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@ARTICLE{Marelli:154262,
      author       = {Marelli, Cecilia and Lavigne, Christian and Stepien,
                      Karolina M and Janssen, Mirian C H and Feillet, Francois and
                      Kožich, Viktor and Jesina, Pavel and Schule, Rebecca and
                      Kessler, Christoph and Redonnet-Vernhet, Isabelle and
                      Regnier, Adeline and Burda, Patricie and Baumgartner,
                      Matthias and Benoist, Jean-Francois and Huemer, Martina and
                      Mochel, Fanny},
      collaboration = {Consortium, E-HOD},
      title        = {{C}linical and molecular characterization of adult patients
                      with late-onset {MTHFR} deficiency.},
      journal      = {Journal of Inherited Metabolic Disease},
      volume       = {44},
      number       = {3},
      issn         = {1573-2665},
      reportid     = {DZNE-2021-00116},
      pages        = {777 - 786},
      year         = {2021},
      note         = {ISSN 1573-2665 not unique: **3 hits**.},
      abstract     = {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.},
      keywords     = {Adolescent / Adult / Age of Onset / Child / Delayed
                      Diagnosis / Epilepsy: diagnosis / Epilepsy: pathology /
                      Female / Homocystinuria: diagnosis / Homocystinuria:
                      pathology / Humans / Intellectual Disability: diagnosis /
                      Intellectual Disability: pathology / Male /
                      Methylenetetrahydrofolate Reductase (NADPH2): deficiency /
                      Middle Aged / Muscle Spasticity: diagnosis / Muscle
                      Spasticity: pathology / Psychotic Disorders: diagnosis /
                      Psychotic Disorders: pathology / Retrospective Studies /
                      Seizures: diagnosis / Seizures: pathology / Young Adult /
                      MTHFR deficiency (Other) / adult (Other) / inherited
                      metabolic disease (Other) / late-onset (Other) / neurology
                      (Other)},
      cin          = {AG Maetzler / Tübingen common},
      cid          = {I:(DE-2719)5000024 / I:(DE-2719)6000018},
      pnm          = {344 - Clinical and Health Care Research (POF3-344) / 353 -
                      Clinical and Health Care Research (POF4-353)},
      pid          = {G:(DE-HGF)POF3-344 / G:(DE-HGF)POF4-353},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:33089527},
      doi          = {10.1002/jimd.12323},
      url          = {https://pub.dzne.de/record/154262},
}