Liver Fibrosis and Steatosis in Alström Syndrome: A Genetic Model for Metabolic Syndrome

Bettini, Silvia; Bombonato, Giancarlo; Dassiè, Francesca; Favaretto, Francesca; Piffer, Luca; Bizzotto, P.; Chemello, Liliana; Senzolo, Marco; Merkel, Carlo; Angeli, Paolo; Vettor, Roberto; Milan, Gabriella; Maffei, Pietro

doi:10.3390/diagnostics11050797

Cited by 11 publications

(9 citation statements)

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“…In fact, the patient was affected by chronic arterial hypertension with mild cardiac involvement, which are well-known risk factors for preeclampsia and fetal death ( Ritter et al, 2020 ). Furthermore, in AS patients, the presence of IR, type 2 diabetes mellitus, nonalcoholic fatty liver disease and renal impairment are among the most frequent clinical manifestations of this syndrome and increase the risk for preeclampsia and eclampsia development ( Raidt et al, 2015 ; Baig et al, 2020 ; Ritter et al, 2020 ; Bettini et al, 2021 ; Shaaban et al, 2021 ; Yu et al, 2021 ; Lee and Kim, 2022 ). What remains unclear is whether the obstetrical complications observed in our patient are directly related to genetic alterations.…”

Section: Discussionmentioning

confidence: 99%

Case Report:Pregnancy and birth in a mild phenotype of Alström syndrome

et al. 2022

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Background: Alström syndrome (AS) is an ultrarare multisystemic progressive disease caused by autosomal recessive variations of the ALMS1 gene (2p13). AS is characterized by double sensory impairment, cardiomyopathy, childhood obesity, extreme insulin resistance, early nonalcoholic fatty liver disease, renal dysfunction, respiratory disease, endocrine and urologic disorders. In female AS patients, hyperandrogenism has been described but fertility issues and conception have not been investigated so far.Case: This case report describes the spontaneous conception, pregnancy, and birth in a 27-year-old woman with AS, characterized by a mild phenotype with late onset of visual impairment, residual perception of light, and hypertension. Before pregnancy, menses were regular with increased levels of dihydrotestosterone and androstanediol glucuronide in the follicular phase, and the ovaries and endometrium were normal during vaginal ultrasound. A thorough clinical follow-up of the maternal and fetal conditions was carried out. A weight gain of 10 kg during pregnancy was recorded, and serial blood and urine tests were all within the normal range, except for mild anemia. The course of pregnancy was uneventful up to 34 weeks of gestation when preeclampsia developed with an abnormally high level of blood pressure and edema in the lower limbs. At 35 weeks + 3 days of gestation, an urgent cesarean section was performed, and a healthy male weighing 1,950 g was born. Histological examination of the placenta showed partial signs of flow obstruction, limited abruption areas, congested fetal vessels and villi, and a small single infarcted area.Conclusion: The present case demonstrates for the first time that conceiving is possible for patients with ALMS. Particular attention should be given to the management of AS systemic comorbidities through the course of pregnancy.

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Section: Discussionmentioning

confidence: 99%

Case Report:Pregnancy and birth in a mild phenotype of Alström syndrome

et al. 2022

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“…Transaminase is usually elevated during early childhood, and liver disease in some patients will progress to cirrhosis or liver failure between the ages of 20 and 30 (2,16). In addition, ALMS patients may also develop portal hypertension with splenomegaly, esophageal varices, ascites and hepatic encephalopathy (2,16). In this case, ALT and AST were increased.…”

Section: Discussionmentioning

confidence: 80%

Section: Discussionmentioning

confidence: 99%

“…ALMS patients show a high incidence of NAFLD and are prone to non-alcoholic steatohepatitis and liver fibrosis (2,16). Transaminase is usually elevated during early childhood, and liver disease in some patients will progress to cirrhosis or liver failure between the ages of 20 and 30 (2,16). In addition, ALMS patients may also develop portal hypertension with splenomegaly, esophageal varices, ascites and hepatic encephalopathy (2,16).…”

Section: Discussionmentioning

confidence: 99%

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A novel variant site of Alstrom syndrome in a Chinese child: a case report

Xu¹,

Zhang²,

Fan³

et al. 2022

Transl Pediatr

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Background: Alstrom syndrome (ALMS) is an ultra-rare multisystem genetic disorder caused by autosomal recessive inheritance of the ALMS1 gene. It manifests as multisystem dysfunction, displaying unique clinical signs and symptoms and various severity, which may lead to delayed prognosis or misdiagnosis in medical practice. Although almost 300 pathogenic variants have been reported, there are some variant sites that have not been recognized yet.Case Description: We report a case of a 14-year-old boy with manifestations, including binocular vision loss, acanthosis nigricans, type 2 diabetes, insulin resistance, elevated transaminase, hepatic fibrosis, and proteinuria. Compound heterozygous variants in the ALMS1 gene have been discovered by whole exon sequencing. One of his variant sites was C. 8158C>T, which was from his father. And the other variant site was C. 3575C>A, which was from his mother. To the great of our knowledge, this site has not been reported before. Both of the variants make the synthesis of the peptide chain terminated in advance and an incomplete polypeptide chain is formed. Conclusions:The clinical presentations of ALMS are complicated and varied. Although early diagnosis can be made according to typical clinical symptoms, whole exon sequencing is necessary for the diagnosis of ALMS, as indicated by our study.

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“…Alterations related to the ECM are undoubtedly key to the appearance of fibrosis in these patients; however, alterations in the β-oxidation of fatty acids, beyond their link to obesity, may contribute to the appearance of fibrotic tissue due to lipid deposits (Serra et al, 2013; Kang et al, 2014). This suggest that the metabolic disorder in patients with ALMS is involved in the progressive development of fibrosis in various organs such as the kidneys and liver (Bettini et al, 2021).…”

Section: Discussionmentioning

confidence: 99%

Loss of the centrosomal protein ALMS1 alters lipid metabolism and the regulation of extracellular matrix-related processes

Bea-Mascato

Gómez-Castañeda

Sánchez-Corrales

et al. 2022

Preprint

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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. Keywords: ALMS1, TGF-β, AKT, primary cilia, ciliopathy, ECM, lipid metabolism, Alström syndrome.

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Liver Fibrosis and Steatosis in Alström Syndrome: A Genetic Model for Metabolic Syndrome

Cited by 11 publications

References 59 publications

Case Report:Pregnancy and birth in a mild phenotype of Alström syndrome

Case Report:Pregnancy and birth in a mild phenotype of Alström syndrome

A novel variant site of Alstrom syndrome in a Chinese child: a case report

Loss of the centrosomal protein ALMS1 alters lipid metabolism and the regulation of extracellular matrix-related processes

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