Mutation‐specific metabolic profiles in presymptomatic amyotrophic lateral sclerosis

Abstract

Background and purpose Growing evidence shows that ALS patients feature a disturbed energy metabolism. However, these features have rarely been investigated in the presymptomatic stage. Methods A total of 60 presymptomatic ALS mutation carriers and 70 age‐ and gender‐matched controls (non‐mutation carriers from the same families) were recruited. All subjects underwent assessments of their metabolic profiles under fasting conditions at enrollment, including body mass index (BMI), blood pressure and serum levels of blood glucose, total cholesterol, triglycerides, high‐density lipoprotein (HDL) and low‐density lipoprotein. Results All mutations combined, no differences between presymptomatic ALS gene carriers and controls were found. From a cardiovascular point of view, presymptomatic chromosome 9 open reading frame 72 (C9ORF72) gene carriers showed lower cardiovascular risk profiles compared to healthy controls, including lower BMI (median 22.9, interquartile range [IQR] 20.6–26.1 kg/m2 vs. 24.9, IQR 22.7–30.5 kg/m2; p = 0.007), lower systolic blood pressure (120, IQR 110–130 mmHg vs. 128, IQR 120–140 mmHg; p = 0.02), lower fasting serum glucose (89.0, IQR 85.0–97.0 mg/dl vs. 96.0, IQR 89.3–102.0 mg/dl; p = 0.005) and higher HDL (1.6, IQR 1.3–1.8 mmol/l vs. 1.2, IQR 1.0–1.4 mmol/l; p = 0.04). However, presymptomatic superoxide dismutase 1 (SOD1) gene mutation carriers showed higher cardiovascular risk profiles compared to healthy controls, including higher BMI (28.0, IQR 26.1–31.5 kg/m2 vs. 24.9, IQR 22.7–30.5 kg/m2; p = 0.02), higher fasting serum glucose (100.0, IQR 94.0–117.0 mg/dl vs. 96.0, IQR 89.3–102.0 mg/dl; p = 0.04) and lower HDL (1.2, IQR 1.0–1.4 mmol/l vs. 1.4, IQR 1.2–1.7 mmol/l; p = 0.01). These features were most prominent in patients carrying SOD1 gene mutations associated with slow disease progression. Conclusions This study identified distinct metabolic profiles in presymptomatic ALS gene carriers, which might be associated with disease progression in the symptomatic phase.

Metabolic alterations precede neurofilament changes in presymptomatic ALS gene carriers

“…These mutation-specific findings are consistent with a recent publication, reporting that presymptomatic C9orf72 mutation carriers, compared to healthy controls, showed a lower metabolic cardiovascular risk profile, including lower BMI, lower fasting serum glucose, and higher HDL, while SOD1 mutation carriers had an opposite profile. 6 Therefore, different metabolic biomarkers have to be considered for the presymptomatic phase for both genes:…”

“…In amyotrophic lateral sclerosis (ALS), the onset of disease is usually defined as the occurrence of first paresis. However, according to the current understanding of the disease, ALS pathology does not only affect the motor system, 1 but is also associated with profound metabolic changes, including hypermetabolism, 2 excessive weight loss, 3,4 and abnormalities of lipid 5,6 and carbohydrate metabolism. 7 These metabolic changes constitute important prognostic factors 5,8 and can be targeted by nutritional interventions.…”

Lipids and amyotrophic lateral sclerosis: A two‐sample Mendelian randomization study

“…In parallel, we explored lipid profiles in asymptomatic ALS gene carriers and implied that 'worse' lipid metabolism profiles were associated with relatively benign ALS mutations [46]. Although both are preclinical studies, the MR study investigated genetic, long-term factors for the risk of disease, while the prospective cohort study focused more on the relation between lipid levels in a relatively short time before disease onset and ALS prognosis.…”

Abnormal energy metabolism in ALS: a key player?

“…Although some contradictory results emerged for mutant SOD1 -ALS patients, they could be explained by the differences in patient cohorts and, notably, the distribution of SOD1 variants. Furthermore, metabolic profiling of presymptomatic ALS gene carriers revealed prevalent alterations in all mutations, but SOD1 and C9ORF72 gene carriers have each distinct profile compared to other ALS gene carriers [45 ▪▪ ,56 ▪▪ ]. C9ORF72 -ALS patients have a lower cardiovascular risk profile, characterized by lower BMI, lower fasting serum glucose, and higher HDL, while SOD1 -ALS patients have an opposite profile [45 ▪▪ ,56 ▪▪ ].…”