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Frontiers in Neurology 2023Spontaneous cervical artery dissection (sCeAD) is an important cause of stroke in young adults. The underlying pathophysiology remains unclear, without validated...
BACKGROUND
Spontaneous cervical artery dissection (sCeAD) is an important cause of stroke in young adults. The underlying pathophysiology remains unclear, without validated biomarkers to identify subjects at risk. Previous studies suggested the role of abnormalities in the connective component of the arterial wall.
PURPOSE
To assess dermal ultrastructural aberrations of connective tissue by skin biopsy and genetic variations in sCeAD patients.
METHOD
We searched the PubMed and Scopus databases until August 2023 with PRISMA guidelines. Original articles assessing skin biopsy in sCeAD patients were included. Two reviewers independently conducted the screening.
FINDINGS
We included 16 studies compromising 459 patients. Thirteen studies assessed ultrastructural changes and found aberrations of collagen and elastic fibers, described as irregular contours and calibers of collagen fibrils, composite flower-like fibrils, fragmented moth-eaten elastin, and microcalcifications, cumulatively in 50.5% of patients. Seven studies showed no causative mutations in collagen type I, III, V, or elastin genes. One study showed linkage between connective tissue alterations and mutation on chromosomes 15q2 and 10q26 using genome-wide linkage analysis, while another study found significant copy number variant enrichments in genes involved in extracellular matrix (COL5A2/COL3A1/SNTA1) and collagen fibril organizations (COL5A2/COL3A1). Finally, differential expression of extracellular proteins was linked to connective tissue disorder in patients with recurrent sCeAD using a quantitative proteomics approach.
CONCLUSION
Current literature supports the hypothesis that an underlying, subclinical connective tissue disorder, likely genetically determined, may predispose to arterial wall weakness and sCeAD. Further studies with larger sample sizes and robust methodology are needed to better define the role of connective tissue in sCeAD pathogenesis.
PubMed: 37885478
DOI: 10.3389/fneur.2023.1241084 -
Frontiers in Endocrinology 2023Preimplantation genetic testing for aneuploidy (PGT-A) is an emerging technology that aims to identify euploid embryos for transfer, reducing the risk of embryonic... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Preimplantation genetic testing for aneuploidy (PGT-A) is an emerging technology that aims to identify euploid embryos for transfer, reducing the risk of embryonic chromosomal abnormalities. However, the clinical benefits of PGT-A in recurrent pregnancy failure (RPF) patients, particularly in young RPF patients, remains uncertain.
OBJECTIVE AND RATIONALE
This meta-analysis aimed to determine whether RPF patients undergoing PGT-A had better clinical outcomes compared to those not undergoing PGT-A, thus assessing the value of PGT-A in clinical practice.
SEARCH METHODS
We systematically searched PubMed, the Cochrane Library, China National Knowledge Infrastructure (CNKI), Wanfang Data, and VIP Database for Chinese Technical Periodicals (VIP) from 2002 to 2022. Thirteen published studies involving 930 RPF patients screened using PGT-A and over 1,434 RPF patients screened without PGT-A were included in this meta-analysis. Clinical outcomes were evaluated based on embryo transfers after PGT-A (n=1,015) and without PGT-A (n=1,799).
CLINICAL OUTCOMES
The PGT-A group demonstrated superior clinical outcomes compared to the fertilization (IVF)/intracytoplasmic sperm injection (ICSI) group. The PGT-A group had a significantly higher implantation rate (IR) (RR=2.01, 95% CI: [1.73; 2.34]), clinical pregnancy rate (CPR) (RR=1.53, 95% CI: [1.36; 1.71]), ongoing pregnancy rate (OPR) (RR=1.76, 95% CI: [1.35; 2.29]), live birth rate (LBR) (RR=1.75, 95% CI: [1.51; 2.03]), and significantly lower clinical miscarriage rate (CMR) (RR=0.74, 95% CI: [0.54; 0.99]). Subgroup analysis based on patient age (under 35 years and 35 years or older) showed that both PGT-A subgroups had significantly better CPR (P<0.01) and LBR (P<0.05) values compared to the IVF/ICSI groups.
SUMMARY
This meta-analysis demonstrates that PGT-A in RPF patients, is associated with improved clinical outcomes, including higher IR, CPR, OPR, and LBR values, and lower CMR compared to the IVF/ICSI group. These findings support the positive clinical application of PGT-A in RPF patients.
SYSTEMATIC REVIEW REGISTRATION
http://INPLASY.com, identifier INPLASY 202320118.
Topics: Pregnancy; Female; Humans; Male; Adult; Preimplantation Diagnosis; Semen; Genetic Testing; Fertilization in Vitro; Abortion, Spontaneous; Aneuploidy
PubMed: 37850092
DOI: 10.3389/fendo.2023.1178294 -
Mutation Research. Genetic Toxicology... Oct 2023Can human peripheral blood cells be used as a surrogate for bone marrow cells, in evaluating the genotoxic effects of stressors? We searched the Pubmed/Medline and... (Meta-Analysis)
Meta-Analysis Review
Can human peripheral blood cells be used as a surrogate for bone marrow cells, in evaluating the genotoxic effects of stressors? We searched the Pubmed/Medline and PubChem databases to identify publications relevant to this question. Micronucleus formation was the genotoxicity endpoint. Three publications comparing exposed vs. non-exposed individuals are included in this analysis; the exposures were to ethylene oxide or ionising radiation (atomic bomb, thorotrast, or radioiodine therapy). Information was extracted on the types of exposure, the numbers of participants, and the micronucleus frequencies. Relative differences (odds ratios) and absolute differences (risk differences) in the numbers of micronuclei between exposed and non-exposed persons were calculated separately for individual cell types (peripheral blood and bone marrow). Random effects meta-analyses for the relative differences in cell abnormalities were performed. The results showed very small differences in the frequencies of micronuclei between exposed and non-exposed individuals, as measured in either peripheral blood or bone marrow cell populations, on both absolute and relative scales. No definite conclusion concerning the relative sensitivities of bone marrow and peripheral blood cells can be made, based on these publications.
Topics: Humans; Bone Marrow; Iodine Radioisotopes; Micronucleus Tests; Blood Cells; Bone Marrow Cells; DNA Damage; Micronuclei, Chromosome-Defective
PubMed: 37770146
DOI: 10.1016/j.mrgentox.2023.503689 -
Cureus Aug 2023Being one of the most prevalent progressive neurodegenerative disorders (falling second only to Alzheimer's disease) with a clinical pattern affecting millions of lives... (Review)
Review
Being one of the most prevalent progressive neurodegenerative disorders (falling second only to Alzheimer's disease) with a clinical pattern affecting millions of lives all over the world, Parkinson's disease (PD) has never failed to attract a formidable interest from the vast majority of neurologists and researchers worldwide. This review article will analyze the pathophysiology, etiology, genetics, and pathological stages of Parkinson's disease with their corresponding clinical sequels. A review article was conducted using research databases including PubMed, PubMed Central, Springer, and Elsevier. The research articles reviewed using databases were written in English, German, Japanese, and Chinese and published within the preceding 50 years. Based on the article's findings, we concluded that Parkinson's disease is a progressive disorder with a variety of motor and non-motor symptoms that are influenced by a cascade of pathological neuronal abnormalities such as Lewy neurites and Lewy bodies that gradually build up with an eventual consequence of neurodegeneration of dopamine-secreting neurons. Multiple genetic mutations, pathophysiological events, and environmental factors act as the foundation to initiate that cascade.
PubMed: 37664277
DOI: 10.7759/cureus.44353 -
Heliyon Jul 2023Axenfeld-Rieger Syndrome (ARS) is comprised of a group of autosomal dominant disorders that are each characterized by anterior segment abnormalities of the eye.... (Review)
Review
Axenfeld-Rieger Syndrome (ARS) is comprised of a group of autosomal dominant disorders that are each characterized by anterior segment abnormalities of the eye. Mutations in the transcription factors or are the most well-studied genetic manifestations of this syndrome. Due to the rarity this syndrome, ARS-associated neurological manifestations have not been well characterized. The purpose of this systematic review is to characterize and describe ARS neurologic manifestations that affect the cerebral vasculature and their early and late sequelae. PRISMA guidelines were followed; studies meeting inclusion criteria were analyzed for study design, evidence level, number of patients, patient age, whether the patients were related, genotype, ocular findings, and nervous system findings, specifically neurostructural and neurovascular manifestations. 63 studies met inclusion criteria, 60 (95%) were case studies or case series. The gene was most commonly found, followed by , then . The most commonly described structural neurological findings were white matter abnormalities in 26 (41.3%) of studies, followed by Dandy-Walker Complex 12 (19%), and agenesis of the corpus callosum 11 (17%). Neurovascular findings were examined in 6 (9%) of studies, identifying stroke, cerebral small vessel disease (CSVD), tortuosity/dolichoectasia of arteries, among others, with no mention of moyamoya. This is the first systematic review investigating the genetic, neurological, and neurovascular associations with ARS. Structural neurological manifestations were common, yet often benign, perhaps limiting the utility of MRI screening. Neurovascular abnormalities, specifically stroke and CSVD, were identified in this population. Stroke risk was present in the presence and absence of cardiac comorbidities. These findings suggest a relationship between ARS and neurovascular findings; however, larger scale studies are necessary inform therapeutic decisions.
PubMed: 37539177
DOI: 10.1016/j.heliyon.2023.e18225 -
Orphanet Journal of Rare Diseases Jun 2023CSF1R mutations cause autosomal-dominant CSF1R-related leukoencephalopathy with axonal spheroids and pigmented glia (CSF1R-ALSP) and autosomal-recessive brain... (Review)
Review
CSF1R mutations cause autosomal-dominant CSF1R-related leukoencephalopathy with axonal spheroids and pigmented glia (CSF1R-ALSP) and autosomal-recessive brain abnormalities, neurodegeneration, and dysosteosclerosis (BANDDOS). The former is increasingly recognized, and disease-modifying therapy was introduced; however, literature is scarce on the latter. This review analyzes BANDDOS and discusses similarities and differences with CSF1R-ALSP.We systematically retrieved and analyzed the clinical, genetic, radiological, and pathological data on the previously reported and our cases with BANDDOS. We identified 19 patients with BANDDOS (literature search according to the PRISMA 2020 guidelines: n = 16, our material: n = 3). We found 11 CSF1R mutations, including splicing (n = 3), missense (n = 3), nonsense (n = 2), and intronic (n = 2) variants and one inframe deletion. All mutations disrupted the tyrosine kinase domain or resulted in nonsense-mediated mRNA decay. The material is heterogenous, and the presented information refers to the number of patients with sufficient data on specific symptoms, results, or performed procedures. The first symptoms occurred in the perinatal period (n = 5), infancy (n = 2), childhood (n = 5), and adulthood (n = 1). Dysmorphic features were present in 7/17 cases. Neurological symptoms included speech disturbances (n = 13/15), cognitive decline (n = 12/14), spasticity/rigidity (n = 12/15), hyperactive tendon reflex (n = 11/14), pathological reflexes (n = 8/11), seizures (n = 9/16), dysphagia (n = 9/12), developmental delay (n = 7/14), infantile hypotonia (n = 3/11), and optic nerve atrophy (n = 2/7). Skeletal deformities were observed in 13/17 cases and fell within the dysosteosclerosis - Pyle disease spectrum. Brain abnormalities included white matter changes (n = 19/19), calcifications (n = 15/18), agenesis of corpus callosum (n = 12/16), ventriculomegaly (n = 13/19), Dandy-Walker complex (n = 7/19), and cortical abnormalities (n = 4/10). Three patients died in infancy, two in childhood, and one case at unspecified age. A single brain autopsy evidenced multiple brain anomalies, absence of corpus callosum, absence of microglia, severe white matter atrophy with axonal spheroids, gliosis, and numerous dystrophic calcifications.In conclusion, BANDDOS presents in the perinatal period or infancy and has a devastating course with congenital brain abnormalities, developmental delay, neurological deficits, osteopetrosis, and dysmorphic features. There is a significant overlap in the clinical, radiological, and neuropathological aspects between BANDDOS and CSF1R-ALSP. As both disorders are on the same continuum, there is a window of opportunity to apply available therapy in CSF1R-ALSP to BANDDOS.
Topics: Humans; Neuroglia; Leukoencephalopathies; Brain; Mutation; Nervous System Malformations; Atrophy
PubMed: 37349768
DOI: 10.1186/s13023-023-02772-9 -
Seizure Jul 2023Interstitial 6q deletions are associated with rare genetic syndromes characterized by different signs, including developmental delay, dysmorphisms, and Prader-Willi...
PURPOSE
Interstitial 6q deletions are associated with rare genetic syndromes characterized by different signs, including developmental delay, dysmorphisms, and Prader-Willi (PWS)-like features. Drug-resistant epilepsy, a relatively rare finding in this condition, is often a challenge in terms of therapeutic approach. Our aim is to present a new case of interstitial 6q deletion and to conduct a systematic review of the literature with an emphasis on the neurophysiological and clinical traits of afflicted individuals.
METHODS
We report a patient with an interstitial 6q deletion. Standard electroencephalograms (EEG), video-EEG with polygraphy and MRI features are discussed. We also conducted a literature review of previously described cases.
RESULTS
We describe a relatively small interstitial 6q deletion (2 Mb circa), detected by CGH-Array, not encompassing the previously described 6q22 critical region for epilepsy occurrence. The patient, a 12-year-old girl, presented with multiple absence-like episodes and startle-induced epileptic spasms since the age of 11, with partial polytherapy control. Treatment with lamotrigine induced the resolution of startle-induced phenomena. From the literature review, we identified 28 patients with overlapping deletions, often larger than our patient's mutation. Seventeen patients presented with PWS-like features. Epilepsy was reported in 4 patients, and 8 patients presented abnormal EEG findings. In our patient, the deletion included genes MCHR2, SIM1, ASCC3, and GRIK2, but, interestingly, it did not encompass the 6q22 critical region for epilepsy occurrence. The involvement of GRIK2 in the deletion may play a role.
CONCLUSION
Literature data are limited, and specific EEG or epileptological phenotypes cannot yet be identified. Epilepsy, although uncommon in the syndrome, deserves a specific diagnostic workup. We speculate on the existence of an additional locus in the 6q16.1-q21 region, different from the already hypothesized q22, promoting the development of epilepsy in affected patients.
Topics: Humans; Prader-Willi Syndrome; Chromosome Deletion; Phenotype; Mutation; Drug Resistant Epilepsy; Epilepsy; DNA Helicases
PubMed: 37210930
DOI: 10.1016/j.seizure.2023.05.011 -
Orphanet Journal of Rare Diseases May 2023Deficiency of adenosine deaminase 2 (DADA2) is a rare monogenic autoinflammatory disease, whose clinical phenotype was expanded since the first cases, originally... (Review)
Review
INTRODUCTION
Deficiency of adenosine deaminase 2 (DADA2) is a rare monogenic autoinflammatory disease, whose clinical phenotype was expanded since the first cases, originally described as mimicker of polyarteritis nodosa, with immunodeficiency and early-onset stroke.
METHODS
A systematic review according to PRISMA approach, including all articles published before the 31st of August 2021 in Pubmed and EMBASE database was performed.
RESULTS
The search identified 90 publications describing 378 unique patients (55.8% male). To date 95unique mutations have been reported. The mean age at disease onset was 92.15 months (range 0-720 months), 32 (8.5%) showed an onset of the first signs/symptoms after 18 years old and 96 (25.4%) after 10 years old. The most frequent clinical characteristics described were cutaneous (67.9%), haematological manifestations (56.3%), recurrent fever (51.3%), neurological as stroke and polyneuropathy (51%), immunological abnormalities (42.3%), arthralgia/arthritis (35.4%), splenomegaly (30.6%), abdominal involvement (29.8%), hepatomegaly (23.5%), recurrent infections (18.5%), myalgia (17.9%), kidney involvement (17.7%) etc. Patients with skin manifestations were older than the others (101.1 months SD ± 116.5, vs. 75.3 SD ± 88.2, p 0.041), while those with a haematological involvement (64.1 months SD ± 75.6 vs. 133.1 SD ± 133.1, p < 0.001) and immunological involvement (73.03 months SD ± 96.9 vs. 103.2 SD ± 112.9, p 0.05) are younger than the others. We observed different correlations among the different clinical manifestations. The use of anti-TNFα and hematopoietic cell stems transplantation (HCST) has improved the current history of the disease.
CONCLUSION
Due to this highly variable phenotype and age of presentation, patients with DADA2 may present to several type of specialists. Given the important morbidity and mortality, early diagnosis and treatment are mandatory.
Topics: Male; Female; Humans; Adenosine Deaminase; Intercellular Signaling Peptides and Proteins; Phenotype; Stroke; Mutation
PubMed: 37179309
DOI: 10.1186/s13023-023-02721-6 -
Biology Apr 2023The aim of this review is to identify possible structural abnormalities of BrS and their potential association with symptoms, risk stratification, and prognosis. (1)... (Review)
Review
The aim of this review is to identify possible structural abnormalities of BrS and their potential association with symptoms, risk stratification, and prognosis. (1) Background: BrS has always been considered a purely electrical disease and imaging techniques do not currently play a specific role in the diagnosis of this arrhythmic syndrome. Some authors have recently hypothesized the presence of structural and functional abnormalities. Therefore, several studies investigated the presence of pathological features in echocardiography and cardiac magnetic resonance imaging (MRI) in patients with BrS, but results were controversial. (2) Methods: We performed a systematic review of the literature on the spectrum of features detected by echocardiography and cardiac MRI. Articles were searched in Pubmed, Cochrane Library, and Biomed Central. Only papers published in English and in peer-reviewed journals up to November 2021 were selected. After an initial evaluation, 596 records were screened; the literature search identified 19 relevant articles. (3) Results: The imaging findings associated with BrS were as follows: right ventricular dilation, right ventricular wall motion abnormalities, delayed right ventricular contraction, speckle and feature tracking abnormalities, late gadolinium enhancement, and fat infiltration in the right ventricle. Furthermore, these features emerged more frequently in patients carrying the genetic mutation on the sodium voltage-gated channel α-subunit 5 (SCN5A) gene. (4) Conclusions: Specific imaging features detected by echocardiography and cardiac magnetic resonance are associated with BrS. However, this population appears to be heterogeneous and imaging anomalies emerged to be more frequent in patients carrying genetic mutations of SCN5A. Future studies with an evaluation of BrS patients are needed to identify the specific association linking the Brugada pattern, imaging abnormalities and their possible correlation with prognosis.
PubMed: 37106806
DOI: 10.3390/biology12040606 -
BMC Medical Genomics Apr 2023Wolfram syndrome type 1 gene (WFS1), which encodes a transmembrane structural protein (wolframin), is essential for several biological processes, including proper inner...
BACKGROUND
Wolfram syndrome type 1 gene (WFS1), which encodes a transmembrane structural protein (wolframin), is essential for several biological processes, including proper inner ear function. Unlike the recessively inherited Wolfram syndrome, WFS1 heterozygous variants cause DFNA6/14/38 and wolfram-like syndrome, characterized by autosomal dominant nonsyndromic hearing loss, optic atrophy, and diabetes mellitus. Here, we identified two WFS1 heterozygous variants in three DFNA6/14/38 families using exome sequencing. We reveal the pathogenicity of the WFS1 variants based on three-dimensional (3D) modeling and structural analysis. Furthermore, we present cochlear implantation (CI) outcomes in WFS1-associated DFNA6/14/38 and suggest a genotype-phenotype correlation based on our results and a systematic review.
METHODS
We performed molecular genetic test and evaluated clinical phenotypes of three WFS1-associated DFNA6/14/38 families. A putative WFS1-NCS1 interaction model was generated, and the impacts of WFS1 variants on stability were predicted by comparing intramolecular interactions. A total of 62 WFS1 variants associated with DFNA6/14/38 were included in a systematic review.
RESULTS
One variant is a known mutational hotspot variant in the endoplasmic reticulum (ER)-luminal domain WFS1(NM_006005.3) (c.2051 C > T:p.Ala684Val), and the other is a novel frameshift variant in transmembrane domain 6 (c.1544_1545insA:p.Phe515LeufsTer28). The two variants were pathogenic, based on the ACMG/AMP guidelines. Three-dimensional modeling and structural analysis show that non-polar, hydrophobic substitution of Ala684 (p.Ala684Val) destabilizes the alpha helix and contributes to the loss of WFS1-NCS1 interaction. Also, the p.Phe515LeufsTer28 variant truncates transmembrane domain 7-9 and the ER-luminal domain, possibly impairing membrane localization and C-terminal signal transduction. The systematic review demonstrates favorable outcomes of CI. Remarkably, p.Ala684Val in WFS1 is associated with early-onset severe-to-profound deafness, revealing a strong candidate variant for CI.
CONCLUSIONS
We expanded the genotypic spectrum of WFS1 heterozygous variants underlying DFNA6/14/38 and revealed the pathogenicity of mutant WFS1, providing a theoretical basis for WFS1-NCS1 interactions. We presented a range of phenotypic traits for WFS1 heterozygous variants and demonstrated favorable functional CI outcomes, proposing p.Ala684Val a strong potential marker for CI candidates.
Topics: Humans; Wolfram Syndrome; Cochlear Implants; Cochlear Implantation; Pedigree; Hearing Loss; Deafness
PubMed: 37041640
DOI: 10.1186/s12920-023-01506-x