title: Characterization and review of MTHFD1 deficiency: four new patients, cellular delineation and response to folic and folinic acid treatment.
abstract: In the folate cycle MTHFD1, encoded by MTHFD1, is a trifunctional enzyme containing 5,10-methylenetetrahydrofolate dehydrogenase, 5,10-methenyltetrahydrofolate cyclohydrolase and 10-formyltetrahydrofolate synthetase activity. To date, only one patient with MTHFD1 deficiency, presenting with hyperhomocysteinemia, megaloblastic anaemia, hemolytic uremic syndrome (HUS) and severe combined immunodeficiency, has been identified (Watkins et al J Med Genet 48:590-2, 2011). We now describe four additional patients from two different families. The second patient presented with hyperhomocysteinemia, megaloblastic anaemia, HUS, microangiopathy and retinopathy; all except the retinopathy resolved after treatment with hydroxocobalamin, betaine and folinic acid. The third patient developed megaloblastic anaemia, infection, autoimmune disease and moderate liver fibrosis but not hyperhomocysteinemia, and was successfully treated with a regime that included and was eventually reduced to folic acid. The other two, elder siblings of the third patient, died at 9 weeks of age with megaloblastic anaemia, infection and severe acidosis and had MTFHD1 deficiency diagnosed retrospectively. We identified a missense mutation (c.806C > T, p.Thr296Ile) and a splice site mutation (c.1674G > A) leading to exon skipping in the second patient, while the other three harboured a missense mutation (c.146C > T, p.Ser49Phe) and a premature stop mutation (c.673G > T, p.Glu225*), all of which were novel. Patient fibroblast studies revealed severely reduced methionine formation from [(14)C]-formate, which did not increase in cobalamin supplemented culture medium but was responsive to folic and folinic acid. These additional cases increase the clinical spectrum of this intriguing defect, provide in vitro evidence of disturbed methionine synthesis and substantiate the effectiveness of folic or folinic acid treatment.
authors: Division of Metabolism and Children's Research Center, University Children's Hospital, Steinwiesstrasse 75, 8032, Zurich, Switzerland.
authors: P
authors: P
authors: Burda
authors: A
authors: A
authors: Kuster
authors: O
authors: O
authors: Hjalmarson
authors: T
authors: T
authors: Suormala
authors: C
authors: C
authors: Bürer
authors: S
authors: S
authors: Lutz
authors: G
authors: G
authors: Roussey
authors: L
authors: L
authors: Christa
authors: J
authors: J
authors: Asin-Cayuela
authors: G
authors: G
authors: Kollberg
authors: B A
authors: BA
authors: Andersson
authors: D
authors: D
authors: Watkins
authors: D S
authors: DS
authors: Rosenblatt
authors: B
authors: B
authors: Fowler
authors: E
authors: E
authors: Holme
authors: D S
authors: DS
authors: Froese
authors: M R
authors: MR
authors: Baumgartner
mesh_terms: D000749:Anemia, Megaloblastic / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D002478:Cells, Cultured; D017809:Fatal Outcome; D005260:Female; D005492:Folic Acid / Q000627:therapeutic use*; D005494:Folic Acid Deficiency / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D006801:Humans; D020138:Hyperhomocysteinemia / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D007223:Infant; D007231:Infant, Newborn; D002955:Leucovorin / Q000627:therapeutic use*; D008297:Male; D008754:Methylenetetrahydrofolate Dehydrogenase (NADP) / Q000172:deficiency* / Q000235:genetics*; D015778:Minor Histocompatibility Antigens; D016511:Severe Combined Immunodeficiency / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D055815:Young Adult
chemical_list: D015778:Minor Histocompatibility Antigens; D005492:Folic Acid; C539735:MTHFD1 protein, human; D008754:Methylenetetrahydrofolate Dehydrogenase (NADP); D002955:Leucovorin
references: J Inherit Metab Dis. 2014 Sep;37(5):841-9
references: 24722857
references: Pediatr Res. 1997 Jan;41(1):145-51
references: 8979304
references: Nature. 2014 Jun 12;510(7504):298-302
references: 24805240
references: Vitam Horm. 2008;79:1-44
references: 18804690
references: J Hum Genet. 2002;47(6):319-24
references: 12111380
references: Eur J Hum Genet. 2006 Jun;14(6):768-72
references: 16552426
references: Genome Res. 2010 Sep;20(9):1297-303
references: 20644199
references: Biochemistry. 2000 May 30;39(21):6325-35
references: 10828945
references: Am J Hum Genet. 2002 Nov;71(5):1207-15
references: 12384833
references: Cancer Epidemiol Biomarkers Prev. 2007 Jun;16(6):1140-7
references: 17548676
references: Bioinformatics. 2009 Aug 15;25(16):2078-9
references: 19505943
references: J Biol Chem. 2004 Oct 8;279(41):42742-9
references: 15292234
references: Nucleic Acids Res. 2003 Jul 1;31(13):3320-3
references: 12824317
references: Nat Methods. 2010 Apr;7(4):248-9
references: 20354512
references: Clin Chem. 2002 Jun;48(6 Pt 1):835-43
references: 12028998
references: Annu Rev Nutr. 2010 Aug 21;30:57-81
references: 20645850
references: J Med Genet. 2011 Sep;48(9):590-2
references: 21813566
references: BMC Med Genet. 2009 Jun 03;10:49
references: 19493349
references: Proc Natl Acad Sci U S A. 2013 Jan 8;110(2):549-54
references: 23267094
references: Pediatrics. 2013 Feb;131(2):e629-34
references: 23296427
references: Mol Cell Biol. 2002 Jun;22(12):4158-66
references: 12024029
references: Nat Protoc. 2009;4(7):1073-81
references: 19561590
references: Clin Cancer Res. 2007 Apr 15;13(8):2526-32
references: 17438114
references: J Biol Chem. 2009 Jan 16;284(3):1533-9
references: 19033438
references: Bioinformatics. 2009 Jul 15;25(14):1754-60
references: 19451168
references: Hum Genet. 1976 Dec 15;34(3):277-83
references: 1002151
references: Hum Mutat. 2009 Feb;30(2):212-20
references: 18767138
references: Nucleic Acids Res. 1988 Nov 25;16(22):10881-90
references: 2849754
references: J Inherit Metab Dis. 2012 Jul;35(4):665-70
references: 22108709