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:
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.
2026-04-10 | 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.
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.
2026-01-20 | 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.
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.
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.
2026-04-10 | 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.
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.
2026-01-20 | 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.
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.
Access all drug discovery papers and probability of success in trials forecasts:
Access all drug discovery papers and probability of success in trials forecasts:
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. |
Let's accelerate rare disease drug discovery
Let's accelerate drug discovery
Get access to Explority AI's forecasts to outperform average preclinical success rates. Whether you're expanding your R&D pipeline, evaluating a partnership, or simply have a question — we'd love to hear from you.