This study compared COVID-19 outcomes between vaccinated and unvaccinated older adults with and without cognitive impairment.
Electronic health records from Israel from March 2020-February 2022 were ...analyzed for a large cohort (N = 85,288) aged 65 + . Machine learning constructed models to predict mortality risk from patient factors. Outcomes examined were COVID-19 mortality and hospitalization post-vaccination.
Our study highlights the significant reduction in mortality risk among older adults with cognitive disorders following COVID-19 vaccination, showcasing a survival rate improvement to 93%. Utilizing machine learning for mortality prediction, we found the XGBoost model, enhanced with inverse probability of treatment weighting, to be the most effective, achieving an AUC-PR value of 0.89. This underscores the importance of predictive analytics in identifying high-risk individuals, emphasizing the critical role of vaccination in mitigating mortality and supporting targeted healthcare interventions.
COVID-19 vaccination strongly reduced poor outcomes in older adults with cognitive impairment. Predictive analytics can help identify highest-risk cases requiring targeted interventions.
Developments in genetics enable detection of fetal genetic abnormalities. The decision whether to abort is affected by culture, perceived severity of abnormality, and legal regulations. The study ...aimed to assess the cultural differences in women’s intention to abort if their fetus is diagnosed with a genetic disease. A cross-sectional study was conducted in Israel, Germany, and Cyprus. A questionnaire presented six scenarios where the fetus of a pregnant woman is diagnosed with a mild, moderate, or severe genetic disease. For each scenario, the participating women were asked to rate their perceived severity of having a child with the disease, sense of control over performing an abortion, and intention to undergo an abortion. 141 Israeli, 121 German, and 96 Cypriot women participated in the study. The results revealed that Israeli women were more inclined to perform an abortion (Israel: Mild-Disease M ± SD = 3.20 ± 1.37; Moderate-Disease 2.90 ± 1.39; Severe-Disease 4.08 ± 1.51) compared to Cyprus (Mild-Disease SD = 2.74 ± 1.52; Moderate-Disease 2.53 ± 1.27; Severe-Disease 3.41 ± 1.70) and Germany (Mild Disease, M ± SD = 2.38 ± 1.42; Moderate Disease 2.23 ± 1.44; Severe-Disease 2.98 ± 1.51). In all cases, Israeli women reported a higher sense of control over performing an abortion and Cypriot women expressed the highest perceived severity. Sense of control, perceived severity, being Israeli, and increased age explained 31% of the variance in the intention to abort (F = 54.39). Intention to abort following the diagnosis of a fetus with a genetic disease varies by country. There is a greater intention to abort when women feel more control, and have a higher perceived severity, regardless of the severity of the disease.
Objective
The leading cause of epilepsy‐related premature mortality is sudden unexpected death in epilepsy (SUDEP). The cause of SUDEP remains unknown. To search for genetic risk factors in SUDEP ...cases, we performed an exome‐based analysis of rare variants.
Methods
Demographic and clinical information of 61 SUDEP cases were collected. Exome sequencing and rare variant collapsing analysis with 2,936 control exomes were performed to test for genes enriched with damaging variants. Additionally, cardiac arrhythmia, respiratory control, and epilepsy genes were screened for variants with frequency of <0.1% and predicted to be pathogenic with multiple in silico tools.
Results
The 61 SUDEP cases were categorized as definite SUDEP (n = 54), probable SUDEP (n = 5), and definite SUDEP plus (n = 2). We identified de novo mutations, previously reported pathogenic mutations, or candidate pathogenic variants in 28 of 61 (46%) cases. Four SUDEP cases (7%) had mutations in common genes responsible for the cardiac arrhythmia disease, long QT syndrome (LQTS). Nine cases (15%) had candidate pathogenic variants in dominant cardiac arrhythmia genes. Fifteen cases (25%) had mutations or candidate pathogenic variants in dominant epilepsy genes. No gene reached genome‐wide significance with rare variant collapsing analysis; however, DEPDC5 (p = 0.00015) and KCNH2 (p = 0.0037) were among the top 30 genes, genome‐wide.
Interpretation
A sizeable proportion of SUDEP cases have clinically relevant mutations in cardiac arrhythmia and epilepsy genes. In cases with an LQTS gene mutation, SUDEP may occur as a result of a predictable and preventable cause. Understanding the genetic basis of SUDEP may inform cascade testing of at‐risk family members. Ann Neurol 2016;79:522–534
Objective:
We examined whether glucose transporter 1 (GLUT1) deficiency causes common idiopathic generalized epilepsies (IGEs).
Methods:
The IGEs are common, heritable epilepsies that usually follow ...complex inheritance; currently little is known about their genetic architecture. Previously considered rare, GLUT1 deficiency, due to mutations in SLC2A1, leads to failure of glucose transport across the blood–brain barrier and inadequate glucose for brain metabolism. GLUT1 deficiency was first associated with an encephalopathy and more recently found in rare dominant families with epilepsy and paroxysmal exertional dyskinesia (PED). Five hundred four probands with IGEs and 470 controls underwent SLC2A1 sequencing. Glucose transport was assayed following expression of SLC2A1 variants in Xenopus oocytes. All available relatives were phenotyped, and SLC2A1 was sequenced.
Results:
Functionally validated mutations in SLC2A1 were present in 7 of 504 (1.4%) probands and 0 of 470 controls. PED, undiagnosed prior to study, occurred in 1 proband and 3 of 13 relatives with mutations. The IGEs in probands and relatives were indistinguishable from typical IGE. Three cases (0.6%) had mutations of large functional effect and showed autosomal dominant inheritance or were de novo. Four (0.8%) cases had a subtle functional effect; 2 showed possible dominant inheritance, and 2 did not. These alleles leading to subtle functional impairment may contribute to complex, polygenic inheritance of IGE.
Interpretation:
SLC2A1 mutations contribute to approximately 1% of IGE both as a dominant gene and as a susceptibility allele in complex inheritance. Diagnosis of GLUT1 deficiency has important treatment (ketogenic diet) and genetic counseling implications. The mechanism of restricted glucose delivery differs from the current focus on IGEs as ion channel disorders. ANN NEUROL 2012;72:807–815
Summary
Objective
IQSEC2 is an X‐linked gene associated with intellectual disability (ID) and epilepsy. Herein we characterize the epilepsy/epileptic encephalopathy of patients with IQSEC2 pathogenic ...variants.
Methods
Forty‐eight patients with IQSEC2 variants were identified worldwide through Medline search. Two patients were recruited from our early onset epileptic encephalopathy cohort and one patient from personal communication. The 18 patients who have epilepsy in addition to ID are the subject of this study. Information regarding the 18 patients was ascertained by questionnaire provided to the treating clinicians.
Results
Six affected individuals had an inherited IQSEC2 variant and 12 had a de novo one (male‐to‐female ratio, 12:6). The pathogenic variant types were as follows: missense (8), nonsense (5), frameshift (1), intragenic duplications (2), translocation (1), and insertion (1). An epileptic encephalopathy was diagnosed in 9 (50%) of 18 patients. Seizure onset ranged from 8 months to 4 years; seizure types included spasms, atonic, myoclonic, tonic, absence, focal seizures, and generalized tonic–clonic (GTC) seizures. The electroclinical syndromes could be defined in five patients: late‐onset epileptic spasms (three) and Lennox‐Gastaut or Lennox‐Gastaut–like syndrome (two). Seizures were pharmacoresistant in all affected individuals with epileptic encephalopathy. The epilepsy in the other nine patients had a variable age at onset from infancy to 18 years; seizure types included GTC and absence seizures in the hereditary cases and GTC and focal seizures in de novo cases. Seizures were responsive to medical treatment in most cases. All 18 patients had moderate to profound intellectual disability. Developmental regression, autistic features, hypotonia, strabismus, and white matter changes on brain magnetic resonance imaging (MRI) were prominent features.
Significance
The phenotypic spectrum of IQSEC2 disorders includes epilepsy and epileptic encephalopathy. Epileptic encephalopathy is a main clinical feature in sporadic cases. IQSEC2 should be evaluated in both male and female patients with an epileptic encephalopathy.
Summary
Synaptic proteins are critical to neuronal function in the brain, and their deficiency can lead to seizures and cognitive impairments. CNKSR2 (connector enhancer of KSR2) is a synaptic ...protein involved in Ras signaling‐mediated neuronal proliferation, migration and differentiation. Mutations in the X‐linked gene CNKSR2 have been described in patients with seizures and neurodevelopmental deficits, especially those affecting language. In this study, we sequenced 112 patients with phenotypes within the epilepsy‐aphasia spectrum (EAS) to determine the frequency of CNKSR2 mutation within this complex set of disorders. We detected a novel nonsense mutation (c.2314 C>T; p.Arg712*) in one Ashkenazi Jewish family, the male proband of which had a severe epileptic encephalopathy with continuous spike‐waves in sleep (ECSWS). His affected brother also had ECSWS with better outcome, whereas the sister had childhood epilepsy with centrotemporal spikes. This mutation segregated in the three affected siblings in an X‐linked manner, inherited from their mother who had febrile seizures. Although the frequency of point mutation is low, CNKSR2 sequencing should be considered in families with suspected X‐linked EAS because of the specific genetic counseling implications.
BackgroundAs populations age globally, effectively managing geriatric health poses challenges for primary care. Comprehensive geriatric assessments (CGAs) aim to address these challenges through ...multidisciplinary screening and coordinated care planning. However, most CGA tools and workflows have not been optimised for routine primary care delivery.ObjectiveThis study aimed to evaluate the impact of a computerised CGA tool, called the Golden Age Visit, implemented in primary care in Israel.MethodsThis study employed a quasiexperimental mixed-methods design to evaluate outcomes associated with the Golden Age electronic health assessment tool. Quantitative analysis used electronic medical records data from Maccabi Healthcare Services, the second largest health management organisation (HMO) in Israel. Patients aged 75 and older were included in analyses from January 2017 to December 2019 and January 2021 to December 2022. For patients, data were also collected on controls who did not participate in the Golden Age Visit programme during the same time period, to allow for comparison of outcomes. For physicians, qualitative data were collected via surveys and interviews with primary care physicians who used the Golden Age Visit SMARTEST e-assessment tool.ResultsA total of 9022 community-dwelling adults aged 75 and older were included in the study: 1421 patients received a Golden Age Visit CGA (intervention group), and 7601 patients did not receive the assessment (control group). After CGAs, diagnosis rates increased significantly for neuropsychiatric conditions and falls. Referrals to physiotherapy, occupational therapy, dietetics and geriatric outpatient clinics also rose substantially. However, no differences were found in rates of hip fracture or relocation to long-term care between groups. Surveys among physicians (n=151) found high satisfaction with the programme.ConclusionImplementation of a large-scale primary care CGA programme was associated with improved diagnosis and management of geriatric conditions. Physicians were also satisfied, suggesting good uptake and feasibility within usual care. Further high-quality studies are still needed but these results provide real-world support for proactively addressing geriatric health needs through structured screening models.
We characterized an autosomal-recessive syndrome of focal epilepsy, dysarthria, and mild to moderate intellectual disability in a consanguineous Arab-Israeli family associated with subtle cortical ...thickening. We used multipoint linkage analysis to map the causative mutation to a 3.2 Mb interval within 16p13.3 with a LOD score of 3.86. The linked interval contained 160 genes, many of which were considered to be plausible candidates to harbor the disease-causing mutation. To interrogate the interval in an efficient and unbiased manner, we used targeted sequence enrichment and massively parallel sequencing. By prioritizing unique variants that affected protein translation, a pathogenic mutation was identified in TBC1D24 (p.F251L), a gene of unknown function. It is a member of a large gene family encoding TBC domain proteins with predicted function as Rab GTPase activators. We show that TBC1D24 is expressed early in mouse brain and that TBC1D24 protein is a potent modulator of primary axonal arborization and specification in neuronal cells, consistent with the phenotypic abnormality described.
Purpose: To evaluate the outcome of children with cryptogenic infantile spasms treated with high‐dose synthetic adrenocorticotropic hormone (ACTH) and the relation between early treatment, within 1 ...month of onset, and outcome.
Methods: We assessed the long‐term cognitive and seizure outcomes of 37 patients with cryptogenic infantile spasms (onset, age 3 to 9 months) receiving standardized treatment regimen of high‐dose tetracosactide depot, 1 mg IM every 48 h for 2 weeks, with a subsequent 8‐ to 10‐week slow taper and followed by oral prednisone, 10 mg/day for a month, with a subsequent slow taper for 5 months or until the infant reached the age of 1 year, whichever came later. Development was assessed before treatment. Seizure outcomes were followed up prospectively. Cognitive outcomes were determined after 6 to 21 years and analyzed in relation to treatment lag and pretreatment regression.
Results: Twenty‐two infants were treated within 1 month of onset of infantile spasms, and 15 after 1 to 6.5 months. Normal cognitive outcome was found in all 22 (100%) patients of the early‐treatment group, and in 40% of the late‐treatment group. Normal cognitive outcome was found in all 25 (100%) patients who had no or only mild mental deterioration at presentation, including four in the late‐treatment group but in only three of the 12 patients who had had marked or severe deterioration before treatment.
Conclusions: Early treatment of cryptogenic infantile spasms with a high‐dose ACTH protocol is associated with favorable long‐term cognitive outcomes. Once major developmental regression lasts for a month or more, the prognosis for normal cognitive outcome is poor. Further studies are needed on the optimal treatment regimen for this disorder.
Summary
Objective: We aimed to determine the type, frequency, and size of microchromosomal copy number variations (CNVs) affecting the neuronal sodium channel α 1 subunit gene (SCN1A) in Dravet ...syndrome (DS), other epileptic encephalopathies, and generalized epilepsy with febrile seizures plus (GEFS+).
Methods: Multiplex ligation‐dependent probe amplification (MLPA) was applied to detect SCN1A CNVs among 289 cases (126 DS, 97 GEFS+, and 66 with other phenotypes). CNVs extending beyond SCN1A were further characterized by comparative genome hybridization (array CGH).
Results: Novel SCN1A CNVs were found in 12.5% of DS patients where sequence‐based mutations had been excluded. We identified the first partial SCN1A duplications in two siblings with typical DS and in a patient with early‐onset symptomatic generalized epilepsy. In addition, a patient with DS had a partial SCN1A amplification of 5–6 copies. The remaining CNVs abnormalities were four partial and nine whole SCN1A deletions involving contiguous genes. Two CNVs (a partial SCN1A deletion and a duplication) were inherited from a parent, in whom there was mosaicism. Array CGH showed intragenic deletions of 90 kb and larger, with the largest of 9.3 Mb deleting 49 contiguous genes and extending beyond SCN1A.
Discussion: Duplication and amplification involving SCN1A are now added to molecular mechanisms of DS patients. Our findings showed that 12.5% of DS patients who are mutation negative have MLPA‐detected SCN1A CNVs with an overall frequency of about 2–3%. MLPA is the established second‐line testing strategy to reliably detect all CNVs of SCN1A from the megabase range down to one exon. Large CNVs extending outside SCN1A and involving contiguous genes can be precisely characterized by array CGH.
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