The Invitae Elevated C16, C16:1, C18 & C18:1 Panel analyzes the two genes that are associated with elevations of C16, C16:1, C18, and C18:1 acylcarnitines on newborn screening (NBS) or plasma acylcarnitines. Genetic testing of these genes 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.
Carnitine-acylcarnitine translocase (CACT) deficiency
Carnitine palmitoyltransferase deficiency type II (CPT2)
Elevated C16, C16:1, C18, and C18:1 acylcarnitines may be detected during newborn screening due to carnitine palmitoyltransferase II (CPT2) deficiency or, more rarely, carnitine-acylcarnitine translocase (CACT) deficiency. These disorders are indistinguishable upon newborn screening, plasma acylcarnitines, total and free carnitines, and urine organic acid analysis; enzymatic testing or molecular testing is needed to make the diagnosis.
Common features of CACT deficiency are hypoketotic hypoglycemia, hyperammonemia, hepatomegaly, cardiomyopathy and/or arrhythmia, and respiratory distress. Lethargy, coma, seizures, and hypotonia have also been reported in some patients. In addition to hypoketotic hypoglycemia with hyperammonemia, some patients may also have elevated creatinine kinase, liver transaminases, and metabolic acidosis. The vast majority of patients present at less than 30 days of age.
Phenotypes in patients with CPT2 deficiency can range in severity from a neonatal lethal form to an adult myopathic form.
Patients with the lethal neonatal form of CPT2 typically present within the first few days of life. Patients can present with hypoketotic hypoglycemia, hepatomegaly, liver failure, respiratory distress, seizures, cardiomyopathy, arrhythmias, facial dysmorphism, brain dysgenesis, neuronal migration defects (such as cystic dysplasia of basal ganglia or agenesis of the corpus callosum [Dandy-Walker malformation]), cystic dysplastic kidneys, and liver calcifications. Even with treatment, the prognosis is very poor in these patients.
Patients with the severe infantile form of CPT2 typically present within the first year of life. These patients typically have hypoketotic hypoglycemia, hepatomegaly, liver failure, cardiomyopathy, and muscle myopathy. Hypoketotic hypoglycemic episodes may be triggered by prolonged fasting or intercurrent illnesses. If left untreated, these patients are at risk of sudden infant death.
The most common form of CPT2 deficiency is the milder myopathic form, which is also the most common cause of hereditary myoglobinuria. Patients with myopathic CPT2 can present from early childhood to adulthood, although the majority present in childhood. Attacks are triggered predominantly by exercise, although intercurrent illness and prolonged fasting may also cause attacks. Patients can have muscle pain and weakness, rhabdomyolysis, and myoglobinuria during attacks, but they are generally asymptomatic between them. End-stage renal disease may be a long-term complication, particularly in patients with frequent myoglobinuria. Some infants with the myopathic form will have normal newborn screening due to the milder nature of this clinical subtype.
CPT2 and CACT are typically treated with a diet low in long-chain fatty acids and high in carbohydrates, with medium-chain triglyceride and carnitine supplementation. Patients with severe disease will have emergency protocols during intercurrent illness.
For patients with clinical and biochemical features consistent with CPT2 and CACT deficiencies (elevated C16, C16:1, C18, and C18:1 on acylcarnitines), greater than 95% are expected to have two pathogenic variants in CPT2 or SLC25A20.
Both causes of elevated C16, C16:1, C18, and C18:1 acylcarnitines, CACT and CPT2, are inherited in an autosomal recessive manner.
The prevalence of elevated C16, C16:1, C18, and C18:1 acylcarnitines is dependent on laboratory cutoffs and ethnicity. Limited data exist on the rates of false-positive elevations of these acylcarnitines. The prevalence of confirmed genetic causes of elevated C16, C16:1, C18, and C18:1 has been reported as high as 1 in 23,000 in some ethnic groups.
This panel may be appropriate for infants who have elevated C16, C16:1, C18, and C18:1 on NBS or confirmatory plasma acylcarnitine analysis.
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.
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