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BioRxiv : the Preprint Server For... Oct 2023Alström Syndrome (AS), a multi-system disease caused by mutations in the gene, includes obesity with disproportionately severe insulin resistant diabetes,...
BACKGROUND
Alström Syndrome (AS), a multi-system disease caused by mutations in the gene, includes obesity with disproportionately severe insulin resistant diabetes, dyslipidemia, and hepatosteatosis. How loss of ALMS1 causes this phenotype is poorly understood, but prior studies have circumstancially implicated impaired adipose tissue expandability. We set out to test this by comparing the metabolic effects of selective knockout in mesenchymal cells including preadipocytes to those of global knockout.
METHODS
Global knockout (KO) mice were generated by crossing floxed and CAG-Cre mice. A -Cre driver was used to abrogate Alms1 function selectively in mesenchymal stem cells (MSCs) and their descendants, including preadipocytes. We combined metabolic phenotyping of global and + -KO mice on a 45% fat diet with measurements of body composition and food intake, and histological analysis of metabolic tissues.
RESULTS
Global KO caused hyperphagia, obesity, insulin resistance, dyslipidaemia, and fatty liver. - driven KO of (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 MSC KO mice. Hyperphagia was not evident in male MSC KO mice, but was found in MSC KO females, despite no neuronal Pdgfr expression.
CONCLUSIONS
Mesenchymal deletion of recapitulates the metabolic features of AS, including severe fatty liver. This confirms a key role for in the adipose lineage, where its loss is sufficient to cause systemic metabolic effects and damage to remote organs. AS should be regarded as a of lipodystrophy. Therapies should prioritise targeting positive energy balance.
PubMed: 37873427
DOI: 10.1101/2023.10.12.562074 -
GeroScience Apr 2024Alström syndrome (AS) is an ultra-rare disorder characterised by early-onset multi-organ dysfunction, such as insulin resistance, obesity, dyslipidaemia, and renal and...
Alström syndrome (AS) is an ultra-rare disorder characterised by early-onset multi-organ dysfunction, such as insulin resistance, obesity, dyslipidaemia, and renal and cardiovascular disease. The objective is to explore whether AS is a disease of accelerated ageing and whether changes over time on echocardiography could reflect accelerated cardiac ageing. Cross-sectional measurement of Phenoage and retrospective analysis of serial echocardiography were performed between March 2012 and November 2022. The setting is a single national tertiary service jointly run by health service and patient charity. Forty-five adult patients aged over 16 years were included, 64% were male and 67% of White ethnicity. The median Phenoage was 48 years (interquartile range [IQR]: 35-72) in the 34 patients for whom this was calculable, which was significantly higher than the median chronological age of 29 years (IQR: 22-39, p<0.001). Phenoage was higher than chronological age in 85% (N=29) of patients, with a median difference of +18 years (IQR: +4, +34). On echocardiography, significant decreases were observed over time in left ventricular (LV) size at end-diastole (average of 0.046 cm per year, p<0.001) and end-systole (1.1% per year, p=0.025), with significant increase in posterior wall thickness at end-diastole (0.009 cm per year, p=0.008). LV systolic function measured by global longitudinal strain reduced (0.34 percentage points per year, p=0.020) and E/e'lat increased (2.5% per year, p=0.019). Most AS patients display a higher Phenoage compared to chronological age. Cardiac changes in AS patients were also reflective of accelerated ageing, with a reduction in LV size and increased wall thickening. AS may be a paradigm disease for premature ageing.
Topics: Humans; Male; Aged; Female; Ventricular Dysfunction, Left; Retrospective Studies; Alstrom Syndrome; Cross-Sectional Studies; Diastole; Echocardiography; Aging
PubMed: 37782438
DOI: 10.1007/s11357-023-00959-3 -
Genes Sep 2023Bardet-Biedl syndrome (BBS) and Alström syndrome (ALMS) are rare multisystem diseases with an autosomal recessive mode of inheritance and genetic heterogeneity,...
Bardet-Biedl syndrome (BBS) and Alström syndrome (ALMS) are rare multisystem diseases with an autosomal recessive mode of inheritance and genetic heterogeneity, characterized by visual impairment, hearing impairment, cardiomyopathy, childhood obesity, and insulin resistance. The purpose of our study was to evaluate the indicators of nervous system changes occurring in patients with ALMS and BBS using optical coherence tomography (OCT) and magnetic resonance spectroscopy (MRS) methods compared to a group of healthy subjects. The OCT results showed significantly lower macular thickness in the patient group compared to the control group ( = 0.002). The MRS study observed differences in metabolite levels between the study and control groups in brain areas such as the cerebellum, thalamus, and white matter. After summing the concentrations from all areas, statistically significant results were obtained for N-acetylaspartate, total N-acetylaspartate, and total creatine. Concentrations of these metabolites were reduced in ALMS/BBS patients by 38% ( = 0.0004), 35% ( = 0.0008), and 28% ( = 0.0005), respectively. Our results may help to understand the pathophysiology of these rare diseases and identify strategies for new therapies.
Topics: Humans; Child; Bardet-Biedl Syndrome; Pediatric Obesity; Alstrom Syndrome; Brain
PubMed: 37761924
DOI: 10.3390/genes14091784 -
The Journal of International Medical... Jul 2023Alstrom syndrome is a rare autosomal recessive disorder resulting from an gene mutation. Here, we present the clinical data of a case of an infant diagnosed with...
Alstrom syndrome is a rare autosomal recessive disorder resulting from an gene mutation. Here, we present the clinical data of a case of an infant diagnosed with Alstrom syndrome through whole-exome sequencing. A 2-month-old male infant was admitted to Sichuan Provincial Maternity and Child Health Care Hospital on 30 May 2019 after "coughing for half a day and dyspnea for 2 hours". He was diagnosed with severe pneumonia, acute congestive heart failure, Grade III cardiac function, acute respiratory failure, and myocarditis. After treatment, he was discharged with a prescription for oral medication. After a 4-month follow-up, the patient's left ventricle exhibited spherical enlargement and a decrease in left ventricular function. The infant's whole-exome sequencing results revealed compound heterozygous mutations in the gene: c.2179dup (p. Y727Lfs*12), a frameshift mutation, that was heterozygous and originated from the mother, while c.11140C>T (p. Q3714*) was a heterozygous nonsense mutation that originated from the father. Both mutations are classified as "category 1-pathogenic mutations" according to the American College of Medical Genetics and Genomics (ACMG) assessment. A novel mutation was identified in this case report, highlighting the importance of genetic testing for the early diagnosis of Alstrom syndrome.
Topics: Female; Pregnancy; Child; Humans; Infant; Male; Alstrom Syndrome; Mutation; Child Health; Cough; Dyspnea
PubMed: 37439038
DOI: 10.1177/03000605231184100 -
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 -
Journal of Pediatric Genetics Jun 2024Alstrom's syndrome (AS) is an autosomal recessively inherited multisystemic disorder that falls under the umbrella of ciliopathy. It is characterized by poor vision,...
Alstrom's syndrome (AS) is an autosomal recessively inherited multisystemic disorder that falls under the umbrella of ciliopathy. It is characterized by poor vision, hearing impairment, cardiomyopathy, childhood obesity, diabetes mellitus type 2, dyslipidemia, pulmonary, hepatic, and renal failure besides systemic fibrosis. Biallelic pathogenic variants in gene cause AS. Retrospective study (1990-2017) included 12 Saudi patients with AS based on their phenotype, biochemical markers, and genotype. The study was approved by Fisal Specialist Hospital and Research Centre, Riyadh (RAC number 2131129) on October 2, 2012. This study showed clinical and genetic heterogeneity; six patients showed a founder mutation (IVS18-2A > T in exon 19), whereas six others showed private mutations. AS in Saudi Arabia is underdiagnosed probably because of its variable clinical manifestations. We report 12 Saudi patients with AS to enhance the awareness about this syndrome.
PubMed: 38721579
DOI: 10.1055/s-0041-1740369 -
Experimental and Clinical... Mar 2024Alstrom syndrome is a genetic disorder with autosomal recessive inheritance and multiple organ failure. Hearing loss, childhood obesity, diabetes mellitus, and...
Alstrom syndrome is a genetic disorder with autosomal recessive inheritance and multiple organ failure. Hearing loss, childhood obesity, diabetes mellitus, and nonalcoholic fatty liver disease are common disorders in this disease. Degree of nonalcoholic fatty liver disease ranges from benign steatosis to cirrhosis. Since it first description in 1959, 89 cases have been reported, and none in the literature underwent liver transplant. In this report, we describe a 19-year-old male patient with a diagnosis of hearingloss, obesity, anddiabetes mellitus startedsince childhood. He was evaluated for bloody vomiting, and grade 3 esophageal varices were detected, with liver cirrhosis findings made with abdominal tomography. The patient had a Model for End-Stage Liver Disease score of 23, and deceased donor liver transplant was planned. After an appropriate donor was identified, the patient underwent liver transplant with an operation lasting approximately 6 hours. Cold ischemia time was about 5 hours, and anastomosis time was about 30 minutes. The patient was extubated on posttransplant day 1. On posttransplant day 10, his vital parameters remained normal, but he had blurred consciousness and loss of orientation. Neurological examination and imaging revealed minimal subdural effusion and mild cerebral cortical dysfunction in electroencephalogram. The patient's symptoms improved after medical treatment, and the patient was discharged on day 13 posttransplant. At the month 24 outpatient follow-up, the patient had no problems. Alstrom syndrome is an autosomal recessive genetic disorder with multiple organ failure. Although various degrees of liver disease have been described in the literature that may progress to cirrhosis of the liver, our present case is considered original because of the absence of liver transplant descriptions in the literature.
Topics: Humans; Liver Transplantation; Male; Treatment Outcome; Young Adult; Alstrom Syndrome; Liver Cirrhosis; Genetic Predisposition to Disease
PubMed: 33535939
DOI: 10.6002/ect.2020.0006