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Clinical and Experimental Medicine Jan 2024Activated phosphoinositide 3-kinase delta syndrome (APDS) is a rare genetic disorder that presents clinically as a primary immunodeficiency. Clinical presentation of...
Activated phosphoinositide 3-kinase delta syndrome (APDS) is a rare genetic disorder that presents clinically as a primary immunodeficiency. Clinical presentation of APDS includes severe, recurrent infections, lymphoproliferation, lymphoma, and other cancers, autoimmunity and enteropathy. Autosomal dominant variants in two independent genes have been demonstrated to cause APDS. Pathogenic variants in PIK3CD and PIK3R1, both of which encode components of the PI3-kinase, have been identified in subjects with APDS. APDS1 is caused by gain of function variants in the PIK3CD gene, while loss of function variants in PIK3R1 have been reported to cause APDS2. We conducted a review of the medical literature and identified 256 individuals who had a molecular diagnosis for APDS as well as age at last report; 193 individuals with APDS1 and 63 with APDS2. Despite available treatments, survival for individuals with APDS appears to be shortened from the average lifespan. A Kaplan-Meier survival analysis for APDS showed the conditional survival rate at the age of 20 years was 87%, age of 30 years was 74%, and ages of 40 and 50 years were 68%. Review of causes of death showed that the most common cause of death was lymphoma, followed by complications from HSCT. The overall mortality rate for HSCT in APDS1 and APDS2 cases was 15.6%, while the mortality rate for lymphoma was 47.6%. This survival and mortality data illustrate that new treatments are needed to mitigate the risk of death from lymphoma and other cancers as well as infection. These analyses based on real-world evidence gathered from the medical literature comprise the largest study of survival and mortality for APDS to date.
Topics: Adult; Humans; Young Adult; Class I Phosphatidylinositol 3-Kinases; Immunologic Deficiency Syndromes; Lymphoma; Mutation; Neoplasms; Phosphatidylinositol 3-Kinase; Phosphatidylinositol 3-Kinases; Primary Immunodeficiency Diseases; Survival Rate; Middle Aged
PubMed: 38280023
DOI: 10.1007/s10238-023-01259-y -
International Journal of Molecular... Jan 2024Hypertrophic cardiomyopathy (HCM) is one of the most common genetic cardiovascular diseases, and it shows an autosomal dominant pattern of inheritance. HCM can be... (Review)
Review
Hypertrophic cardiomyopathy (HCM) is one of the most common genetic cardiovascular diseases, and it shows an autosomal dominant pattern of inheritance. HCM can be clinically silent, and sudden unexpected death due to malignant arrhythmias may be the first manifestation. Thus, the HCM diagnosis could be performed at a clinical and judicial autopsy and offer useful findings on morphological features; moreover, it could integrate the knowledge on the genetic aspect of the disease. This review aims to systematically analyze the literature on the main post-mortem investigations and the related findings of HCM to reach a well-characterized and stringent diagnosis; the review was performed using PubMed and Scopus databases. The articles on the post-mortem evaluation of HCM by gross and microscopic evaluation, imaging, and genetic test were selected; a total of 36 studies were included. HCM was described with a wide range of gross findings, and there were cases without morphological alterations. Myocyte hypertrophy, disarray, fibrosis, and small vessel disease were the main histological findings. The post-mortem genetic tests allowed the diagnosis to be reached in cases without morpho-structural abnormalities; clinical and forensic pathologists have a pivotal role in HCM diagnosis; they contribute to a better definition of the disease and also provide data on the genotype-phenotype correlation, which is useful for clinical research.
Topics: Humans; Cardiomyopathy, Hypertrophic; Genetic Testing; Arrhythmias, Cardiac; Autopsy; Fibrosis; Phenotype; Death, Sudden, Cardiac
PubMed: 38279275
DOI: 10.3390/ijms25021275 -
Neurological Sciences : Official... May 2024Myophosphorylase deficiency, also known as McArdle disease or Glycogen Storage Disease type V (GSD-V), is an autosomal recessive metabolic myopathy that results in... (Review)
Review
INTRODUCTION AND METHODS
Myophosphorylase deficiency, also known as McArdle disease or Glycogen Storage Disease type V (GSD-V), is an autosomal recessive metabolic myopathy that results in impaired glycogen breakdown in skeletal muscle. Despite being labelled as a "pure myopathy," cardiac involvement has been reported in some cases, including various cardiac abnormalities such as electrocardiographic changes, coronary artery disease, and cardiomyopathy. Here, we present a unique case of a 72-year-old man with GSD-V and both mitral valvulopathy and coronary artery disease, prompting a systematic review to explore the existing literature on cardiac comorbidities in McArdle disease.
RESULTS
Our systematic literature revision identified 7 case reports and 1 retrospective cohort study. The case reports described 7 GSD-V patients, averaging 54.3 years in age, mostly male (85.7%). Coronary artery disease was noted in 57.1% of cases, hypertrophic cardiomyopathy in 28.5%, severe aortic stenosis in 14.3%, and genetic dilated cardiomyopathy in one. In the retrospective cohort study, five out of 14 subjects (36%) had coronary artery disease.
DISCUSSION AND CONCLUSION
Despite McArdle disease primarily affecting skeletal muscle, cardiac involvement has been observed, especially coronary artery disease, the frequency of which was moreover found to be higher in McArdle patients than in the background population in a previous study from a European registry. Exaggerated cardiovascular responses during exercise and impaired glycolytic metabolism have been speculated as potential contributors. A comprehensive cardiological screening might be recommended for McArdle disease patients to detect and manage cardiac comorbidities. A multidisciplinary approach is crucial to effectively manage both neurological and cardiac aspects of the disease and improve patient outcomes. Further research is required to establish clearer pathophysiological links between McArdle disease and cardiac manifestations in order to clarify the existing findings.
PubMed: 38802689
DOI: 10.1007/s10072-024-07600-x -
Nephrology, Dialysis, Transplantation :... Oct 2023Although renin-angiotensin-aldosterone system (RAAS) blockers have been considered the primary treatment for patients with Alport syndrome (AS) for a decade, there is no... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Although renin-angiotensin-aldosterone system (RAAS) blockers have been considered the primary treatment for patients with Alport syndrome (AS) for a decade, there is no comprehensive review with evidence-based analysis evaluating the effectiveness of RAAS blockers in AS.
METHODS
A systematic review and meta-analysis was performed of published studies that compared outcomes related to disease progression between patients with AS receiving RAAS blockers with those taking non-RAAS treatment. Outcomes were meta-analyzed using the random effects models. Cochrane risk-of-bias, Newcastle-Ottawa Scale and Grading of Recommendations Assessment, Development and Evaluation methodology (GRADE) assessment determined the certainty of evidence.
RESULTS
A total of eight studies (1182 patients) were included in the analysis. Overall, the risk of bias was low to moderate. Compared with non-RAAS treatment, RAAS blockers could reduce the rate of progression to end-stage kidney disease (ESKD) [four studies; hazard ratio (HR) 0.33, 95% confidence interval (CI) 0.24-0.45; moderate certainty evidence]. After stratified by genetic types, a similar benefit was detected: male X-linked AS (XLAS) (HR 0.32, 95% CI 0.22-0.48), autosomal recessive AS (HR 0.25, 95% CI 0.10-0.62), female XLAS and autosomal dominant AS (HR 0.40, 95% CI 0.21-0.75). In addition, RAAS blockers showed a clear gradient of benefit depending on the stage of disease at the initiation of treatment.
CONCLUSION
This meta-analysis suggested that RAAS blockers could be considered as a specific therapy to delay of ESKD for AS with any genetic type, especially at the early stage of the disease, and every further more-effective therapy would be advised to be applied on top of this standard of care.
Topics: Humans; Male; Female; Renin-Angiotensin System; Angiotensin-Converting Enzyme Inhibitors; Nephritis, Hereditary; Kidney Failure, Chronic
PubMed: 37218713
DOI: 10.1093/ndt/gfad105 -
Epilepsia Mar 2024KCTD7-related progressive myoclonic epilepsy (PME) is a rare autosomal-recessive disorder. This study aimed to describe the clinical details and genetic variants in a...
OBJECTIVE
KCTD7-related progressive myoclonic epilepsy (PME) is a rare autosomal-recessive disorder. This study aimed to describe the clinical details and genetic variants in a large international cohort.
METHODS
Families with molecularly confirmed diagnoses of KCTD7-related PME were identified through international collaboration. Furthermore, a systematic review was done to identify previously reported cases. Salient demographic, epilepsy, treatment, genetic testing, electroencephalographic (EEG), and imaging-related variables were collected and summarized.
RESULTS
Forty-two patients (36 families) were included. The median age at first seizure was 14 months (interquartile range = 11.75-22.5). Myoclonic seizures were frequently the first seizure type noted (n = 18, 43.9%). EEG and brain magnetic resonance imaging findings were variable. Many patients exhibited delayed development with subsequent progressive regression (n = 16, 38.1%). Twenty-one cases with genetic testing available (55%) had previously reported variants in KCTD7, and 17 cases (45%) had novel variants in KCTD7 gene. Six patients died in the cohort (age range = 1.5-21 years). The systematic review identified 23 eligible studies and further identified 59 previously reported cases of KCTD7-related disorders from the literature. The phenotype for the majority of the reported cases was consistent with a PME (n = 52, 88%). Other reported phenotypes in the literature included opsoclonus myoclonus ataxia syndrome (n = 2), myoclonus dystonia (n = 2), and neuronal ceroid lipofuscinosis (n = 3). Eight published cases died over time (14%, age range = 3-18 years).
SIGNIFICANCE
This study cohort and systematic review consolidated the phenotypic spectrum and natural history of KCTD7-related disorders. Early onset drug-resistant epilepsy, relentless neuroregression, and severe neurological sequalae were common. Better understanding of the natural history may help future clinical trials.
Topics: Adolescent; Child; Child, Preschool; Humans; Infant; Young Adult; Electroencephalography; Epilepsies, Myoclonic; Myoclonic Epilepsies, Progressive; Potassium Channels; Seizures; Unverricht-Lundborg Syndrome
PubMed: 38231304
DOI: 10.1111/epi.17880 -
Pediatric Nephrology (Berlin, Germany) Sep 2023Autosomal dominant polycystic kidney disease (ADPKD) is among the most common inherited kidney diseases. Hypertension is a frequent cardiovascular manifestation,... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Autosomal dominant polycystic kidney disease (ADPKD) is among the most common inherited kidney diseases. Hypertension is a frequent cardiovascular manifestation, especially in adults, but elevated blood pressure is also found in children and adolescents. Acknowledgment of pediatric hypertension early is critical, as it can result in serious complications long-term if left undiagnosed.
OBJECTIVE
We aim to identify the influence of hypertension on cardiovascular outcomes, mainly left ventricular hypertrophy, carotid intima media thickness, and pulse wave velocity.
METHODS
We performed an extensive search on Medline, Embase, CINAHL, and Web of Science databases through March 2021. Original studies with a mix of retrospective, prospective, case-control studies, cross sectional studies, and observational studies were included in the review. There was no restriction on age group.
RESULTS
The preliminary search yielded 545 articles with 15 articles included after inclusion and exclusion criteria. In this meta-analysis, LVMI (SMD: 3.47 (95% CI: 0.53-6.41)) and PWV (SMD: 1.72 (95% CI: 0.08-3.36)) were found to be significantly higher in adults with ADPKD compared to non-ADPKD; however, CIMT was not found to be significantly different. Also, LVMI was observed to be significantly higher among hypertensive adults with ADPKD (n = 56) as compared to adults without ADPKD (SMD: 1.43 (95% CI: 1.08-1.79)). Fewer pediatric studies were available with heterogeneity among patient populations and results.
CONCLUSIONS
Adult patients with ADPKD were found to have worse indicators of cardiovascular outcomes, including LVMI and PWV, as compared to non-ADPKD. This study demonstrates the importance of identifying and managing hypertension, especially early, in this population. Further research, particularly in younger patients, is necessary to further elucidate the relationship between hypertension in patients with ADPKD and cardiovascular disease.
REGISTRATION NUMBER
PROSPERO REGISTRATION: 343,013.
Topics: Adult; Adolescent; Humans; Child; Polycystic Kidney, Autosomal Dominant; Retrospective Studies; Prospective Studies; Carotid Intima-Media Thickness; Cross-Sectional Studies; Pulse Wave Analysis; Hypertension
PubMed: 36811694
DOI: 10.1007/s00467-023-05893-2 -
Journal of Affective Disorders Oct 2023A disruption of the kynurenine (KYN) pathway may exist in major depressive disorder (MDD). However, the changing pattern of the KYN pathway across the different disease... (Meta-Analysis)
Meta-Analysis
BACKGROUND
A disruption of the kynurenine (KYN) pathway may exist in major depressive disorder (MDD). However, the changing pattern of the KYN pathway across the different disease states in MDD is unclear. Herein, we performed a meta-analysis to examine the differences in KYN metabolites between patients in the current episode of MDD (cMDD) and patients in remission (rMDD), as well as the changes after treatments.
METHODS
Literature was systematically searched from electronic databases, from inception up to September 2022. Random-effect models were used to quantify the differences in KYN metabolites between patients with MDD across acute depressive episode and remission phases, as well as the changes after treatments.
RESULTS
Fifty-one studies involving 7056 participants were included. Tryptophan (TRP), KYN, kynurenic acid (KYNA), KYNA/quinolinic acid (QA), KYNA/3-hydroxykynurenine (3-HK), and KYNA/KYN were significantly lower, while KYN/TRP was significantly higher in patients with cMDD. Moreover, these effect sizes were generally larger in medication-free patients. No significant differences were found between patients with rMDD and HCs. Additionally, KYNA was found negatively correlated with depression severity and significantly increased after treatments, while the alteration was not found in QA.
LIMITATIONS
The number of included studies of patients with rMDD and longitudinal studies investigating the change of the KYN metabolites after treatment with antidepressants was limited. In addition, the heterogeneity across included studies was relatively high.
CONCLUSIONS
These findings showed a comprehensive image of the unique dysfunction pattern of the KYN pathway across different MDD states and highlighted KYNA as a potentially sensitive biomarker of MDD.
Topics: Humans; Kynurenine; Depressive Disorder, Major; Tryptophan; Depression; Biomarkers; Kynurenic Acid; Quinolinic Acid
PubMed: 37467793
DOI: 10.1016/j.jad.2023.07.078 -
Cureus Jul 2023Cystic fibrosis (CF) is an autosomal recessive genetic disorder resulting from defects in the cystic fibrosis transmembrane conductance regulator (CFTR) protein, which... (Review)
Review
Cystic fibrosis (CF) is an autosomal recessive genetic disorder resulting from defects in the cystic fibrosis transmembrane conductance regulator (CFTR) protein, which in turn results in a multi-systemic disorder. There are numerous known CF alleles associated with different mutations of the CFTR gene, with the most common CF allele being a three-base-pair deletion known as ΔF508. One common manifestation of CF is glycemic dysregulation associated with decreased insulin secretion, often progressing into a distinct form of diabetes known as cystic fibrosis-related diabetes (CFRD). In the past decade, a class of drugs known as CFTR modulators has entered clinical practice. These drugs interact with the CFTR protein to restore its function, with different modulators (or combinations of modulators) suitable for patients with different CFTR mutations. Previous research has established that the modulator ivacaftor is effective in decreasing blood glucose and sometimes resolving CFRD in patients with certain CFTR mutations (class III mutations). However, early modulator therapies for individuals with the common ΔF508 mutation (e.g., a combination of the modulators lumacaftor and ivacaftor) have largely proven ineffective in improving glucose regulation. More recently, a combination therapy of three modulators, namely elexacaftor, tezacaftor, and ivacaftor (ETI), has entered clinical practice for patients with the ΔF508 mutation. However, it is not clear whether this therapy is effective in treating dysglycemia. We searched for studies of any design that examined the effects of ETI on measures of blood glucose. All available studies were observational studies comparing patients before and after initiating ETI therapy. Measures of daily-life blood glucose (those obtained with continuous glucose monitoring systems or by measuring glycated hemoglobin (HbA1c)) and post-prandial glucose spikes from oral glucose tolerance tests showed significant improvements in at least some studies. The majority of studies showed significant improvements from pre- to post-ETI in one or more blood glucose measures. While the interpretation of this evidence is complicated by the lack of randomized controlled trials, it appears that ETI therapy is associated with improved glucose regulation for at least some patients with the ΔF508 mutation.
PubMed: 37575762
DOI: 10.7759/cureus.41697 -
The Australasian Journal of Dermatology Mar 2024Recent literature highlights the potential of biologics in the management of inherited disorders of keratinisation. In this study, we conducted a systematic review of...
BACKGROUND/OBJECTIVES
Recent literature highlights the potential of biologics in the management of inherited disorders of keratinisation. In this study, we conducted a systematic review of existing literature on treatment outcomes of inherited keratinisation disorders treated with biologics.
METHODS
Eligible records were retrieved through searches of the electronic databases MEDLINE, Embase, PubMed and Scopus. Databases were searched from inception to July 2023 for eligible records. A snowballing method was employed to search the references of the retrieved records for the identification of potentially relevant articles.
RESULTS
One hundred and four eligible studies consisting of a total of 166 patients with an inherited disorder of keratinisation were included. Patients had a median age of 19 years (range: 0.5 to 70 years). The most common disorders were Netherton syndrome (n = 63; 38%), autosomal recessive congenital ichthyoses (n = 27; 16%), CARD14-associated papulosquamous eruptions (n = 17; 10%) and familial pityriasis rubra pilaris (PRP) (n = 15; 9%).Of the 207 times biologics were employed, the three most frequently employed biologics were secukinumab (n = 47; 23%), dupilumab (n = 44; 21%) and ustekinumab (n = 37; 18%). Complete remission was observed in 10 (5%) instances, partial remission in 129 (62%), no or limited response to biologic therapy in 68 (32%) cases, and results are still pending in one case. A total of 33 adverse events were reported.
CONCLUSIONS
Whilst biologics may be considered in cases of inherited keratinisation disorders recalcitrant to standard therapy, definitive conclusions are prohibited by the low-level of evidence and substantial heterogeneity in methodology across the included studies. Establishment of consensus definitions, and randomised clinical trials may help ascertain the efficacy and safety of biologic therapy in this context and establish the best agent and dosing protocol for each disorder.
Topics: Humans; Infant; Child, Preschool; Child; Adolescent; Young Adult; Adult; Middle Aged; Aged; Biological Products; Ustekinumab; Tumor Necrosis Factor-alpha; Pityriasis Rubra Pilaris; Guanylate Cyclase; Membrane Proteins; CARD Signaling Adaptor Proteins
PubMed: 38126177
DOI: 10.1111/ajd.14197 -
NeuroRehabilitation 2024NF2-schwannomatosis (NF2) is an autosomal dominant disorder prone to hearing loss. Auditory brainstem implants (ABIs) offer a promising solution for hearing... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
NF2-schwannomatosis (NF2) is an autosomal dominant disorder prone to hearing loss. Auditory brainstem implants (ABIs) offer a promising solution for hearing rehabilitation in NF2.
OBJECTIVE
To synthesize existing literature on ABI implantation in NF2, focusing on audiological outcomes and ABI-related complications.
METHODS
The systematic review followed PRISMA guidelines and was registered in the PROSPERO database (CRD42022362155). Relevant studies were identified by searching PubMed, EMBASE, CENTRAL, CMB, and CNKI from inception to August 2023. Data on environmental sound discrimination, open-set discrimination, closed-set discrimination, and ABI-related complications were extracted and subjected to meta-analysis. Publication bias was evaluated using funnel plots and Egger's test.
RESULTS
Thirty-three studies were included. The pooled estimate was 58% (95% CI 49-66%) for environmental sound discrimination and 55% (95% CI 40-69%) for closed-set discrimination. Regarding open-set discrimination, the pooled estimates were 30% (95% CI 19-42%) for sound only, 46% (95% CI 37-54%) for lip-reading only, and 63% (95% CI 55-70%) for sound plus lip-reading. The pooled occurrence of ABI-related complications was 33% (95% CI 15-52%).
CONCLUSION
This meta-analysis underscores the effectiveness and safety of ABIs in NF2, providing valuable insights for evidence-based decision-making and hearing rehabilitation strategies.
Topics: Humans; Auditory Brain Stem Implants; Neurofibromatosis 2; Auditory Brain Stem Implantation; Treatment Outcome; Hearing; Retrospective Studies; Neurilemmoma; Skin Neoplasms; Neurofibromatoses
PubMed: 38427506
DOI: 10.3233/NRE-230198