The Invitae Ketolysis Disorders Panel analyzes 2 genes, ACAT1 and OXCT1, which are associated with disorders of impaired ketone body metabolism. Genetic testing of these genes may confirm a diagnosis and help guide treatment and management decisions. Additionally, identification of disease-causing variants provides accurate genetic counseling, recognition of at-risk family members and assessment of carrier status.
For a broader analysis of the genetics of organic acidemias:
Beta-ketothiolase deficiency and SCOT deficiency are disorders of impaired ketone body metabolism. Ketones are an alternative fuel source used by extrahepatic tissues during times of glucose scarcity, and failure to utilize ketones can result in recurrent episodes of severe ketoacidosis, with or without, hypoglycemia.
Beta-ketothiolase deficiency is due to reduced or absent activity of the enzyme acetoacetyl-CoA thiolase (T2). T2 participates in ketone synthesis and cleavage, as well as the final step of isoleucine metabolism. Affected individuals essentially manifest an organic acidemia with excessive ketosis. Symptoms are not evident at birth and typically develop between 6 to 24 months of age following a period of fasting and/or infection. As ketones are unable to be catabolized as a fuel source by extrahepatic tissues, affected individuals present severe ketoacidosis, vomiting, dehydration, respiratory difficulties, lethargy and potentially, seizures. Episodes of decompensation are often recurrent with intervening asymptomatic periods. Biochemical findings typically include normal glucose levels, hyperketosis, elevations of isoleucine intermediates on urine organic acids (tiglylglycine, 2-methy-3-hydroxybutyrate (2M3HB), and 2-methylacetoacetate) and possibly elevated C5:1 acylcarnitine and C5OH acylcarnitine species.
SCOT deficiency also causes impaired ketolysis and is more clinically severe than beta ketothiolase deficiency. It is also characterized by recurrent episodes of severe ketoacidosis with asymptomatic periods in between, but most individuals exhibit chronic ketosis. Approximately half of affected individuals present in the first days of life and the other half between 5 months and two years of age. Symptoms include severe ketoacidosis, respiratory compromise, hypotonia and even coma. SCOT deficiency does not have a characteristic organic acid profile and milder cases may not manifest characteristic chronic ketosis.
Prognosis is good in both conditions once the diagnosis has been made and prophylactic treatment protocols can be implemented. Long term neurologic sequelae occur in some individuals and are a consequence of ketoacidotic episodes.
ACAT1 and OXCT1 are the only genes known to be associated with primary defects in ketone body utilization. However, due to the rarity of these conditions, the percent of primary ketolysis disorders attributed to pathogenic variants in ACAT1 or OXCT1 is currently unknown.
Ketolysis disorders are inherited in an autosomal recessive manner.
A recent newborn screening study has estimated the prevalence of beta-ketothiolase deficiency at 1 in 1,000,000. SCOT deficiency is much more rare with only a few patients reported in the literature.
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|