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International Journal of Cardiology Aug 2024>40% of infants with Alström Syndrome (AS) present with a transient, severe cardiomyopathy in the first months of life, with apparent recovery in survivors. One in five...
BACKGROUND
>40% of infants with Alström Syndrome (AS) present with a transient, severe cardiomyopathy in the first months of life, with apparent recovery in survivors. One in five individuals then develop a later-onset cardiomyopathy but wide clinical variability is observed, even within the same family. The rationale for this study is to provide a comprehensive evaluation of the cardiovascular phenotype in adults with AS.
METHODS
Adults attending the National Centre for AS in England were studied. All patients underwent biochemical, 12- lead electrocardiography, echocardiography, and cardiovascular magnetic resonance imaging.
RESULTS
47 adults with AS (64% male; mean age 33 years; 66% white British) were studied. Seven (15%) survived infantile cardiomyopathy and 23 (49%) developed adult-onset cardiomyopathy. Conventional risk factors for cardiovascular disease were present in 39 (83%). Abnormalities were present on biomarkers in 16 (34%), ECG 30 (64%), echocardiography 19 (40%) and CMR 31 (66%). Coronary artery imaging was performed in six (13%), with abnormalities in two. Cardiac, renal, and liver markers were more often impaired in older patients, with impaired left ventricular ejection fraction, reduced global longitudinal strain and late enhancement. 6 (13%) had severe pulmonary hypertension (mean pulmonary artery pressure 46 mmHg) due to left heart disease on invasive testing.
CONCLUSION
Cardiomyopathy is common in adults with AS, complicated in a significant proportion by atherosclerotic coronary artery disease and restrictive cardiomyopathy, confirmed on CMR and invasive testing. With advancing age, cardiovascular complications are compounded by contemporaneous renal and liver disease.
Topics: Humans; Male; Female; Adult; Phenotype; Alstrom Syndrome; Middle Aged; Young Adult; Adolescent; Electrocardiography; Echocardiography; Cardiomyopathies
PubMed: 38806112
DOI: 10.1016/j.ijcard.2024.132212 -
Yonago Acta Medica May 2024Alström syndrome is a form of inherited obesity caused by a single gene abnormality and is inherited as an autosomal recessive trait. It is characterised by a variety... (Review)
Review
Alström syndrome is a form of inherited obesity caused by a single gene abnormality and is inherited as an autosomal recessive trait. It is characterised by a variety of clinical manifestations, including progressive visual and hearing impairment, type 2 diabetes mellitus, dilated cardiomyopathy, and hepatic and renal dysfunction, in addition to obesity. Recent insights underline the pivotal involvement of the disease-associated gene () in cilia formation and function, leading to the classification of its clinical manifestations as a ciliopathy. This review delineates the diverse clinical indicators defining the syndrome and elucidates its pathological underpinnings.
PubMed: 38803594
DOI: 10.33160/yam.2024.05.010 -
Disease Models & Mechanisms May 2024Alström Syndrome (AS), a multisystem disorder caused by biallelic ALMS1 mutations, features major early morbidity and mortality due to cardiac complications. These are...
Alström Syndrome (AS), a multisystem disorder caused by biallelic ALMS1 mutations, features major early morbidity and mortality due to cardiac complications. These are biphasic, including infantile dilated cardiomyopathy and distinct adult-onset cardiomyopathy, and are poorly understood. We assessed cardiac function of Alms1 knockout mice by echocardiography. Cardiac function was unaltered in global Alms1 knockout mice of both sexes at postnatal day 15 (P15) and 8 weeks. At 23 weeks, female, but not male knockout mice showed increased left atrial area and decreased isovolumic relaxation time, consistent with early restrictive cardiomyopathy, as well as reduced ejection fraction. No histological or transcriptional changes were seen in myocardium of 23-week-old female Alms1 global knockout mice. Female mice with Pdgfrα-Cre-driven Alms1 deletion in cardiac fibroblasts and a small proportion of cardiomyocytes did not recapitulate the phenotype of global knockout at 23 weeks. In conclusion, adult female, but not male, Alms1-deficient mice show echocardiographic evidence of cardiac dysfunction, consistent with the cardiomyopathy of AS. The explanation for sexual dimorphism remains unclear, but may involve metabolic or endocrine differences between sexes.
PubMed: 38756069
DOI: 10.1242/dmm.050561 -
BMC Medical Genomics Apr 2024Syndromic ciliopathies are a group of congenital disorders characterized by broad clinical and genetic overlap, including obesity, visual problems, skeletal anomalies,...
BACKGROUND
Syndromic ciliopathies are a group of congenital disorders characterized by broad clinical and genetic overlap, including obesity, visual problems, skeletal anomalies, mental retardation, and renal diseases. The hallmark of the pathophysiology among these disorders is defective ciliary functions or formation. Many different genes have been implicated in the pathogenesis of these diseases, but some patients still remain unclear about their genotypes.
METHODS
The aim of this study was to identify the genetic causes in patients with syndromic ciliopathy. Patients suspected of or meeting clinical diagnostic criteria for any type of syndromic ciliopathy were recruited at a single diagnostic medical center in Southern Taiwan. Whole exome sequencing (WES) was employed to identify their genotypes and elucidate the mutation spectrum in Taiwanese patients with syndromic ciliopathy. Clinical information was collected at the time of patient enrollment.
RESULTS
A total of 14 cases were molecularly diagnosed with syndromic ciliopathy. Among these cases, 10 had Bardet-Biedl syndrome (BBS), comprising eight BBS2 patients and two BBS7 patients. Additionally, two cases were diagnosed with Alström syndrome, one with Oral-facial-digital syndrome type 14, and another with Joubert syndrome type 10. A total of 4 novel variants were identified. A recurrent splice site mutation, BBS2: c.534 + 1G > T, was present in all eight BBS2 patients, suggesting a founder effect. One BBS2 patient with homozygous c.534 + 1G > T mutations carried a third ciliopathic allele, TTC21B: c.264_267dupTAGA, a nonsense mutation resulting in a premature stop codon and protein truncation.
CONCLUSIONS
Whole exome sequencing (WES) assists in identifying molecular pathogenic variants in ciliopathic patients, as well as the genetic hotspot mutations in specific populations. It should be considered as the first-line genetic testing for heterogeneous disorders characterized by the involvement of multiple genes and diverse clinical manifestations.
Topics: Humans; Male; Female; Taiwan; Ciliopathies; Child; Child, Preschool; Mutation; Exome Sequencing; Bardet-Biedl Syndrome; Adolescent; Infant; Abnormalities, Multiple; Retina; Syndrome; Cilia; Eye Abnormalities; Cerebellum; Proteins; Kidney Diseases, Cystic
PubMed: 38671463
DOI: 10.1186/s12920-024-01880-0 -
Molecular Metabolism Jun 2024Alström Syndrome (AS), caused by biallelic ALMS1 mutations, includes obesity with disproportionately severe insulin resistant diabetes, dyslipidemia, and fatty liver....
OBJECTIVE
Alström Syndrome (AS), caused by biallelic ALMS1 mutations, includes obesity with disproportionately severe insulin resistant diabetes, dyslipidemia, and fatty liver. Prior studies suggest that hyperphagia is accounted for by loss of ALMS1 function in hypothalamic neurones, whereas disproportionate metabolic complications may be due to impaired adipose tissue expandability. We tested this by comparing the metabolic effects of global and mesenchymal stem cell (MSC)-specific Alms1 knockout.
METHODS
Global Alms1 knockout (KO) mice were generated by crossing floxed Alms1 and CAG-Cre mice. A Pdgfrα-Cre driver was used to abrogate Alms1 function selectively in MSCs and their descendants, including preadipocytes. We combined metabolic phenotyping of global and Pdgfrα+ Alms1-KO mice on a 45% fat diet with measurements of body composition and food intake, and histological analysis of metabolic tissues.
RESULTS
Assessed on 45% fat diet to promote adipose expansion, global Alms1 KO caused hyperphagia, obesity, insulin resistance, dyslipidaemia, and fatty liver. Pdgfrα-cre driven KO of Alms1 (MSC KO) recapitulated insulin resistance, fatty liver, and dyslipidaemia in both sexes. Other phenotypes were sexually dimorphic: increased fat mass was only present in female Alms1 MSC KO mice. Hyperphagia was not evident in male Alms1 MSC KO mice, but was found in MSC KO females, despite no neuronal Pdgfrα expression.
CONCLUSIONS
Mesenchymal deletion of Alms1 recapitulates metabolic features of AS, including fatty liver. This confirms a key role for Alms1 in the adipose lineage, where its loss is sufficient to cause systemic metabolic effects and damage to remote organs. Hyperphagia in females may depend on Alms1 deficiency in oligodendrocyte precursor cells rather than neurones. AS should be regarded as a forme fruste of lipodystrophy.
Topics: Animals; Mice; Mice, Knockout; Male; Female; Mesenchymal Stem Cells; Alstrom Syndrome; Cell Cycle Proteins; Insulin Resistance; Fatty Liver; Obesity; Hyperphagia; Adipose Tissue; Mice, Inbred C57BL; Body Composition
PubMed: 38583571
DOI: 10.1016/j.molmet.2024.101933 -
Annals of Medicine and Surgery (2012) Apr 2024Alstrom syndrome is one of the rarest monogenic ciliopathy belonging to autosomal recessive disorder. The pathophysiology of Alstrom syndrome is not well understood but...
INTRODUCTION AND IMPORTANCE
Alstrom syndrome is one of the rarest monogenic ciliopathy belonging to autosomal recessive disorder. The pathophysiology of Alstrom syndrome is not well understood but based upon the available medical literature its mechanism can be linked with recessive mutation in Alstrom syndrome 1(ALSM1) gene resulting in various multiple organ involvement and poor prognosis. Moreover the co-occurrence of such syndrome simultaneously in twins in same period of time is considered rare.
CASE PRESENTATION
Monochorionic diamniotic twins male born to healthy parents with significant antenatal and natal history along with decreased vision in both eyes in both twins since neonatal period. Throughout the childhood the disease progressed without any confirmatory diagnosis during which the twins underwent simultaneous multiple systemic involvement such as legal blindness in both twins at the age of 11 years, insulin resistance and features of diabetes mellitus, sensorineural hearing loss, subclinical hypothyroidism and various deranged metabolic panels. Certain diagnosis of Alstrom syndrome was made at the age of 16 years in both twins after whole-exome sequencing.
CLINICAL DISCUSSION
Based on genetic profile alstrom syndrome is a unique diagnosis. Along with its multi-organ involvement features, its progression and prognosis should also be looked upon while diagnosis and management in such syndromic patients. The diagnostic delay in such cases is also a matter of concern which can result in further delay in halting adverse effects of the disease itself. The multidisciplinary approach with involvement of endocrionologist, ophthalmologist and audiologist can bring upon improvement in quality of life of the patients.
CONCLUSION
With the prevalence of 1 in million cases Alstrom Hallgren syndrome is one of the rare genetic disorder with poor prognosis. In our case we present classical findings in twins who were diagnosed as Alstrom syndrome concurrently and further diseases progressed simultaneously.
PubMed: 38576930
DOI: 10.1097/MS9.0000000000001796 -
CircALMS1 Alleviates Pulmonary Microvascular Endothelial Cell Dysfunction in Pulmonary Hypertension.Journal of the American Heart... Mar 2024Circular RNAs can serve as regulators influencing the development of pulmonary hypertension (PH). However, their function in pulmonary vascular intimal injury remains...
BACKGROUND
Circular RNAs can serve as regulators influencing the development of pulmonary hypertension (PH). However, their function in pulmonary vascular intimal injury remains undefined. Thus, we aimed to identify specifically expressed circular RNAs in pulmonary microvascular endothelial cells (PMECs) under hypoxia and PH.
METHODS AND RESULTS
Deep RNA sequencing and quantitative real-time polymerase chain reaction revealed that circALMS1 (circular RNA Alstrom syndrome protein 1) was reduced in human PMECs under hypoxia (<0.0001). Molecular biology and histopathology experiments were used to elucidate the roles of circALMS1 in regulating PMEC dysfunction among patients with PH. The circALMS1 expression was decreased in the plasma of patients with PH (=0.0315). Patients with lower circALMS1 levels had higher risk of death (=0.0006). Moreover, the circALMS1 overexpression of adeno-associated viruses improved right ventricular function and reduced pulmonary vascular remodeling in monocrotaline-PH and sugen/hypoxia-PH rats (<0.05). Furthermore, circALMS1 overexpression promoted apoptosis and inhibited PMEC proliferation and migration under hypoxia by directly downregulating miR-17-3p (<0.05). Dual luciferase assay confirmed the direct binding of circALMS1 to miR-17-3p and miR-17-3p binding to its target gene YT521-B homology domain-containing family protein 2 (YTHDF2) (<0.05). The YTHDF2 levels were also downregulated in hypoxic PMECs (<0.01). The small interfering RNA YTHDF2 reversed the effects of miR-17-3p inhibitors on PMEC proliferation, migration, and apoptosis. Finally, the results indicated that, although YTHDF2, as an N(6)-methyladenosine reader protein, contributes to the degradation of many circular RNAs, it could not regulate the circALMS1 levels in PMECs (=0.9721).
CONCLUSIONS
Our study sheds new light on circALMS1-regulated dysfunction of PMECs by the miR-17-3p/YTHDF2 pathway under hypoxia and provides insights into the underlying pathogenesis of PH.
Topics: Humans; Rats; Animals; Hypertension, Pulmonary; MicroRNAs; Endothelial Cells; RNA, Circular; Pulmonary Artery; Hypoxia; Cell Proliferation
PubMed: 38497483
DOI: 10.1161/JAHA.123.031867 -
JACC. Case Reports Mar 2024We present the case of a patient with Alström syndrome who was found to have evidence of a prothrombotic state on autopsy after sudden cardiac death. To the best of our...
We present the case of a patient with Alström syndrome who was found to have evidence of a prothrombotic state on autopsy after sudden cardiac death. To the best of our knowledge, this case of persistent prothrombotic milieu is the first described in a patient with Alström syndrome.
PubMed: 38464801
DOI: 10.1016/j.jaccas.2023.102215 -
Brazilian Journal of Otorhinolaryngology 2024To report two new variants of ALMS1 gene and to discuss the audiological evolution and clinical phenotype in two pairs of siblings with Alström syndrome.
OBJECTIVES
To report two new variants of ALMS1 gene and to discuss the audiological evolution and clinical phenotype in two pairs of siblings with Alström syndrome.
REPORT
This paper is a multi-disciplinary diagnostic evaluation, with genetic and audiological analysis that aims to report two new variants of the ALMS1 gene and to discuss the audiological evolution and clinical phenotype in a case series of patients with familial Alström syndrome. Therefore, we describe 4 cases presenting a complete audiometric profile of two pairs of unrelated siblings, to provide a better understanding of this very rare disease. Additionally, the present study identified two heterozygous mutations in the ALMS1 gene.
CONCLUSION
This Clinical Capsule Report highlights the importance of audiological monitoring throughout the development of patients with Alström syndrome. The two variants found were not previously reported in the literature, which expands the spectrum of ALMS1 variants in Alström syndrome.
Topics: Child, Preschool; Female; Humans; Male; Alstrom Syndrome; Cell Cycle Proteins; Mutation; Phenotype; Infant; Adult
PubMed: 38428329
DOI: 10.1016/j.bjorl.2024.101402 -
Frontiers in Genetics 2023Monogenic diabetes (MD) accounts for 3%-6% of all cases of diabetes. This prevalence is underestimated due to its overlapping clinical features with type 1 and type 2...
Monogenic diabetes (MD) accounts for 3%-6% of all cases of diabetes. This prevalence is underestimated due to its overlapping clinical features with type 1 and type 2 diabetes. Hence, genetic testing is the most appropriate tool for obtaining an accurate diagnosis. In Tunisia, few cohorts of MD have been investigated until now. The aim of this study is to search for pathogenic variants among 11 patients suspected of having MD in Tunisia using whole-exome sequencing (WES). WES was performed in 11 diabetic patients recruited from a collaborating medical center. The pathogenicity of genetic variation was assessed using combined filtering and bioinformatics prediction tools. The online ORVAL tool was used to predict the likelihood of combinations of pathogenic variations. Then, Sanger sequencing was carried out to confirm likely pathogenic predicted variants among patients and to check for familial segregation. Finally, for some variants, we performed structural modeling to study their impact on protein function. We identified novel variants related to MD in Tunisia. Pathogenic variants are located in several MODY and non-MODY genes. We highlighted the presence of syndromic forms of diabetes, including the Bardet-Biedl syndrome, Alström syndrome, and severe insulin resistance, as well as the presence of isolated diabetes with significantly reduced penetrance for Wolfram syndrome-related features. Idiopathic type 1 diabetes was also identified in one patient. In this study, we emphasized the importance of genetic screening for MD in patients with a familial history of diabetes, mainly among admixed and under-represented populations living in low- and middle-income countries. An accurate diagnosis with molecular investigation of MD may improve the therapeutic choice for better management of patients and their families. Additional research and rigorous investigations are required to better understand the physiopathological mechanisms of MD and implement efficient therapies that take into account genomic context and other related factors.
PubMed: 38162681
DOI: 10.3389/fgene.2023.1224284