Primary Carnitine Deficiency and Newborn Screening for Disorders of the Carnitine Cycle

Abstract

Carnitine is needed for transfer of long-chain fatty acids across the inner mitochondrial membrane for subsequent β-oxidation. Carnitine can be synthesized by the body and is also obtained in the diet through consumption of meat and dairy products. Defects in carnitine transport such as those caused by defective activity of the OCTN2 transporter encoded by the SLC22A5 gene result in primary carnitine deficiency, and newborn screening programmes can identify patients at risk for this condition before irreversible damage. Initial biochemical diagnosis can be confirmed through molecular testing, although direct study of carnitine transport in fibroblasts is very useful to confirm or exclude primary carnitine deficiency in individuals with genetic variations of unknown clinical significance or who continue to have low levels of carnitine despite negative molecular analyses. Genetic defects in carnitine biosynthesis do not generally result in low plasma levels of carnitine. However, deletion of the trimethyllysine hydroxylase gene, a key gene in carnitine biosynthesis, has been associated with non-dysmorphic autism. Thus, new roles for carnitine are emerging that are unrelated to classic inborn errors of metabolism.

l-Carnitine and Acetyl-l-carnitine Roles and Neuroprotection in Developing Brain

“…Deficiency in the OCTN2 carnitine transporter is a rare inherited disease that leads to systemic primary carnitine deficiency [62, 63]. It is associated with depletion of intracellular carnitine, low serum carnitine concentrations and increased urinary excretion of carnitine and its derivatives [62, 63].…”

“…It is associated with depletion of intracellular carnitine, low serum carnitine concentrations and increased urinary excretion of carnitine and its derivatives [62, 63]. Patients normally respond to pharmacological doses of oral L-carnitine, particularly if supplementation is implemented prior to organ damage [64].…”

A mutation creating an upstream translation initiation codon in SLC22A5 5′UTR is a frequent cause of primary carnitine deficiency

“…Because carnitine is essential for the transport of long‐chain fatty acids into the mitochondrion for β‐oxidation, the lack of carnitine results in impaired fatty acid oxidation which affects in particular organs that rely on energy production by fatty acid oxidation such as the heart, skeletal muscle and liver (Houten, Violante, Ventura, & Wanders, ; Longo, Frigeni, & Pasquali, ). The clinical presentation of primary carnitine deficiency shows great variability ranging from hypoketotic hypoglycemia and hepatic encephalopathy early in life, skeletal‐ and cardiomyopathy later in life, sudden death from cardiac arrhythmia to only fatigue, or no clinical symptoms at all (see for review (Longo, ; Magoulas & El‐Hattab, )). The first individuals identified with primary carnitine deficiency all presented with severe clinical symptoms, including acute metabolic decompensation or cardiomyopathy, but because the disorder has been included in many neonatal screening programs worldwide, an increasing number of individuals with milder or no clinical symptoms have been identified.…”

“…. The clinical presentation of primary carnitine deficiency shows great variability ranging from hypoketotic hypoglycemia and hepatic encephalopathy early in life, skeletal-and cardiomyopathy later in life, sudden death from cardiac arrhythmia to only fatigue, or no clinical symptoms at all (see for review (Longo, 2016;Magoulas & El-Hattab, 2012)). The first individuals identified with primary carnitine deficiency all presented with severe clinical symptoms, including acute metabolic decompensation or cardiomyopathy, but because the disorder has been included in many neonatal screening programs worldwide, an increasing number of individuals with milder or no clinical symptoms have been identified.…”

“…These include asymptomatic mothers with this condition, identified via neonatal screening of their newborn children, who are carriers and picked up due to maternal carnitine deficiency (Longo, 2016;Schimmenti et al, 2007). Although these mothers are usually asymptomatic, they may be at risk for sudden death from arrhythmia (Longo, 2016;Schimmenti et al, 2007).…”