Alstrom syndrome: an ultra-rare monogenic disorder as a model for insulin resistance, type 2 diabetes mellitus and obesity

Background Alstrom syndrome (ALMS) is a monogenic ultra-rare disorder with a prevalence of one per million inhabitants caused by pathogenic variants of ALMS1 gene. ALMS1 is located on chromosome 2p13, spans 23 exons and encodes a predicted 461.2-kDa protein of 4169 amino acids. The infantile cone-rod dystrophy with nystagmus and severe visual impairment is the earliest and most consistent clinical manifestation of ALMS. In addition, infantile transient cardiomyopathy, early childhood obesity with hyperphagia, deafness, insulin resistance (IR), type 2 diabetes mellitus (T2DM), systemic fibrosis and progressive renal or liver dysfunction are common findings. ALMS1 encodes a large ubiquitously expressed protein that is associated with the centrosome and the basal body of primary cilium. Current research The localisation of ALMS1 to the ciliary basal body suggests its contribution to ciliogenesis and/or normal ciliary function, or centriolar stability. ALMS1 regulate glucose transport through the actin cytoskeleton, which plays an important role in insulin-stimulated GLUT4 transport. Both extreme IR and beta-cell failure are the two determinant factors responsible for the development of glucose metabolism alterations in ALMS. Treatment Currently, there is no known cure for ALMS other than managing the underlying systemic diseases. When possible, individuals with ALMS and families should be referred to a centre of expertise and followed by a multidisciplinary team. Lifestyle modification, aerobic exercise and dietary induced weight loss are highly recommended as primary treatment for ALMS patients with T2DM and obesity. Conclusion Managing a rare disease requires not only medical care but also a support network including patient associations.

Automated summary

Alstrom syndrome is a rare monogenic disorder caused by pathogenic variants of the ALMS1 gene, with common manifestations including retinal dystrophy, cardiomyopathy, obesity, deafness, insulin resistance, diabetes, fibrosis, and progressive renal or liver dysfunction. The ALMS1 protein is associated with the ciliary basal body and may play a role in ciliogenesis and normal ciliary function. Treatment options are currently limited to managing systemic diseases and lifestyle modifications for associated conditions like diabetes and obesity.