Coenzyme A (CoA), synthesized from pantothenate, is an essential cofactor required for numerous pivotal enzymatic reactions. Abnormal acylcarnitine profiles similar to those observed in carnitine palmitoyltransferase 1 (CPT1) deficiency have been reported in patients with coenzyme A synthetase (COASY)-related diseases and phosphopantothenoylcysteine synthetase (PPCS) deficiency. To the best our knowledge, a CPT1-like acylcarnitine profile has not yet been reported in patients with pantothenate kinase-associated neurodegeneration (PKAN). We aimed to evaluate whether the acylcarnitine profile could serve as a diagnostic clue for PKAN. All patients diagnosed with PKAN and followed at our center were included in the study. Clinical, biochemical, and genetic data were retrospectively extracted from medical records. The study cohort comprised five patients from five unrelated families. Three patients presented with classic PKAN, while two had atypical PKAN. CPT1-like acylcarnitine profiles were detected in patients with classic PKAN. Two patients exhibited elevated C0 and C0/(C16+C18) ratios; in one case, these values returned to normal during follow-up. In the third patient, only the C0/(C16 + C18) ratio was elevated, while C0 remained within the normal range. Different genetic variants were detected in our patients. Elevated C0 and/or elevated C0/(C16 + C18) ratio may serve as a diagnostic clue for PKAN, similar to other inherited disorders of CoA biosynthesis.

Carnitine palmitoyltransferase 1 A (CPT1A) deficiency is an ultra-rare autosomal recessive disorder of the carnitine cycle caused by biallelic pathogenic variants in the CPT1A gene. It mainly presents with a hepatic phenotype and is a target disease of newborn screening programs worldwide. Disease-specific and diagnostic abnormalities of CPT1A deficiency comprise elevated concentrations of free carnitine as well as an elevated metabolite ratio [C0/(C16 + C18)] in blood, but the ideal sample material has been a matter of debate. We present biochemical data of five CPT1A deficient patients, of whom four were diagnosed by newborn screening from dried blood spots. Our cases demonstrate that acylcarnitine profiles and especially concentrations of free carnitine can be normal in plasma in infants with CPT1AD at confirmation diagnosis after screening and during follow-up. Even the [C0/(C16 + C18)] ratio yielded normal results in some cases. Our data show, that dried blood is the preferred sample material for the diagnosis of CPT1A deficiency as it is superior to serum/plasma with respect to diagnostic sensitivity and reliability in quantification of the ratio [C0/(C16 + C18)]. CPT1A deficiency can be missed, if the analysis is only performed in serum or plasma, and confirmatory diagnostics in serum or plasma after screening can be false negative.

Fatty acid oxidation disorders (FAODs) are a group of rare genetic metabolic disorders caused by mutations in genes responsible for transporting and metabolizing fatty acids in the mitochondria. One crucial enzyme involved in this process is carnitine palmitoyltransferase I (CPT1), which transports long-chain fatty acids to the mitochondrial matrix for beta-oxidation. Defects in beta-oxidation enzymes often lead to pigmentary retinopathy; however, the underlying mechanisms are not entirely understood. To investigate FAOD and its impact on the retina, we employed zebrafish as a model organism. Specifically, we used antisense-mediated knockdown strategies to target the cpt1a gene and examined the resulting retinal phenotypes. We demonstrated that the cpt1a MO-injected fish significantly reduced the length of connecting cilia and severely affected photoreceptor cell development. Moreover, our findings highlight that the loss of functional cpt1a disrupted energy homeostasis in the retina, leading to lipid droplet deposition and promoting ferroptosis, which is likely attributed to the photoreceptor degeneration and visual impairments observed in the cpt1a morphants.

To identify the possible pathogenesis of a neonate with carnitine palmitoyltransferase 1A (CPT1A) deficiency by analyzing gene variants. Potential variants were detected with an Ion Torrent semiconductor sequencer using a gene panel for inherited diseases, and gene variants were verified by Sanger sequencing. Genetic testing indicated that the neonate has carried c.1895T>A(p.Leu632X) and c.1153G>A (p.Ala385Thr) compound heterozygous variants of the CPT1A gene, which were inherited from his father and mother, respectively. Both variants were verified as novel through the retrieval of HGMD database, ClinVar database and literature. According to the standards and guidelines of the American College of Medical Genetics and Genomics, the c.1895T>A variant was predicted to be pathogenic (PVS1+PM2+PP4) and c.1153G>A as likely pathogenic (PM1+PM2+PM3+PP3). The c.1895T>A and c.1153G>A compound heterozygous variants of the CPT1A gene might underlie the pathogenesis of this child. Above results have provided a basis for clinical diagnosis and genetic counseling, and enriched the variant spectrum of the CPT1 deficiency.