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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 -
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 -
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 -
Proceedings of the National Academy of... Jun 2023Retinitis pigmentosa (RP) is an ocular disease characterized by the loss of night vision, followed by the loss of daylight vision. Daylight vision is initiated in the...
Retinitis pigmentosa (RP) is an ocular disease characterized by the loss of night vision, followed by the loss of daylight vision. Daylight vision is initiated in the retina by cone photoreceptors, which are gradually lost in RP, often as bystanders in a disease process that initiates in their neighboring rod photoreceptors. Using physiological assays, we investigated the timing of cone electroretinogram (ERG) decline in RP mouse models. A correlation between the time of loss of the cone ERG and the loss of rods was found. To investigate a potential role of the visual chromophore supply in this loss, mouse mutants with alterations in the regeneration of the retinal chromophore, 11- retinal, were examined. Reducing chromophore supply via mutations in or resulted in greater cone function and survival in a RP mouse model. Conversely, overexpression of and , genes that can drive the regeneration of the chromophore, led to greater cone degeneration. These data suggest that abnormally high chromophore supply to cones upon the loss of rods is toxic to cones, and that a potential therapy in at least some forms of RP is to slow the turnover and/or reduce the level of visual chromophore in the retina.
Topics: Mice; Animals; Retina; Retinal Cone Photoreceptor Cells; Retinal Rod Photoreceptor Cells; Retinitis Pigmentosa; Color Vision; Disease Models, Animal
PubMed: 37252956
DOI: 10.1073/pnas.2217885120 -
PloS One 2023Hypertrophic cardiomyopathy (HCM) is the most common heart disease in cats with a suspected genetic origin. Previous studies have identified five HCM-associated variants...
Hypertrophic cardiomyopathy (HCM) is the most common heart disease in cats with a suspected genetic origin. Previous studies have identified five HCM-associated variants in three genes (Myosin binding protein C3: MYBPC3 p.A31P, p.A74T, p.R820W; Myosin heavy chain 7: MYH7 p.E1883K; Alstrom syndrome protein 1: ALMS1 p.G3376R). These variants are considered breed-specific, with the exception of MYBPC3 p.A74T, and have rarely been found in other breeds. However, genetic studies on HCM-associated variants across breeds are still insufficient because of population and breed bias caused by differences in genetic background. This study investigates the ubiquitous occurrence of HCM-associated genetic variants among cat breeds, using 57 HCM-affected, 19 HCM-unaffected, and 227 non-examined cats from the Japanese population. Genotyping of the five variants revealed the presence of MYBPC3 p.A31P and ALMS1 p.G3376R in two (Munchkin and Scottish Fold) and five non-specific breeds (American Shorthair, Exotic Shorthair, Minuet, Munchkin and Scottish Fold), respectively, in which the variants had not been identified previously. In addition, our results indicate that the ALMS1 variants identified in the Sphynx breed might not be Sphynx-specific. Overall, our results suggest that these two specific variants may still be found in other cat breeds and should be examined in detail in a population-driven manner. Furthermore, applying genetic testing to Munchkin and Scottish Fold, the breeds with both MYBPC3 and ALMS1 variants, will help prevent the development of new HCM-affected cat colonies.
Topics: Cats; Animals; Japan; Carrier Proteins; Cardiomyopathy, Hypertrophic; Cytoskeletal Proteins; Health Status; Mutation
PubMed: 37071642
DOI: 10.1371/journal.pone.0283433 -
Clinical Case Reports Feb 2023Alstrom syndrome is a rare genetic disorder with an autosomal recessive mutation in the ALMS1 gene. The disease's manifestations include ophthalmic problems, hearing...
Alstrom syndrome is a rare genetic disorder with an autosomal recessive mutation in the ALMS1 gene. The disease's manifestations include ophthalmic problems, hearing loss, obesity, and cardiovascular disorders. In addition, medical cases include other organ complications. However, the overlapping variety of such symptoms with other diseases may delay the diagnosis. In this article, we describe the case of a 7-year-old female patient with Alstrom syndrome, and cardiovascular and hyperphenylalaninemia diseases since birth. Other symptoms included diabetes and ophthalmologic problems with skeletal disability. Blindness and hearing impairment were diagnosed, along with recurrence of respiratory problems at the age of 7 years. The patient's obesity-induced snoring predisposed her to uncontrolled blood glucose. In fact, respiratory tract problems and sleep disorders had occurred as a degraded cycle and left her with a severe disability for years. The similarity of the symptoms with other diseases had misled the physician in diagnosis. However, a polysomnography test (because of complaints of short sleep duration) recognized the source of the patient's sleep disorders and breathing problems. Eventually, we delivered a portable ventilator to the child for continuous positive airway pressure (CPAP) therapy. The child's breathing and oxygenation conditions improved. Using the ventilator and the CPAP system, we discharged her from the hospital without requiring oxygenation, in a stable condition. The procedure could prevent the patient from hypoxia and retinal problem.
PubMed: 36777792
DOI: 10.1002/ccr3.6894