Background: the deficiency of 5,10-Methylenetetrahydrofolate reductase (MTHFR) constitutes a rare and severe metabolic disease and is included in most expanded newborn screening (NBS) programs worldwide. Patients with severe MTHFR deficiency develop neurological disorders and premature vascular disease. Timely diagnosis through NBS allows early treatment, resulting in improved outcomes. Methods: we report the diagnostic yield of genetic testing for MTHFR deficiency diagnosis, in a reference Centre of Southern Italy between 2017 and 2022. MTHFR deficiency was suspected in four newborns showing hypomethioninemia and hyperhomocysteinemia; otherwise, one patient born in pre-screening era showed clinical symptoms and laboratory signs that prompted to perform genetic testing for MTHFR deficiency. Results: molecular analysis of the MTHFR gene revealed a genotype compatible with MTHFR deficiency in two NBS-positive newborns and in the symptomatic patient. This allowed for promptly beginning the adequate metabolic therapy. Conclusions: our results strongly support the need for genetic testing to quickly support the definitive diagnosis of MTHFR deficiency and start therapy. Furthermore, our study extends knowledge of the molecular epidemiology of MTHFR deficiency by identifying a novel mutation in the MTHFR gene.

Background: A brief resolved unexplained event (BRUE) is a brief, sudden episode occurring in infants younger than 1 year of age, characterized by some combination of absent, decreased, or irregular breathing, an altered level of responsiveness, color change, and change in muscle tone. Although inappropriate feeding has been suggested as playing a role in the occurrence of BRUEs, only anecdotal reports have been described. The main objective of our study was to objectively evaluate whether overfeeding may represent a risk factor for the occurrence of BRUEs. Methods: We enrolled 42 infants aged 0–6 months and admitted for BRUE episodes and the same number of age- and sex-matched healthy infants who served as controls. Data about feeding practices and auxological parameters of each enrolled infant were collected and analyzed, along with clinical data about the pre- and post-natal period. The primary outcome measures were mean daily body weight gain, daily number of feedings, mean volume of feedings, and average daily volume only for bottle-fed infants. Results: The mean (±SD) daily body weight gain, the only available and reliable parameter to assess feeding adequacy in both breast- and formula-fed infants, was 41 ± 15 g in infants with BRUEs vs. 35 ± 11 g in healthy infants (95% CI [0.21; 11.8], p = 0.042). Moreover, infants with BRUEs were more likely to receive mixed breastfeeding than controls, although this difference did not reach statistical significance (33% vs. 17%, 95 CI [−0.04; 0.37], p = 0.131). Conclusions: Overfeeding seems to be a risk factor for BRUEs, either through milk inhalation, choking, or GER worsening. Detecting inappropriate feeding practices and providing appropriate education may help prevent the BRUE produced by either scenario.

Introduction: Elevated succinylacetone (SA) is the hallmark of tyrosinemia type 1, which requires immediate treatment. Mild SA elevation has also been recently reported in maleylacetoacetate isomerase deficiency (MAAID). Methods: We report on two cases of MAAID, review clinical features of MAAID and discuss its management. Results: Both cases displayed elevated SA and normal Tyrosine levels at newborn screening. Case 1 showed intermittent SA elevation; Nitisinone and dietary treatment were started, then discontinued after the identification of two variants in the GSTZ1 gene and the definitive diagnosis of MAAID. Case 2, showing no SA elevation at the confirmatory tests and two variants in the GSTZ1 gene, did not start treatment. mRNA analysis confirmed the pathogenicity of the c.68-12G>A variant, found in both patients. Discussion: MAAID should be considered in newborns showing elevated SA and no variants in the FAH gene. Our study reports for the first time the course of SA in a patient affected by MAAID. Furthermore, it expands the molecular epidemiology of this rare disease, also investigating the pathogenicity of a novel splicing mutation. Although our data argue against medical treatment in MAAID, longer follow-up data are warranted.