Primary carnitine deficiency (OMIM 212140) is an autosomal recessive disorder of fatty acid oxidation due to the lack of functional OCTN2 carnitine transporters. Primary carnitine deficiency has a frequency of about 1:40,000 newborns in Japan [Koizumi et al., 1999
] and 1:37,000-1:100,000 newborns in Australia [Wilcken et al., 2001
]. In the USA and Europe, the frequency of primary carnitine deficiency has not been defined, but from the reported cases, it seems similar to that in Japan.
The lack of the plasma membrane carnitine transporter results in urinary carnitine wasting, low serum carnitine levels (0-5 μM, normal 25-50 μM), and decreased intracellular carnitine accumulation. Patients with primary carnitine deficiency lose most (90-95%) of the filtered carnitine in urine and their heterozygous parents lose 2 to 3 times the normal amount, explaining their mildly reduced plasma carnitine levels [Scaglia et al., 1998
Affected patients can have a predominant metabolic or cardiac presentation. The metabolic presentation is more frequent before two years of age. Typically, these children start refusing feedings and become irritable for an upper respiratory tract infection or an acute gastroenteritis. Subsequently, they become lethargic and minimally responsive. In most cases, they have hepatomegaly in addition to signs and symptoms of the triggering condition. Laboratory evaluation usually reveals hypoglycemia with minimal or no ketones in urine and hyperammonemia with variably elevated liver function tests. Creatine kinase (CK) can also be mildly elevated. If children are not treated promptly with intravenous glucose, they progress to coma and death. Cardiomyopathy is more frequent in older patients associated sometimes with hypotonia. Chest radiograms may show an enlarged heart and decreased ventricular ejection fraction can be measured by echocardiography. Cardiomyopathy can also be seen in older patients with a metabolic presentation, even if asymptomatic from a cardiac standpoint. A few patients, have been completely asymptomatic for all of their life and have been diagnosed following the birth of an affected child [Spiekerkoetter et al., 2003
]. Other children, diagnosed because of an affected sibling, had only mild developmental delays [Wang et al., 2001
Key to the diagnosis is the measurement of plasma carnitine levels. Free and acylated carnitine are extremely reduced (free carnitine < 5 μM, normal 25-50 μM) and urine organic acids do not show any consistent anomaly, although a non-specific dicarboxylic aciduria has been reported [Scaglia et al., 1998
]. Diagnosis is confirmed by demonstrating reduced carnitine transport in skin fibroblasts from the patient. This is usually reduced below 10% of the value of matched controls. There is a correlation between residual carnitine transport activity in fibroblasts and severity of the mutations, with nonsense mutations associated with absent carnitine transport activity. However, there is no correlation between genotype and clinical presentation [Amat Di San Filippo and Longo 2004
; Dobrowolski et al., 2005
; Scaglia et al., 1998
; Wang et al., 2000a
; Wang et al., 2001
; Wang et al., 2000b
; Wang et al., 1999
]. Heterozygous parents of affected children have half-normal carnitine transport in their fibroblasts and might have borderline low levels of plasma carnitine [Scaglia et al., 1998
]. Cardiac hypertrophy has been reported in heterozygotes approaching middle age [Koizumi et al., 1999
]. It is unclear whether this is associated with any health problem.
Several patients with primary carnitine deficiency have been identified by newborn screening programs in the past few years. The only anomaly on the acylcarnitine profile is a low level of free carnitine and all acylcarnitine species. Carnitine is transferred by the placenta to the growing fetus and plasma levels decrease rapidly after birth [Wilcken et al., 2001
]. However, plasma carnitine levels can be in the normal range if obtained too early in life. For this reason, several cases referred to us have been from states performing a repeated newborn screening after one week of age. These patients are usually completely asymptomatic at time of diagnosis and confirmation should be obtained by measuring plasma carnitine levels (free and total) and with appropriate transport studies in fibroblasts. Recently, a few infants were found with extremely low carnitine levels on newborn screening. However, their carnitine levels increased briskly on carnitine supplementation. These patients did not have primary carnitine deficiency, but their mothers did and remained asymptomatic all of their lives. Therefore, low carnitine levels in infants might unmask primary carnitine deficiency in the mother.
DNA studies have identified heterogeneous mutations in the SLC22A5 gene encoding the OCTN2 carnitine transporter in patients with primary carnitine deficiency. Our database includes 49 different mutations, summarized in and . Most families have private mutations and a few mutations, occurring at mutation-prone DNA sequences, have been reported more than once.
Mutations in the carnitine transporter OCTN2 in patients with primary carnitine deficiency
Mutations in the OCTN2 carnitine transporter in primary carnitine deficiency
Patients with primary carnitine deficiency respond to dietary carnitine supplementation (100-400 mg/kg/day), if started before irreversible organ damage occurs. The dose of carnitine should be adapted to each individual patient by serial measurements of plasma carnitine levels. Carnitine has few side effects. It can cause diarrhea and intestinal discomfort with high doses. This is usually self limiting, resolving by reducing carnitine dosage. Sometimes, bacterial metabolism in the intestine can result in carnitine degradation, with production of trimethylamine, a non-toxic chemical with a very unpleasant odor. This responds to oral therapy with metronidazole, an antibiotic active against anaerobic bacteria. The long-term prognosis is favorable as long as children remain on carnitine supplements. Repeated attacks of hypoglycemia or sudden death from arrhythmia even without cardiomyopathy have been reported in patients discontinuing carnitine against medical advice.
Primary carnitine deficiency should be differentiated from other causes of carnitine deficiency. These include a number of organic acidemias, defects of fatty acid oxidation and of the carnitine cycle (28). In all these disorders, analysis of urine organic acids, plasma amino acids and acylcarnitine profile, in conjunction with the clinical presentation, allows a definitive diagnosis. Low carnitine levels can also be seen in patients with generalized renal tubular dysfunction, such as renal Fanconi syndrome. In this case, the urinary wasting of other compounds, such as bicarbonate, phosphorus and amino acids, allows a net differentiation, since patients with primary carnitine deficiency have selective carnitine losses.