Compound heterozygous FLAD1 mutations leading to Multiple Acyl-CoA Dehydrogenase deficiency-like phenotype



Poster Number: 196


Dana O'Rourke, MD, UCLA Neuromuscular Medicine Fellowship, Perry Shieh, MD, PhD, University of California, Los Angeles, Leigh Maria Ramos-Platt, MD, Children's Hospital Los Angeles/USC, Jennifer Cotter, MD, Children's Hospital Los Angeles (CHLA)

Multiple Acyl-CoA Dehydrogenase deficiency (MADD), or glutaric aciduria type 2, are a heterogenous group of disorders leading to disruption of fatty acid oxidation. Autosomal recessive mutations in FLAD1, which encode FAD Synthase, are associated with a MADD-like phenotype.

Objective: We describe a patient with compound heterozygous mutations in FLAD1 leading to a MADD-like phenotype with riboflavin responsive myopathy.

Results: Patient is a 22 year old female with hypotonia since birth. She required tracheostomy with mechanical ventilation and G-tube in the neonatal period. Despite significant hypotonia, she achieved developmental milestones on a delayed timeline including ability to ambulate. She continued to have significant respiratory weakness and remained ventilator dependent. In adolescence, she developed recurrent episodes of rhabdomyolysis which were triggered by either illness or activity, and had prolonged recovery periods with each episode. She had two muscle biopsies with results suggestive of a mitochondrial myopathy. Whole exome sequencing revealed a de novo variant c.95A>T (p.Lys32lle) in ASB5 of uncertain significance. The ASB5 gene is not associated with a known clinical condition. Subsequent Invitae Comprehensive Neuromuscular Disorders Panel identified two heterozygous mutations in FLAD1 (c.1033C>T (p.Arg345Cys), c.1589G>A (p.Arg530His)). She was started on Riboflavin 50mg BID with subsequent improvement in motor strength testing in the clinic after 6 months of supplementation.

FLAD1 MADD-like phenotypes have primarily been identified in patients with autosomal recessive mutations. There is a case series of patients with compound heterozygous variants in FLAD1 (Olsen et al. 2016). Our patient’s presentation adds to the growing literature of this rare metabolic myopathy. She went undiagnosed for many years until being tested with focused gene panels. Early identification and treatment with riboflavin may help prevent progression of myopathy.