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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 -
Saudi Journal of Ophthalmology :... 2023Mutations in the gene have been linked to isolated inherited retinal dystrophy or Alström syndrome. This report illustrates the unique pattern of -associated diseases...
Mutations in the gene have been linked to isolated inherited retinal dystrophy or Alström syndrome. This report illustrates the unique pattern of -associated diseases in a set of three simplex Saudi patients originating from unrelated consanguineous families. A detailed ophthalmological assessment was performed at the Department of Ophthalmology at King Saud University, Riyadh, Saudi Arabia. Next-generation sequencing vision panel revealed recessive mutations (reference sequence NM_015120). As a result, three distinct pathogenic mutations were identified; the first one is a nonsense mutation (c.8158C>T: p.R2720X) which has recently been identified in a Chinese patient, while the other two are known to have a founder effect in the Saudi population (the frameshift: C.848dupA: p.E283fs and the splicing: C.11870-2A>T: p.?). Clinically, a prominent nerve fiber layer was observed in the three studied patients with variable expectations of vessel attenuation. In addition, two of our patients observed unusual presentation of specific retinal pigment epithelium pigmentations in semi/halo-arrangement around the macula. Thus far, our report expands the phenotypic-genotypic spectrum of -associated diseases and supports the principles of applying precision medicine in Saudi Arabia by utilizing the fact that common founder mutations were identified and unique phenotype was observed.
PubMed: 38155680
DOI: 10.4103/sjopt.sjopt_129_22 -
Molecular & Cellular Proteomics : MCP Jan 2024Alström syndrome (ALMS) is a very rare autosomal-recessive disorder, causing a broad range of clinical defects most notably retinal degeneration, type 2 diabetes, and...
Alström syndrome (ALMS) is a very rare autosomal-recessive disorder, causing a broad range of clinical defects most notably retinal degeneration, type 2 diabetes, and truncal obesity. The ALMS1 gene encodes a complex and huge ∼0.5 MDa protein, which has hampered analysis in the past. The ALMS1 protein is localized to the centrioles and the basal body of cilia and is involved in signaling processes, for example, TGF-β signaling. However, the exact molecular function of ALMS1 at the basal body remains elusive and controversial. We recently demonstrated that protein complex analysis utilizing endogenously tagged cells provides an excellent tool to investigate protein interactions of ciliary proteins. Here, CRISPR/Cas9-mediated endogenously tagged ALMS1 cells were used for affinity-based protein complex analysis. Centrosomal and microtubule-associated proteins were identified, which are potential regulators of ALMS1 function, such as the centrosomal protein 70 kDa (CEP70). Candidate proteins were further investigated in ALMS1-deficient hTERT-RPE1 cells. Loss of ALMS1 led to shortened cilia with no change in structural protein localization, for example, acetylated and ɣ-tubulin, Centrin-3, or the novel interactor CEP70. Conversely, reduction of CEP70 resulted in decreased ALMS1 at the ciliary basal body. Complex analysis of CEP70 revealed domain-specific ALMS1 interaction involving the TPR-containing C-terminal (TRP-CT) fragment of CEP70. In addition to ALMS1, several ciliary proteins, including CEP135, were found to specifically bind to the TPR-CT domain. Data are available via ProteomeXchange with the identifier PXD046401. Protein interactors identified in this study provide candidate lists that help to understand ALMS1 and CEP70 function in cilia-related protein modification, cell death, and disease-related mechanisms.
Topics: Humans; Alstrom Syndrome; Cell Cycle Proteins; Diabetes Mellitus, Type 2; Microtubule-Associated Proteins; Obesity; Tubulin
PubMed: 38122899
DOI: 10.1016/j.mcpro.2023.100701 -
Biology Direct Dec 2023Alström syndrome (ALMS) is a rare autosomal recessive disease that is associated with mutations in ALMS1 gene. The main clinical manifestations of ALMS are retinal...
BACKGROUND
Alström syndrome (ALMS) is a rare autosomal recessive disease that is associated with mutations in ALMS1 gene. The main clinical manifestations of ALMS are retinal dystrophy, obesity, type 2 diabetes mellitus, dilated cardiomyopathy and multi-organ fibrosis, characteristic in kidneys and liver. Depletion of the protein encoded by ALMS1 has been associated with the alteration of different processes regulated via the primary cilium, such as the NOTCH or TGF-β signalling pathways. However, the cellular impact of these deregulated pathways in the absence of ALMS1 remains unknown.
METHODS
In this study, we integrated RNA-seq and proteomic analysis to determine the gene expression profile of hTERT-BJ-5ta ALMS1 knockout fibroblasts after TGF-β stimulation. In addition, we studied alterations in cross-signalling between the TGF-β pathway and the AKT pathway in this cell line.
RESULTS
We found that ALMS1 depletion affects the TGF-β pathway and its cross-signalling with other pathways such as PI3K/AKT, EGFR1 or p53. In addition, alterations associated with ALMS1 depletion clustered around the processes of extracellular matrix regulation and lipid metabolism in both the transcriptome and proteome. By studying the enriched pathways of common genes differentially expressed in the transcriptome and proteome, collagen fibril organisation, β-oxidation of fatty acids and eicosanoid metabolism emerged as key processes altered by the absence of ALMS1. Finally, an overactivation of the AKT pathway was determined in the absence of ALMS1 that could be explained by a decrease in PTEN gene expression.
CONCLUSION
ALMS1 deficiency disrupts cross-signalling between the TGF-β pathway and other dependent pathways in hTERT-BJ-5ta cells. Furthermore, altered cross-signalling impacts the regulation of extracellular matrix-related processes and fatty acid metabolism, and leads to over-activation of the AKT pathway.
Topics: Humans; Lipid Metabolism; Diabetes Mellitus, Type 2; Proteome; Phosphatidylinositol 3-Kinases; Proteomics; Proto-Oncogene Proteins c-akt; Cell Cycle Proteins; Alstrom Syndrome; Transforming Growth Factor beta; Extracellular Matrix
PubMed: 38062477
DOI: 10.1186/s13062-023-00441-2 -
Frontiers in Molecular Biosciences 2023Alström syndrome (ALMS) and Bardet-Biedl syndrome (BBS) are among the so-called ciliopathies and are associated with the development of multiple systemic...
Alström syndrome (ALMS) and Bardet-Biedl syndrome (BBS) are among the so-called ciliopathies and are associated with the development of multiple systemic abnormalities, including early childhood obesity and progressive neurodegeneration. Given the progressive deterioration of patients' quality of life, in the absence of defined causal treatment, it seems reasonable to identify the metabolic background of these diseases and search for their progression markers. The aim of this study was to find metabolites characteristic to ALMS and BBS, correlating with clinical course parameters, and related to the diseases progression. Untargeted metabolomics of serum samples obtained from ALMS and BBS patients (study group; n = 21) and obese/healthy participants (control group; each of 35 participants; n = 70) was performed using LC-QTOF-MS method at the study onset and after 4 years of follow-up. Significant differences in such metabolites as valine, acylcarnitines, sphingomyelins, phosphatidylethanolamines, phosphatidylcholines, as well as lysophosphatidylethanolamines and lysophosphatidylcholines were observed when the study group was compared to both control groups. After a follow-up of the study group, mainly changes in the levels of lysophospholipids and phospholipids (including oxidized phospholipids) were noted. In addition, in case of ALMS/BBS patients, correlations were observed between selected phospholipids and glucose metabolism parameters. We also found correlations of several LPEs with patients' age ( < 0.05), but the level of only one of them (hexacosanoic acid) correlated negatively with age in the ALMS/BBS group, but positively in the other groups. Patients with ALMS/BBS have altered lipid metabolism compared to controls or obese subjects. As the disease progresses, they show elevated levels of lipid oxidation products, which may suggest increased oxidative stress. Selected lipid metabolites may be considered as potential markers of progression of ALMS and BBS syndromes.
PubMed: 38028552
DOI: 10.3389/fmolb.2023.1251905 -
Case Reports in Ophthalmological... 2023A case of a patient with the Alström syndrome (AS) that was misdiagnosed as Leber's hereditary optic neuropathy or retinitis pigmentosa for 13 years is presented. AS is...
A case of a patient with the Alström syndrome (AS) that was misdiagnosed as Leber's hereditary optic neuropathy or retinitis pigmentosa for 13 years is presented. AS is a rare genetic disorder caused by mutations in the gene. AS may lead to abnormal ciliary formation and function. AS affects metabolism, and symptomatology includes type 2 diabetes mellitus (), obesity, hypogonadism and gynecomastia in males, progressive bilateral sensorineural hearing loss, cardiomyopathy, nonalcoholic fatty liver disease (), cirrhosis, and chronic progressive kidney disease. The onset of the above symptoms may vary significantly. The ophthalmic manifestation is early onset cone-rod dystrophy that starts as progressive vision loss, photophobia, and nystagmus in the first months of life. An accurate diagnosis may enable specialists to facilitate a significantly positive effect in the everyday life of a patient. Genetic counseling may also be recommended for these patients. Diagnosis was confirmed by DNA testing, thus highlighting its necessity in everyday practice.
PubMed: 38022732
DOI: 10.1155/2023/9409036 -
Orphanet Journal of Rare Diseases Nov 2023Poorly coordinated care can have major impacts on patients and families affected by rare conditions, with negative physical health, psychosocial and financial...
BACKGROUND
Poorly coordinated care can have major impacts on patients and families affected by rare conditions, with negative physical health, psychosocial and financial consequences. This study aimed to understand how care is coordinated for rare diseases in the United Kingdom.
METHODS
We undertook a national survey in the UK involving 760 adults affected by rare diseases, 446 parents/carers of people affected by rare diseases, and 251 healthcare professionals who care for people affected by rare diseases.
RESULTS
Findings suggested that a wide range of patients, parents and carers do not have coordinated care. For example, few participants reported having a care coordinator (12% patients, 14% parents/carers), attending a specialist centre (32% patients, 33% parents/carers) or having a care plan (10% patients, 44% parents/carers). A very small number of patients (2%) and parents/carers (5%) had access to all three-a care coordinator, specialist centre and care plan. Fifty four percent of patients and 33% of parents/carers reported access to none of these. On the other hand, a higher proportion of healthcare professionals reported that families with rare conditions had access to care coordinators (35%), specialist centres (60%) and care plans (40%).
CONCLUSIONS
Care for families with rare conditions is generally not well coordinated in the UK, with findings indicating limited access to care coordinators, specialist centres and care plans. Better understanding of these issues can inform how care coordination might be improved and embrace the needs and preferences of patients and families affected by rare conditions.
Topics: Adult; Humans; Caregivers; Cross-Sectional Studies; Rare Diseases; United Kingdom; Delivery of Health Care
PubMed: 37996938
DOI: 10.1186/s13023-023-02934-9 -
Molecular Genetics & Genomic Medicine Jan 2024Alström syndrome (AS) represents an exceptionally rare genetic disorder characterized by a constellation of features including cardiomyopathy, progressive hearing and... (Review)
Review
BACKGROUND
Alström syndrome (AS) represents an exceptionally rare genetic disorder characterized by a constellation of features including cardiomyopathy, progressive hearing and vision impairment, as well as obesity. This study seeks to elucidate the genetic underpinnings of this syndrome within the Saudi Arabian population.
METHODS
Employing an extended family cohort, we conducted an exhaustive molecular genetic assessment to delineate the presence of Alström syndrome. Additionally, we conducted an extensive review of existing literature from Saudi population to contextualize our findings within the broader understanding of the disorder in our country.
RESULTS
Within our studied extended family, we identified two individuals harboring the homozygous pathogenic mutation (c.2729C>G) in the ALMS1 gene [NM_015120.4:c.2729C>G (p.Ser910*)]. Notably, carrier status was observed in the parents, whereas some siblings exhibited typical alleles while others were carriers of the mutation. Intriguingly, a review of the literature unveiled six distinct reports documenting a total of 20 Alström syndrome patients within the Saudi Arabian population, each presenting with distinct novel mutations.
CONCLUSIONS
In cases featuring cardiomyopathy, obesity, and progressive hearing and vision loss, Alström syndrome merits inclusion within the differential diagnosis. To confirm the diagnosis, molecular genetic assessment of the ALMS1 gene is imperative, offering definitive clarity amidst the complex clinical presentation. This investigation reinforces the importance of genetic scrutiny for precise diagnosis and highlights the unique genetic landscape of Alström syndrome within the Saudi Arabian population.
Topics: Humans; Alstrom Syndrome; Cell Cycle Proteins; Extended Family; Saudi Arabia; Obesity; Mutation; Cardiomyopathies
PubMed: 37937857
DOI: 10.1002/mgg3.2314