Riboflavin is the precursor of FAD, which acts as an electron acceptor in a number of acyl-CoA dehydrogenation reactions involved in mitochondrial fatty acid oxidation and branched-chain amino acid catabolism (Gregersen et al. 2008
). An inherited or acquired deficiency of riboflavin will therefore mimic the biochemical presentation observed in classical MADD, which was indeed observed in a riboflavin-deficient rat (Goodman 1981
). The biochemical abnormalities observed in our patients are reminiscent of the mild forms of MADD, originally described as ethylmalonic/adipic aciduria (Tanaka et al. 1977
). Our data suggest that the short-chain and medium-chain acyl-CoA dehydrogenases are more vulnerable to the shortage of the physiological electron acceptor than the long-chain analogues. Similarly, glutaryl-CoA dehydrogenase was only mildly affected, in contrast to the D-2 hydroxyglutarate dehydrogenase.
Based on the profiles of acylcarnitines and organic acids it is difficult to make the distinction between the riboflavin transporter defect and the ETHE defect. Both conditions, however, have their own diagnostic analytes, i.e., riboflavin in the riboflavin transporter defect (Brown-Vialetto-Van Laere / Fazio Londe syndrome) and thiosulfate and sulfo(thio)cysteine in ETHE (Duran et al. 1997
). Metabolic studies in intact fibroblasts were normal in the transporter defect cells, probably because the riboflavin in the cell culture medium corrected the defect resulting in a normal fatty acid oxidation. Likewise, maternal riboflavin supply is the probable cause of the normal clinical condition of the patients at birth and the fact that the acylcarnitines were normal in the newborn blood spots of patients 1 and 2.
Riboflavin deficiency usually presents with different clinical symptoms (Powers 2003
), but neurological symptoms resolving with riboflavin supplementation have been previously reported in a child with moderate riboflavin deficiency (Leshner 1981
). Although further pathophysiological studies are needed to explain the clinical symptoms, we demonstrate that the riboflavin deficiency in our patients resulted from a defect in the riboflavin transporter, encoded by the C20orf54
Remarkably, at the same time that we discovered the molecular defects in our patients, causing a defective intestinal riboflavin transport, Green et al. (2010
) reported the identification of mutations in the C20orf54
gene as the cause of the Brown-Vialetto-Van Laere Syndrome (MIM 211530). Indeed, the clinical presentation of all three patients is compatible with the diagnosis of Brown-Vialetto-van Laere (patient 3) or the Fazio Londe (patients 1 and 2) syndrome. This implies that at least part of the clinical signs and symptoms observed in these syndromes are caused by a deficiency of riboflavin and subsequently of FAD and FMN. The striking clinical and biochemical improvement on riboflavin supplementation seen in our patients strongly supports this hypothesis. We therefore presume that riboflavin may be an effective therapy in the Brown-Vialetto-Van Laere syndrome, at least in young patients. Early treatment appears to be crucial as diaphragmatic paralysis may be irreversible. Furthermore, in spite of the riboflavin supplementation since the age of 6 months, patient three now, at age 7, demonstrates the neurological deterioration frequently observed in untreated Brown-Vialetto-Van Laere patients. This can be due to damage which already occurred during the extended periods of low FAD values probably present during the first 6 months of life as well as around the age of four, or to periods of limited riboflavin availability during intercurrent illnesses, as she demonstrated clinical deterioration mostly during periods of viral illness. On the other hand, it is possible that riboflavin supplementation only shifts the clinical course of the Brown-Vialetto-Van Laere / Fazio Londe syndrome to a later presentation of the clinical symptoms. A long term follow up of a cohort of early treated children, and more insight in the pathophysiology is warranted.
Finally, our results demonstrate that selective metabolic screening, including acylcarnitine profiling and organic acid analysis of the urine, is warranted in all patients with unexplained hypotonia and that plasma flavins should be measured in patients with riboflavin responsive MADD in whom sequencing of the relevant genes fails to detected a mutation.