Alström syndrome

Alström syndrome typically presents in infancy with nystagmus due to cone-rod dystrophy or with infantile cardiomyopathy. Cone-rod dystrophy is associated with photodysphoria, progressive visual loss, and abnormal full-field electroretinography from birth. More than 40% of affected infants develop a transient but severe between three weeks and four months of age, and approximately 20% later develop progressive restrictive cardiomyopathy during adolescence or adulthood. Early-childhood obesity, progressive bilateral sensorineural hearing loss, severe insulin resistance progressing to type 2 diabetes mellitus by the third decade, hepatic steatosis with a risk of advanced NAFLD and cirrhosis, slowly progressive renal disease that may reach end-stage kidney disease in late adolescence, hypogonadism, and hypothyroidism evolve through adolescence and adulthood. Clinical variability is considerable, including among affected siblings.

Alström syndrome is an ultra-rare disorder with an estimated prevalence of approximately 1 in 1,000,000 individuals, although higher frequencies have been reported in genetically isolated populations.

Alström syndrome is caused by biallelic germline pathogenic variants in ALMS1 on chromosome 2p13.1. ALMS1 encodes a large centrosome- and basal body-associated protein that is involved in the function and maintenance of primary cilia. Additional roles in intracellular trafficking, cytoskeletal organisation, cell-cycle regulation, adipogenesis, and glucose metabolism have been proposed. Most pathogenic variants are truncating variants, including nonsense and frameshift variants, that are predicted to result in loss of normal protein function. Locus-specific databases catalogue the reported variant spectrum.

Alström syndrome is inherited in an autosomal recessive manner. At conception, each sibling of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing of at-risk relatives requires prior identification of the familial pathogenic ALMS1 variants.

The diagnosis is based on characteristic clinical findings and can be supported by the age-specific diagnostic criteria proposed by . These criteria define major and minor findings across three age groups (birth to 2 years, 3 to 14 years, and ≥15 years). The diagnosis can be confirmed by the identification of biallelic pathogenic variants in the ALMS1 gene. Supporting investigations include full-field electroretinography, which is typically abnormal from birth, echocardiography for infantile or restrictive cardiomyopathy, cardiovascular MRI for the assessment of myocardial fibrosis, and renal and liver imaging.

Main differential diagnoses include:

• : later-onset rod-cone dystrophy, polydactyly, and more frequent cognitive impairment; BBS1, BBS10, MKKS, and others
• : overlapping cardiomyopathy, sensorineural hearing loss, and retinopathy, often accompanied by neurological involvement and muscle weakness; mitochondrial DNA and nuclear genes
• : isolated infantile retinal dystrophy with little or no systemic involvement; CEP290, RPE65, GUCY2D, and others

• Establishing the diagnosis: Identification of biallelic pathogenic variants in ALMS1 confirms the molecular diagnosis in individuals with clinical features suggestive of Alström syndrome, thereby enabling condition-specific surveillance and individualised management.
• Identification of the underlying familial pathogenic variants enables predictive testing of at-risk relatives and provides information relevant to reproductive counselling.

• Paisey RB, Steeds R, Barrett T, Williams D, Geberhiwot T, Gunay-Aygun M. Alström syndrome. In: Adam MP, Bick S, Mirzaa GM, et al., editors. GeneReviews^® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2026. PMID: .
• Tahani N, Maffei P, Dollfus H, Paisey R, Valverde D, Milan G, et al. Consensus clinical management guidelines for Alström syndrome. Orphanet J Rare Dis. 2020;15(1):253. PMID: .