Objective: To describe body composition and peripheral sensitivity to insulin (PSI) in early stage and presymptomatic spinocerebellar ataxia type 3/Machado Joseph disease (SCA3/MJD) individuals and to correlate the findings with disease severity and expanded CAG repeat length at ATXN3 gene.

Background: SCA3/MJD is the most frequent SCA worldwide and its phenotype was previously described as exclusively neurologic until the descriptions of reduced body mass index (BMI) and increased PSI in moderate/advanced disease.

Methods: A case control study was conducted. BMI, lean (LMI) and fat mass index (FMI), %lean mass (%LM) and basal metabolic ratio/weight (BMR) were determined with bioimpedance. Fast insulin and glucose, and glucose 2h post 75g glucose load test (GLT) were measured. >10 years of disease duration or previous endocrine disease diagnosis were exclusion criteria. Mean±sd and logarithmic (Ln) transformation for non-parametric data are provided.

Results: 65 symptomatic SCA3/MJD (age 41±9y, 34 females, duration: 6±2y, CAGn: 75±3; Scale for the Assessment and Rating of Ataxia – SARA: 10±4) and 48 healthy control subjects (age 40±13y, 28 females) were recruited. LnBMI (p=0.103), %LM (p=0.175) and BMR (0.176) were similar between groups. LnBMI was inversely correlated with CAGn (R=-0.541, p=0.001). LnLMI was lower in cases (2.87±0.1) than in controls (2.92±0.1, p=0.03). LnLMI and LnFMI inversely correlated with CAGn. In a subgroup analysis of <38 years individuals (29 cases/24 controls), cases presented lower BMI, %LM, BMR, LnLMI, LnFMI (p<0.001). 12 presymptomatic individuals (age 32.4±8.1y; 7 females; CAGn:73.5±3) carriers of ATXN3 expansions were evaluated. No differences were seen between presymptomatic individuals and controls or symptomatic SCA3/MJD patients in body composition parameters. Again, an inverse correlation of LnBMI and CAGn was seen in presymptomatic group (R=-0.585, p=0.046). Glucose after GLT was lower in cases than in the controls (p=0.007) with a direct correlation with age at onset (R=0.585, p=0.033), independent from CAGn. No differences in GLT were seen among presymptomatic, symptomatic and control groups (p=0.997).

Conclusions: : In early stages of SCA3/MJD, low BMI is present only in younger individuals, with larger CAGn. Early SCA3/MJD present higher PSI, which is more evident for individuals with early disease onset (independent from CAGn), suggesting a disease modifier effect.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/peripheral-insulin-sensitivity-and-body-composition-alterations-in-early-stage-machado-joseph-disease/