# Growth differentiation factor 15: a valuable biomarker for the diagnosis and prognosis of late-onset form of multiple Acyl-CoA dehydrogenation deficiency

## TL;DR

This study shows that GDF15 is a promising biomarker for diagnosing and tracking the severity of late-onset multiple acyl-CoA dehydrogenation deficiency.

## Contribution

The study identifies GDF15 as a novel biomarker for late-onset MADD linked to mitochondrial dysfunction and the ISR pathway.

## Key findings

- Serum GDF15 levels in late-onset MADD patients were 18.8 times higher than in healthy controls.
- GDF15 levels correlated with anorexia symptoms and decreased as the disease progressed.
- Muscle mRNA expression of GDF15 and ISR-related factors was elevated in MADD patients.

## Abstract

Multiple acyl-CoA Dehydrogenation Deficiency (MADD) is a hereditary metabolic disorder affecting the metabolism of fatty acids, amino acids, and choline, typically presenting with fat accumulation and mitochondrial abnormalities in muscle pathology. Growth differentiation factor 15 (GDF15) is a stress-responsive cytokine implicated in energy metabolism. Therefore, this study aimed to assess the level of GDF15 in patients with late-onset MADD and to evaluate its potential as a reliable biomarker for diagnosing symptoms and determining the severity of late-onset MADD.

In this study, consecutive patients with MADD mitochondrial diseases were recruited from the Neuromuscular Center of Qilu Hospital, Shandong University, between April 2015 and October 2021. We measured serum GDF15 levels in patients with late-onset MADD and healthy controls. Additionally, we analyzed the messenger RNA(mRNA) expression of GDF15 and integrated stress response (ISR)-related factors, including CHOP, ATF5, and TRIB3, in the muscles.

Serum GDF15 levels in patients with late-onset MADD were 18.8 times higher than those in healthy controls. GDF15 levels decreased as the disease progressed, and its elecated levels correlated with anorexia symptoms. The mRNA expression of GDF15 and ISR-related factors in the muscles was higher in patients with late-onset MADD than in controls.

GDF15 levels were significantly elevated in symptomatic patients with late-onset MADD, likely due to mitochondrial dysfunction activating the ISR pathway. These findings suggest that GDF15 is a valuable biomarker for monitoring disease severity and symptomatology in patients with late-onset MADD.

The online version contains supplementary material available at 10.1186/s13023-025-03651-1.