Hematopoietic stem cells and metabolic deterioration in Alström syndrome, a rare genetic model of the metabolic syndrome

Purpose: Alström syndrome (AS) is a rare genetic disease caused by ALMS1 mutations, characterized by short stature, vision and hearing loss. AS patients develop the metabolic syndrome, long-term organ complications, and die prematurely. We explored the association between AS and shortage of hematopoietic stem/progenitor cells (HSPCs), which is linked with metabolic diseases and predict diabetic complications. Methods: We included patients with AS at a national referral Center. We measured HSPCs with flow cytometry at baseline and follow-up. We followed patients up to January 2022 for metabolic worsening and end-organ damage. We evaluated HSPC levels and mobilization as well as bone marrow histology in a murine model of AS. Results: In 23 patients with AS, we found significantly lower circulating HSPCs compared to healthy blood donors (-40%; p = 0.002) and age/sex matched patients (-25%; p = 0.022). Longitudinally, HSPCs significantly declined by further 20% in AS patients over a median of 36 months (IQR 30-44). AS patients who displayed metabolic deterioration over 5.3 years had lower levels of HSPCs both at baseline and at last observation, as compared to those who did not deteriorate. Alms1-mutated mice were obese and insulin-resistant and displayed significantly reduced circulating HSPCs, despite no overt hematological abnormality. Contrary to what observed in diabetic mice, HSPC mobilization and bone marrow structure were unaffected. Conclusion: We found depletion of HSPCs in AS patients, which was recapitulated in Alms1-mutated mice. Larger and longer studies will be needed to establish HSPCs shortage as a driver of metabolic deterioration leading to end-organ damage in AS.