Late-Onset Multiple Acyl-CoA Dehydrogenase Deficiency (MADD): Clinical Features, Diagnostic Challenges, and the Role of Oxidative Stress in Pathophysiology.

INTRODUCTION

Multiple Acyl-CoA Dehydrogenase Deficiency (MADD) is an autosomal recessive metabolic disorder resulting from mutations in the genes that encode the electron transfer flavoprotein (ETF) or its associated dehydrogenase (ETFDH), resulting in defects in mitochondrial fatty acid oxidation and a broad range of clinical presentations, most notably in the form of muscle weakness; exercise intolerance; and, in some cases, life-threatening metabolic crises. Late-onset MADD represents the most common form of lipid storage myopathy, but its diagnosis can be elusive due to its varied and often nonspecific clinical symptoms and may resemble other neuromuscular conditions, like inflammatory myopathies or other peripheral neuropathies, complicating the diagnostic process and delaying appropriate treatment.

AIMS: This case series aims to provide additional insights into the clinical presentation of MADD, highlighting diagnostic challenges in differentiating metabolic myopathies and emphasizing the role of muscle biopsy in diagnosing these conditions.

RESULTS

We describe five clinical cases of patients who were diagnosed with MADD, their clinical manifestations, and the diagnostic processes undertaken to arrive at this diagnosis. Notably, three patients were initially misdiagnosed with inflammatory myopathy, and one was misdiagnosed with Guillain-Barré syndrome. The correct diagnosis was established following a muscle biopsy, which revealed characteristic findings consistent with lipid storage myopathy and prompted subsequent biochemical analyses and genetic testing that confirmed the diagnosis of MADD.

CONCLUSIONS

MADD is an underdiagnosed condition, and the description of new patients with various clinical presentations could support the development of clinical tools to promptly recognize this disease and allow physicians to deliver the most appropriate and effective therapy protocol, with Riboflavin and Carnitine supplementations, avoiding inappropriate treatments. The muscle biopsy was essential for a correct diagnostic assessment.