Clinical Findings of Late-onset Long-Chain Fatty Acid Oxidation Disorders Overlap with Neuromuscular Conditions in a Sponsored Genetic Testing Program



Poster Number: 130


Vanessa Rangel Miller MS, MBA, Tobin Chettiath PharmD, Britt Johnson PhD, Deborah Marsden MBBS, FACMG, Dee McKnight PhD, Sue Sarafrazi PhD, Andrew Willcock MS, Nicole Miller PhD


1. Ultragenyx Pharmaceutical, 2. Ultragenyx Pharmaceutical, 3. Invitae Corporation, 4. Ultragenyx Pharmaceutical, 5. Invitae Corporation, 6. Ultragenyx Pharmaceutical, 7. Invitae Corporation, 8. Ultragenyx Pharmaceutical

Background: Long-chain fatty acid oxidation disorders (LC-FAOD) are rare, life-threatening, autosomal recessive conditions. Clinical symptoms of LC-FAOD are heterogeneous and primarily affect organs that rely on energy production from fatty acid oxidation such as heart, skeletal muscle, and liver. Two LC-FAOD, very long-chain acyl co-enzyme A dehydrogenase (VLCAD deficiency, ACADVL gene) and carnitine palmitoyltransferase II (CPT II deficiency, CPT2 gene), may show late-onset presentation and clinical signs that overlap with neuromuscular findings. Here we report findings from a genetic testing program that provides a no-charge sponsored gene panel test for patients known to have or suspected of having LC-FAOD. Method: Patients in the U.S. and Canada who have either a clinical diagnosis or suspicion of LC-FAOD are eligible. Next-generation sequencing analysis with copy number variant detection was performed using a panel of up to 35 genes associated with LC-FAOD or other conditions that cause an abnormal plasma acylcarnitine profile. In this abstract, program data were analyzed for adolescent/adult patients, age 13 years (y) and older. Results: As of January 20, 2021, 161 patients were tested, 51 (31%) were adolescents/adults aged 13-92 y. Of these 51, 38 were reported to have one or more clinical signs as follows: muscle myopathy: 23, elevated creatine kinase: 14, rhabdomyolysis: 11, hypoketotic hypoglycemia: 4, and myoglobinuria: 3. Gene panel testing identified 17/161 (11%) patients with a positive or potential positive molecular diagnosis in LC-FAOD genes, including 11 ACADVL and 3 CPT2. Of these 17 patients, 4 were adolescents/adults with the following histories: 42y (CPT2) with an elevated creatine kinase, muscle myopathy, rhabdomyolysis; 36y (ACADVL) with exercise intolerance; 19y (ACADVL) with rhabdomyolysis, elevated creatine kinase, elevated transaminases, and a reported LC-FAOD type of VLCAD; and 17y (ACADVL) without clinical history reported. Conclusion: Adolescents and adults with VLCAD and CPTII reported clinical signs that overlap with neuromuscular disorders, including muscle myopathy, rhabdomyolysis, elevated creatine kinase, and myoglobinuria. Currently, not all states offer newborn screening for all LC-FAOD ( Our findings suggest that adolescent and adult patients may not have received newborn screening for LC-FAOD, thus highlighting the value of gene panel testing for symptomatic patients of all ages.