Views: 0 Author: Site Editor Publish Time: 2023-04-21 Origin: Site
In August 1979 and January 1982, two infants died of carnitine deficiency at the age of 3 months.The same family, at Seattle Children's Hospital,
Ronald Scott Rare Disease Specialist
Systemic primary carnitine deficiency (SPCD) is an inborn error of fatty acid transport caused by a defect in the transporter responsible for moving carnitine across the plasma membrane.Carnitine is an important amino acid for fatty acid metabolism.When carnitine cannot be delivered to tissues, fatty acid oxidation is impaired, resulting in a variety of symptoms including chronic muscle weakness, cardiomyopathy, hypoglycemia, and liver dysfunction.The specific transporter associated with SPCD is OCTN2, encoded by the SLC22A5 gene located on chromosome 5. SPCD is inherited in an autosomal recessive manner, with the mutant allele coming from both parents.Acute attacks caused by SPCD are usually preceded by metabolic stress, such as prolonged fasting, infection, or vomiting.Cardiomyopathy can develop without an acute attack and may lead to death. SPCD results in increased urinary carnitine excretion and decreased plasma carnitine levels.In most areas where newborn screening has been expanded, SPCD can be recognized and treated shortly after birth. High-dose carnitine supplementation is effective but requires strict lifelong maintenance.
The presentation of patients with SPCD varies widely, ranging from asymptomatic to fatal cardiac manifestations.Early case reports of hepatic dysfunction, muscle abnormalities (weakness and hypoplasia), hypoketotic hypoglycemia, cardiac hypertrophy, cardiomyopathy, and marked carnitine deficiency in plasma and tissue with increased urinary excretion.Patients with clinical manifestations of SPCD are divided into two categories, one with metabolic manifestations with hypoglycemia and one with cardiac manifestations, which is characterized by cardiomyopathy.Muscle weakness can be found with both manifestations.
In countries that have expanded newborn screening, SPCD can be detected shortly after birth.Affected infants showed low levels of free carnitine and all other acylcarnitine species by tandem mass spectrometry.Not all infants with low levels of free carnitine are affected by SPCD.Some people may have carnitine deficiency secondary to another metabolic condition or due to maternal carnitine deficiency.Appropriate follow-up of newborn screening results for low free carnitine includes studies of the mother to determine whether her carnitine deficiency is due to SPCD or secondary to metabolic disease or diet.Confirmation rate of SPCD maternal cases is higher than expected, Common in asymptomatic women.Newborn screening has also identified some mothers with previously undiagnosed cardiomyopathy.The identification and treatment of these asymptomatic individuals is still under development, as it is unclear whether they require the same level of intervention as patients with SPCD identified early in life on the basis of clinical presentation.
SPCD is an autosomal recessive disorder, meaning that the mutated allele must be inherited from each parent in order to be affected.The gene responsible for the OCTN2 carnitine transporter is SLC22A5, located at 5q31.1-32. SLC22A5 is regulated by peroxisome proliferator-activated receptor alpha.The transporter OCTN2 is located in the apical membrane of tubular cells and plays a role in tubular reabsorption.Defective OCTN2 is unable to recapture carnitine before it is excreted in the urine, leading to the characteristic biochemical outcome of massively elevated urinary carnitine levels and markedly reduced plasma carnitine levels.Reduced plasma carnitine levels inhibit fatty acid oxidation during times of excess energy demand.Carnitine is needed to transport long-chain fatty acids into the mitochondria,where they can be broken down to produce acetyl-CoA.Individuals with SPCD are unable to produce ketone bodies for energy due to disrupted fatty acid oxidation.Although SPCD is an autosomal recessive disorder, heterozygotes have been shown to be at increased risk for benign cardiomyopathy compared with wild-type individuals.
SPCD is first suspected in patients with nonspecific findings because of extremely low plasma carnitine levels.When combined with increased carnitine concentrations in urine, suspicion of SPCD can often be confirmed by molecular testing or functional studies assessing carnitine uptake in cultured fibroblasts.
Identification of presymptomatic patients through newborn screening allows for early intervention and treatment.Treatment for SPCD involves high-dose carnitine supplements, which must be taken for life.Individuals identified and treated at birth have excellent outcomes, including prevention of cardiomyopathy.Mothers who are diagnosed after a positive newborn screen but are asymptomatic are also often given carnitine supplements. Long-term outcomes in asymptomatic adults with SPCD are unknown, but finding mothers with undiagnosed cardiomyopathy and SPCD raises the possibility that recognition and treatment can prevent onset manifestations in adults.
Worldwide, SPCD is most common in the Faroe Islands, where at least one in every 1,000 inhabitants has the disease, according to the Faroe Islands Ministry of Health.Scientists believe that approximately 10% of the Faroese population are carriers of the variant that causes SPCD.These individuals are not ill, but may have lower levels of carnitine in their blood than noncarriers.In 1995, the first Faroese patient was diagnosed with SPCD,Since then, several young people and children in the Faroe Islands have died of cardiac arrest due to SPCD.Adding the SPCD to the newborn screening panel provided insight into the incidence of the disease around the world.In Taiwan, the incidence of neonatal SPCD is estimated to be approximately 1:67,000, while the incidence of maternal cases is even higher at approximately 1:33,000.The increased incidence of SPCD in mothers compared with neonates is not fully understood.SPCD estimates for Japan show a similar incidence of 1:40,000.