Comprehensive Endocrine-Metabolic Evaluation of Patients With Alström Syndrome Compared With BMI-Matched Controls

Abstract

Background: Alström syndrome (AS), a monogenic form of obesity, is caused by recessive mutations in the centrosome- and basal body-associated gene ALMS1. AS is characterized by retinal dystrophy, sensory hearing loss, cardiomyopathy, childhood obesity, and metabolic derangements.

Objective: We sought to characterize the endocrine and metabolic features of AS while accounting for obesity as a confounder by comparing patients with AS to body mass index (BMI)-matched controls.

Methods: We evaluated 38 patients with AS (age 2 to 38 years) who were matched with 76 controls (age 2 to 48 years) by age, sex, race, and BMI. Fasting biochemistries, mixed meal test (MMT), indirect calorimetry, dual-energy X-ray absorptiometry, and MRI/magnetic resonance spectroscopy were performed.

Results: Frequent abnormalities in AS included 76% obesity, 37% type 2 diabetes mellitus (T2DM), 29% hypothyroidism (one-third central, two-thirds primary), 3% central adrenal insufficiency, 57% adult hypogonadism (one-third central, two-thirds primary), and 25% female hyperandrogenism. Patients with AS and controls had similar BMI z scores, body fat, waist circumference, abdominal visceral fat, muscle fat, resting energy expenditure (adjusted for lean mass), free fatty acids, glucagon, prolactin, ACTH, and cortisol. Compared with controls, patients with AS were shorter and had lower IGF-1 concentrations (Ps ≤ 0.001). Patients with AS had significantly greater fasting and MMT insulin resistance indices, higher MMT glucose, insulin, and C-peptide values, higher HbA1c, and higher prevalence of T2DM (Ps < 0.001). Patients with AS had significantly higher triglycerides, lower high-density lipoprotein cholesterol, and a 10-fold greater prevalence of metabolic syndrome (Ps < 0.001). Patients with AS demonstrated significantly greater liver triglyceride accumulation and higher transaminases (P < 0.001).

Conclusion: Severe insulin resistance and T2DM are the hallmarks of AS. However, patients with AS may present with multiple other endocrinopathies affecting growth and development.

Trial registration: ClinicalTrials.gov NCT00068224 NCT00001195 NCT00001522 NCT00001723 NCT00005669 NCT00006073 NCT00030238 NCT00320177 NCT00758108 NCT01517048.

Figure 1.

Liver and muscle fat content in patients with AS compared with controls. (A) Positive correlations of liver fat and BMI z score shown in a scatterplot. Pearson correlations and linear regressions were performed with the angular transformation (arcsine square root) of liver fat percentage measured by MRS. Significant difference in intercept of linear regressions indicate higher liver fat values for patients with AS compared with controls for any given BMI (P = 0.0001). (B) Positive correlations of right lateral midthigh quadriceps fat and BMI z score shown in a scatterplot. Pearson correlations and linear regressions were performed with the angular transformation (arcsine square root) of muscle fat percentage measured by MRS. Possible trends in the difference in intercept of linear regressions indicate a tendency for higher muscle fat values for patients with AS compared with controls for any given BMI (P = 0.08). (C) Liver fat percentage adjusted for age, sex, race, and BMI z score. Patients with AS had higher adjusted liver fat compared with controls. (D) Serum ALT and (E) aspartate aminotransferase adjusted for age, sex, race, and BMI z score. Patients with AS had higher adjusted liver function tests compared with controls.

Figure 2.

Energy balance and glucose homeostasis in patients with AS compared with controls. (A) Adjusted respiratory quotient from indirect calorimetry. Higher respiratory quotient in AS indicates greater utilization of carbohydrate vs fat as the energy substrate. (B) Adjusted WBISI. Patients with AS had lower insulin sensitivity. (C) Unadjusted glucose values and (D) adjusted glucose AUC during the MMT. Patients with AS had higher glucose AUC compared with controls. (E) Unadjusted insulin values and (F) adjusted insulin AUC during the MMT. Patients with AS had higher insulin AUC compared with controls. For (A), (B), (D), and (F), the covariates for adjustment were age, sex, race, and BMI z score.

Figure 3.

BP, lipid profile, and MS in patients with AS compared with controls. (A) Systolic and (B) diastolic BP z scores adjusted for age, sex, race, and BMI z score. Subjects taking BP-lowering medications were excluded. (C) Triglycerides, (D) HDL-cholesterol, and (E) LDL-cholesterol adjusted for age, sex, race, and BMI z score. Subjects taking lipid-altering medications were excluded. (F) Percentage meeting MS criteria (three or more of the following: abdominal obesity, hypertriglyceridemia, low HDL-cholesterol, elevated BP, or impaired glucose tolerance).