Context: Alström syndrome (AS) is a monogenic form of infancy-onset obesity and insulin resistance, caused by ALMS1 mutations. The natural history of the insulin resistance is unknown, in particular how this relates to changes in body composition. It is also unclear how ALMS1 mutations relate to the characteristic phenotype.

Objectives: To characterize body composition and metabolic parameters; to establish ALMS1 mutation spectrum of UK AS patients and determine whether a genotype-phenotype correlation exists.

Design & Patients: Cross-sectional cohort study of 12 unrelated subjects with AS. Age-standardized body composition was assessed by anthropometry and dual energy x-ray absorptiometry (DXA), and insulin sensitivity by homeostasis model assessment (HOMA). The exons and intron-exon boundaries of ALMS1 were directly sequenced.

Setting: The study was performed during the annual Alström Syndrome UK multidiscliplinary screening clinic.

Results: AS patients have early-onset obesity, but BMI, waist circumference and body fat from DXA were negatively correlated with age (r = -0.37, P = 0.2; r = -0.84, P = 0.002 and r = -0.6, P = 0.05). Despite this insulin resistance increased, demonstrated by raised fasting insulin and fall in HOMA S% with age (r = -0.64, P = 0.02).

ALMS1 mutations were identified in 10/12 patients, with a potential founder mutation in exon 16 present in 5 (np 10775del (C); Del3592fs/ter3597). No genotype-phenotype correlation was observed.

Conclusions: We identified mutations in ALMS1 in > 80% of patients with no genotype-phenotype correlation. In AS, severe childhood obesity, waist circumference and body fat decrease with age, while insulin resistance increases. The abdominal obesity, insulin resistance, diabetes, hypertriglyceridemia and hypertension suggest that AS could represent a monogenic model for the metabolic syndrome.