycine levels in the cerebrospinal fluid. Conclusion Perampanel reduced fast excitatory neuronal activity, which was induced by an α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor, followed by prolonged electrical depolarizations due to an N-methyl-D-aspartate receptor. Furthermore, the ketogenic diet may have modulated the excessive neurotoxic cascade through the N-methyl-D-aspartate receptor. Perampanel and ketogenic diet were effective for seizure control in our patient.

Brain MRI-findings in Ph - negative myeloproliferative disorders

2019 ◽  
Vol 91 (7) ◽  
pp. 29-34 ◽  
Author(s):  
M M Tanashyan ◽  
A L Melikyan ◽  
P I Kuznetsova ◽  
A A Raskurazhev ◽  
A A Shabalina ◽  
...  
Keyword(s):  
Cerebrovascular Disease ◽  
Sinus Thrombosis ◽  
Cerebral Arteries ◽  
Brain Mri ◽  
Myeloproliferative Disorders ◽  
Cerebral Venous Sinus Thrombosis ◽  
Mri Findings ◽  
Cerebral Lesions ◽  
Cerebrovascular Pathology ◽  
Underlying Mechanisms

Myeloproliferative disorders (MPD) are accompanied by a high proportion of thrombotic complications, which may lead to cerebrovascular disease (CVD). Aim. To describe MRI-findings in patients with Ph - negative MPD and evaluate any cerebrovascular disease. Materials and methods. We included 104 patients with Ph - negative MPD (age varied between 20 and 58) with clinical correlates of cerebrovascular pathology. Results. Brain MRI showed post - stroke lesions in 20% of patients (7 hemispheric infarcts due to thrombotic occlusion of one of the large cerebral arteries, 14 - cortical infarcts). 37 patients (36%) had vascular cerebral lesions. Cerebral venous sinus thrombosis occurred in 5 patients - in 7% (n=3) of patients with polycythemia vera and 5% (n=2) - in patients with essential thrombocythemia. The incidence of vascular cerebral lesions was associated with higher levels of the following: erythrocyte, platelet count, fibrinogen, and with the decrease in fibrinolytic activity, as well. Conclusion. The pioneering results of the study include the description and analysis of brain MRI-findings in patients with Ph - negative MPD. The underlying mechanisms of cerebrovascular pathology in these patients are associated with certain blood alterations (particularly, hemorheology) which present a major risk factor.

scholarly journals Comparisons of clinical characteristics, brain MRI findings, and responses to epidural blood patch between spontaneous intracranial hypotension and post-dural puncture headache: retrospective study

BMC Neurology ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Gha-Hyun Lee ◽  
Jiyoung Kim ◽  
Hyun-Woo Kim ◽  
Jae Wook Cho
Keyword(s):  
Intracranial Hypotension ◽  
Dural Puncture ◽  
Epidural Blood Patch ◽  
Brain Mri ◽  
Spontaneous Intracranial Hypotension ◽  
Vein Of Galen ◽  
Mri Findings ◽  
Post Dural Puncture Headache ◽  
Straight Sinus ◽  
Blood Patch

Abstract Background Spontaneous intracranial hypotension and post-dural puncture headache are both caused by a loss of cerebrospinal fluid but present with different pathogeneses. We compared these two conditions concerning their clinical characteristics, brain imaging findings, and responses to epidural blood patch treatment. Methods We retrospectively reviewed the records of patients with intracranial hypotension admitted to the Neurology ward of the Pusan National University Hospital between January 1, 2011, and December 31, 2019, and collected information regarding age, sex, disease duration, hospital course, headache intensity, time to the appearance of a headache after sitting, associated phenomena (nausea, vomiting, auditory symptoms, dizziness), number of epidural blood patch treatments, and prognosis. The brain MRI signs of intracranial hypotension were recorded, including three qualitative signs (diffuse pachymeningeal enhancement, venous distention of the lateral sinus, subdural fluid collection), and six quantitative signs (pituitary height, suprasellar cistern, prepontine cistern, mamillopontine distance, the midbrain-pons angle, and the angle between the vein of Galen and the straight sinus). Results A total of 105 patients (61 spontaneous intracranial hypotension patients and 44 post-dural puncture headache patients) who met the inclusion criteria were reviewed. More patients with spontaneous intracranial hypotension required epidural blood patch treatment than those with post-dural puncture headache (70.5% (43/61) vs. 45.5% (20/44); p = 0.01) and the spontaneous intracranial hypotension group included a higher proportion of patients who underwent epidural blood patch treatment more than once (37.7% (23/61) vs. 13.6% (6/44); p = 0.007). Brain MRI showed signs of intracranial hypotension in both groups, although the angle between the vein of Galen and the straight sinus was greater in the post-dural puncture headache group (median [95% Confidence Interval]: 85° [68°-79°] vs. 74° [76°-96°], p = 0.02). Conclusions Patients with spontaneous intracranial hypotension received more epidural blood patch treatments and more often needed multiple epidural blood patch treatments. Although both groups showed similar brain MRI findings, the angle between the vein of Galen and the straight sinus differed significantly between the groups.

scholarly journals Genetic Neonatal-Onset Epilepsies and Developmental/Epileptic Encephalopathies with Movement Disorders: A Systematic Review

2021 ◽  
Vol 22 (8) ◽  
pp. 4202
Author(s):  
Carlotta Spagnoli ◽  
Carlo Fusco ◽  
Antonio Percesepe ◽  
Vincenzo Leuzzi ◽  
Francesco Pisani
Keyword(s):  
Movement Disorders ◽  
Time Course ◽  
Neonatal Period ◽  
Age Of Onset ◽  
Brain Mri ◽  
Neonatal Seizure ◽  
Mri Findings ◽  
Epileptic Encephalopathies ◽  
Pathogenic Variants ◽  
Neonatal Onset

Despite expanding next generation sequencing technologies and increasing clinical interest into complex neurologic phenotypes associating epilepsies and developmental/epileptic encephalopathies (DE/EE) with movement disorders (MD), these monogenic conditions have been less extensively investigated in the neonatal period compared to infancy. We reviewed the medical literature in the study period 2000–2020 to report on monogenic conditions characterized by neonatal onset epilepsy and/or DE/EE and development of an MD, and described their electroclinical, genetic and neuroimaging spectra. In accordance with a PRISMA statement, we created a data collection sheet and a protocol specifying inclusion and exclusion criteria. A total of 28 different genes (from 49 papers) leading to neonatal-onset DE/EE with multiple seizure types, mainly featuring tonic and myoclonic, but also focal motor seizures and a hyperkinetic MD in 89% of conditions, with neonatal onset in 22%, were identified. Neonatal seizure semiology, or MD age of onset, were not always available. The rate of hypokinetic MD was low, and was described from the neonatal period only, with WW domain containing oxidoreductase (WWOX) pathogenic variants. The outcome is characterized by high rates of associated neurodevelopmental disorders and microcephaly. Brain MRI findings are either normal or nonspecific in most conditions, but serial imaging can be necessary in order to detect progressive abnormalities. We found high genetic heterogeneity and low numbers of described patients. Neurological phenotypes are complex, reflecting the involvement of genes necessary for early brain development. Future studies should focus on accurate neonatal epileptic phenotyping, and detailed description of semiology and time-course, of the associated MD, especially for the rarest conditions.

Delayed post-hypoxic leukoencephalopathy: Case report

2017 ◽  
Vol 41 (S1) ◽  
pp. s839-s839 ◽  
Author(s):  
M. Solerdelcoll Arimany ◽  
M. Garriga ◽  
E. Parellada
Keyword(s):  
Neuropsychiatric Symptoms ◽  
Brain Mri ◽  
Clinical History ◽  
Good Prognosis ◽  
Mri Findings ◽  
The Mean ◽  
Competing Interest ◽  
Weighted Sequences ◽  
Direct Toxicity ◽  
Progressive Cognitive Impairment

IntroductionDelayed post-hypoxic leukoencephalopathy (DPHL) is an underrecognized syndrome of delayed demyelination, where patients manifest neuropsychiatric symptoms after a period of 2–40 days of apparent recovery from a cerebral hypo-oxygenation episode.ObjectivesWe report a case of a patient who successfully recovered from an overdose of heroin, but then suffered a delayed abrupt neurological deterioration.AimsTo improve assessment and recognition of DPHL.MethodsAn adequate retrospective collection of clinical data and nonsystematic review of the literature was performed.ResultsA 43-year-old male with schizoaffective disorder who attempted suicide with an overdose of heroin, was successfully revived and return to his previously mental status, but 3 weeks after, he abruptly developed progressive cognitive impairment with akinetic mutism and ataxia. He was admitted to our acute psychiatric unit after brain CT and chemistry analyses were unremarkable. Brain MRI showed diffusely symmetric hyperintensity in the white matter (WM), pronominally the periventricular WM, on FLAIR and T2 weighted sequences. At 16 weeks postoverdose, he presented improvement both cognitive and motor symptoms, lasting deficits in frontal-executive functions.DiscussionDPHL is characterized by similar clinical and neuroimaging features regardless of the initial insult. The mean lucid interval coincides with the replacement half-life for myelin related lipids and proteins. Prolonged mild-to-moderate hypo-oxygenation of WM is thought to disrupt myelin turnover. It appears probable that these were responsible for DPHL in our patient rather than a direct toxicity.ConclusionDPHL can be diagnosed when clinical history, laboratory assessments and MRI findings are concordant. DPHL requires extensive support care and carries a relatively good prognosis.Disclosure of interestThe authors have not supplied their declaration of competing interest.

scholarly journals Postoperative cerebral air embolism with delayed abnormal brain MRI findings

2021 ◽  
Vol 22 ◽  
pp. 100305
Author(s):  
Yuwa Oka ◽  
Koji Tsuzaki ◽  
Mayu Kamei ◽  
Akihiro Kikuya ◽  
Toshiaki Hamano
Keyword(s):  
Brain Mri ◽  
Air Embolism ◽  
Mri Findings ◽  
Cerebral Air Embolism ◽  
Abnormal Brain

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.

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