Hematologic presentation and the role of untargeted metabolomics analysis in monitoring treatment for riboflavin transporter deficiency

Abstract

Riboflavin transporter deficiency (RTD) (MIM #614707) is a neurogenetic disorder with its most common manifestations including sensorineural hearing loss, peripheral neuropathy, respiratory insufficiency, and bulbar palsy. Here, we present a 2-year-old boy whose initial presentation was severe macrocytic anemia necessitating multiple blood transfusions and intermittent neutropenia; he subsequently developed ataxia and dysarthria. Trio-exome sequencing detected compound heterozygous variants in SLC52A2 that were classified as pathogenic and a variant of uncertain significance. Bone marrow evaluation demonstrated megaloblastic changes. Notably, his anemia and neutropenia resolved after treatment with oral riboflavin, thus expanding the clinical phenotype of this disorder. We reiterate the importance of starting riboflavin supplementation in a young child who presents with macrocytic anemia and neurological features while awaiting biochemical and genetic work up. We detected multiple biochemical abnormalities with the help of untargeted metabolomics analysis associated with abnormal flavin adenine nucleotide function which normalized after treatment, emphasizing the reversible pathomechanisms involved in this disorder. The utility of untargeted metabolomics analysis to monitor the effects of riboflavin supplementation in RTD has not been previously reported.

Comparison of Untargeted Metabolomic Profiling vs Traditional Metabolic Screening to Identify Inborn Errors of Metabolism

“…Details of positive diagnosed cases and known and novel disease-related secondary analytes revealed by metabolomics 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 are reported in Table 2 and eTable 3 in the Supplement . Among the 655 families in the suggestive category ( Figure 1 B), 40 families (6.1%) were confirmed by further testing, including 36 families (90.0%) confirmed via molecular testing.…”

“…However, our results and those of others demonstrate that metabolomics can detect many disorders not included in most NBS panels. 12 , 13 , 14 , 21 , 39 Therefore, plasma metabolomic analysis should be considered as an initial screening approach when screening for IEMs, and it may also be useful to provide functional evidence for genomic variants of uncertain significance. 22 …”

A narrative review of metabolomics in the era of “-omics”: integration into clinical practice for inborn errors of metabolism

“…VUS, variant of uncertain significance; IEMs, inborn errors of metabolism; WGS, whole genome sequencing. (77,78). Pillai and colleagues reported a patient with riboflavin transporter deficiency with bi-allelic variants one pathogenic and one a variant of uncertain significance (VUS) in SLC52A2 (77).…”

“…With increased throughput and understanding of individual metabolites in disease pathogenesis, metabolomic signatures could be built upon to incorporate response to treatment. There are already examples in the literature of untargeted metabolomic analysis assisting in treatment monitoring for IEMs ( 77 , 78 ). Pillai and colleagues reported a patient with riboflavin transporter deficiency with bi-allelic variants one pathogenic and one a variant of uncertain significance (VUS) in SLC52A2 ( 77 ).…”

“…There are already examples in the literature of untargeted metabolomic analysis assisting in treatment monitoring for IEMs ( 77 , 78 ). Pillai and colleagues reported a patient with riboflavin transporter deficiency with bi-allelic variants one pathogenic and one a variant of uncertain significance (VUS) in SLC52A2 ( 77 ). Untargeted metabolomic analysis identified multiple compounds associated with abnormal flavin adenine nucleotide function, which normalized after riboflavin therapy.…”