The Invitae Elevated C16-OH, C16:1-OH, C18-OH & C18:1-OH Panel analyzes the two genes that are associated with elevations of C16-OH, C16:1-OH, C18-OH, and C18:1-OH acylcarnitines on newborn screening (NBS) or plasma acylcarnitine analysis. 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.
Elevated C16-OH, C16:1-OH, C18-OH, and C18:1-OH acylcarnitines may be detected during newborn screening (NBS) or acylcarnitine analysis due to long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency or trifunctional protein (TFP) deficiency. Isolated LCHAD deficiency is due to biallelic pathogenic variants in the alpha-subunit (HADHA) of the mitochondrial trifunctional protein, whereas TFP deficiency is caused by biallelic pathogenic variants of either the alpha (HADHA) or the beta subunit (HADHB) of the trifunctional protein.
Patients with isolated trifunctional protein deficiency typically present within the first few months of life and before two years of age. Most patients present with acute metabolic crisis including hypoketotic hypoglycemia, vomiting, lethargy, hypotonia, hepatopathy, hepatomegaly, cardiomyopathy, coma, and seizures. Apnea, cardiac arrest, cardiac arrhythmias, and sudden death can also occur. Some patients may present with a more chronic picture of liver disease, failure to thrive, feeding difficulties, and hypotonia. Acute attacks can be precipitated by prolonged fasting or intercurrent illness. Elevated lactate, plasma creatine kinase, and ammonia may be present. Prognosis is generally poor in these patients. For those who survive, long-term complications that are not typically seen in fatty acid oxidation disorders, such as pigmentary retinopathy and peripheral neuropathy, can occur in patients with LCHAD deficiency. Patients can be mistaken as presenting with Reye syndrome. Females carriers of LCHAD deficiency who are pregnant with LCHAD deficient fetuses are at a greater risk of developing HELLP (hemolysis, elevated liver enzymes, and low platelets) syndrome and acute fatty liver of pregnancy.
Patients with TFP deficiency have similar presentations to those with LCHAD deficiency, but their symptoms tend to be more severe and to have an earlier onset. TFP deficiency patients present by the first few months of life, with approximately half presenting in the neonatal period. Patients can present with acute metabolic decompensation, including hypoketotic hypoglycemia with cardiac failure. Patients can have muscle myopathy, cardiomyopathy, recurrent Reye-like syndrome, and recurrent myoglobinuria. Patients may also develop peripheral neuropathy and pigmentary retinopathy. Elevated plasma lactate, plasma creatine kinase, and ammonia levels are common findings during metabolic crises. Early mortality is high in this disorder. Females carriers of TFP deficiency who are pregnant with TFP deficient fetuses are at a greater risk of developing HELLP syndrome and acute fatty liver of pregnancy.
Patients with LCHAD or TFP deficiency will have elevations of C16-OH, C16:1-OH, C18-OH, and C18:1-OH on NBS and acylcarnitine analysis. Patients may also have secondary carnitine deficiency. On urine organic acid analysis, patients can have characteristic elevations of long-chain 3-hydroxy fatty acids. Fatty acid oxidation in vitro probe assays may show elevation of hydroxylated long chain (C16-OH, C16:1-OH, C18:OH, C18:1-OH) acylcarnitine species, but this assay typically requires a skin biopsy. To distinguish LCHAD from TFP, enzyme assays or molecular testing is needed.
A low-fat, high-carbohydrate diet and avoidance of fasting have been used to treat patients with LCHAD/TFP deficiency. Emergency protocols may also be implemented during times of intercurrent illness to avoid catabolism. Although early therapy may reduce mortality, significant morbidity may still be present.
For patients with biochemical features consistent with LCHAD/TFP deficiency (elevated C16-OH, C16:1-OH, C18-OH & C18:1-OH), approximately >99% will have two pathogenic variants in either the HADHA or the HADHB gene.
LCHAD and TFP deficiencies are inherited in an autosomal recessive manner.
The prevalence of elevated C16-OH, C16:1-OH, C18-OH, and C18:1-OH acylcarnitines is dependent on laboratory cutoffs and ethnicity. The overall prevalence of confirmed LCHAD deficiency has been estimated at 1 in 334,000, but it can be as high as 1 in 2,900 in some ethnic populations. TFP deficiency is much more rare.
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 in the transcript listed below. In addition, analysis covers the select non-coding variants specifically defined in the table below. Any variants that fall outside these regions are not analyzed. Any specific limitations in the analysis of these genes are also listed in the table below.
Based on validation study results, this assay achieves >99% analytical sensitivity and specificity for single nucleotide variants, insertions and deletions <15bp in length, and exon-level deletions and duplications. Invitae's methods also detect insertions and deletions larger than 15bp but smaller than a full exon but sensitivity for these may be marginally reduced. Invitae’s deletion/duplication analysis determines copy number at a single exon resolution at virtually all targeted exons. However, in rare situations, single-exon copy number events may not be analyzed due to inherent sequence properties or isolated reduction in data quality. Certain types of variants, such as structural rearrangements (e.g. inversions, gene conversion events, translocations, etc.) or variants embedded in sequence with complex architecture (e.g. short tandem repeats or segmental duplications), may not be detected. Additionally, it may not be possible to fully resolve certain details about variants, such as mosaicism, phasing, or mapping ambiguity. Unless explicitly guaranteed, sequence changes in the promoter, non-coding exons, and other non-coding regions are not covered by this assay. Please consult the test definition on our website for details regarding regions or types of variants that are covered or excluded for this test. This report reflects the analysis of an extracted genomic DNA sample. In very rare cases, (circulating hematolymphoid neoplasm, bone marrow transplant, recent blood transfusion) the analyzed DNA may not represent the patient's constitutional genome.
|Gene||Transcript reference||Sequencing analysis||Deletion/Duplication analysis|