Post-mortem detection of FLAD1 mutations in 2 Turkish siblings with hypotonia in early infancy

Abstract

Inherited defects of vitamin B2 (riboflavin) metabolism may cause different phenotypes with common biochemical markers of multiple acyl-CoA dehydrogenase deficiency (MADD). Most recently, mutations in FLAD1, which encodes flavin adenine dinucleotide (FAD) synthase, has been implicated in MADD with combined respiratory chain deficiency in nine patients. Here, we describe two siblings with FAD synthase deficiency, who were diagnosed post-mortem upon suspicion of this newly-described disease. Hypotonia was evident at two months of age in both infants, followed by feeding difficulties, respiratory distress and death in six months despite partial response to riboflavin. The older sibling had documented lipid storage myopathy and biochemical markers of MADD. Our observations support the previous reports of unexpected riboflavin-responsiveness in frameshift mutations in the second exon of FLAD1 and suggest dysmorphic auricular helix and hypospadias as possible additional clinical features. More reports and studies are needed to better describe and treat FAD synthase deficiency.