The Invitae Low C0 Test analyzes the SLC22A5 gene, which is associated with low C0 (free carnitine) on newborn screening (NBS), plasma acylcarnitine analysis, and total and free carnitine in plasma. Genetic testing of this gene may confirm a diagnosis and help guide treatment and management decisions.
The Invitae Fatty Acid Oxidation Defects Panel has been designed to provide a broad genetic analysis of this class of disorders. Depending on the individual’s clinical and family history, this broader panel may be appropriate. It can be ordered at no additional cost.
Primary carnitine deficiency
Low C0 (free carnitine) may be detected during newborn screening, acylcarnitine analysis, and total and free carnitine in plasma due to primary carnitine deficiency or secondary carnitine deficiency. Secondary carnitine deficiency can be caused both by genetic causes (other fatty acid oxidation disorders, organic acidemias) and by non-genetic causes (e.g., malnutrition, prematurity). Patients with primary carnitine deficiency may be differentiated from genetic causes of secondary carnitine deficiency through characteristic elevations of acylcarnitine species and possibly organic acids for these disorders. In patients with secondary carnitine deficiency due to non-genetic causes, characteristic elevation of free carnitine in urine will not be present. Healthy babies with abnormal newborn screening for low C0 may also be picked up due to maternal primary carnitine deficiency.
Patients with primary carnitine deficiency show a range in severity and may present in the infantile period (three months to two years), early childhood (two to four years), or as an adult, or they may be asymptomatic. Patients with the infantile-onset form have the typical metabolic features of a fatty acid oxidation disorder: poor feeding, irritability, lethargy, hepatomegaly, hypoketotic hypoglycemia, hyperammonemia, and elevated liver transaminases. Prolonged fasting or intercurrent illness may precipitate bouts of metabolic decompensation in these patients.
Patients with the childhood-onset form have a myopathic presentation that may include hypotonia, dilated cardiomyopathy, skeletal muscle myopathy, and elevated creatine kinase. Patients with this myopathic form are at risk of sudden cardiac death. Adult females have been detected through abnormal newborn screening findings in their babies. Roughly half of these adult patients have clinical symptoms and half are asymptomatic, despite having low carnitine. The most common symptom is fatigue, though cardiomyopathy and arrhythmias have been reported.
Carnitine supplementation is used to treat patients with primary carnitine deficiency. Emergency protocols are also implemented during times of metabolic crises, most commonly caused by illness, infection, or prolonged periods of fasting; if left untreated, it can lead to coma and death. On continued carnitine supplementation, patients have a good prognosis, so early diagnosis and detection may improve the long-term outcome of these patients.
For patients with biochemical features that are consistent with primary carnitine deficiency (low free, total, and acylcarnitine fractions in plasma or serum with elevated free carnitine in urine), greater than 70% will have two pathogenic variants in SLC22A5.
Primary carnitine deficiency is inherited in an autosomal recessive manner.
The prevalence of low C0 is dependent on laboratory cutoffs and ethnicity. The overall prevalence of confirmed primary carnitine deficiency has been estimated at 1 in 55,500, though it can be as high as 1 in 5,500 in some ethnic populations.
This test may be appropriate for patients:
For considerations for testing please refer to:
Invitae is a College of American Pathologists (CAP)-accredited and Clinical Laboratory Improvement Amendments (CLIA)-certified clinical diagnostic laboratory performing full-gene sequencing and deletion/duplication analysis using next-generation sequencing technology (NGS).
Our sequence analysis covers clinically important regions of each gene, including coding exons, +/- 10 base pairs of adjacent intronic sequence, and select noncoding variants. Our assay provides a Q30 quality-adjusted mean coverage depth of 350x (50x minimum, or supplemented with additional analysis). Variants classified as pathogenic or likely pathogenic are confirmed with orthogonal methods, except individual variants that have high quality scores and previously validated in at least ten unrelated samples.
Our analysis detects most intragenic deletions and duplications at single exon resolution. However, in rare situations, single-exon copy number events may not be analyzed due to inherent sequence properties or isolated reduction in data quality. If you are requesting the detection of a specific single-exon copy number variation, please contact Client Services before placing your order.
|Gene||Transcript reference||Sequencing analysis||Deletion/Duplication analysis|