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Medicina (Kaunas, Lithuania) Nov 2022: Marfan syndrome (MS) is a genetic disorder with autosomal dominant inheritance that affects the connective tissue and consequently many organ systems. The... (Review)
Review
: Marfan syndrome (MS) is a genetic disorder with autosomal dominant inheritance that affects the connective tissue and consequently many organ systems. The cardiovascular manifestations of MS are notorious and include aortic root dilatation or acute aortic dissection, which can cause morbidity and early mortality. However, surgical treatment of aortic pathology may be complicated by musculoskeletal deformity of the chest wall, as in pectus excavatum. In this regard, single-stage combined Bentall and Ravitch surgery is an extreme rarity that has also been scarcely reported in the literature. : We present the medical history and single-stage Bentall and modified Ravitch surgical treatment of an 18-year-old male MS patient with symptomatic and severe pectus excavatum (PEX) in conjunction with a pear-shaped aortic root aneurysm. To discuss our case in the context of a synopsis of similar published cases, we present a systematic review of combined Bentall surgical aortic aneurysm repair and Ravitch correction of PEX. : A total of four studies (one case series and three case reports) and a case from our institution describing a single-stage combined Bentall and Ravitch operation were included. Patients were 22 ± 5.9 years of age (median = 22.5 years) and predominantly male (60%). All cases reported a midline vertical skin incision over the sternum. The most common surgical approach was midsternotomy (80%). In all cases metal struts were used to reinforce the corrected chest wall. Postoperative mortality was zero. : Single-stage combined Bentall and Ravitch surgery is an underutilized surgical approach. Its use in MS patients with concomitant PEX and ascending aortic aneurysm that require surgical treatment warrants further investigation. Midsternotomy seems to be a viable access route that provides sufficient exposure in the single-stage surgical setting. Although operative time is long, the intraoperative and postoperative risks appear to be low and manageable.
Topics: Humans; Male; Young Adult; Adult; Adolescent; Female; Funnel Chest; Marfan Syndrome; Sternum; Aortic Dissection; Aorta; Treatment Outcome
PubMed: 36556976
DOI: 10.3390/medicina58121774 -
Frontiers in Aging Neuroscience 2022To investigate the association between diffusion tensor imaging (DTI) findings and domain-specific cognitive impairment in cerebral small vessel disease (CSVD).
OBJECTIVE
To investigate the association between diffusion tensor imaging (DTI) findings and domain-specific cognitive impairment in cerebral small vessel disease (CSVD).
METHODS
Databases such as PubMed, Excerpta Medical Database (EMBASE), Web of Science, Cochrane Library, Chinese National Knowledge Infrastructure Databases (CNKI), Wanfang, Chinese Biomedical Literature Database (SinoMed), and Chongqing Chinese Science and Technology Periodical Database (VIP) were comprehensively retrieved for studies that reported correlation coefficients between cognition and DTI values. Random effects models and meta-regression were applied to account for heterogeneity among study results. Subgroup and publication bias analyses were performed using Stata software.
RESULTS
Seventy-seven studies involving 6,558 participants were included in our meta-analysis. The diagnosis classification included CSVD, white matter hyperintensities (WMH), subcortical ischemic vascular disease, cerebral microbleeding, cerebral amyloid angiopathy (CAA), cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), and Fabry disease. The pooled estimates showed that the fractional anisotropy (FA)-overall exhibited a moderate correlation with general cognition, executive function, attention, construction, and motor performance ( = 0.451, 0.339, 0.410, and 0.319), and the mean diffusitivity/apparent diffusion coefficient (MD/ADC)-overall was moderately associated with general cognition, executive function, and memory ( = -0.388, -0.332, and -0.303, respectively; < 0.05). Moreover, FA in cingulate gyrus (CG), cerebral peduncle (CP), corona radiata (CR), external capsule (EC), frontal lobe (FL), fornix (FOR), internal capsule (IC), and thalamic radiation (TR) was strongly correlated with general cognition ( = 0.591, 0.584, 0.543, 0.662, 0.614, 0.543, 0.597, and 0.571), and a strong correlation was found between MD/ADC and CG ( = -0.526), normal-appearing white matter (NAWM; = -0.546), and whole brain white matter (WBWM; = -0.505). FA in fronto-occipital fasciculus (FOF) ( = 0.523) and FL ( = 0.509) was strongly associated with executive function. Only MD/ADC of the corpus callosum (CC) was strongly associated with memory ( = -0.730). Besides, FA in CG ( = 0.532), CC ( = 0.538), and FL ( = 0.732) was strongly related to the attention domain. Finally, we found that the sample size, etiology, magnetic resonance imaging (MRI) magnet strength, study type, and study quality contributed to interstudy heterogeneity.
CONCLUSION
Lower FA or higher MD/ADC values were related to more severe cognitive impairment. General cognition and executive function domains attracted the greatest interest. The FL was commonly examined and strongly associated with general cognition, executive function, and attention. The CC was strongly associated with memory and attention. The CG was strongly related to general cognition and attention. The CR, IC, and TR were also strongly related to general cognition. Indeed, these results should be validated in high-quality prospective studies with larger sample sizes.
SYSTEMATIC REVIEW REGISTRATION
http://www.crd.york.ac.uk/PROSPERO, identifier: CRD42021226133.
PubMed: 36483114
DOI: 10.3389/fnagi.2022.1019088 -
Neurological Sciences : Official... Mar 2023Hereditary spastic paraplegia (HSP) is a rare genetic disorder associated with mutations in > 80 loci designated SPG (SPastic parapleGia). The phenotypic spectrum of... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Hereditary spastic paraplegia (HSP) is a rare genetic disorder associated with mutations in > 80 loci designated SPG (SPastic parapleGia). The phenotypic spectrum of HSP can extend to include other neurologic features, including movement disorders. Our aim was to investigate genotype-phenotype associations in HSP with a focus on movement disorders.
METHODS
We performed a systematic review and individual participant data (IPD)-level meta-analysis by retrieving publications from Medline/EMBASE/Web of Science on HSP with a SPG genotype. Studies were included only if individual-level information was accessible and at least one patient with a movement disorder was reported for that genotype. Out of 21,957 hits, 192 manuscripts with a total of 1413 HSP cases were eligible. Data were compared between two HSP groups: manifested with (HSP-MD, n = 767) or without (HSP-nMD, n = 646) a movement disorder.
RESULTS
The HSP-MD group had an older age of onset (20.5 ± 16.0 vs. 17.1 ± 14.2 yr, p < 0.001) and less frequent autosomal dominant inheritance (7.6% vs. 30.1%, p < 0.001) compared to HSP-nMD. SPG7 (31.2%) and SPG11 (23.8%) were the most frequent genotypes in the HSP-MD group. HSP-MD with SPG7 had higher frequency of later onset during adulthood (82.9% vs. 8.5%), ataxia (OR = 12.6), extraocular movement disturbances (OR = 3.4) and seizure (OR = 3.7) compared to HSP-MD with SPG11. Conversely, SPG11 mutations were more frequently associated with consanguinity (OR = 4.1), parkinsonism (OR = 7.8), dystonia (OR = 5.4), peripheral neuropathy (OR = 26.9), and cognitive dysfunction (OR = 34.5).
CONCLUSION
This systematic IPD-level meta-analysis provides the largest data on genotype-phenotype associations in HSP-MD. Several clinically relevant phenotypic differences were found between various genotypes, which can possibly facilitate diagnosis in resource-limited settings.
Topics: Humans; Spastic Paraplegia, Hereditary; Paraplegia; Mutation; Movement Disorders; Phenotype; Proteins
PubMed: 36441344
DOI: 10.1007/s10072-022-06516-8 -
Movement Disorders Clinical Practice Nov 2022Cerebellar ataxias comprise a large group of heterogeneous disorders with both motor and non-motor symptoms (NMS). (Review)
Review
BACKGROUND
Cerebellar ataxias comprise a large group of heterogeneous disorders with both motor and non-motor symptoms (NMS).
OBJECTIVE
We wanted to ascertain the reported prevalence of NMS in different subtypes of hereditary cerebellar ataxias.
METHODS
Systematic review of studies of hereditary cerebellar ataxias (involving >5 patients) who were assessed for NMS, published in the English literature in PUBMED and EMBASE databases from 1947 to 2021.
RESULTS
A total of 35 papers, with data from 1311 autosomal dominant spinocerebellar ataxia (SCA), 893 autosomal recessive cerebellar ataxia (ARCA), and 53 X-linked ataxia cases were included with a total of 450 controls. Mean age for SCA cases at diagnosis was 47.6 (SD, 14.9) years, for ARCA cases was 34.6 (SD, 14.7) years and for X-linked ataxia cases was 68.6 (9.1) years. The prevalence of cognitive problems in SCAs was between 23% and 75% (ranging from mild to severe), being least prevalent in SCA6. The prevalence of depression in SCAs was between 13% and 69% and sleep disorders were between 7% and 80%. Pain was reported by 18% to 60% of patients, especially in SCA3, and fatigue by 53% to 70%. The prevalence of reported cognitive dysfunction in ARCA was 12.5% to 100% and depression between 14% and 51%. The prevalence of anxiety in X-linked ataxias (FXTAS) was 17 % and depression 55%.
CONCLUSIONS
The presence of NMS in hereditary cerebellar ataxias is common. The prevalence and spectrum of NMS in SCAs, ARCAs, and X-linked ataxias vary. In routine clinical practice, NMS in cerebellar ataxias are under-recognized and certainly under-reported. Therefore, they are unlikely to be addressed adequately. Improved ascertainment of NMS in cerebellar ataxias in clinical practice will enable holistic treatment of these patients.
PubMed: 36339305
DOI: 10.1002/mdc3.13532 -
Journal of Dairy Science Jan 2023Mastitis, the most frequent disease in dairy cattle. Resistance to mastitis is a complex, polygenic trait controlled by several genes, each with small effects....
Mastitis, the most frequent disease in dairy cattle. Resistance to mastitis is a complex, polygenic trait controlled by several genes, each with small effects. Genome-wide association studies have been widely used to identify genomic variants associated with complex traits, including resistance to mastitis, to elucidate the underlying genetic architecture of the trait. However, no systematic review and gene prioritization analysis have been conducted to date on GWAS results for resistance to mastitis in dairy cattle. Hence, the objective was to perform a systematic review and gene prioritization analysis of GWAS studies to identify potential functional candidate genes associated with resistance to mastitis-related traits in dairy cattle. Four electronic databases were searched from inception to December 2020, supplemented with multiple sources of gray literature, to identify eligible articles. Annotation for genes and quantitative trait loci (QTL), and QTL enrichment analysis were conducted using GALLO. Gene prioritization analysis was performed by a guilty-by-association approach using GUILDify and ToppGene. From 52 articles included within this systematic review, 30 articles were used for further functional analyses. Gene and QTL annotation resulted in 9,125 and 43,646 unique genes and QTL, respectively, from 39 studies. In general, overlapping of genes across studies was very low (mean ± SD = 0.02% ± 0.07%). Most annotated genes were associated with somatic cell count-related traits and the Holstein breed. Within all annotated genes, 74 genes were shared among Holstein, Jersey, and Ayrshire breeds. Approximately 7.5% of annotated QTL were related to QTL class "health." Within the health QTL class, 2.6 and 2.2% of QTL were associated with clinical mastitis and somatic cell count-related traits. Enrichment analysis of QTL demonstrated that many enriched QTL were associated with somatic cell score located in Bos taurus autosomes 5, 6, 16, and 20. The prioritization analysis resulted in 427 significant genes after multiple test correction (false discovery rate of 5%) from 26 studies. Most prioritized genes were located in Bos taurus autosomes 19 and 7, and most top-ranked genes were from the cytokine superfamily (e.g., chemokines, interleukins, transforming growth factors, and tumor necrosis factor genes). Although most prioritized genes (397) were associated with somatic cell count-related traits, only 54 genes were associated with clinical mastitis-related traits. Twenty-four genes (ABCC9, ACHE, ADCYAP1, ARC, BCL2L1, CDKN1A, EPO, GABBR2, GDNF, GNRHR, IKBKE, JAG1, KCNJ8, KCNQ1, LIFR, MC3R, MYOZ3, NFKB1, OSMR, PPP3CA, PRLR, SHARPIN, SLC1A3, and TNFRSF25) were reported for both somatic cell count and clinical mastitis-related traits. Prioritized genes were mainly associated with immune response, regulation of secretion, locomotion, cell proliferation, and development. In conclusion, this study provided a fine-mapping of previously identified genomic regions associated with resistance to mastitis and identified key functional candidate genes for resistance to mastitis, which can be used to develop enhanced genomic strategies to combat mastitis by increasing mastitis resistance through genetic selection.
Topics: Female; Cattle; Animals; Genome-Wide Association Study; Polymorphism, Single Nucleotide; Quantitative Trait Loci; Mastitis, Bovine; Cattle Diseases
PubMed: 36333139
DOI: 10.3168/jds.2022-21923 -
Cerebral Circulation - Cognition and... 2022The term Cerebral Amyloid Angiopathy (CAA) refers to a group of neurovascular disorders characterized by amyloid deposition within the walls of leptomeningeal and...
The term Cerebral Amyloid Angiopathy (CAA) refers to a group of neurovascular disorders characterized by amyloid deposition within the walls of leptomeningeal and cortical blood vessels of the brain, with specific predilection for arterioles, and (less often) capillaries and veins. Most CAA cases in the general population are sporadic in nature, and represent primarily an age-related condition affecting individuals in the fifth decade of life and beyond. Sporadic CAA is caused by deposition of amyloid-β (Aβ), originating from proteolytic cleavage of the Amyloid Precursor Protein (APP), within the walls of cerebral small caliber vessels. However, hereditary forms of CAA have also been described, generally presenting as rare familial disorder with monogenic (predominantly autosomal dominant) inheritance patterns. Hereditary CAA forms tend to affect younger individuals, and their course and clinical progression is more severe. Studies to date primarily focused on the vascular manifestations of sporadic and hereditary CAA, chiefly symptomatic lobar Intracerebral Hemorrhage (ICH). However, in the past decade sporadic CAA has also been consistently linked to progressive neurocognitive, neurobehavioral, and neuropsychiatric symptoms. This systematic review focuses on the genetics, pathogenesis, neuroimaging, neuropathology, and clinical manifestations of hereditary CAA with specific emphasis on previously overlooked cognitive, behavioral, and psychiatric symptoms.
PubMed: 36324420
DOI: 10.1016/j.cccb.2022.100124 -
International Journal of Molecular... Oct 2022The CTNNB1 Syndrome is a rare neurodevelopmental disorder associated with developmental delay, intellectual disability, and delayed or absent speech. The aim of the... (Review)
Review
The CTNNB1 Syndrome is a rare neurodevelopmental disorder associated with developmental delay, intellectual disability, and delayed or absent speech. The aim of the present study is to systematically review the available data on the prevalence of clinical manifestations and to evaluate the correlation between phenotype and genotype in published cases of patients with CTNNB1 Syndrome. Studies were identified by systematic searches of four major databases. Information was collected on patients' genetic mutations, prenatal and neonatal problems, head circumference, muscle tone, EEG and MRI results, dysmorphic features, eye abnormalities, early development, language and comprehension, behavioral characteristics, and additional clinical problems. In addition, the mutations were classified into five groups according to the severity of symptoms. The study showed wide genotypic and phenotypic variability in patients with CTNNB1 Syndrome. The most common moderate-severe phenotype manifested in facial dysmorphisms, microcephaly, various motor disabilities, language and cognitive impairments, and behavioral abnormalities (e.g., autistic-like or aggressive behavior). Nonsense and missense mutations occurring in exons 14 and 15 were classified in the normal clinical outcome category/group because they had presented an otherwise normal phenotype, except for eye abnormalities. A milder phenotype was also observed with missense and nonsense mutations in exon 13. The autosomal dominant CTNNB1 Syndrome encompasses a wide spectrum of clinical features, ranging from normal to severe. While mutations cannot be more generally categorized by location, it is generally observed that the C-terminal protein region (exons 13, 14, 15) correlates with a milder phenotype.
Topics: Pregnancy; Female; Humans; Codon, Nonsense; Phenotype; Intellectual Disability; Syndrome; Genotype; Mutation; Eye Abnormalities; beta Catenin
PubMed: 36293418
DOI: 10.3390/ijms232012564 -
Frontiers in Genetics 2022The study aims to identify genetic variants in five Chinese families with Keratoconus (KC) and describe the characteristics of parental corneal topography. Fifteen...
The study aims to identify genetic variants in five Chinese families with Keratoconus (KC) and describe the characteristics of parental corneal topography. Fifteen participants, including five probands and ten parents from five Chinese families with KC, were recruited for genetic and clinical analyses. Targeted next-generation sequencing using a custom-designed panel for KC was applied on the probands for variant identification. Sanger sequencing and cosegregation analysis of the suspected pathogenic variants were performed on the family members. The pathogenicities of variants were evaluated according to the American College of Medical Genetics and Genomics guidelines (ACMG). Pentacam 3D anterior segment analysis system was applied for keratectasia detection and the Corvis ST for corneal biomechanics measurement. Fifteen parameters were recorded, including nine keratectasia indicators (BAD-D, TP, Kmax, Df, Db, Dp, Dt, Da, ARTH), six corneal biomechanical indicators (CBI, DA ratio, SP-A1, IR, bIOP, TBI). A total of six novel variants, including five missense variants and one frameshift variant, were detected in the and genes in five probands, all of which showed co-segregation of genotype and clinical phenotype and were determined to be pathogenic. The genetic model was autosomal dominant (AD) in four families and autosomal recessive (AR) in 1 family. The analysis of keratectasia and corneal biomechanical indicators of the proband's parents (first-generation relatives) in AD families revealed that there were several abnormal indexes in BAD-D, TP, Kmax, Df, Db, Dp, Dt, Da, CBI, DA ratio, SP-A1, IR, bIOP and TBI test indexes, showing clinical characteristics of incipient KC. Our study shows that variants in and were associated with KC. Our study extends the gene spectrum associated with KC, provides novel insights into KC phenotypic assessments, and contributes to early diagnosis for these patients.
PubMed: 36276932
DOI: 10.3389/fgene.2022.978684 -
Behavioural Neurology 2022Aromatic L-amino acid decarboxylase (AADC) deficiency is a rare congenital autosomal recessive metabolic disorder caused by pathogenic homozygous or compound... (Review)
Review
Aromatic L-amino acid decarboxylase (AADC) deficiency is a rare congenital autosomal recessive metabolic disorder caused by pathogenic homozygous or compound heterozygous variants in the dopa decarboxylase (DDC) gene. Adeno-associated viral vector-mediated gene transfer of the human AADC gene into the putamina has become available. This systematic review on PubMed, Scopus databases, and other sources is aimed at describing the AADC whole phenotypic spectrum in order to facilitate its early diagnosis. Literature reviews, original articles, retrospective and comparative studies, large case series, case reports, and short communications were considered. A database was set up using Microsoft Excel to collect clinical, molecular, biochemical, and therapeutic data. By analysing 261 patients from 41 papers with molecular and/or biochemical diagnosis of AADC deficiency for which individuality could be determined with certainty, we found symptom onset to occur in the first 6 months of life in 93% of cases. Hypotonia and developmental delay are cardinal signs, reported as present in 73.9% and 72% of cases, respectively. Oculogyric crises were seen in 67% of patients while hypokinesia in 42% and ptosis in 26%. Dysautonomic features have been revealed in 53% and gastrointestinal symptoms in 19% of cases. With 37% and 30% of patients reported being affected by sleep and behavioural disorders, it seems to be commoner than previously acknowledged. Although reporting bias cannot be excluded, there is still a need for comprehensive clinical descriptions of symptoms at onset and during follow-up. In fact, our review suggests that most of the neurological and extraneurological symptoms and signs reported, although quite frequent in this condition, are not pathognomonic, and therefore, ADCC deficiency can remain an underdiscovered disorder.
Topics: Humans; Dopa Decarboxylase; Retrospective Studies; Amino Acid Metabolism, Inborn Errors; Amino Acids
PubMed: 36268467
DOI: 10.1155/2022/2210555 -
Neurological Sciences : Official... Feb 2023Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a genetic small vessel disease responsible for recurrent ischemic... (Review)
Review
BACKGROUND
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a genetic small vessel disease responsible for recurrent ischemic strokes, often with a progressive course leading to dementia and disability. On MRI, lacunes, microbleeds, and severe white matter alterations are typical features of the disease. In case of acute stroke, because of the bleeding risk associated with the disease and the doubtful efficacy of fibrinolytic treatment in a disease with poor evidence of thrombosis, the efficacy of intravenous thrombolysis remains unproven. Nevertheless, stroke is a frequent occurrence in CADASIL patients, and clinicians not unlikely may face in the emergency room the situation of a CADASIL patient with an acute stroke within the time window for thrombolysis.
OBJECTIVE
We report on two CADASIL patients treated with intravenous alteplase for acute ischemic stroke, and we present a review of literature aimed to report epidemiological data, efficacy and safety of intravenous thrombolysis in CADASIL patients.
METHODS
We performed a systematic review of medical literature published until August 2, 2022. Case reports and series in English language reporting on CADASIL patients and acute stroke were included.
RESULTS
Both patients were treated with intravenous thrombolysis without complications and had a good clinical outcome. The systematic review identified three case reports of CADASIL patients who were treated with intravenous alteplase for acute ischemic stroke; no bleedings complications were described.
CONCLUSIONS
Available data on intravenous thrombolysis in CADASIL patients are scarce but suggest that this treatment can be taken into consideration for these patients.
Topics: Humans; CADASIL; Tissue Plasminogen Activator; Ischemic Stroke; Stroke; Magnetic Resonance Imaging; Thrombolytic Therapy; Receptor, Notch3
PubMed: 36255541
DOI: 10.1007/s10072-022-06449-2