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JCEM Case Reports Jan 2023Diabetes mellitus is one of the most common diseases worldwide and is a major cause of morbidity and mortality. Type 2 diabetes, with its hallmark being insulin...
Diabetes mellitus is one of the most common diseases worldwide and is a major cause of morbidity and mortality. Type 2 diabetes, with its hallmark being insulin resistance, constitutes the majority of cases. Although usually related to modifiable risk factors, insulin resistance can have genetic causes. Here, we present one of the rare causes of insulin resistance. A 21-year-old man, who was deaf and blind, presented with a 3-week history of polyuria and polydipsia. He was found to have significant hyperglycemia, managed initially with insulin infusion, then he was transitioned to subcutaneous injections. Because he required high doses of insulin and had acanthosis nigricans, insulin resistance was suspected. Putting together his insulin resistance and chronic history of syndromic features, Alström syndrome was considered. Genetic testing revealed a mutation in the gene. The patient was then started on insulin sensitizers with a tapering of insulin with good response. Insulin resistance should be suspected if the insulin requirement is high and if acanthosis nigricans is present. Alström syndrome is a rare causes of insulin resistance. Affected individuals will usually have insulin-resistant diabetes by a young age and associated blindness and deafness. Insulin sensitizers are an important part of the treatment.
PubMed: 37908279
DOI: 10.1210/jcemcr/luac012 -
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 -
Obesity (Silver Spring, Md.) Nov 2023Alström syndrome (AS) is a rare multisystem disorder of which early onset childhood obesity is a cardinal feature. Like humans with AS, animal models with Alms1...
OBJECTIVE
Alström syndrome (AS) is a rare multisystem disorder of which early onset childhood obesity is a cardinal feature. Like humans with AS, animal models with Alms1 loss-of-function mutations develop obesity, supporting the notion that ALMS1 is required for the regulatory control of energy balance across species. This study aimed to determine which component(s) of energy balance are reliant on ALMS1.
METHODS
Comprehensive energy balance phenotyping was performed on Alms1 mice at both 8 and 18 weeks of age.
RESULTS
It was found that adiposity gains occurred early and rapidly in Alms1 male mice but much later in females. Rapid increases in body fat in males were due to a marked reduction in energy expenditure (EE) during early life and not due to any genotype-specific increases in energy intake under chow conditions. Energy intake did increase in a genotype-specific manner when mice were provided a high-fat diet, exacerbating the effects of reduced EE on obesity progression. The EE deficit observed in male Alms1 mice did not persist as mice aged.
CONCLUSIONS
Either loss of ALMS1 causes a developmental delay in the mechanisms controlling early life EE or activation of compensatory mechanisms occurs after obesity is established in AS. Future studies will determine how ALMS1 modulates EE and how sex moderates this process.
Topics: Female; Male; Child; Humans; Mice; Animals; Aged; Alstrom Syndrome; Cell Cycle Proteins; Pediatric Obesity; Disease Models, Animal; Adipose Tissue
PubMed: 37712194
DOI: 10.1002/oby.23877 -
Zhonghua Yi Xue Yi Chuan Xue Za Zhi =... Sep 2023To explore the clinical characteristics and genetic etiology of a Chinese pedigree affected with Alström syndrome.
OBJECTIVE
To explore the clinical characteristics and genetic etiology of a Chinese pedigree affected with Alström syndrome.
METHODS
A pedigree with 5 members affected with Alström syndrome who had visited the First Affiliated Hospital of Zhengzhou University in February 2021 was selected as the study subject. Clinical data of the pedigree were collected, and peripheral venous blood samples were collected for the extraction of genomic DNA. Genetic testing was carried out for the eldest daughter and third son through whole exome sequencing (WES). Candidate variant was verified by Sanger sequencing and bioinformatic analysis.
RESULTS
The eldest daughter (14 years old) and the third son (11 years old) both had congenital nystagmus, amblyopia, growth retardation and type 2 diabetes. WES revealed that both had harbored homozygous c.3538A>T (p.Lys1180*) variant of the ALMS1 gene. Sanger sequencing confirmed that the father, mother, and second daughter were all heterozygous carriers. Based on the Guidelines for Genetic Variation and the Technical Standards for Interpretation and Reporting of Primary Copy Number Variations, the variant was predicted as pathogenic (PVS1+PM2_Supporting+PP4).
CONCLUSION
The homozygous c.3538A>T (p.Lys1180*) variant of the ALSM1 gene probably underlay the Alström syndrome in this pedigree, which has provided a reference for the clinical treatment.
Topics: Adolescent; Child; Humans; Alstrom Syndrome; Diabetes Mellitus, Type 2; DNA Copy Number Variations; East Asian People; Pedigree; Male; Female
PubMed: 37643959
DOI: 10.3760/cma.j.cn511374-20211004-00798 -
American Journal of Physiology. Renal... Oct 2023Inactivating mutations in the gene in humans cause Alström syndrome, characterized by the early onset of obesity, insulin resistance, and renal dysfunction. However,...
Inactivating mutations in the gene in humans cause Alström syndrome, characterized by the early onset of obesity, insulin resistance, and renal dysfunction. However, the role of ALMS1 in renal function and hemodynamics is unclear. We previously found that ALMS1 is expressed in thick ascending limbs, where it binds and decreases Na-K-2Cl cotransporter activity. We hypothesized that ALMS1 is expressed in macula densa cells and that its deletion enhances tubuloglomerular feedback (TGF) and reduces glomerular filtration rate (GFR) in rats. To test this, homozygous ALMS1 knockout (KO) and littermate wild-type Dahl salt-sensitive rats were studied. TGF sensitivity was higher in ALMS1 KO rats as measured by in vivo renal micropuncture. Using confocal microscopy, we confirmed immunolabeling of ALMS1 in macula densa cells (nitric oxide synthase 1 positive), supporting a role for ALMS1 in TGF regulation. Baseline glomerular capillary pressure was higher in ALMS1 KO rats, as was mean arterial pressure. Renal interstitial hydrostatic pressure was lower in ALMS1 KO rats, which is linked to increased Na reabsorption and hypertension. GFR was reduced in ALMS1 KO rats. Seven-week-old ALMS1 KO rats were not proteinuric, but proteinuria was present in 18- to 22-wk-old ALMS1 KO rats. The glomerulosclerosis index was higher in 18-wk-old ALMS1 KO rats. In conclusion, ALMS1 is involved in the control of glomerular hemodynamics in part by enhancing TGF sensitivity, and this may contribute to decreased GFR. Increased TGF sensitivity, enhanced glomerular capillary pressure, and hypertension may lead to glomerular damage in ALMS1 KO rats. These are the first data supporting the role of ALMS1 in TGF and glomerular hemodynamics. ALMS1 is a novel protein involved in regulating tubuloglomerular feedback (TGF) sensitivity, glomerular capillary pressure, and blood pressure, and its dysfunction may reduce renal function and cause glomerular damage.
Topics: Humans; Rats; Animals; Alstrom Syndrome; Rats, Inbred Dahl; Kidney Diseases; Glomerular Filtration Rate; Hemodynamics; Hypertension
PubMed: 37560774
DOI: 10.1152/ajprenal.00017.2023 -
Endocrinology Aug 2023
Topics: Humans; Alstrom Syndrome; Metabolic Syndrome; Models, Genetic; Hematopoietic Stem Cells; Bone Marrow Cells
PubMed: 37449512
DOI: 10.1210/endocr/bqad110 -
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 -
Nefrologia 2023
Topics: Humans; Alstrom Syndrome; Kidney Transplantation; Hypertension, Portal; Gastrointestinal Hemorrhage
PubMed: 37419720
DOI: 10.1016/j.nefroe.2023.06.003