Association Between Body Mass Index and Disease Severity in Chinese Spinocerebellar Ataxia Type 3 Patients

Abstract

Spinocerebellar ataxia type 3 (SCA3), the most common subtype of SCA worldwide, is caused by mutation of CAG repeats expansion in ATXN3. Body mass index (BMI) is an important modulatory factor in the progression of neurodegenerative disorders such as Huntington disease and amyotrophic lateral sclerosis. However, its relevance in SCA3 is not well understood. In this study, BMI was investigated in 134 molecularly confirmed SCA3 patients and 136 healthy controls from China. The multivariable linear regression models were performed to establish the putative risk factors for BMI, and whether BMI could affect the severity of ataxia. We found that BMI was significantly lower in the case group than that in the control group. The age at onset (positive correlation) and severity of ataxia (negative correlation) were the risk factors affecting BMI. Conversely, BMI along with the disease duration, the age at onset, and the numbers of CAG repeats could also have influence on the severity of ataxia. In conclusion, SCA3 patients had lower BMI than matched controls and BMI is a predictor of disease progression in SCA3. Nutritional intervention to promote weight gain could be a promising strategy to impede SCA3 progression.

Body Mass Index Is Significantly Associated With Disease Severity in Spinocerebellar Ataxia Type 2 Patients

“…In fact, declining BMI has been noted in patients with HD and presymptomatic mutation carriers [17][18][19][20]38 and in patients with SCA1, SCA2, SCA3, SCA6, SCA7, and SCA17 or genetic mouse models for these disorders. [21][22][23][24][25][26][29][30][31] Besides, significant associations between BMI and CAG repeat length or markers of disease severity have been reported for HD, SCA1, SCA2, and SCA3, 18,21,24 suggesting BMI as a disease biomarker common to several polyglutamine disorders and possibly severe neurodegenerative diseases in general. Indeed, low BMI was associated with increased risk for incident Alzheimer's disease, 39 increased risk for Parkinson's disease, and worse motor performance and life prognosis of patients with Parkinson's disease, [40][41][42] and high BMI was associated with better long-term survival of patients with amyotrophic lateral sclerosis.…”

“…Similar results have been reported in other polyglutamine disorders. In fact, declining BMI has been noted in patients with HD and presymptomatic mutation carriers 17‐20,38 and in patients with SCA1, SCA2, SCA3, SCA6, SCA7, and SCA17 or genetic mouse models for these disorders 21‐26,29‐31 . Besides, significant associations between BMI and CAG repeat length or markers of disease severity have been reported for HD, SCA1, SCA2, and SCA3, 18,21,24 suggesting BMI as a disease biomarker common to several polyglutamine disorders and possibly severe neurodegenerative diseases in general.…”

“…[17][18][19][20] In addition, weight loss has been associated with SCA1, SCA2, SCA3, SCA6, SCA7, and SCA17 both in patients and in mouse models. [21][22][23][24][25][26] Ataxin-2 knockout mice have increased body weight compared with wild-type mice, 27,28 whereas SCA2 models, such as the BAC-Q72 transgenic mouse or the Atxn2-CAG42 and Atxn2-CAG100 knock-in mice, showed lower body weight compared with wild-type mice, [29][30][31] suggesting that ataxin-2 is involved in lipid storage and energy metabolism. In addition, genetic variants in ATXN2 and ataxin-2 binding protein 1 (A2BP1) genes have been linked to obesity in humans.…”

Trehalose alleviates the phenotype of Machado–Joseph disease mouse models

“…Despite being a sugar, trehalose has no adverse effects on metabolism [59,[63][64][65]. Some studies even reported a positive effect of trehalose against weight loss in mice [16,20], which would constitute an advantage as MJD patients have decreased body mass index [66,67]. A Phase 2 open label trial to access safety, tolerability and efficacy of trehalose in MJD patients is on-going.…”

Broad Influence of Mutant Ataxin-3 on the Proteome of the Adult Brain, Young Neurons, and Axons Reveals Central Molecular Processes and Biomarkers in SCA3/MJD Using Knock-In Mouse Model

“…We demonstrated many dysregulated proteins related to the mitochondrial compartment, which corresponds with the reduced body weight gain in Ki91. Notably, the BMI of SCA3 patients is significantly lower, and BMI decrease correlated with faster disease progression ( Diallo et al, 2017 ; Yang et al, 2018 ). The energy metabolism was the most common pathway, and the proteins related to metabolism were dysregulated already in 4-month-old presymptomatic Ki91 mice.…”