Gene variants in patients referred for genetic testing with suspicion of long chain fatty acid oxidation disorder (LCFAOD) have a diverse composition, according to a new study published in Neuromuscular Disorders. Based on this finding, the study authors said that approaches to resolve variants of uncertain significance and identify previously undetected variants “are important and necessary.”

In the United States, patients with a suspicion of LCFAOD are eligible for a free next-generation sequencing analysis that includes 6 genes known to be associated with the disease. The analysis also contains 18 additional genes associated with conditions that lead to abnormal acylcarnitine profiles.

The researchers reported that as of October 28, 2021, more than a third (37%) of 417 patients tested had LCFAOD gene variants. Patients’ symptoms included myopathy, elevated creatine kinase levels, and rhabdomyolysis if they were aged 13 years and above, and elevated creatine kinase levels and myopathy if they were under the age of 13 years. 


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Of the reported gene variants, 83 were of uncertain significance. There were 102 pathogenic gene variants, while 8 were likely pathogenic.

Of those 417 patients, 23 had positive LCFAOD results (2 pathogenic or likely pathogenic variants) and 19 had potential positive results, which consisted of 2 variants, at least 1 of which was of uncertain significance.

Following this, researchers conducted a resolution analysis of variants of uncertain significance and reclassified 6 of these as likely pathogenic or pathogenic. 

Five patients had variants in 2 or more genes associated with LCFAOD, while 22 had variants in 1 such gene and at least 1 other gene not associated with the disease. Fifty-one patients had only 1 gene variant associated with LCFAOD. 

LCFAOD is the name given to a group of rare metabolic disorders characterized by impaired fat metabolism resulting in acute crises of energy production and chronic energy deficiency.

Reference

Marsden D, Miller V, Baker P II, et al. Gene variant and neuromuscular findings from a long-chain fatty acid oxidation disorder gene panel program. Neuromuscul Disord. 2022;32(Suppl 1):S74. doi:10.1016/j.nmd.2022.07.135