Syndromic Obesity and Diabetes: Changes in Body Composition with Age and Mutation Analysis of ALMS1 in 12 United Kingdom Kindreds with Alström Syndrome

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...

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Published in:The journal of clinical endocrinology and metabolism 2006-08, Vol.91 (8), p.3110-3116
Main Authors: Minton, J A. L, Owen, K R, Ricketts, C J, Crabtree, N, Shaikh, G, Ehtisham, S, Porter, J R, Carey, C, Hodge, D, Paisey, R, Walker, M, Barrett, T G
Format: Article
Language:English
Subjects:
Absorptiometry, Photon
Adipose Tissue
Adolescent
Adult
Aging
Anthropometry
Biological and medical sciences
Body Composition
Body Mass Index
Child
Child, Preschool
Diabetes Mellitus - genetics
Diabetes Mellitus - physiopathology
Diabetes. Impaired glucose tolerance
DNA Mutational Analysis
Endocrine pancreas. Apud cells (diseases)
Endocrinopathies
Etiopathogenesis. Screening. Investigations. Target tissue resistance
Female
Founder Effect
Fundamental and applied biological sciences. Psychology
Genotype
Hearing Loss, Sensorineural - genetics
Humans
Hyperinsulinism - genetics
Hypertension - genetics
Hypertriglyceridemia - genetics
Insulin Resistance - genetics
Male
Medical sciences
Mutation
Obesity - genetics
Obesity - physiopathology
Phenotype
Proteins - genetics
Syndrome
United Kingdom
Vertebrates: endocrinology
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Summary: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:Our objectives were to characterize body composition and metabolic parameters, to establish ALMS1 mutation spectrum of United Kingdom AS patients, and to determine whether a genotype-phenotype correlation exists. DESIGN AND PATIENTS:We conducted a cross-sectional cohort study of 12 unrelated subjects with AS. Age-standardized body composition was assessed by anthropometry and dual-energy x-ray absorptiometry and insulin sensitivity by homeostasis model assessment. The exons and intron-exon boundaries of ALMS1 were directly sequenced. SETTING:The study was performed during the annual Alström Syndrome UK multidisciplinary screening clinic. RESULTS:AS patients have early-onset obesity, but body mass index, waist circumference, and body fat from dual-energy x-ray absorptiometry 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 homeostasis model assessment insulin sensitivity with age (r = −0.64, P = 0.02). ALMS1 mutations were identified in 10 of 12 patients, with a potential founder mutation in exon 16 present in five [np 10775del (C); Del3592fs/ter3597]. No genotype-phenotype correlation was observed. CONCLUSIONS:We identified mutations in ALMS1 in more than 80% of patients with no genotype-phenotype correlation. In AS, severe childhood obesity, waist circumference, and body fat decrease with age, whereas insulin resistance increases. The abdominal obesity, insulin resistance, diabetes, hypertriglyceridemia, and hypertension suggest that AS could represent a monogenic model for the metabolic syndrome.
ISSN:0021-972X
1945-7197
DOI:10.1210/jc.2005-2633