Nonalcoholic fatty liver disease in spinal and bulbar muscular atrophy

Abstract

Objective:To determine the prevalence and features of fatty liver disease in spinal and bulbar muscular atrophy (SBMA).Methods:Two groups of participants with SBMA were evaluated. In the first group, 22 participants with SBMA underwent laboratory analysis and liver imaging. In the second group, 14 participants with SBMA were compared to 13 female carriers and 23 controls. Liver biopsies were done in 4 participants with SBMA.Results:Evidence of fatty liver disease was detected by magnetic resonance spectroscopy in all participants with SBMA in the first group, with an average dome intrahepatic triacylglycerol of 27% (range 6%–66%, ref ≤5.5%). Liver dome magnetic resonance spectroscopy measurements were significantly increased in participants with SBMA in the second group relative to age- and sex-matched controls, with average disease and male control measurements of 17% and 3%, respectively. Liver biopsies were consistent with simple steatosis in 2 participants and nonalcoholic steatohepatitis in 2 others.Conclusions:We observed evidence of nonalcoholic liver disease in nearly all of the participants with SBMA evaluated. These observations expand the phenotypic spectrum of the disease and provide a potential biomarker that can be monitored in future studies.

Polyglutamine-Expanded Androgen Receptor Alteration of Skeletal Muscle Homeostasis and Myonuclear Aggregation Are Affected by Sex, Age and Muscle Metabolism

“…Spinal and bulbar muscular atrophy (SBMA), also known as Kennedy's disease, is an X-linked neuromuscular disease characterized by the selective dysfunction and degeneration of brainstem and spinal cord motor neurons (MNs) [1]. In addition, patients present with a wide array of peripheral organ and tissue dysfunction, including skeletal muscle weakness, wasting and atrophy [2,3]. SBMA is caused by exonic expansions of a CAG tandem repeat, resulting in an aberrantly elongated polyglutamine (polyQ) tract in the androgen receptor (AR) gene [4].…”

Polyglutamine-expanded androgen receptor disrupts muscle triad, calcium dynamics and the excitation-contraction coupling gene expression program

“…In addition, patients develop signs of androgen insensitivity syndrome, such as gynecomastia, erectile dysfunction and reduced fertility (5,6). Moreover, patients may present signs of metabolic syndrome, such as insulin resistance, glucose intolerance, hyperlipidemia and non-alcoholic fatty liver (6)(7)(8). Among polyQ diseases, a unique feature of SBMA is sex-specificity with males primarily affected, and females showing only mild disease manifestations even if homozygous for the mutation (9).…”

Molecular Mechanisms and Therapeutics for SBMA/Kennedy's Disease

“…Dysregulation of other metabolic indicators have also been reported in a subset of SBMA patients, including low body mass index, bone density, and HDL, and high blood pressure, total cholesterol, and triglycerides [12,14,33]. Moreover, SBMA patients are at a high risk for nonalcoholic fatty liver disease [32]. Interestingly, hepatic AR-knockout mice similarly develop insulin resistance, indicating that loss of AR function in SBMA patients may contribute to this phenotype [35].…”

“…Metabolic disturbances have also been reported in SBMA patients, with a number of recent studies greatly expanding our understanding of and appreciation for the system-wide effects of mutant AR. For example, impaired glucose homeostasis is now understood to be a common feature of SBMA [12,32,33]. Although the results of these studies offer conflicting evidence for whether fasting blood glucose levels are normal [14], low [33], or high [12,32,34] in SBMA patients, there seems to be consensus regarding an increase in insulin resistance in SBMA patients, as measured by the homeostasis model assessment of insulin resistance (HOMO-IR) [32][33][34].…”