Aída Ormazábal Herrero

Classical homocystinuria (HCY) due to cystathionine beta-synthase (CBS) deficiency is included in many newborn screening programs, which traditionally use dried blood spot (DBS) methionine as the primary biomarker. However, some patients have normal or only mildly elevated methionine in the neonatal period, leading to false-negative results. We report a four-month-old male infant referred for sagittal craniosynostosis, whose metabolic evaluation revealed markedly elevated plasma methionine and total homocysteine concentrations. Genetic analysis identified a homozygous, pathogenic variant (c.1007G>A) in the CBS gene, confirming HCY. On retrospective review, the DBS sample had been collected at 48 h of life, and methionine was within the reference range. Consequently, the screening algorithm had not triggered second-tier total homocysteine testing. Sanger sequencing of the original DBS sample confirmed the same homozygous CBS variant, ruling out sample swap and establishing the case as a true false-negative result. Treatment with pyridoxine and folic acid rapidly normalized biochemical parameters, consistent with a pyridoxine-responsive phenotype. This case illustrates that normal neonatal methionine does not exclude CBS deficiency and that genomic newborn screening approaches could detect this disease more reliably.

In inborn errors of intermediate protein metabolism (IEM), the effect of special low-protein foods (SLPFs) on dietary intake has been scarcely studied. The aim of this study was to compare the nutritional profile of SLPFs with usual foods and to assess whether their intake determines the dietary pattern and affects the plasma biochemical profile in children with IEMs with different protein restrictions. A database with the nutritional composition of 250 SLPFs was created. A total of 59 children with IEMs were included in this cross-sectional observational study. The greatest significant differences in macronutrient composition were observed between dairy, meat, fish, and egg SLPFs and regular foods. After stratifying subjects by SLPFs, the participants with the highest intake (>32%) had a higher total energy intake and lower intake of natural protein than those in the lowest tertile (p < 0.05). However, when stratifying subjects by dairy SLPF intake, children in the highest tertile (>5%) showed a higher intake of sugars, total and saturated fats, and higher plasma levels of total and low-density lipoprotein cholesterol than those in the first tertile (p < 0.05). The variability in the nutritional composition of SLPFs highlights the need for up-to-date databases which would greatly assist in optimizing individualized recommendations for children with IEMs and protein restrictions.