RARE DISEASE
Alström syndrome
Alström syndrome
Alström syndrome
Drug discovery
4
drugs
With orphan designations
Overview
Alström syndrome is a rare autosomal recessive ciliopathy caused by mutations in ALMS1, leading to multisystem complications. Key features include cone-rod dystrophy (progressive blindness), sensorineural hearing loss, childhood obesity, insulin resistance, type 2 diabetes mellitus, dilated cardiomyopathy, and progressive renal/hepatic dysfunction [1][5][7]. Prognosis is poor, with most patients surviving into their 40s–50s [1][4][16].
Burden
Morbidity: Progressive multisystem failure (50% develop end-stage renal disease by adolescence) [7][11], 30%–60% incidence of cardiomyopathy [12][14]
Mortality: Median lifespan <50 years due to cardiac/hepatic/renal complications [16][17]
Quality of life: Severe visual/hearing impairment, obesity-related disabilities, and high caregiver dependency [7][8][16]
Therapies
Multidisciplinary care: Glycemic control (metformin, insulin), cardiomyopathy management (β-blockers, ACE inhibitors), hearing aids, and renal replacement therapy [2][8][13]
Symptom monitoring: Regular cardiac/renal/hepatic evaluations and early intervention for respiratory/sleep disorders (e.g., CPAP) [3][6][14]
No disease-modifying therapies: Clinical trials for ciliopathy-targeted agents remain exploratory [11][18]
Categories: rare cardiac diseases, rare developmental anomalies during embryogenesis, rare endocrine diseases, rare genetic diseases, rare neurological diseases, rare ophthalmic disorders, rare otorhinolaryngological diseases, rare renal diseases, rare transplant-related disorders
Research Papers
69 drug discovery papers about Alström syndrome, with 1 first-in-class and 3 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
69 drug discovery papers about Alström syndrome, with 1 first-in-class and 3 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
proteins
2026-04-10 | A case of Alström syndrome with growth hormone deficiency and dyslipidemia: a novel homozygous frameshift variant of ALMS1 c.5763del.
Alström syndrome (AS, OMIM #203800) is a rare autosomal recessive disorder caused by biallelic pathogenic variants in ALMS1, characterized by obesity, cardiomyopathy, retinal dystrophy, sensorineural hearing loss, and progressive hepatic and renal involvement. We report a pediatric case of AS complicated by growth hormone deficiency (GHD), focusing on the clinical course and potential metabolic effects of growth hormone (GH) replacement therapy. A 13-year-old girl with AS presented with severe dyslipidemia, including hypertriglyceridemia (727 mg/dL), elevated total cholesterol (251 mg/dL), and low high-density lipoprotein cholesterol (23 mg/dL), together with dilated cardiomyopathy. She was diagnosed with GHD at 3 years of age, with a height of -3.6 SD. GH replacement therapy led to sustained improvement in linear growth, reaching -1.9 SD, and was associated with long-term maintenance of lipid parameters within the normal range. Whole-exome sequencing identified a previously unreported homozygous frameshift variant in ALMS1 (NM_001378454.1:c.5763del; p.(Phe1921Leufs*18)). This case suggests that GH replacement therapy may contribute to improved lipid metabolism in patients with AS complicated by GHD. In addition, it expands the mutational spectrum of ALMS1 and highlights the potential metabolic benefits of early endocrine intervention in AS.
2025-10-17 | Effect of Tirzepatide in an Adolescent With Early-Onset Obesity, Hyperphagia, and Type 2 Diabetes
Early-onset severe obesity is rare and largely treatment-resistant to standard measures. Etiologies include syndromic disorders (Prader-Willi, Bardet-Biedl and Alström syndromes), monogenic defects of appetite-regulating pathways - most significantly melanocortin-4-receptor (MC4R) deficiency, but also leptin receptor (LEPR), pro-opiomelanocortin (POMC), and secondary hypothalamic injury, most commonly craniopharyngiomas. Most childhood obesity, however, is polygenic, arising from interactions of environmental and genetic factors. In many patients, no clear etiology is identified. Treatment remains challenging, particularly if hyperphagia and reduced satiety are predominant presenting features. We describe the case of a 19-year-old male with a history of autism spectrum disorder, attention-deficit hyperactivity disorder (ADHD), type 2 diabetes mellitus (T2DM) and morbid obesity, who showed a clinically significant response to tirzepatide therapy following failed conventional interventions. This case highlights the potential role of dual incretin therapy in adolescents with severe early-onset obesity and hyperphagia, even in the absence (based on present knowledge) of identifiable hypothalamic or genetic pathology.
2025-04-30 | Effectiveness of the Dual GIP/GLP1-Agonist Tirzepatide in 2 Cases of Alström Syndrome, a Rare Obesity Syndrome.
Tirzepatide, a dual glucose-dependent insulinotropic peptide/glucagon-like peptide 1 (GIP/GLP1) receptor agonist, was recently approved for type 2 diabetes and weight management. Alström syndrome (AS) is a rare, genetic, multisystemic disorder, characterized by cone-rod dystrophy, progressive hearing loss, obesity, and diabetes with profound insulin resistance due to marked hyperphagia. Here we highlight the potential of tirzepatide as a novel therapeutic option for improving glycemic outcomes, metabolic dysfunction-associated steatotic liver disease (MASLD), and effectively reducing body weight in individuals with AS. We present the first 2 reported cases of people living with AS treated with tirzepatide. Two individuals with AS, previously treated with semaglutide, received tirzepatide at our clinic. The first, a 23-year-old man with 18 months of treatment, experienced a weight loss of -28 kg (113.6 to 83 kg, -26.9%); glycated hemoglobin A1c decreased by -0.4% (6.7% to 6.3%), with considerable reductions in daily insulin doses of -96 IU/day (-83%; 58 to 20 IU insulin glargine and 58 to 0 IU prandial insulin), while maintaining oral antidiabetics. Hepatic steatosis, with a previous fat fraction of 20%, resolved as confirmed by magnetic resonance imaging (MRI). The second, a 20-year-old man with previously well-controlled diabetes, was followed up for 9 months and showed a weight reduction of -9.5 kg (132 kg to 122.5 kg; -7.2%) with a reduction of hepatic lipid content from 21% at the latest MRI to 11% after approximately 3 months of therapy. Tirzepatide shows great effectiveness with regard to body weight, MASLD, and insulin resistance in AS. Follow-up studies with larger cohorts have to be performed to confirm these findings.
2024-05-01 | Thick Ascending Limbs (TALs)-specific deletion of ALMS1 (Alstrom syndrome 1) increases surface NKCC2 expression and NaCl reabsorption in the TAL
The regulation of NKCC2 mediated NaCl reabsorption in Thick Ascending Libs (TALs) is essential to salt homeostasis and blood pressure regulation. Previously, our lab showed that NKCC2 activity is regulated by membrane traffcking and inhibiting endocytosis enhanced surface NKCC2 expression and NaCl reabsorption. We also found that ALMS1, a protein mutated in Alström syndrome, is expressed in TALs. Whole animal gene deletion of ALMS1 caused hypertension, and inhibits NKCC2 endocytosis, increasing its surface expression and renal NaCl reabsorption. Little is known about additional functions of ALMS1, however, global gene deletion of ALMS1 induces obesity, and that, in turn may affect TAL and NKCC2 function. We hypothesized that ALMS1 is a part of protein complex that binds apical NKCC2 in TALs and promotes its endocytosis. To dissect the specific role of ALMS1 in TALs, without interference of systemic effects, we studied surface NKCC2 expression and TAL mediated Na transport after inducible deletion of ALMS1 in TALs. To do this, we generated a loxP flanked exon 7 ALMS1 transgenic mouse line, that we crossed with TAL specific inducible Umod-ERT2 Cre mice (Umod-ALMS1 KO). 3 weeks after inducing Cre expression with tamoxifen, ALMS1 expression in TAL suspensions decreased by 85% (p<0.01) (n=5). In Umod-ALMS1 KO TALs the surface to total NKCC2 ratio, was increased by 37±15% compared to control floxed ALMS1 (p<0.01) (n=5). Recombinant ALMS1 (GST-Carboxyl terminus-ALMS1), or immunoprecipitation of ALMS1, pulled down NKCC2 from TAL lysates (n=3), suggesting that the mechanism by which ALMS1 regulates surface NKCC2 involves protein-protein interactions. Three weeks after inducing ALMS1 deletion, we measured bumetanide-induced natriuresis (4h) as an index of NKCC2-mediated NaCl absorption. We found that bumetanide induced UNa excretion was enhanced in Umod-ALMS1 KO, compared to control (control: 110±7 vs Umod-ALMS1 KO: 173±26 μmols Na/4h, p<0.01). We conclude that ALMS1, binds NKCC2 to regulate its surface expression. Depletion of ALMS1, specifically in the TAL enhances surface NKCC2 and TAL NaCl reabsorption. Our data indicate that regulation of the ALMS1-NKCC2 interaction in the TAL is important for renal NaCl reabsorption. Decreased ALMS1 function or expression increased TAL NaCl reabsorption and this may contribute to the hypertension and kidney disease that is associated with SNPs in the ALMS1 gene in the general population, or in patients with Alstrom Syndrome. NIH R01, Henry Ford Fund. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
2023-12-27 | Glucagon-like peptide-1 analogues in monogenic syndromic obesity: Real-world data from a large cohort of Alström syndrome patients.
Abstract Aim To examine the real‐world efficacy of glucagon‐like peptide‐1 receptor agonists (GLP‐1 RAs) in monogenic obesity in patients with Alström syndrome (ALMS). Methods We screened 72 UK adult patients with ALMS and offered treatment to 34 patients meeting one of the following criteria: body mass index of 25 kg/m 2 or higher, insulin resistance, suboptimal glycaemic control on antihyperglycaemic medications or non‐alcoholic fatty liver disease. Results In total, 30 patients, with a mean age of 31 ± 11 years and a male to‐female ratio of 2:1, completed 6 months of treatment with GLP‐1 RAs either in the form of semaglutide or exenatide. On average, treatment with GLP‐1 RAs reduced body weight by 5.4 ± 1.7 (95% confidence interval [CI] 3.6‐7) kg and HbA1c by 12 ± 3.3 (95% CI 8.7‐15.3) mmol/mol, equating to 6% weight loss ( P < .01) and 1.1% absolute reduction in HbA1c ( P < .01). Significant improvements were also observed in serum total cholesterol, triglycerides, low‐density lipoprotein cholesterol, high‐density lipoprotein cholesterol and alanine aminotransferase. The improvement of metabolic variables in our cohort of monogenic syndromic obesity was comparable with data for polygenic obesity, irrespective of weight loss. Conclusions Data from our centre highlight the non‐inferiority of GLP‐1 RAs in monogenic syndromic obesity to the available GLP‐1 RA‐use data in polygenic obesity, therefore, these agents can be considered as a treatment option in patients with ALMS, as well as other forms of monogenic obesity.
small molecules
2026-08-14 | Case Report: Efficacy and safety of SGLT2 inhibitors in patients with Alström syndrome: a follow-up report of two siblings from the same family.
Ertugliflozin, a sodium-glucose cotransporter-2 (SGLT2) inhibitor, is approved for the glycemic management of patients with type 2 diabetes. Alström syndrome (AS) is a rare autosomal recessive disorder caused by mutations in the ALMS1 gene, leading to ciliary dysfunction and multisystem involvement. AS is characterized by progressive neurosensory decline and metabolic disturbances, with symptoms such as retinal degeneration, which begins in childhood, sensorineural hearing loss, obesity, and cardiomyopathy. The 2020 European Alström Syndrome Clinical Management Guidelines, developed by experts from various medical fields, offer evidence-based recommendations for managing these symptoms and improving the quality of life of affected individuals. Severe insulin resistance, type 2 diabetes, non-alcoholic fatty liver disease, and renal failure significantly affect the quality of life and lifespan of patients with AS. To investigate the efficacy and safety of ertugliflozin in improving glycemic control, lipid metabolism, and insulin sensitivity in patients with AS. We retrospectively analyzed the clinical data of two sibling with AS treated at the Department of Endocrinology in our hospital. Follow-up data were collected and analyzed to evaluate the efficacy and safety of ertugliflozin in patients with AS. During an 11-month observation period, ertugliflozin treatment exerted favorable effects on multiple metabolic parameters in the two patients. Glycemic control improved in both patients, as evidenced by significant reductions in HbA1c levels observed at 2 months. The homeostatic model assessment of insulin resistance (HOMA-IR) showed marked improvement in Patient 1. Patient 2 showed significant early improvement in HOMA-IR, but a rebound trend was observed later, potentially related to the inherent, rapidly progressive, severe insulin resistance characteristic of puberty in this patient. Further comprehensive evaluation is required to distinguish the long-term effects of SGLT2 inhibitors, such as ertugliflozin, from the progression of type 2 diabetes. Additionally, ertugliflozin demonstrated significant regulatory effects on lipid metabolism, and no adverse events occurred during the treatment period, indicating good safety. Consistent with current clinical management guidelines for Alström syndrome, ertugliflozin demonstrated clinically meaningful reductions in fasting and postprandial glucose concentrations in two patients with AS, as documented in this longitudinal case report. Modest improvements in total cholesterol levels were also observed; however, the isolated effect of ertugliflozin on triglycerides could not be ascertained in one patient due to concurrent fibrate therapy. Early enhancements in insulin sensitivity-assessed via HOMA-IR and dynamic glucose tolerance testing-were observed during the initial treatment phase; however, this effect waned over time in Patient 2, the younger patient. The agent was generally well tolerated, with no serious adverse events reported. Owing to the inherent limitations of this analysis-including a small sample size (n = 2), absence of a control group, and lack of histopathological or mechanistic biomarker data-these observations remain preliminary and warrant validation in adequately powered, prospective, controlled clinical trials.
2026-01-19 | Clinical Presentation of a Child With a Novel ALMS1 Variant Associated With Alström Syndrome and Favorable Response to GLP-1 Receptor Agonist Therapy.
Alström syndrome (AS) is a rare autosomal-recessive ciliopathy caused by biallelic variants in ALMS1, with an incidence of 1 in 10,000 to 1 in 1,000,000 live births. We report a female diagnosed at age 5 with a previously unreported homozygous nonsense variant in ALMS1: c.4740C>G (p.Tyr1580Ter), located in exon 8, a known hotspot for pathogenic variants. The variant aligns with the loss-of-function mechanism seen in most ALMS1-related AS cases and is found within a 15 Mb run of homozygosity, consistent with her history of parental consanguinity. Her clinical picture included progressive hearing loss, dyslipidemia, and worsening hyperglycemia despite lifestyle interventions. Due to accelerated weight gain and declining glycemic control, dulaglutide, a glucagon-like peptide-1 receptor agonist (GLP-1 RA), was initiated. Over 48 weeks, BMI decreased from 190% to 160% of the 95th percentile, with a 0.95 z-score reduction, 1.2% HbA1c decrease into the normal range. This case expands our understanding of the ALMS1 mutational spectrum and provides the first longitudinal report of GLP-1 RA benefit in AS, supporting its consideration as adjunctive therapy and highlighting the need for further study.
2025-10-15 | Efficacy of Semaglutide in Pediatric Patients With Bardet-Biedl Syndrome and Alström Syndrome
Abstract Bardet-Biedl syndrome (BBS) and Alström syndrome (AS) are rare autosomal recessive ciliopathies characterized by severe multisystemic involvement, including metabolic, sensory, and developmental impairments. Both conditions result from primary cilia dysfunction, disrupting pathways such as leptin and insulin signaling, which leads to obesity and insulin resistance. While setmelanotide, a melanocortin-4 receptor agonist, may be an effective therapy for obesity in these conditions (especially BBS), its cost limits accessibility for many patients. We describe two pediatric cases (one with BBS and another with AS) demonstrating significant metabolic improvements with semaglutide, a glucagon-like peptide-1 receptor agonist. These observations suggest that some cases of BBS and AS may be treated with semaglutide.
2025-10-04 | Endocrine metabolism characteristics of Alström syndrome in 25 Chinese patients and identification of a new splice site in the ALMS1 gene.
Alström syndrome is a serious monogenic rare disease with lacking systematic analyses of its endocrine and metabolic characteristics. Clinical data were obtained from Alström syndrome, and group comparison analyses were conducted. Whole exome sequencing was used for molecular diagnosis, and miniGene experiments were performed for the ALMS1 c.9539G > A mutation. Twenty-five patients, 14 males and 11 females, with an average age of diagnosis of 7.3 years, were included. Obesity, insulin resistance, diabetes, thyroid nodules and subclinical hypothyroidism, hyperlipidemia, fatty liver, mild scoliosis and sex hormone abnormalities were common endocrine and metabolic abnormalities, whereas hypokalaemia and pancreatitis occurred only in a single case in this cohort. Among patients with Alström syndrome, the 2-h blood glucose and type III procollagen N-terminal peptide (PIIIPN-P) levels in non-obesity group were significantly greater than that in obesity group. And the TG level of Alström syndrome patients in diabetes group was higher than that in non-diabetes group. Nonsense and frameshift mutations were the main types of ALMS1 gene mutations (90%, 45/50), with c.9151_9152delCT and c.10,822 C > T being the two variants with the highest mutation frequency, accounting for 10% and 8%. c.9539G > A is a variant that affects splicing, resulting in 298 bp deletion of exon 10. Diabetes may exacerbate the development of hyperlipidaemia in Alström syndrome. Obesity management strategies may be adjusted relaxed appropriately for patients with Alström syndrome patients. c.9151_9152delCT and c.10,822 C > T mutations of ALMS1 had the highest variant frequency in this cohort, and c.9539G > A was a new likely pathogenic as splicing variant.
2025-10-01 | SUN-648 Monogenic Syndromic Obesity of Alström Syndrome as a Model of Premature Aging
Abstract Disclosure: S. Ali: None. P. Thomas: None. N. Duggal: None. G. da Silva: None. T. Geberhiwot: None. In recent years, cellular senescence has emerged as a key contributor to the pathogenesis of metabolic syndrome (MetS) and its associated complications, including obesity and type 2 diabetes (T2D). We have previously shown that patients with Alström syndrome (AS), a monogenic form of obesity characterized by extreme insulin resistance (IR) and MetS, exhibit an increased biological phenotypic age. In this study, we propose AS as a model of accelerated aging.Patients with AS (n=10) were matched with healthy control volunteers (n=10) based on gender, BMI, and age, and underwent clinical assessments along with adipose tissue and skeletal muscle biopsies. We performed β-galactosidase staining and RNA sequencing (RNA-Seq) with SanMayo analysis on subcutaneous adipose tissue (AT). The IMM-AGE metric was used to assess immune age in peripheral blood mononuclear cells (PBMCs) via fluorescence-activated cell sorting (FACS). Reverse transcription polymerase chain reaction (RT-PCR) was performed on skeletal muscle (SM) to assess the expression of senescence- associated gene sets.Our results showed a significant increase in β-galactosidase staining (55.4 ± 11.3-fold) in adipocytes of AS patients compared to controls. Differential gene expression analysis of RNA-Seq data from AT revealed significant changes in the expression of 10 genes associated with increased senescence in adipocytes, including ANG, BMP6, FGF1, IL10, IL18, IQGAP2, PGF, PLAT, SELPLG, and SPX. In parallel, RT-PCR of SM exhibited similar gene expression changes in at least half of the senescence-associated gene sets identified in AT. Furthermore, the IMM-AGE score demonstrated a significant increase in immunological age relative to chronological age in AS patients compared to controls (P < 0.01).In conclusion, our findings demonstrate that cellular senescence is prevalent in both adipose tissue and skeletal muscle in AS. Although the mechanisms underlying senescence in AS remain unclear, our results suggest that senotherapy, combined with pharmacological and/or lifestyle interventions, could emerge as a potential treatment option for obesity and its associated complications Presentation: Sunday, July 13, 2025
gene therapies
2026-01-20 | Comparative analysis of Alström syndrome and achromatopsia: Genetic insights and ocular distinctions
Abstract PURPOSE: The study compared the clinical features and ocular examination results between patients with Alström syndrome (AS) and those with achromatopsia (ACHM). MATERIALS AND METHODS: Four patients with AS and seven patients with ACHM were analyzed using whole-exome sequencing (and subsequent Sanger sequencing) to identify ALMS1 and ACHM-related disease-causing variants. Genetic profiles and clinical characteristics were assessed, with color fundus imaging, fundus autofluorescence, spectral domain optical coherence tomography (SD-OCT), and electroretinography results compared between the two groups. RESULTS: Fundus imaging revealed progressive retinal changes and extra-macular degeneration in patients with AS but stationary macular alterations in those with ACHM. SD-OCT showed that three patients with AS had outer nuclear layer (ONL) thinning and ellipsoid zone loss beyond the fovea, whereas one patient had severe retinal changes. By contrast, all patients with ACHM exhibited subfoveal ONL thinning. Full-field electroretinography revealed diminished rod and cone responses in three patients with AS but rod function preservation in all patients with ACHM. Furthermore, systemic involvement distinguished AS from ACHM. Notably, one patient with ACHM exhibited a digenic triallelic inheritance pattern. CONCLUSION: This study improves our understanding of the genetic and phenotypic differences between AS and ACHM, thereby increasing diagnostic precision.
2024-09-28 | Diseases of the primary cilia: a clinical characteristics review.
Ciliopathies encompass a broad spectrum of diseases stemming from dysfunction of the primary (non-motile) cilia, present on almost all cells in the human body. These disorders include autosomal dominant and recessive polycystic kidney diseases, nephronophthisis, and multisystem ciliopathies such as Joubert, Meckel, Bardet-Biedl, Alström, oral-facial-digital syndromes, and skeletal ciliopathies. The majority of these ciliopathies are associated with fibrocystic kidney disease resulting in progressive kidney dysfunction. In addition, many ciliopathies are associated with extra-renal manifestations including congenital hepatic fibrosis, retinal dystrophy, obesity, and brain and skeletal anomalies. The diagnoses may be challenging due to their overlapping clinical features and molecular heterogeneity. To date, over 190 genes encoding proteins that localize to the primary cilia have been identified as disease-causing. This review will discuss the clinical features of the most frequently encountered disorders of primary cilia.
2024-08-27 | Obesity in Alström Syndrome: Molecular Insights From the ALMS1 Protein and its Role in Primary Cilia
Alström syndrome is a ciliopathy caused by mutations in the ALMS1 protein. Among the classic ciliopathy-associated phenotypes, childhood obesity is one of the most penetrant clinical manifestations of Alström syndrome, affecting up to 98% of all patients.
2015-08-18 | Genetic evaluation of patients with Alström syndrome in the Polish population
Alström syndrome (AS) is a rare syndromic form of obesity and type 2 diabetes (T2D) in children coexisting with retinal dystrophy and disorders of many organs caused by the mutations in ALMS1 gene. Aim of this study was to identify the causative mutations in ALMS1 in a group of 12 patients of Polish origin with clinical symptoms of AS, and their 21 first-degree relatives. Using DNA sequencing, nine different mutations including three novel were identified. These mutations were not present in 212 Polish individuals with no symptoms of AS, subjected to whole-exome sequencing and collected in a national registry. Looking for genotype-phenotype relationships, we confirmed a severe phenotype in a boy with homozygous mutation in exon 16, and a relationship between a presence of T2D and mutations in exon 19. Evaluation of the type of mutation and its clinical effects gives hope for earlier diagnosis of AS in future patients and more advanced therapeutic approaches for patients with already diagnosed AS.
antibodies
2026-03-10 | Neutralization of DBI/ACBP for the prevention of ciliopathy-associated obesity.
Obesity is a feature of only a subset of ciliopathies, including Alström syndrome, a rare genetic disorder caused by ALMS1 deficiency. In our recent work, we applied integrative multi-omics network analysis to one of these ciliopathies that develop with obesity, the Alms1-deficient mouse model and identified DBI/ACBP (diazepam binding inhibitor, acyl-CoA binding protein) as a central driver of ciliopathy-associated obesity. We found that ALMS1 deficiency induces early hepatic dyslipidemia accompanied by impaired macroautophagy/autophagy and pathological accumulation of DBI/ACBP, preceding overt obesity. Importantly, prophylactic DBI/ACBP neutralization with monoclonal antibodies prevents weight gain and metabolic alterations without restoring autophagic markers, indicating that DBI/ACBP acts as an obesogenic effector downstream of, or parallel to, defective autophagy. These findings position DBI/ACBP as a metabolically relevant autophagy-associated regulator in ciliopathy and suggest that therapeutic benefit can be achieved by targeting autophagy-linked effectors without directly correcting autophagic flux. This punctum discusses our results in the context of hepatic autophagy and lipid metabolism, highlighting DBI/ACBP as a mechanistic link between ciliary dysfunction, altered autophagy, and metabolic disease.
2026-01-10 | Identification of ACBP as a potential target in ciliopathic obesity through multi-omics network analysis.
Ciliopathies are genetic disorders characterized by defective primary cilia function, with obesity as a clinical manifestation in certain cases, including Alström syndrome, which is caused by ALMS1 mutations. The link between cilia and lipid metabolism remains poorly understood, but evidence suggests a role for impaired autophagy. Autophagy affects both intra- and extracellular levels of ACBP, which can act as an obesogenic factor. Our multi-omics study reveals early hepatic dyslipidemia, impaired autophagy, and hepatic accumulation of ACBP in presymptomatic male mice lacking Alms1 gene. These conditions are consistent with the obesogenic phenotype and with alterations in the gut microbiota that manifest as the mice age and develop obesity. Importantly, reducing excessive ACBP with a neutralizing monoclonal antibody limits weight gain and metabolic defects in Alms1-/- mice in an autophagy-independent manner. Altogether, the data support the idea that ciliopathy-associated obesity, particularly Alström syndrome, may be mitigated by ACBP neutralization.
proteins
2026-04-10 | A case of Alström syndrome with growth hormone deficiency and dyslipidemia: a novel homozygous frameshift variant of ALMS1 c.5763del.
Alström syndrome (AS, OMIM #203800) is a rare autosomal recessive disorder caused by biallelic pathogenic variants in ALMS1, characterized by obesity, cardiomyopathy, retinal dystrophy, sensorineural hearing loss, and progressive hepatic and renal involvement. We report a pediatric case of AS complicated by growth hormone deficiency (GHD), focusing on the clinical course and potential metabolic effects of growth hormone (GH) replacement therapy. A 13-year-old girl with AS presented with severe dyslipidemia, including hypertriglyceridemia (727 mg/dL), elevated total cholesterol (251 mg/dL), and low high-density lipoprotein cholesterol (23 mg/dL), together with dilated cardiomyopathy. She was diagnosed with GHD at 3 years of age, with a height of -3.6 SD. GH replacement therapy led to sustained improvement in linear growth, reaching -1.9 SD, and was associated with long-term maintenance of lipid parameters within the normal range. Whole-exome sequencing identified a previously unreported homozygous frameshift variant in ALMS1 (NM_001378454.1:c.5763del; p.(Phe1921Leufs*18)). This case suggests that GH replacement therapy may contribute to improved lipid metabolism in patients with AS complicated by GHD. In addition, it expands the mutational spectrum of ALMS1 and highlights the potential metabolic benefits of early endocrine intervention in AS.
2025-10-17 | Effect of Tirzepatide in an Adolescent With Early-Onset Obesity, Hyperphagia, and Type 2 Diabetes
Early-onset severe obesity is rare and largely treatment-resistant to standard measures. Etiologies include syndromic disorders (Prader-Willi, Bardet-Biedl and Alström syndromes), monogenic defects of appetite-regulating pathways - most significantly melanocortin-4-receptor (MC4R) deficiency, but also leptin receptor (LEPR), pro-opiomelanocortin (POMC), and secondary hypothalamic injury, most commonly craniopharyngiomas. Most childhood obesity, however, is polygenic, arising from interactions of environmental and genetic factors. In many patients, no clear etiology is identified. Treatment remains challenging, particularly if hyperphagia and reduced satiety are predominant presenting features. We describe the case of a 19-year-old male with a history of autism spectrum disorder, attention-deficit hyperactivity disorder (ADHD), type 2 diabetes mellitus (T2DM) and morbid obesity, who showed a clinically significant response to tirzepatide therapy following failed conventional interventions. This case highlights the potential role of dual incretin therapy in adolescents with severe early-onset obesity and hyperphagia, even in the absence (based on present knowledge) of identifiable hypothalamic or genetic pathology.
2025-04-30 | Effectiveness of the Dual GIP/GLP1-Agonist Tirzepatide in 2 Cases of Alström Syndrome, a Rare Obesity Syndrome.
Tirzepatide, a dual glucose-dependent insulinotropic peptide/glucagon-like peptide 1 (GIP/GLP1) receptor agonist, was recently approved for type 2 diabetes and weight management. Alström syndrome (AS) is a rare, genetic, multisystemic disorder, characterized by cone-rod dystrophy, progressive hearing loss, obesity, and diabetes with profound insulin resistance due to marked hyperphagia. Here we highlight the potential of tirzepatide as a novel therapeutic option for improving glycemic outcomes, metabolic dysfunction-associated steatotic liver disease (MASLD), and effectively reducing body weight in individuals with AS. We present the first 2 reported cases of people living with AS treated with tirzepatide. Two individuals with AS, previously treated with semaglutide, received tirzepatide at our clinic. The first, a 23-year-old man with 18 months of treatment, experienced a weight loss of -28 kg (113.6 to 83 kg, -26.9%); glycated hemoglobin A1c decreased by -0.4% (6.7% to 6.3%), with considerable reductions in daily insulin doses of -96 IU/day (-83%; 58 to 20 IU insulin glargine and 58 to 0 IU prandial insulin), while maintaining oral antidiabetics. Hepatic steatosis, with a previous fat fraction of 20%, resolved as confirmed by magnetic resonance imaging (MRI). The second, a 20-year-old man with previously well-controlled diabetes, was followed up for 9 months and showed a weight reduction of -9.5 kg (132 kg to 122.5 kg; -7.2%) with a reduction of hepatic lipid content from 21% at the latest MRI to 11% after approximately 3 months of therapy. Tirzepatide shows great effectiveness with regard to body weight, MASLD, and insulin resistance in AS. Follow-up studies with larger cohorts have to be performed to confirm these findings.
2024-05-01 | Thick Ascending Limbs (TALs)-specific deletion of ALMS1 (Alstrom syndrome 1) increases surface NKCC2 expression and NaCl reabsorption in the TAL
The regulation of NKCC2 mediated NaCl reabsorption in Thick Ascending Libs (TALs) is essential to salt homeostasis and blood pressure regulation. Previously, our lab showed that NKCC2 activity is regulated by membrane traffcking and inhibiting endocytosis enhanced surface NKCC2 expression and NaCl reabsorption. We also found that ALMS1, a protein mutated in Alström syndrome, is expressed in TALs. Whole animal gene deletion of ALMS1 caused hypertension, and inhibits NKCC2 endocytosis, increasing its surface expression and renal NaCl reabsorption. Little is known about additional functions of ALMS1, however, global gene deletion of ALMS1 induces obesity, and that, in turn may affect TAL and NKCC2 function. We hypothesized that ALMS1 is a part of protein complex that binds apical NKCC2 in TALs and promotes its endocytosis. To dissect the specific role of ALMS1 in TALs, without interference of systemic effects, we studied surface NKCC2 expression and TAL mediated Na transport after inducible deletion of ALMS1 in TALs. To do this, we generated a loxP flanked exon 7 ALMS1 transgenic mouse line, that we crossed with TAL specific inducible Umod-ERT2 Cre mice (Umod-ALMS1 KO). 3 weeks after inducing Cre expression with tamoxifen, ALMS1 expression in TAL suspensions decreased by 85% (p<0.01) (n=5). In Umod-ALMS1 KO TALs the surface to total NKCC2 ratio, was increased by 37±15% compared to control floxed ALMS1 (p<0.01) (n=5). Recombinant ALMS1 (GST-Carboxyl terminus-ALMS1), or immunoprecipitation of ALMS1, pulled down NKCC2 from TAL lysates (n=3), suggesting that the mechanism by which ALMS1 regulates surface NKCC2 involves protein-protein interactions. Three weeks after inducing ALMS1 deletion, we measured bumetanide-induced natriuresis (4h) as an index of NKCC2-mediated NaCl absorption. We found that bumetanide induced UNa excretion was enhanced in Umod-ALMS1 KO, compared to control (control: 110±7 vs Umod-ALMS1 KO: 173±26 μmols Na/4h, p<0.01). We conclude that ALMS1, binds NKCC2 to regulate its surface expression. Depletion of ALMS1, specifically in the TAL enhances surface NKCC2 and TAL NaCl reabsorption. Our data indicate that regulation of the ALMS1-NKCC2 interaction in the TAL is important for renal NaCl reabsorption. Decreased ALMS1 function or expression increased TAL NaCl reabsorption and this may contribute to the hypertension and kidney disease that is associated with SNPs in the ALMS1 gene in the general population, or in patients with Alstrom Syndrome. NIH R01, Henry Ford Fund. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
2023-12-27 | Glucagon-like peptide-1 analogues in monogenic syndromic obesity: Real-world data from a large cohort of Alström syndrome patients.
Abstract Aim To examine the real‐world efficacy of glucagon‐like peptide‐1 receptor agonists (GLP‐1 RAs) in monogenic obesity in patients with Alström syndrome (ALMS). Methods We screened 72 UK adult patients with ALMS and offered treatment to 34 patients meeting one of the following criteria: body mass index of 25 kg/m 2 or higher, insulin resistance, suboptimal glycaemic control on antihyperglycaemic medications or non‐alcoholic fatty liver disease. Results In total, 30 patients, with a mean age of 31 ± 11 years and a male to‐female ratio of 2:1, completed 6 months of treatment with GLP‐1 RAs either in the form of semaglutide or exenatide. On average, treatment with GLP‐1 RAs reduced body weight by 5.4 ± 1.7 (95% confidence interval [CI] 3.6‐7) kg and HbA1c by 12 ± 3.3 (95% CI 8.7‐15.3) mmol/mol, equating to 6% weight loss ( P < .01) and 1.1% absolute reduction in HbA1c ( P < .01). Significant improvements were also observed in serum total cholesterol, triglycerides, low‐density lipoprotein cholesterol, high‐density lipoprotein cholesterol and alanine aminotransferase. The improvement of metabolic variables in our cohort of monogenic syndromic obesity was comparable with data for polygenic obesity, irrespective of weight loss. Conclusions Data from our centre highlight the non‐inferiority of GLP‐1 RAs in monogenic syndromic obesity to the available GLP‐1 RA‐use data in polygenic obesity, therefore, these agents can be considered as a treatment option in patients with ALMS, as well as other forms of monogenic obesity.
small molecules
2026-08-14 | Case Report: Efficacy and safety of SGLT2 inhibitors in patients with Alström syndrome: a follow-up report of two siblings from the same family.
Ertugliflozin, a sodium-glucose cotransporter-2 (SGLT2) inhibitor, is approved for the glycemic management of patients with type 2 diabetes. Alström syndrome (AS) is a rare autosomal recessive disorder caused by mutations in the ALMS1 gene, leading to ciliary dysfunction and multisystem involvement. AS is characterized by progressive neurosensory decline and metabolic disturbances, with symptoms such as retinal degeneration, which begins in childhood, sensorineural hearing loss, obesity, and cardiomyopathy. The 2020 European Alström Syndrome Clinical Management Guidelines, developed by experts from various medical fields, offer evidence-based recommendations for managing these symptoms and improving the quality of life of affected individuals. Severe insulin resistance, type 2 diabetes, non-alcoholic fatty liver disease, and renal failure significantly affect the quality of life and lifespan of patients with AS. To investigate the efficacy and safety of ertugliflozin in improving glycemic control, lipid metabolism, and insulin sensitivity in patients with AS. We retrospectively analyzed the clinical data of two sibling with AS treated at the Department of Endocrinology in our hospital. Follow-up data were collected and analyzed to evaluate the efficacy and safety of ertugliflozin in patients with AS. During an 11-month observation period, ertugliflozin treatment exerted favorable effects on multiple metabolic parameters in the two patients. Glycemic control improved in both patients, as evidenced by significant reductions in HbA1c levels observed at 2 months. The homeostatic model assessment of insulin resistance (HOMA-IR) showed marked improvement in Patient 1. Patient 2 showed significant early improvement in HOMA-IR, but a rebound trend was observed later, potentially related to the inherent, rapidly progressive, severe insulin resistance characteristic of puberty in this patient. Further comprehensive evaluation is required to distinguish the long-term effects of SGLT2 inhibitors, such as ertugliflozin, from the progression of type 2 diabetes. Additionally, ertugliflozin demonstrated significant regulatory effects on lipid metabolism, and no adverse events occurred during the treatment period, indicating good safety. Consistent with current clinical management guidelines for Alström syndrome, ertugliflozin demonstrated clinically meaningful reductions in fasting and postprandial glucose concentrations in two patients with AS, as documented in this longitudinal case report. Modest improvements in total cholesterol levels were also observed; however, the isolated effect of ertugliflozin on triglycerides could not be ascertained in one patient due to concurrent fibrate therapy. Early enhancements in insulin sensitivity-assessed via HOMA-IR and dynamic glucose tolerance testing-were observed during the initial treatment phase; however, this effect waned over time in Patient 2, the younger patient. The agent was generally well tolerated, with no serious adverse events reported. Owing to the inherent limitations of this analysis-including a small sample size (n = 2), absence of a control group, and lack of histopathological or mechanistic biomarker data-these observations remain preliminary and warrant validation in adequately powered, prospective, controlled clinical trials.
2026-01-19 | Clinical Presentation of a Child With a Novel ALMS1 Variant Associated With Alström Syndrome and Favorable Response to GLP-1 Receptor Agonist Therapy.
Alström syndrome (AS) is a rare autosomal-recessive ciliopathy caused by biallelic variants in ALMS1, with an incidence of 1 in 10,000 to 1 in 1,000,000 live births. We report a female diagnosed at age 5 with a previously unreported homozygous nonsense variant in ALMS1: c.4740C>G (p.Tyr1580Ter), located in exon 8, a known hotspot for pathogenic variants. The variant aligns with the loss-of-function mechanism seen in most ALMS1-related AS cases and is found within a 15 Mb run of homozygosity, consistent with her history of parental consanguinity. Her clinical picture included progressive hearing loss, dyslipidemia, and worsening hyperglycemia despite lifestyle interventions. Due to accelerated weight gain and declining glycemic control, dulaglutide, a glucagon-like peptide-1 receptor agonist (GLP-1 RA), was initiated. Over 48 weeks, BMI decreased from 190% to 160% of the 95th percentile, with a 0.95 z-score reduction, 1.2% HbA1c decrease into the normal range. This case expands our understanding of the ALMS1 mutational spectrum and provides the first longitudinal report of GLP-1 RA benefit in AS, supporting its consideration as adjunctive therapy and highlighting the need for further study.
2025-10-15 | Efficacy of Semaglutide in Pediatric Patients With Bardet-Biedl Syndrome and Alström Syndrome
Abstract Bardet-Biedl syndrome (BBS) and Alström syndrome (AS) are rare autosomal recessive ciliopathies characterized by severe multisystemic involvement, including metabolic, sensory, and developmental impairments. Both conditions result from primary cilia dysfunction, disrupting pathways such as leptin and insulin signaling, which leads to obesity and insulin resistance. While setmelanotide, a melanocortin-4 receptor agonist, may be an effective therapy for obesity in these conditions (especially BBS), its cost limits accessibility for many patients. We describe two pediatric cases (one with BBS and another with AS) demonstrating significant metabolic improvements with semaglutide, a glucagon-like peptide-1 receptor agonist. These observations suggest that some cases of BBS and AS may be treated with semaglutide.
2025-10-04 | Endocrine metabolism characteristics of Alström syndrome in 25 Chinese patients and identification of a new splice site in the ALMS1 gene.
Alström syndrome is a serious monogenic rare disease with lacking systematic analyses of its endocrine and metabolic characteristics. Clinical data were obtained from Alström syndrome, and group comparison analyses were conducted. Whole exome sequencing was used for molecular diagnosis, and miniGene experiments were performed for the ALMS1 c.9539G > A mutation. Twenty-five patients, 14 males and 11 females, with an average age of diagnosis of 7.3 years, were included. Obesity, insulin resistance, diabetes, thyroid nodules and subclinical hypothyroidism, hyperlipidemia, fatty liver, mild scoliosis and sex hormone abnormalities were common endocrine and metabolic abnormalities, whereas hypokalaemia and pancreatitis occurred only in a single case in this cohort. Among patients with Alström syndrome, the 2-h blood glucose and type III procollagen N-terminal peptide (PIIIPN-P) levels in non-obesity group were significantly greater than that in obesity group. And the TG level of Alström syndrome patients in diabetes group was higher than that in non-diabetes group. Nonsense and frameshift mutations were the main types of ALMS1 gene mutations (90%, 45/50), with c.9151_9152delCT and c.10,822 C > T being the two variants with the highest mutation frequency, accounting for 10% and 8%. c.9539G > A is a variant that affects splicing, resulting in 298 bp deletion of exon 10. Diabetes may exacerbate the development of hyperlipidaemia in Alström syndrome. Obesity management strategies may be adjusted relaxed appropriately for patients with Alström syndrome patients. c.9151_9152delCT and c.10,822 C > T mutations of ALMS1 had the highest variant frequency in this cohort, and c.9539G > A was a new likely pathogenic as splicing variant.
2025-10-01 | SUN-648 Monogenic Syndromic Obesity of Alström Syndrome as a Model of Premature Aging
Abstract Disclosure: S. Ali: None. P. Thomas: None. N. Duggal: None. G. da Silva: None. T. Geberhiwot: None. In recent years, cellular senescence has emerged as a key contributor to the pathogenesis of metabolic syndrome (MetS) and its associated complications, including obesity and type 2 diabetes (T2D). We have previously shown that patients with Alström syndrome (AS), a monogenic form of obesity characterized by extreme insulin resistance (IR) and MetS, exhibit an increased biological phenotypic age. In this study, we propose AS as a model of accelerated aging.Patients with AS (n=10) were matched with healthy control volunteers (n=10) based on gender, BMI, and age, and underwent clinical assessments along with adipose tissue and skeletal muscle biopsies. We performed β-galactosidase staining and RNA sequencing (RNA-Seq) with SanMayo analysis on subcutaneous adipose tissue (AT). The IMM-AGE metric was used to assess immune age in peripheral blood mononuclear cells (PBMCs) via fluorescence-activated cell sorting (FACS). Reverse transcription polymerase chain reaction (RT-PCR) was performed on skeletal muscle (SM) to assess the expression of senescence- associated gene sets.Our results showed a significant increase in β-galactosidase staining (55.4 ± 11.3-fold) in adipocytes of AS patients compared to controls. Differential gene expression analysis of RNA-Seq data from AT revealed significant changes in the expression of 10 genes associated with increased senescence in adipocytes, including ANG, BMP6, FGF1, IL10, IL18, IQGAP2, PGF, PLAT, SELPLG, and SPX. In parallel, RT-PCR of SM exhibited similar gene expression changes in at least half of the senescence-associated gene sets identified in AT. Furthermore, the IMM-AGE score demonstrated a significant increase in immunological age relative to chronological age in AS patients compared to controls (P < 0.01).In conclusion, our findings demonstrate that cellular senescence is prevalent in both adipose tissue and skeletal muscle in AS. Although the mechanisms underlying senescence in AS remain unclear, our results suggest that senotherapy, combined with pharmacological and/or lifestyle interventions, could emerge as a potential treatment option for obesity and its associated complications Presentation: Sunday, July 13, 2025
gene therapies
2026-01-20 | Comparative analysis of Alström syndrome and achromatopsia: Genetic insights and ocular distinctions
Abstract PURPOSE: The study compared the clinical features and ocular examination results between patients with Alström syndrome (AS) and those with achromatopsia (ACHM). MATERIALS AND METHODS: Four patients with AS and seven patients with ACHM were analyzed using whole-exome sequencing (and subsequent Sanger sequencing) to identify ALMS1 and ACHM-related disease-causing variants. Genetic profiles and clinical characteristics were assessed, with color fundus imaging, fundus autofluorescence, spectral domain optical coherence tomography (SD-OCT), and electroretinography results compared between the two groups. RESULTS: Fundus imaging revealed progressive retinal changes and extra-macular degeneration in patients with AS but stationary macular alterations in those with ACHM. SD-OCT showed that three patients with AS had outer nuclear layer (ONL) thinning and ellipsoid zone loss beyond the fovea, whereas one patient had severe retinal changes. By contrast, all patients with ACHM exhibited subfoveal ONL thinning. Full-field electroretinography revealed diminished rod and cone responses in three patients with AS but rod function preservation in all patients with ACHM. Furthermore, systemic involvement distinguished AS from ACHM. Notably, one patient with ACHM exhibited a digenic triallelic inheritance pattern. CONCLUSION: This study improves our understanding of the genetic and phenotypic differences between AS and ACHM, thereby increasing diagnostic precision.
2024-09-28 | Diseases of the primary cilia: a clinical characteristics review.
Ciliopathies encompass a broad spectrum of diseases stemming from dysfunction of the primary (non-motile) cilia, present on almost all cells in the human body. These disorders include autosomal dominant and recessive polycystic kidney diseases, nephronophthisis, and multisystem ciliopathies such as Joubert, Meckel, Bardet-Biedl, Alström, oral-facial-digital syndromes, and skeletal ciliopathies. The majority of these ciliopathies are associated with fibrocystic kidney disease resulting in progressive kidney dysfunction. In addition, many ciliopathies are associated with extra-renal manifestations including congenital hepatic fibrosis, retinal dystrophy, obesity, and brain and skeletal anomalies. The diagnoses may be challenging due to their overlapping clinical features and molecular heterogeneity. To date, over 190 genes encoding proteins that localize to the primary cilia have been identified as disease-causing. This review will discuss the clinical features of the most frequently encountered disorders of primary cilia.
2024-08-27 | Obesity in Alström Syndrome: Molecular Insights From the ALMS1 Protein and its Role in Primary Cilia
Alström syndrome is a ciliopathy caused by mutations in the ALMS1 protein. Among the classic ciliopathy-associated phenotypes, childhood obesity is one of the most penetrant clinical manifestations of Alström syndrome, affecting up to 98% of all patients.
2015-08-18 | Genetic evaluation of patients with Alström syndrome in the Polish population
Alström syndrome (AS) is a rare syndromic form of obesity and type 2 diabetes (T2D) in children coexisting with retinal dystrophy and disorders of many organs caused by the mutations in ALMS1 gene. Aim of this study was to identify the causative mutations in ALMS1 in a group of 12 patients of Polish origin with clinical symptoms of AS, and their 21 first-degree relatives. Using DNA sequencing, nine different mutations including three novel were identified. These mutations were not present in 212 Polish individuals with no symptoms of AS, subjected to whole-exome sequencing and collected in a national registry. Looking for genotype-phenotype relationships, we confirmed a severe phenotype in a boy with homozygous mutation in exon 16, and a relationship between a presence of T2D and mutations in exon 19. Evaluation of the type of mutation and its clinical effects gives hope for earlier diagnosis of AS in future patients and more advanced therapeutic approaches for patients with already diagnosed AS.
antibodies
2026-03-10 | Neutralization of DBI/ACBP for the prevention of ciliopathy-associated obesity.
Obesity is a feature of only a subset of ciliopathies, including Alström syndrome, a rare genetic disorder caused by ALMS1 deficiency. In our recent work, we applied integrative multi-omics network analysis to one of these ciliopathies that develop with obesity, the Alms1-deficient mouse model and identified DBI/ACBP (diazepam binding inhibitor, acyl-CoA binding protein) as a central driver of ciliopathy-associated obesity. We found that ALMS1 deficiency induces early hepatic dyslipidemia accompanied by impaired macroautophagy/autophagy and pathological accumulation of DBI/ACBP, preceding overt obesity. Importantly, prophylactic DBI/ACBP neutralization with monoclonal antibodies prevents weight gain and metabolic alterations without restoring autophagic markers, indicating that DBI/ACBP acts as an obesogenic effector downstream of, or parallel to, defective autophagy. These findings position DBI/ACBP as a metabolically relevant autophagy-associated regulator in ciliopathy and suggest that therapeutic benefit can be achieved by targeting autophagy-linked effectors without directly correcting autophagic flux. This punctum discusses our results in the context of hepatic autophagy and lipid metabolism, highlighting DBI/ACBP as a mechanistic link between ciliary dysfunction, altered autophagy, and metabolic disease.
2026-01-10 | Identification of ACBP as a potential target in ciliopathic obesity through multi-omics network analysis.
Ciliopathies are genetic disorders characterized by defective primary cilia function, with obesity as a clinical manifestation in certain cases, including Alström syndrome, which is caused by ALMS1 mutations. The link between cilia and lipid metabolism remains poorly understood, but evidence suggests a role for impaired autophagy. Autophagy affects both intra- and extracellular levels of ACBP, which can act as an obesogenic factor. Our multi-omics study reveals early hepatic dyslipidemia, impaired autophagy, and hepatic accumulation of ACBP in presymptomatic male mice lacking Alms1 gene. These conditions are consistent with the obesogenic phenotype and with alterations in the gut microbiota that manifest as the mice age and develop obesity. Importantly, reducing excessive ACBP with a neutralizing monoclonal antibody limits weight gain and metabolic defects in Alms1-/- mice in an autophagy-independent manner. Altogether, the data support the idea that ciliopathy-associated obesity, particularly Alström syndrome, may be mitigated by ACBP neutralization.
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Drug Discovery Landscape
4 orphan drug designations for Alström syndrome.
4 orphan drug designations for Alström syndrome.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
setmelanotide | small molecules | FDA | 2020-03-04 | — | Rhythm Pharmaceuticals, Inc |
Setmelanotide | small molecules | EMA | 2020-01-09 | — | Rhythm Pharmaceuticals Netherlands B.V. |
3-pentylbenzeneacetic acid sodium salt | small molecules | FDA | 2017-02-28 | — | Liminal BioSciences Limited |
Setogepram sodium [PBI-4050] | small molecules | EMA | 2017-01-12 | — | [INACTIVE] Prometic Pharma SMT B.V. |
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