FLAD1‐associated multiple acyl‐CoA dehydrogenase deficiency identified by newborn screening

Abstract

Background Multiple acyl‐CoA dehydrogenase deficiency (MADD), also known as glutaric aciduria type II, is a mitochondrial fatty acid oxidation disorder caused by variants in ETFA, ETFB, and ETFDH. Recently, riboflavin transporter genes and the mitochondrial FAD transporter gene have also been associated with MADD‐like phenotype. Methods We present a case of MADD identified by newborn biochemical screening in a full‐term infant suggestive of both medium‐chain acyl‐CoA dehydrogenase deficiency and MADD. Urine organic acid GC/MS analysis was also concerning for both disorders. However, panel sequencing of ETFA, ETFB, ETFDH, and ACADM was unrevealing. Ultimately, a variant in the FAD synthase gene, FLAD1 was found explaining the clinical presentation. Results Exome sequencing identified compound heterozygous variants in FLAD1: NM_025207.4: c.[442C>T];[1588C>T], p.[Arg148*];[Arg530Cys]. The protein damaging effects were confirmed by Western blot. The patient remained asymptomatic and there was no clinical decompensation during the first year of life. Plasma acylcarnitine and urinary organic acid analyses normalized without any treatment. Riboflavin supplementation was started at 15 months. Conclusion Newborn screening, designed to screen for specific treatable congenital metabolic diseases, may also lead to the diagnosis of additional, very rare metabolic disorders such as FLAD1 deficiency. The case further illustrates that even milder forms of FLAD1 deficiency are detectable in the asymptomatic state by newborn screening.

Riboflavin Deficiency—Implications for General Human Health and Inborn Errors of Metabolism

“…The expression of FADS6, encoded by a downstream ATG in exon 2, could be a possible explanation [9,136]. ETF, ETF-QO, ACADs and ETC decompensation have been observed in the patients at various extent, as a direct consequence of FAD depletion [9,138,139,142]. Interestingly, in LSMFLAD patients both FMN (FADS substrate) and FAD (FADS product) are decreased [9,139].…”

“…In 2016, FLAD1 variants were outlined in nine individuals with a MADD-like biochemical profile [9,137]. Six novel patients have been reported in the last four years and new patients are under investigation [138][139][140][141][142]. The phenotype of patients is extremely heterogeneous, ranging from early-onset and severe cardiac and respiratory insufficiency, often with a poor prognosis, to late-onset myopathies.…”

Riboflavin metabolism: role in mitochondrial function

“…The recently described clinical spectrum for FAD synthase deficiency has ranged from neonatal-onset, a lethal disease with metabolic myopathy, cardiomyopathy, swallowing, speech difficulties, and respiratory insufficiency, to later-onset, a potentially treatable neuromuscular disorder with lipid storage myopathy, MADD-like metabolic aberrations, and combined respiratory-chain deficiency [34] . To date, sixteen patients have been reported with age of onset ranging from birth to 44 years [34,[39][40][41][42][43][44][45] . Most patients (92%) have however presented in infancy, with five out of thirteen dying within the first twelve months of life.…”

“…Riboflavin supplementation resulted in clinical improvements in nine of ten patients treated [34,[39][40][41][42]44,45] . All five children who presented in infancy and treated with riboflavin were alive, two at 8 years, one at 22 years, one at 15 months [44] ), and one at 2 years 5 months [45] . Treatment with riboflavin in two patients carrying homozygous c.401_404delTTCT mutations in FLAD1 at age three months resulted in milder improvements in spontaneous activity, muscle tone, vomiting, and alertness; however, it failed to prevent disease progression and demise by six and five months, respectively [41] .…”

Abnormal VLCADD newborn screening resembling MADD in four neonates with decreased riboflavin levels and VLCAD activity

“…FAD is a main co‐factor for correct functioning and linking of acyl‐CoA dehydrogenases to the electron respiratory chain 1,2 . Since defects in the transport or metabolism of riboflavin, the precursor of the biologically active cofactor flavin adenine dinucleotide (FAD), can also cause MADD(‐like) metabolite abnormalities, 10‐17 we investigated the riboflavin status of these subjects. Plasma concentrations of FAD and the precursors flavin mononucleotide (FMN) and riboflavin were determined and were all decreased for subjects 1, 2, and 4, except for FAD in subject 2.…”