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The current German newborn screening (NBS) panel includes 13 inherited metabolic diseases (IMDs). In addition, a NBS pilot study in Southwest Germany identifies individuals with propionic acidemia (PA), methylmalonic acidemia (MMA), combined and isolated remethylation disorders (e.g., cobalamin [cbl] C and methylenetetrahydrofolate reductase [MTHFR] deficiency), cystathionine β‐synthase (CBS) deficiency, and neonatal cbl deficiency through one multiple‐tier algorithm. The long‐term health benefits of screened individuals are evaluated in a multicenter observational study. Twenty seven screened individuals with IMDs (PA [N = 13], MMA [N = 6], cblC deficiency [N = 5], MTHFR deficiency [N = 2] and CBS deficiency [N = 1]), and 42 with neonatal cbl deficiency were followed for a median of 3.6 years. Seventeen screened IMD patients (63%) experienced at least one metabolic decompensation, 14 of them neonatally and six even before the NBS report (PA, cbl‐nonresponsive MMA). Three PA patients died despite NBS and immediate treatment. Fifteen individuals (79%) with PA or MMA and all with cblC deficiency developed permanent, mostly neurological symptoms, while individuals with MTHFR, CBS, and neonatal cbl deficiency had a favorable clinical outcome. Utilizing a combined multiple‐tier algorithm, we demonstrate that NBS and specialized metabolic care result in substantial benefits for individuals with MTHFR deficiency, CBS deficiency, neonatal cbl deficiency, and to some extent, cbl‐responsive MMA and cblC deficiency. However, its advantage is less evident for individuals with PA and cbl‐nonresponsive MMA. Synopsis: Early detection through newborn screening and subsequent specialized metabolic care improve clinical outcomes and survival in individuals with MTHFR deficiency and cystathionine‐β‐synthase deficiency, and to some extent in cobalamin‐responsive methylmalonic acidemia (MMA) and cblC deficiency while the benefit for individuals with propionic acidemia and cobalamin‐nonresponsive MMA is less evident due to the high (neonatal) decompensation rate, mortality, and long‐term complications. [ABSTRACT FROM AUTHOR]

MTHFR deficiency is a severe inborn error of metabolism leading to impairment of the remethylation of homocysteine to methionine. Neonatal and early‐onset patients mostly exhibit a life‐threatening acute neurologic deterioration. Furthermore, data on early‐onset patients' long‐term outcomes are scarce. The aims of this study were (1) to study and describe the clinical and laboratory parameters of early‐onset MTHFR‐deficient patients (i.e., ≤3 months of age) and (2) to identify predictive factors for severe neurodevelopmental outcomes in a cohort with early and late onset MTHFR‐deficient patients. To this end, we conducted a retrospective, multicentric, international cohort study on 72 patients with MTHFR deficiency from 32 international metabolic centres. Characteristics of the 32 patients with early‐onset MTHFR deficiency were described at time of diagnosis and at the last follow‐up visit. Logistic regression analysis was used to identify predictive factors of severe neurodevelopmental outcome in a broader set of patients with early and non‐early‐onset MTHFR deficiency. The majority of early‐onset MTHFR‐deficient patients (n = 32) exhibited neurologic symptoms (76%) and feeding difficulties (70%) at time of diagnosis. At the last follow‐up visit (median follow‐up time of 8.1 years), 76% of treated early‐onset patients (n = 29) exhibited a severe neurodevelopmental outcome. Among the whole study population of 64 patients, pre‐symptomatic diagnosis was independently associated with a significantly better neurodevelopmental outcome (adjusted OR 0.004, [0.002–0.232]; p = 0.003). This study provides evidence for benefits of pre‐symptomatic diagnosis and appropriate therapeutic management, highlighting the need for systematic newborn screening for MTHFR deficiency and pre‐symptomatic treatment that may improve outcome. [ABSTRACT FROM AUTHOR]

5,10‐Methylenetetrahydrofolate reductase (MTHFR) deficiency usually presents as a severe neonatal disease. This study aimed to characterize natural history, biological and molecular data, and response to treatment of patients with late‐onset MTHFR deficiency. The patients were identified through the European Network and Registry for Homocystinuria and Methylation Defects and the Adult group of the French Society for Inherited Metabolic Diseases; data were retrospectively colleted. To identify juvenile to adult‐onset forms of the disease, we included patients with a diagnosis established after the age of 10 years. We included 14 patients (median age at diagnosis: 32 years; range: 11‐54). At onset (median age: 20 years; range 9‐38), they presented with walking difficulties (n = 8), cognitive decline (n = 3) and/or seizures (n = 3), sometimes associated with mild mental retardation (n = 6). During the disease course, symptoms were almost exclusively neurological with cognitive dysfunction (93%), gait disorders (86%), epilepsy (71%), psychiatric symptoms (57%), polyneuropathy (43%), and visual deficit (43%). Mean diagnostic delay was 14 years. Vascular events were observed in 28% and obesity in 36% of the patients. One patient remained asymptomatic at the age of 55 years. Upon treatment, median total homocysteine decreased (from 183 μmol/L, range 69‐266, to 90 μmol/L, range 20‐142) and symptoms improved (n = 9) or stabilized (n = 4). Missense pathogenic variants in the C‐terminal regulatory domain of the protein were over‐represented compared to early‐onset cases. Residual MTHFR enzymatic activity in skin fibroblasts (n = 4) was rather high (17%‐58%). This series of patients with late‐onset MTHFR deficiency underlines the still unmet need of a prompt diagnosis of this treatable disease. [ABSTRACT FROM AUTHOR]