Primary carnitine deficiency is a genetic disorder inherited in an autosomal recessive manner. It results in carnitine transport defects, which causes a reduction in intracellular carnitine. 

When a healthy individual is fasting, fatty acids become the main source of energy. Beta oxidation of fatty acids in the liver, heart, and skeletal muscles releases energy. The oxidation of long chain fatty acids occurs exclusively within the mitochondria. However, due to the impermeability of the mitochondria, long chain fatty acids can only enter via carnitine shuttles. 

When a person is deficient in carnitines, long chain fatty acids cannot be transported into the mitochondria; hence, oxidation does not occur and the Krebs cycle is interrupted. When fatty acids are unavailable for energy production during fasting states, glucose is readily consumed, albeit without replenishment from gluconeogenesis. Fatty acids that have been released accumulate in various organs, which may impair their normal function. 


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Primary carnitine deficiency, a long chain fatty acid oxidation disorder, usually presents in pediatric patients with symptoms of lethargy, irritability, and hepatomegaly. There is, however, heterogeneity in terms of the severity of symptoms. The clinical presentation of carnitine deficiency is affected by factors such as the age of onset and the organ systems involved. 

Read more about long chain fatty acid oxidation etiology 

“About half of the affected individuals present at a younger age, between three months and two years, with attacks of metabolic decompensation in a form of hepatic encephalopathy characterized by poor feeding, lethargy, and irritability,” Dakash and Sankararaman wrote in Carnitine Deficiency. “The attacks occur particularly during periods of catabolism when fatty acids oxidation and gluconeogenesis are mostly needed, eg, fasting or during common illnesses such as acute gastroenteritis.” 

Lethargy and Apnea in a Neonate 

In the Archives of Medicine and Health Sciences, Rasania and colleagues reported on a case of primary carnitine deficiency in a neonate. 

The female infant was born at 34 weeks gestation to a mother with pregnancy-induced hypertension. The infant was admitted to neonatal intensive care due to prematurity, low birth weight, and respiratory distress. She was prescribed antibiotics and oxygen and discharged 18 days after birth. 

One week later, her parents brought the patient back to the hospital due to lethargy. Her physicians detected a low random blood sugar. After another week, the infant presented with apnea and vomiting. Upon examination, her physicians discovered hypothermia, hypotonia, a delay in capillary refill time, and a random blood sugar of 23 mg/dL. 

The infant was given a dextrose 10 bolus injection and any electrolyte imbalances were corrected. She was prescribed antibiotics and inotropes. Upon recovery, the infant was restored to full feed. 

Aside from lethargy, the patient did not display any other signs of sepsis; in addition, septic screen and blood culture were negative. Her physicians suspected a metabolic disorder, given that the infant had refractory hypoglycemia. 

A neonatal carnitine screening revealed palmitoylcarnitine (C16) levels of 0.15 μmol/L (normal: <12.50 μmol/L) and octadecanoylcarnitine (C18) levels of 0.60 μmol/L (normal: 0.60-3.50 μmol/L). This demonstrated that the infant had decreased levels of carnitine in the blood. 

The patient was diagnosed with primary carnitine deficiency and was prescribed syrup L-carnitine at 100 mg/kg/day 3 times a day before being discharged. 

Diagnosing Carnitine Deficiency 

In this case, carnitine deficiency was not suspected until the patient was seen by physicians for the third time. This is not unusual, considering that the symptoms of carnitine deficiency can be variable and vague. In addition, physicians are more likely to suspect an acute cause for clinical deterioration (such as sepsis). 

“There is usually a poor correlation between genotype and phenotypic expression in [primary carnitine deficiency].  Some investigators have noted nonsense and frameshift mutations more commonly in symptomatic patients,” Dakash and Sankararaman wrote.

In the United States, primary carnitine deficiency is part of the newborn screening test. Low levels of free carnitine in the plasma are detected via tandem mass spectrometry. However, fetal plasma creatinine levels can reflect that of the mother, since placental transfer of carnitine occurs from the mother to the fetus. Hence, if a baby is positive for carnitine deficiency, both mother and baby are retested 2 weeks later. 

Read more about long chain fatty acid oxidation treatment

In countries that do not offer newborn screening tests for primary carnitine deficiency, it can be difficult to discern between the clinical presentation of fatty acid oxidation defects and carnitine shuttle disorders. Both disorders often result in hypoketotic hypoglycemia, as well as skeletal and cardiac myopathies. Symptoms usually manifest upon fasting or intercurrent illnesses. 

In this case study, the patient was prescribed L-carnitine. Studies have shown that maintenance therapy with L-carnitine can improve plasma levels. The dose of the drug prescribed is titrated based on plasma carnitine levels, as well as treatment response. Maintenance therapy with L-carnitine can prevent hypoglycemic episodes and improve myopathy. 

Studies have demonstrated that the early diagnosis of primary carnitine deficiency and immediate treatment with L-carnitine can significantly improve clinical outcomes. For the vast majority of cases, symptoms can be controlled by maintenance therapy with L-carnitine. On the other hand, this condition can be fatal if untreated, potentially leading to sudden death. 

References

Rasania M, Ahmed NM, Prafulchandra BV, Jain S. Primary carnitine deficiency in a neonate. Arch Med Sci. Published online December 29, 2021. doi:10.4103/amhs.amhs_174_21

Dahash BA, Sankararaman S. Carnitine deficiency. In: StatPearls. StatPearls Publishing; 2022. Accessed June 1, 2022.