Laboratory diagnosis of disorders of peroxisomal biogenesis and function: a technical standard of the American College of Medical Genetics and Genomics (ACMG)

Abstract

Disclaimer: This technical standard is designed primarily as an educational resource for clinical laboratory geneticists to help them provide quality clinical laboratory genetic services. Adherence to this standard is voluntary and does not necessarily assure a successful medical outcome. This standard should not be considered inclusive of all proper procedures and tests or exclusive of other procedures and tests that are reasonably directed to obtaining the same results. In determining the propriety of any specific procedure or test, the clinical laboratory geneticist should apply his or her own professional judgment to the specific circumstances presented by the individual patient or specimen. Clinical laboratory geneticists are encouraged to document in the patient's record the rationale for the use of a particular procedure or test, whether or not it is in conformance with this standard. They also are advised to take notice of the date any particular standard was adopted, and to consider other relevant medical and scientific information that becomes available after that date. It also would be prudent to consider whether intellectual property interests may restrict the performance of certain tests and other procedures. Peroxisomal disorders are a clinically and genetically heterogeneous group of diseases caused by defects in peroxisomal biogenesis or function, usually impairing several metabolic pathways. Peroxisomal disorders are rare; however, the incidence may be underestimated due to the broad spectrum of clinical presentations. The inclusion of X-linked adrenoleukodystrophy to the Recommended Uniform Screening Panel for newborn screening programs in the United States may increase detection of this and other peroxisomal disorders. The current diagnostic approach relies heavily on biochemical genetic tests measuring peroxisomal metabolites, including very long-chain and branched-chain fatty acids in plasma and plasmalogens in red blood cells. Molecular testing can confirm biochemical findings and identify the specific genetic defect, usually utilizing a multiple-gene panel or exome/genome approach. When next-generation sequencing is used as a first-tier test, evaluation of peroxisome metabolism is often necessary to assess the significance of unknown variants and establish the extent of peroxisome dysfunction. This document provides a resource for laboratories developing and implementing clinical biochemical genetic testing for peroxisomal disorders, emphasizing technical considerations for sample collection, test performance, and result interpretation. Additionally, considerations on confirmatory molecular testing are discussed.

Laboratory analysis of acylcarnitines, 2020 update: a technical standard of the American College of Medical Genetics and Genomics (ACMG)

“…18,19 However, this latter group of disorders are better diagnosed by plasma VLCFA and branched-chain fatty acid analysis. 20 Organic acidemias are a heterogeneous group of inborn errors of metabolism (IEM). 21 Classic organic acidemias typically present with recurrent episodes of acute lifethreatening illness, hypo-or hypertonia, failure to thrive, and developmental delay.…”

Metabolomics to Improve the Diagnostic Efficiency of Inborn Errors of Metabolism

“…The current GC-MS method for VLCFA analysis tends to be laborious, time-consuming and expensive to perform [6]. Peroxisomal disorders is a specific example discussed in a statement by the American College of Medical Genetics and Genomics (ACMG), where the complexity of differentiating specific sub-types lends itself well to early molecular testing, particularly relevant with the introduction of x-linked adrenoleukodystrophy to the recommended uniform screening panel in the United States [26].…”

NovelDNM1Lvariants impair mitochondrial dynamics through divergent mechanisms

“…Unlike PBD patients though, DNM1L patients do not typically develop renal or hepatic dysfunction, skeletal abnormalities, or cataracts ( Waterham & Ebberink, 2012 ). Given these similarities, and the peroxisome fission abnormalities in many DNM1L patients, one might hypothesize that DNM1L patients would display similar biochemical profiles, with elevated very long-chain and branched-chain fatty acids ( De Biase et al, 2019 ). Unfortunately, there remains a dearth of DNM1L patient reports that analyse both peroxisomal morphology and perform the necessary analyses to fully evaluate peroxisomal function.…”