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The American Journal of Psychiatry Jan 2023The aim of this study was to catalog and evaluate response biomarkers correlated with autism spectrum disorder (ASD) symptoms to improve clinical trials. (Meta-Analysis)
Meta-Analysis Review
OBJECTIVE
The aim of this study was to catalog and evaluate response biomarkers correlated with autism spectrum disorder (ASD) symptoms to improve clinical trials.
METHODS
A systematic review of MEDLINE, Embase, and Scopus was conducted in April 2020. Seven criteria were applied to focus on original research that includes quantifiable response biomarkers measured alongside ASD symptoms. Interventional studies or human studies that assessed the correlation between biomarkers and ASD-related behavioral measures were included.
RESULTS
A total of 5,799 independent records yielded 280 articles for review that reported on 940 biomarkers, 755 of which were unique to a single publication. Molecular biomarkers were the most frequently assayed, including cytokines, growth factors, measures of oxidative stress, neurotransmitters, and hormones, followed by neurophysiology (e.g., EEG and eye tracking), neuroimaging (e.g., functional MRI), and other physiological measures. Studies were highly heterogeneous, including in phenotypes, demographic characteristics, tissues assayed, and methods for biomarker detection. With a median total sample size of 64, almost all of the reviewed studies were only powered to identify biomarkers with large effect sizes. Reporting of individual-level values and summary statistics was inconsistent, hampering mega- and meta-analysis. Biomarkers assayed in multiple studies yielded mostly inconsistent results, revealing a "replication crisis."
CONCLUSIONS
There is currently no response biomarker with sufficient evidence to inform ASD clinical trials. This review highlights methodological imperatives for ASD biomarker research necessary to make definitive progress: consistent experimental design, correction for multiple comparisons, formal replication, sharing of sample-level data, and preregistration of study designs. Systematic "big data" analyses of multiple potential biomarkers could accelerate discovery.
Topics: Humans; Autism Spectrum Disorder; Biomarkers; Phenotype; Magnetic Resonance Imaging; Research Design
PubMed: 36475375
DOI: 10.1176/appi.ajp.21100992 -
European Journal of Medical Genetics Oct 2021Hereditary Diffuse Gastric Cancer (HDGC) is a cancer predisposing syndrome mainly caused by germline inactivating variants in CDH1, encoding E-cadherin. Early-onset...
Hereditary Diffuse Gastric Cancer (HDGC) is a cancer predisposing syndrome mainly caused by germline inactivating variants in CDH1, encoding E-cadherin. Early-onset diffuse gastric cancer (DGC) and/or invasive lobular breast cancer (LBC) are the main phenotypes in CDH1-associated HDGC. CTNNA1, encoding for α-E-catenin, and E-cadherin-partner in the adherens junction complex, has been recently classified as a HDGC predisposing gene. Nevertheless, little is known about CTNNA1 tumor spectrum in variant carriers and variant-type associated causality. Herein, we systematically reviewed the literature searching for CTNNA1 germline variants carriers, further categorized them according to HDGC clinical criteria (HDGC vs non-HDGC), collected phenotypes, classified variants molecularly and according to CDH1 ACMG/AMP guidelines and performed genotype-phenotype analysis. We found 41 families carrying CTNNA1 germline variants encompassing in total 105 probands and relatives. All probands from 13 HDGC families presented DGC and their average age of onset was 40 ± 17 years; 10/13 (77%) HDGC families carried a pathogenic (P) variant. Most probands from 28 non-HDGC families developed unspecified-BC, as well as most of their relatives; 4/28 (14%) carried a P variant, 16/28 (57%) carried a likely pathogenic (LP) variant, 7/28 (25%) carried variants of unknown significance (VUS) and 1/28 (4%) carried a likely benign variant. Regardless of clinical criteria, 97% (32/33) of probands and relatives from P variant-carrier families had DGC/unspecified-GC. In LP variant-carrier families, 82% (28/34) of probands and relatives had unspecified-BC. Only 2/105 individuals had LBC. A cluster of frameshift and nonsense variants was found in CTNNA1 last exon of non-HDGC families and classified as VUS. In conclusion, current available data confirms an association of CTNNA1 P variants with early-onset DGC, but not with LBC. We demonstrate that in ascertained cohorts, CTNNA1 P variants explain <2% of HDGC families and support the use of ACMG/AMP CDH1 specific variant curation guidelines, while no specific guidelines are developed for CTNNA1 variant classification. Moreover, we demonstrated that truncating variants at the CTNNA1 NMD-incompetent last exon have limited deleteriousness, and that CTNNA1 LP variants have lower actionability than CDH1 LP variants. Current knowledge supports considering only CTNNA1 P variants as clinically actionable in HDGC carrying families.
Topics: Antigens, CD; Cadherins; Gene Frequency; Genetic Predisposition to Disease; Germ-Line Mutation; Heterozygote; Humans; Pedigree; Phenotype; Stomach Neoplasms; alpha Catenin
PubMed: 34425242
DOI: 10.1016/j.ejmg.2021.104316 -
Journal of Crohn's & Colitis Oct 2016Little is known of the clinical outcome of patients with older-onset inflammatory bowel disease [IBD]. We performed a systematic review to determine phenotype and... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Little is known of the clinical outcome of patients with older-onset inflammatory bowel disease [IBD]. We performed a systematic review to determine phenotype and outcomes of older-onset IBD compared with younger-onset subjects.
METHODS
A systematic search of Embase and Medline up to June 2015 identified studies investigating phenotype and outcomes of older-onset [diagnosed at age ≥ 50 years] Crohn's disease [CD] and ulcerative colitis [UC] subjects. Pooled analyses of disease phenotype, medication use, and disease-related surgery were calculated.
RESULTS
We analysed findings from 43 studies comprising 8274 older-onset and 34641 younger-onset IBD subjects. Compared with younger-onset patients, older-onset CD patients were more likely to have colonic disease (odds ratio [OR] 2.56, 95% confidence interval [CI] 1.88 - 3.48) and inflammatory behaviour [OR 1.19, 95% CI 1.07 - 1.33], and less likely to have penetrating disease or perianal involvement. More older-onset UC patients had left-sided colitis [OR 1.49, 95% CI 1.18 - 1.88]. Although fewer older-onset IBD patients received immunomodulators [CD: OR 0.44; UC: OR 0.60] or biologicals [CD: OR 0.34; UC: OR 0.41], older-onset CD was similar in the need for surgery [OR 0.70, 95% CI 0.40 - 1.22] whereas more older-onset UC patients underwent surgery [OR 1.36, 95% CI 1.18 - 1.57].
CONCLUSIONS
Elderly IBD patients present with less complicated disease, but have similar or higher rates of surgery than non-elderly patients. Whether this reflects a non-benign disease course, physicians' reluctance to employ immunomodulators, or both, merits further study which is essential for improving the care of IBD in the elderly.
Topics: Age of Onset; Aged; Aged, 80 and over; Combined Modality Therapy; Disease Progression; Humans; Immunologic Factors; Inflammatory Bowel Diseases; Middle Aged; Models, Statistical; Phenotype; Prognosis
PubMed: 26928965
DOI: 10.1093/ecco-jcc/jjw054 -
Movement Disorders : Official Journal... Feb 2022Pathogenic variants in 5 genes (GCH1, TH, PTS, SPR, and QDPR), involved in dopamine/tetrahydrobiopterin biosynthesis or recycling, have been linked to Dopa-responsive... (Review)
Review
BACKGROUND
Pathogenic variants in 5 genes (GCH1, TH, PTS, SPR, and QDPR), involved in dopamine/tetrahydrobiopterin biosynthesis or recycling, have been linked to Dopa-responsive dystonia (DRD). Diagnosis and treatment are often delayed due to high between- and within-group variability.
OBJECTIVES
Comprehensively analyzed individual genotype, phenotype, treatment response, and biochemistry information.
METHODS
734 DRD patients and 151 asymptomatic GCH1 mutation carriers were included using an MDSGene systematic literature review and an automated classification approach to distinguish between different forms of monogenic DRDs.
RESULTS
Whereas dystonia, L-Dopa responsiveness, early age at onset, and diurnal fluctuations were identified as red flags, parkinsonism without dystonia was rarely reported (11%) and combined with dystonia in only 18% of patients. While sex was equally distributed in autosomal recessive DRD, there was female predominance in autosomal dominant DYT/PARK-GCH1 patients accompanied by a lower median age at onset and more dystonia in females compared to males. Accordingly, the majority of asymptomatic heterozygous GCH1 mutation carriers (>8 years of age) were males. Multiple other subgroup-specific characteristics were identified, showing high accuracy in the automated classification approach: Seizures and microcephaly were mostly seen in DYT/PARK-PTS, autonomic symptoms appeared commonly in DYT/PARK-TH and DYT/PARK-PTS, and sleep disorders and oculogyric crises in DYT/PARK-SPR. Biochemically, homovanillic acid and 5-hydroxyindoleacetic acid in CSF were reduced in most DRDs, but neopterin and biopterin were increased only in DYT/PARK-PTS and DYT/PARK-SPR. Hyperphenylalaninemia was seen in DYT/PARK-PTS, DYT/PARK-QDPR, and rarely reported in autosomal recessive DYT/PARK-GCH1.
CONCLUSIONS
Our indicators will help to specify diagnosis and accelerate start of treatment. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
Topics: Dystonia; Dystonic Disorders; Female; GTP Cyclohydrolase; Genotype; Humans; Male; Phenotype
PubMed: 34908184
DOI: 10.1002/mds.28874 -
Reproductive Health Feb 2022Eating disorders (EDs) are common conditions that mainly affect women of reproductive age and have a major impact on fertility. Our systematic review focuses on the... (Review)
Review
BACKGROUND
Eating disorders (EDs) are common conditions that mainly affect women of reproductive age and have a major impact on fertility. Our systematic review focuses on the prevalence of EDs in patients in the process of assisted reproductive technique (ART) and describes the phenotypes of EDs identified.
METHODS
Our systematic review is based on the PRISMA criteria. Articles were collected using the Medline/Pubmed, Web Of Science and Cochrane databases. The articles chosen had to mention the prevalence of ED in infertile patients undergoing ART and be cohort or case-control studies assessing the prevalence of ED during fertility treatment.
MAIN FINDINGS
Fifteen articles were included in this review. The prevalence of active ED varied between 0.13 and 44% depending on the types considered in each study. The main phenotypes described were EDNOS (eating disorder not otherwise specified) and binge eating disorders (BED) occurring in women with a normal body mass index (BMI) and a history of ED. Mainly subthreshold forms with cognitive distortions were described.
CONCLUSION
This review highlights a 6 times higher prevalence of EDs in infertile patients undergoing fertility treatment compared to regular pregnant women. However, diagnosing these conditions is complex. As a result, it is essential that professionals in contact with this population are alert to symptoms consistent with these conditions in order to refer them to specialized psychiatric care.
Topics: Feeding and Eating Disorders; Female; Humans; Phenotype; Pregnancy; Pregnant Women; Prevalence; Reproduction
PubMed: 35130918
DOI: 10.1186/s12978-022-01341-w -
Journal of Medical Genetics Dec 2023Alström syndrome (ALMS; #203800) is an ultrarare monogenic recessive disease. This syndrome is associated with variants in the gene, which encodes a... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Alström syndrome (ALMS; #203800) is an ultrarare monogenic recessive disease. This syndrome is associated with variants in the gene, which encodes a centrosome-associated protein involved in the regulation of several ciliary and extraciliary processes, such as centrosome cohesion, apoptosis, cell cycle control and receptor trafficking. The type of variant associated with ALMS is mostly complete loss-of-function variants (97%) and they are mainly located in exons 8, 10 and 16 of the gene. Other studies in the literature have tried to establish a genotype-phenotype correlation in this syndrome with limited success. The difficulty in recruiting a large cohort in rare diseases is the main barrier to conducting this type of study.
METHODS
In this study we collected all cases of ALMS published to date. We created a database of patients who had a genetic diagnosis and an individualised clinical history. Lastly, we attempted to establish a genotype-phenotype correlation using the truncation site of the patient's longest allele as a grouping criteria.
RESULTS
We collected a total of 357 patients, of whom 227 had complete clinical information, complete genetic diagnosis and meta-information on sex and age. We have seen that there are five variants with high frequency, with p.(Arg2722Ter) being the most common variant, with 28 alleles. No gender differences in disease progression were detected. Finally, truncating variants in exon 10 seem to be correlated with a higher prevalence of liver disorders in patients with ALMS.
CONCLUSION
Pathogenic variants in exon 10 of the gene were associated with a higher prevalence of liver disease. However, the location of the variant in the gene does not have a major impact on the phenotype developed by the patient.
Topics: Humans; Alstrom Syndrome; Cell Cycle Proteins; Phenotype; Exons; Genetic Association Studies
PubMed: 37321834
DOI: 10.1136/jmg-2023-109175 -
International Journal of Nursing Studies Aug 2015This study focused on older adults living in communities, primarily to investigate the relationship between physical frailty and mortality, and secondly to examine... (Meta-Analysis)
Meta-Analysis Review
AIM
This study focused on older adults living in communities, primarily to investigate the relationship between physical frailty and mortality, and secondly to examine gender and age effects on the relationship between frailty and mortality.
BACKGROUND
The World Health Organization indicated that frailty has become an indicator of a lack of successful aging. Systematic literature reviews have yet to focus on the association between various frailty phases and mortality. Meanwhile, few studies researched gender and age effects on the correlation between physical frailty and mortality among older adults living in communities.
DESIGN
A systematic review and meta-analysis of prospective studies.
METHOD
Frailty was assessed according to the Cardiovascular Health Study by Fried et al., who defined a frail phenotype as exhibiting the following five properties: weight loss, exhaustion, weakness, low physical activity, and mobility impairment. We included original epidemiologic population-based studies, cohort surveys, systematic reviews, and meta-analyses. Study samples included only adults aged 65 years or older who lived in communities. We excluded studies investigating hospitalised, institutionalised older adults, and those that examined disease-specific targets. We performed a pooled analysis of mortality of frailty by employing a random-effects model.
RESULTS
A total of 35,538 older adults and 7994 deaths were included in the meta-analysis. We identified 11 population-based studies that examined the relationship between mortality and frailty status in older adults. Compared with robust older adults, older people with frailty have the highest risks of mortality, followed by older people in the pre-frail phase. Older men with frailty have a higher risk of mortality than do frail older women. No age threshold for mortality risk was observed.
CONCLUSION
Frailty is a prevalent and critical geriatric syndrome associated with decreased survival. Through geriatric assessment of frailty, essential information pertaining to mortality among older adults can be obtained.
Topics: Aged; Cohort Studies; Frail Elderly; Humans; Mortality; Phenotype
PubMed: 25986959
DOI: 10.1016/j.ijnurstu.2015.04.005 -
Journal of Neurology, Neurosurgery, and... Jun 2022Functional movement disorder (FMD) is a common manifestation of functional neurological disorder presenting with diverse phenotypes such as tremor, weakness and gait... (Meta-Analysis)
Meta-Analysis
Functional movement disorder (FMD) is a common manifestation of functional neurological disorder presenting with diverse phenotypes such as tremor, weakness and gait disorder. Our current understanding of the basic epidemiological features of this condition is unclear. We aimed to describe and examine the relationship between age at onset, phenotype and gender in FMD in a large meta-analysis of published and unpublished individual patient cases. An electronic search of PubMed was conducted for studies from 1968 to 2019 according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Individual patient data were collected through a research network. We described the distribution of age of onset and how this varied by gender and motor phenotype. A one-stage meta-analysis was performed using multilevel mixed-effects linear regression, including random intercepts for country and data source. A total of 4905 individual cases were analysed (72.6% woman). The mean age at onset was 39.6 years (SD 16.1). Women had a significantly earlier age of onset than men (39.1 years vs 41.0 years). Mixed FMD (23.1%), tremor (21.6%) and weakness (18.1%) were the most common phenotypes. Compared with tremor (40.7 years), the mean ages at onset of dystonia (34.5 years) and weakness (36.4 years) were significantly younger, while gait disorders (43.2 years) had a significantly later age at onset. The interaction between gender and phenotype was not significant. FMD peaks in midlife with varying effects of gender on age at onset and phenotype. The data gives some support to 'lumping' FMD as a unitary disorder but also highlights the value in 'splitting' into individual phenotypes where relevant.
Topics: Conversion Disorder; Dystonia; Female; Humans; Movement Disorders; Phenotype; Tremor
PubMed: 35217516
DOI: 10.1136/jnnp-2021-328462 -
Movement Disorders : Official Journal... Jul 2021This Movement Disorder Society Genetic mutation database Systematic Review focuses on monogenic atypical parkinsonism with mutations in the ATP13A2, DCTN1, DNAJC6,...
This Movement Disorder Society Genetic mutation database Systematic Review focuses on monogenic atypical parkinsonism with mutations in the ATP13A2, DCTN1, DNAJC6, FBXO7, SYNJ1, and VPS13C genes. We screened 673 citations and extracted genotypic and phenotypic data for 140 patients (73 families) from 77 publications. In an exploratory fashion, we applied an automated classification procedure via an ensemble of bootstrap-aggregated ("bagged") decision trees to distinguish these 6 forms of monogenic atypical parkinsonism and found a high accuracy of 86.5% (95%CI, 86.3%-86.7%) based on the following 10 clinical variables: age at onset, spasticity and pyramidal signs, hypoventilation, decreased body weight, minimyoclonus, vertical gaze palsy, autonomic symptoms, other nonmotor symptoms, levodopa response quantification, and cognitive decline. Comparing monogenic atypical with monogenic typical parkinsonism using 2063 data sets from Movement Disorder Society Genetic mutation database on patients with SNCA, LRRK2, VPS35, Parkin, PINK1, and DJ-1 mutations, the age at onset was earlier in monogenic atypical parkinsonism (24 vs 40 years; P = 1.2647 × 10) and levodopa response less favorable than in patients with monogenic typical presentations (49% vs 93%). In addition, we compared monogenic to nonmonogenic atypical parkinsonism using data from 362 patients with progressive supranuclear gaze palsy, corticobasal degeneration, multiple system atrophy, or frontotemporal lobar degeneration. Although these conditions share many clinical features with the monogenic atypical forms, they can typically be distinguished based on their later median age at onset (64 years; IQR, 57-70 years). In conclusion, age at onset, presence of specific signs, and degree of levodopa response inform differential diagnostic considerations and genetic testing indications in atypical forms of parkinsonism. © 2021 International Parkinson and Movement Disorder Society.
Topics: Genotype; Humans; Levodopa; Parkinson Disease; Parkinsonian Disorders; Phenotype
PubMed: 34396589
DOI: 10.1002/mds.28517 -
European Journal of Neurology Oct 2023Most episodic ataxias (EA) are autosomal dominantly inherited and characterized by recurrent attacks of ataxia and other paroxysmal and non-paroxysmal features. EA is... (Review)
Review
BACKGROUND
Most episodic ataxias (EA) are autosomal dominantly inherited and characterized by recurrent attacks of ataxia and other paroxysmal and non-paroxysmal features. EA is often caused by pathogenic variants in the CACNA1A, KCNA1, PDHA1, and SLC1A3 genes, listed as paroxysmal movement disorders (PxMD) by the MDS Task Force on the Nomenclature of Genetic Movement Disorders. Little is known about the genotype-phenotype correlation of the different genetic EA forms.
METHODS
We performed a systematic review of the literature to identify individuals affected by an episodic movement disorder harboring pathogenic variants in one of the four genes. We applied the standardized MDSGene literature search and data extraction protocol to summarize the clinical and genetic features. All data are available via the MDSGene protocol and platform on the MDSGene website (https://www.mdsgene.org/).
RESULTS
Information on 717 patients (CACNA1A: 491, KCNA1: 125, PDHA1: 90, and SLC1A3: 11) carrying 287 different pathogenic variants from 229 papers was identified and summarized. We show the profound phenotypic variability and overlap leading to the absence of frank genotype-phenotype correlation aside from a few key 'red flags'.
CONCLUSION
Given this overlap, a broad approach to genetic testing using a panel or whole exome or genome approach is most practical in most circumstances.
Topics: Humans; Ataxia; Movement Disorders; Genotype; Phenotype
PubMed: 37422902
DOI: 10.1111/ene.15969