Abstract

Primary lipid myopathies (PLMs) are a heterogeneous group of rare, inherited neuromuscular disorders caused by defects in fatty acid transport, mitochondrial β-oxidation, or lipid droplet metabolism. These genetic abnormalities disrupt energy production in muscle cells, leading to clinical manifestations that range from exercise intolerance and recurrent rhabdomyolysis to cardiomyopathy and multisystem involvement.

This narrative review provides a comprehensive overview of the pathophysiological mechanisms, genetic classifications, clinical features, diagnostic strategies, and current treatment approaches for PLMs. Disorders are categorized by the metabolic pathway and subcellular compartment affected: (i) primary carnitine deficiency, (ii) cytoplasmic enzyme or transporter defects [e.g., neutral lipid storage disease (NLSD), Lipin 1 gene- (LPIN1), Carnitine-Acylcarnitine Translocase (CACT)-related], and (iii) mitochondrial fatty acid oxidation disorders [e.g., Carnitine Palmitoyl Transferase II (CPT II), Very-Long-Chain Acyl-CoA Dehydrogenase (VLCAD), Multiple Acyl-CoA Dehydrogenase deficiency (MADD)]. Clinical presentations are highly variable and may be triggered by metabolic stress, fasting, or exertion.

Diagnosis requires the integration of biochemical assays, muscle imaging, histopathology, and genetic testing, with tandem mass spectrometry and next-generation sequencing playing pivotal roles. Timely recognition is essential, as early dietary and pharmacologic interventions, including carnitine or riboflavin supplementation, can prevent irreversible complications.

While treatment remains largely supportive, emerging therapeutic avenues such as gene therapy and enzyme replacement strategies hold promise. Increased clinician awareness, multidisciplinary management, and future advancements in molecular diagnostics and personalized medicine are essential to improve outcomes for individuals affected by these rare disorders.