Primary systemic carnitine deficiency: Phenotypic variability, diagnostic challenges, and long-term outcomes.

Background: Primary systemic carnitine deficiency (CDSP) is a rare inherited metabolic disorder characterized by impaired carnitine transport due to mutations in the SLC22A5 gene, leading to impaired mitochondrial fatty acid oxidation. The aim of this retrospective, descriptive study was to investigate the clinical, biochemical, and molecular features of CDSP in Turkey, where the lack of a national expanded metabolic screening program contributes to delayed diagnosis and severe complications.

Methods: The clinical, biochemical, and molecular profiles of 12 patients from eight families diagnosed between 2003 and 2025 were retrospectively analyzed. Data on family history, consanguinity, clinical manifestations-including cardiomyopathy, muscle weakness, neurological symptoms, and liver dysfunction-plasma free carnitine levels, and echocardiographic measurements were collected and analyzed.

Results: The majority of patients (92%) were from consanguineous families. Cardiomyopathy was the most common clinical feature (75%), followed by muscle weakness (50%), neurological symptoms (42%), and liver dysfunction (33%). A novel SLC22A5 variant (c.125T>C; p.Leu42Pro) was identified that expands the known genetic spectrum of CDSP. Oral carnitine supplementation significantly increased plasma free carnitine levels (p = 0.01) and improved long-term interventricular septal thickness Z-scores (p = 0.045). In addition, cholestasis was observed in two patients, suggesting an expanded disease phenotype.

Conclusion: These results emphasize the crucial role of early detection and family screening in the prevention of life-threatening complications associated with CDSP. Long-term carnitine therapy improves metabolic and cardiac outcomes, underscoring the need for early intervention and inclusion of CDSP in national newborn screening programs.