Carnitine Inborn Errors of Metabolism

Abstract

Carnitine plays essential roles in intermediary metabolism. In non-vegetarians, most of carnitine sources (~75%) are obtained from diet whereas endogenous synthesis accounts for around 25%. Renal carnitine reabsorption along with dietary intake and endogenous production maintain carnitine homeostasis. The precursors for carnitine biosynthesis are lysine and methionine. The biosynthetic pathway involves four enzymes: 6-N-trimethyllysine dioxygenase (TMLD), 3-hydroxy-6-N-trimethyllysine aldolase (HTMLA), 4-N-trimethylaminobutyraldehyde dehydrogenase (TMABADH), and γ-butyrobetaine dioxygenase (BBD). OCTN2 (organic cation/carnitine transporter novel type 2) transports carnitine into the cells. One of the major functions of carnitine is shuttling long-chain fatty acids across the mitochondrial membrane from the cytosol into the mitochondrial matrix for β-oxidation. This transport is achieved by mitochondrial carnitine-acylcarnitine cycle, which consists of three enzymes: carnitine palmitoyltransferase I (CPT I), carnitine-acylcarnitine translocase (CACT), and carnitine palmitoyltransferase II (CPT II). Carnitine inborn errors of metabolism could result from defects in carnitine biosynthesis, carnitine transport, or mitochondrial carnitine-acylcarnitine cycle. The presentation of these disorders is variable but common findings include hypoketotic hypoglycemia, cardio(myopathy), and liver disease. In this review, the metabolism and homeostasis of carnitine are discussed. Then we present details of different inborn errors of carnitine metabolism, including clinical presentation, diagnosis, and treatment options. At the end, we discuss some of the causes of secondary carnitine deficiency.

Keywords: carnitine; carnitine palmitoyltransferase; carnitine transporter; trimethyllysine (TML) dioxygenase.

Figure 1

(a) Carnitine biosynthetic pathway. Only trimethyllysine dioxygenase (TMLD) and γ-butyrobetaine dioxygenase (BBD) deficiencies have been reported; both are denoted with asterisks. (b) Carnitine transport and mitochondrial carnitine–acylcarnitine cycle. IMM: inner mitochondrial membrane; OMM: outer mitochondrial membrane; CPT I: carnitine palmitoyltransferase I; CACT: carnitine-acylcarnitine translocase; CPT II: carnitine palmitoyltransferase II; OCTN2: organic cation/carnitine transporter novel type 2.