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3-methylcrotonyl-CoA carboxylase deficiency (3MCCD) is a hereditary disorder of leucine catabolism caused by pathogenetic variants in the MCCC1 or MCCC2 genes. Typically diagnosed through newborn screening (NBS), 3MCCD is characterized by elevation of 3-hydroxyisovalerylcarnitine (C5OH) in blood as well as increased excretion of 3-methylcrotonylglycine (3-MCG) in urine. While most diagnosed children remain asymptomatic, data on adults are scarce. To date, only 39 molecularly confirmed adult individuals have been reported, all being mothers diagnosed subsequent to their child NBS results. Herein, we present a 36-year-old asymptomatic man who was incidentally diagnosed with 3MCCD following his son NBS recall. Molecular analysis revealed compound heterozygosity for two pathogenic variants in the MCCC1 gene. This is the first molecularly confirmed adult man with 3MCCD reported. This case highlights the need for additional longitudinal follow-up data on individuals with 3MCCD to clarify the clinical significance of this condition and guide clinical practice, including NBS strategy., Competing Interests: The authors declare that there is no potential conflict of interest related to this work., (© 2024 The Authors. Published by Elsevier Inc.)

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.

Introduction: Short/branched-chain acyl-CoA dehydrogenase deficiency (SBCADD) is an inherited disorder of L-isoleucine metabolism due to mutations in the ACADSB gene. The role of current diagnostic biomarkers [i.e., blood 2-methylbutyrylcarnitine (C5) and urine 2-methylbutyrylglycine (2MBG)] in patient monitoring and the effects of proposed treatments remain uncertain as follow-data are lacking. This study presents first systematic longitudinal biochemical assessment in SBCADD patients., Methods: A retrospective, observational single-center study was conducted on newborns born between 2017 and 2020 and suspected with SBCADD. Biochemical, molecular, clinical and dietary data collected upon NBS recall and during the subsequent follow-up were recorded., Results: All enrolled subjects ( n = 10) received adequate protein intake and L-carnitine supplementation. Nine subjects were diagnosed with SBCADD. During the follow-up [median: 20.5 (4-40) months] no patient developed symptoms related to SBCADD. No patient normalized serum C5 and urine 2MBG values. In 7/9 SBCADD patients mean serum C5 values decreased or stabilized compared to their first serum C5 value. A major increase in serum C5 values was observed in two patients after L-carnitine discontinuation and during intercurrent illness, respectively. Urine 2MBG values showed moderate intra-patient variability., Discussion: The relatively stable serum C5 values observed during L-carnitine supplementation together with C5 increase occurring upon L-carnitine discontinuation/intercurrent illness may support the value of serum C5 as a monitoring biomarker and the benefit of this treatment in SBCADD patients. The role of urine 2MBG in patient monitoring remains uncertain. As all patients were asymptomatic, no association between biochemical parameters and clinical phenotype could be investigated in this study., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Rossi, Turturo, Albano, Fecarotta, Barretta, Crisci, Gallo, Perfetto, Uomo, Vallone, Villani, Strisciuglio, Parenti, Frisso and Ruoppolo.)