Systemic
primary carnitine deficiency (
CDSP) is an autosomal recessive disorder of
carnitine transportation. The clinical manifestations of
CDSP can vary widely with respect to age of onset, organ involvement, and severity of symptoms, but are typically characterized by episodes of hypoketotic
hypoglycemia,
hepatomegaly, elevated
transaminases, and
hyperammonemia in infants; skeletal
myopathy, elevated
creatine kinase (CK), and
cardiomyopathy in childhood; or
cardiomyopathy, arrhythmias, or fatigability in adulthood. The diagnosis can be suspected on newborn screening, but is established by demonstration of low plasma free
carnitine concentration (<5 μM, normal 25-50 μM), reduced fibroblast
carnitine transport (<10% of controls), and molecular testing of the SLC22A5 gene. The incidence of
CDSP varies depending on ethnicity; however the frequency in the United States is estimated to be approximately 1 in 50,000 individuals based on newborn screening data.
CDSP is caused by recessive mutations in the SLC22A5 gene. This gene encodes organic
cation transporter type 2 (OCTN2) which transport
carnitine across cell membranes. Over 100 mutations have been reported in this gene with the c.136C > T (p.P46S) mutation being the most frequent mutation identified.
CDSP should be differentiated from secondary causes of
carnitine deficiency such as various organic acidemias and
fatty acid oxidation defects.
CDSP is an autosomal recessive condition; therefore the recurrence risk in each pregnancy is 25%. Carrier screening for at-risk individuals and family members should be obtained by performing targeted mutation analysis of the SLC22A5 gene since plasma
carnitine analysis is not a sufficient methodology for determining carrier status. Antenatal diagnosis for pregnancies at increased risk of
CDSP is possible by molecular genetic testing of extracted
DNA from chorionic villus sampling or amniocentesis if both mutations in SLC22A5 gene are known. Once the diagnosis of
CDSP is established in an individual, an echocardiogram, electrocardiogram, CK concentration, liver transaminanses measurement, and pre-prandial
blood sugar levels, should be performed for baseline assessment. Primary treatment involves supplementation of oral
levocarnitine (
L-carnitine) at a dose of 50-400 mg/kg/day divided into three doses. No formal surveillance guidelines for individuals with
CDSP have been established to date, however the following screening recommendations are suggested: annual echocardiogram and electrocardiogram, frequent plasma
carnitine levels, and CK and liver
transaminases measurement can be considered during acute illness. Adult women with
CDSP who are planning to or are pregnant should meet with a metabolic or genetic specialist ideally before conception to discuss management of
carnitine levels during pregnancy since
carnitine levels are typically lower during pregnancy. The prognosis for individuals with
CDSP depends on the age, presentation, and severity of symptoms at the time of diagnosis; however the long-term prognosis is favorable as long as individuals remain on
carnitine supplementation.