Researchers found a novel genotype and partial carnitine transporter deficiency associated with a severe phenotype of the infantile hepatocardiomuscular form of a long chain fatty acid oxidation disorder (LCFAOD) and published their results in Molecular Genetics and Metabolism.

The study included a cohort of 9 patients previously diagnosed with carnitine palmitoyltransferase 2 (CPT2) deficiency. Out of all patients, 7 had the classic myopathic form characterized by a later onset, 1 had the severe lethal neonatal form, and 1 had the infantile hepatocardiomuscular form.

All participants underwent DNA sequencing of the CPT2 gene, revealing all patients with the classic myopathic form had at least 1 copy of a mild pathogenic variant; the only lethal neonatal case was homozygous for the severe variant. Finally, the individual with severe manifestations in the form of the hepatocardiomuscular presentation unexpectedly showed a mild genotype.

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Read more about LCFAOD etiology

The latter patient was diagnosed at 1 year of age with a form of LCFAOD after noticing the loss of consciousness and severe hypoglycemia. Further testing revealed increased creatine kinase and low carnitine levels with free carnitine of 5 μM, vs normal values that begin at 25 μM. Compared to healthy subjects, the patient had a 35% decrease in the carnitine transport activity in fibroblasts.

“These results suggest that the severity of myopathic CPT2 deficiency at time of presentation may in part be explained by variations in carnitine transporter activity,” the authors wrote.

Moreover, plasma samples from all patients revealed higher C16, C18, C18:1, and C18:2 carnitines compared to healthy individuals, and 3 patients with the classic myopathic form had a 13% to 15% reduction of CPT2 activity in fibroblasts. These findings are consistent with this type of LCFAOD that is generated by a CPT2 deficiency.

The severity and time of onset of the case are usually predicted by each patient’s genotype, finding at least 1 copy of a milder variant in more benign forms with later onset. However, some patients with greater manifestations still carry a milder variant, and to this date, the reasoning behind this has not yet been defined.

“This study has further characterized the clinical and biochemical phenotype of CPT2 deficiency. Additionally, we provided the first reported example of the phenotype severity being influenced by variants outside of the CPT2 gene,” the authors concluded.


Shayota B, Balakrishnan B, Botto L, Pasquali M, Longo N. Clinical and biochemical characterization of carnitine palmitoyltransferase-2 deficiency and novel case exacerbated by heterozygosity with partial carnitine transporter deficiency. Mol Genet Metab. 2022;135(4):298. doi:10.1016/j.ymgme.2022.01.085