Carnitine palmitoyltransferase 2 (CPT-2) deficiency is a disorder of the carnitine cycle that impairs long-chain fatty-acid oxidation. It can present at birth with a lethal neonatal form, in infancy/childhood with an infantile hepatocardiomuscular form, and later in life with a myopathic form. Patients with the lethal neonatal form have null pathogenic variants in the CPT2 gene that result in the complete absence of enzyme activity. By contrast, patients with the other forms have at least one copy of a less impactful variant allowing for some residual enzyme activity. It remains unclear why some patients with at least one copy of a milder variant present with a more severe phenotype.
Subjects were gathered from our database of known CPT2 deficient patients followed within our single institution at the University of Utah. In total, we gathered our experience with 9 patients with diagnosed CPT-2 deficiency. Biochemical and molecular testing was performed on a clinical basis. Genetic testing variants reported using HGVS NM 000098.3.
Our cohort of CPT deficient patients consisted of 7 with the classical later onset myopathic form, 1 with the severe lethal neonatal form, and 1 with infantile hepatocardiomuscular form. The plasma acylcarnitine profile identified increased C16- (0.53±0.35, normal <0.1 μM), C18- (0.26±0.16, normal <0.04 μM), C18:1- (0.6±0.5, normal <0.17 μM), and C18:2- (0.27±0.2, normal <0.08 μM) carnitines in all cases. CPT-2 activity in fibroblasts of 3 patients with the myopathic form was reduced to 13-15% of normal CPT2 enzyme activity compared to controls. DNA sequencing of the CPT2 gene identified at least one copy of a mild pathogenic variant (c.338C>T/p.S113L) in 7 of the 9 patients along with a second variant. One exception to this was the lethal neonatal case with homozygosity for a severe truncating variant (c.370C>T/p.R124X).
One subject with a suspected mild genotype (c.338C>T/p.S113L; c.534_558 delinsT) had a more severe phenotype with an infantile hepatocardiomuscular form, presenting at 1 year of age with loss of consciousness, severe hypoglycemia, carnitine deficiency, and mildly increased CK. Further investigation revealed a significant carnitine deficiency at time of presentation (free carnitine= 5 μM versus 29.2±4.5 μM in the others), suggesting possible impairment of the carnitine transporter. Carnitine transport was reduced to 35% of normal activity in fibroblast from this subject, which is consistent with carrier status and was not seen in 2 others with the classical myopathic form of CPT2 deficiency. 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.