Syndromic obesity and diabetes:: Changes in body composition with age and mutation analysis of ALMS1 in 12 United Kingdom kindreds with Alstrom syndrome
Syndromic obesity and diabetes:: Changes in body composition with age and mutation analysis of ALMS1 in 12 United Kingdom kindreds with Alstrom syndrome
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DOI：
10.1210/jc.2005-2633
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发表时间：
2006-08-01
影响因子：
5.8
通讯作者：
Barrett, T. G.
中科院分区：
文献类型：
--
作者：
Minton, J. A. L.;Owen, K. R.;Barrett, T. G.
背景：Alstrom综合征（AS）是一种单基因型婴儿期肥胖和胰岛素抵抗，由ALMS 1突变引起。胰岛素抵抗的自然史是未知的，特别是它如何与身体组成的变化有关。目前还不清楚如何ALMS 1突变与特征phenotype.Objectives：我们的目标是表征身体组成和代谢参数，建立ALMS 1突变谱的英国AS患者，并确定是否存在基因型-表型相关性existing.Design和患者：我们进行了一项横断面队列研究的12个无关的主题AS。通过人体测量和双能X线吸收测定法评估了标准化的身体成分，通过稳态模型评估了胰岛素敏感性。结果：AS患者有早发性肥胖，但体重指数、腰围和双能X线吸收法测定的体脂与年龄呈负相关（r =-0.37，P = 0.2; r =-0.84，P = 0.002; r =-0.6，P = 0.05）。尽管如此，胰岛素抵抗增加，表现为空腹胰岛素升高和稳态模型评估胰岛素敏感性随年龄的下降（r =-0.64，P = 0.02）。在12例患者中的10例中鉴定出ALMS 1突变，其中5例存在外显子16中的潜在创始者突变[np 10775 del（C）; Del 3592 fs/ter 3597]。没有基因型-表型相关性observed.Conclusions：我们确定了ALMS 1突变在80%以上的患者没有基因型-表型相关性。在AS中，严重的儿童肥胖、腰围和体脂随着年龄的增长而减少，而胰岛素抵抗增加。腹型肥胖、胰岛素抵抗、糖尿病、高血糖和高血压提示AS可能是代谢综合征的单基因模型。
Context: Alstrom 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 Alstrom 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.