Influence of early identification and therapy on long‐term outcomes in early‐onset <scp>MTHFR</scp> deficiency
Mathilde Yverneau, Stéphanie Leroux, Apolline Imbard, Florian Gleich, Alina Arion, Caroline Moreau, Marie‐Cécile Nassogne, Marie Szymanowski, M. Tardieu, Guy Touati, María Bueno, Kimberly A. Chapman, Yin‐Hsiu Chien, Martina Huemer, Pavel Ješina, Mirian C. H. Janssen, Stefan Kölker, Viktor Kožich, Christian Lavigne, Allan M. Lund, Fanny Mochel, Andrew A. M. Morris, Mónica Ruiz Pons, Gloria Liliana Porras‐Hurtado, Jean‐François Benoist, Léna Damaj, Manuel Schiff
Abstract
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.