Newborn screening has become an indispensable part of modern medicine. Prior to it, congenital/genetic diseases often required clinical manifestation to a relatively obvious degree before a diagnosis could be made. Newborn screening now allows physicians to diagnose a disease even before a single clinical symptom is noted, allowing for better treatment planning and better outcomes. 

Depending on the healthcare jurisdictions that hospitals and clinical facilities operate under, there are a number of diseases commonly screened for during newborn screening. Among them are inborn errors of metabolism (such as classic galactosemia and biotinidase deficiency), endocrinopathies (such as congenital adrenal hyperplasia and congenital hypothyroidism), and hemoglobinopathies (such as sickle cell disease and thalassemia). 

Another category of diseases commonly screened for in newborn screening is fatty acid oxidation defects. There is a relatively long list of fatty acid oxidation disorders that may be screened for at birth, such as medium chain fatty acid oxidation disorder, glutaric acidemia type III, and long chain fatty acid oxidation disorders, including trifunctional protein deficiency and primary carnitine deficiency. 

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Primary carnitine deficiency is a disease of carnitine transportation that can cause impairment in fatty acid oxidation. It is inherited in an autosomally recessive manner. The clinical picture of a patient with primary carnitine deficiency is one of low serum carnitine, continuous kidney loss of carnitine, and defective ketogenesis; combined, this results in cardiomyopathy and arrhythmias, as well as muscle pain and weakness. 

Read more about long chain fatty acid oxidation disorder etiology 

The good news is that primary carnitine deficiency is a highly treatable condition; hence, it is a perfect candidate for newborn screening since early detection makes a sizable difference in eventual clinical outcomes. 

Chinese Study Findings 

In Clinica Chimica Acta, Lin and colleagues published a study they conducted on the features of primary carnitine deficiency as detected through newborn screening in Quanzhou, China. 

They reported that out of 364,545 neonates who underwent newborn screening, 36 received a diagnosis of primary carnitine deficiency. This roughly translates to 0.01% of the sample. They also discovered that the most prevalent variant in the patients tested was c.760C > T (p.R254*). 

In addition, they reported that 25 of the 36 neonates received L-carnitine supplementation, with one discontinuing treatment and subsequently experiencing sudden infant death syndrome. One sibling experienced persistent fatigue, hypoglycemia, and coma, but these symptoms were resolved upon the commencement of treatment. 

Lin and colleagues concluded, “[Newborn screening] is effective in identifying [primary carnitine deficiency], and sudden death may be prevented with timely treatment.” 

Genetic and Biochemical Features

Newborn screening for primary carnitine deficiency is conducted via tandem mass spectrometry; clinicians measure if the free carnitine levels fall below the cut-off value in the dried blood spot samples collected. Primary carnitine deficiency is then diagnosed by either the genetic analysis of the SLC22A5 gene or by confirming lower levels of carnitine transport activity in the fibroblasts. 

Because the measurement of carnitine transport levels is only performed in selected laboratories, genetic testing remains the more common method for diagnosing primary carnitine deficiency. 

“However, it is noteworthy that some disease-causing pathogenic variants can escape detection because the genetic diagnostic yield for PCD has been relatively low,” Lin and colleagues wrote in the Orphanet Journal of Rare Diseases. 

It is notable that the study by Lin et al was conducted in China, as studies show that primary carnitine deficiency is the most common fatty acid metabolic disease in China. Hence, the Chinese government has sought to implement newborn screening for this disease in most parts of the country, with diagnosed patients usually treated with L-carnitine therapy. 

Read more about long chain fatty acid oxidation disorder epidemiology

Limitations of Screening for Primary Carnitine Deficiency

However, it should also be noted that newborn screening for primary carnitine deficiency has its limitations. For example, the rate of false-positive results is relatively high, owing to the fact that carnitine concentration at birth can be influenced by multiple factors, including maternal levels of carnitine. 

Because of this, both neonate and mother are usually recalled for a second review of their carnitine levels. It is also important to note that while false positives can occur, false negatives can take place too. Once again, this is due to the influence of maternal carnitine concentrations on the neonate’s carnitine levels. 

“Therefore, [newborn screening] for [primary carnitine deficiency] faces challenges, and combining [newborn screening] with genetic testing is crucial to improve screening efficiency,” Lin and colleagues wrote. 

Despite some of the limitations of newborn screening, history teaches us that its implementation has brought about tremendous benefit to human lives across the globe. If left untreated, primary carnitine deficiency can be lethal, as demonstrated by the death of the patient in Lin et al’s research who stopped L-carnitine therapy. 

“Because early diagnosis by newborn screening facilitates early intervention, the outcome of newborn screening programs has been favorable,” El-Hattab and colleagues wrote in Pediatric Clinics of North America. “Several studies of long-term follow-up of individuals ascertained by newborn screening indicated significant improvement in morbidity and mortality for all diseases that have been studied including fatty acid oxidation defects.” 


El-Hattab AW, Almannai M, Sutton VR. Newborn screening: history, current status, and future directionsPediatr Clin North Am. 2018;65(2):389-405. doi:10.1016/j.pcl.2017.11.013

Lin W, Wang K, Zheng Z, et al. Newborn screening for primary carnitine deficiency in Quanzhou, ChinaClin Chim Acta. 2021;512:166-171. doi:10.1016/j.cca.2020.11.005

Lin Y, Lin B, Chen Y, et al. Biochemical and genetic characteristics of patients with primary carnitine deficiency identified through newborn screeningOrphanet J Rare Dis. 2021;16(1):503. doi:10.1186/s13023-021-02126-3