Iron-Refractory Iron Deficiency Anemia May Not Lead to Neurocognitive Dysfunction: A Case Report

Abstract

Iron deficiency is a common cause of anemia (IDA) in infancy and can be associated with neurocognitive impairments. Iron-refractory IDA (IRIDA) has recently been described as an inherited cause of IDA due to loss-of-function mutations in the TMPRSS6 gene. IRIDA is characterized by a lack of response to iron replacement. Here we report a new case of IRIDA with its biological parameters and its functional consequences, including neuropsychological impact. The latter was evaluated by the Wechsler Preschool and Primary Scale of Intelligence–Fourth Edition and subtests. We report a 5-year-old French Canadian boy who was incidentally diagnosed with a severe microcytic anemia at 2 years of age (hemoglobin 52 g/L, mean corpuscular volume 50 fL). Except mild pallor, he was asymptomatic of his anemia. Although he had a slight response to intravenous iron therapy, his hemoglobin remained <92 g/L, with persistent microcytosis, low serum iron, but normal ferritin levels. Blood hepcidin level was higher than those of his parents and control (patient 11.2 nM, father 9.06 nM, mother 4.07 nM). Compound heterozygosity for TMPRSS6 paternally inherited c.1324G>A and maternally inherited c.1807G>C mutations were eventually identified. The patient had normal development and growth. Neuropsychological evaluation revealed excellent performance, with high Wechsler Preschool and Primary Scale of Intelligence–Fourth Edition scores (ie, 82nd percentile for both global intelligence and general ability index). In conclusion, TMPRSS6 c.1807G>C in conjunction with c.1324G>A results in IRIDA. In contrast to the usual form of IDA, IRIDA may not be associated with neuropsychological deficits.

Functional diversity of TMPRSS6 isoforms and variants expressed in hepatocellular carcinoma cell lines

“…Therefore, we investigated the effect of the V736A variant (Hep3B) and the missense mutation V795I (HepG2) on the protease’s properties. We compared these mutants to TMPRSS6 isoform 2 along with the uncharacterized G603R mutation (rs769083817) found in two patients suffering from IRIDA 12 , 13 . Notably, two other missense mutations are annotated at position 603 according to ExAC Browser 44 but are not associated with IRIDA.…”

“…Moreover, we have identified six TMPRSS6 single nucleotide polymorphisms (SNPs) in Hep3B and HepG2 cell lines. Using heterologous expression, we have characterized some properties of TMPRSS6 variant V736A and mutant V795I identified in Hep3B and HepG2 cell lines, respectively, and an uncharacterized mutant (G603R), found in two patients suffering from IRIDA 12 , 13 , thus providing insight into the molecular basis of IRIDA.…”

Transcriptome analysis reveals TMPRSS6 isoforms with distinct functionalities

“…TMPRSS6 (also known as matriptase‐2) was first identified from foetal liver cDNA analysis, and genetic mutations were later associated with iron‐refractory iron deficiency anaemia (IRIDA) . Since then, over 40 TMPRSS6 mutations related to IRIDA have been identified . Mechanistically, TMPRSS6 acts as a negative regulator of the HAMP gene, which codes for a circulatory hormone called hepcidin that lowers iron levels through ferroportin internalization .…”

A novel homozygous nonsense mutation (p.Y78*) in TMPRSS6 gene causing iron-refractory iron deficiency anemia (IRIDA) in two siblings

“…Interestingly, in contrast to the usual form of IDA, IRIDA may not be associated with neuropsychological impairments as affected cases display normal growth and intellectual development. 2,8 The potential role of TMPRSS6 in brain iron homeostasis was speculated, and it was hypothesized that inappropriately elevated hepcidin and normal to high ferritin levels compared with poor iron reserves may protect the brain in IRIDA. 8 As expected in IRIDA cases, our patient displayed findings of defective iron utilization as evidenced by an elevation of ferritin levels after intravenous iron therapy with an only mild correction of his anemia.…”