Huemer, Martina ORCID: 0000-0002-0590-678X, Mulder-Bleile, Regina, Burda, Patricie, Froese, D. Sean, Suormala, Terttu, Ben Zeev, Bruria, Chinnery, Patrick F., Dionisi-Vici, Carlo ORCID: 0000-0002-0007-3379, Dobbelaere, Dries, Gokcay, Gulden, Demirkol, Muebeccel, Haeberle, Johannes, Lossos, Alexander, Mengel, Eugen, Morris, Andrew A., Niezen-Koning, Klary E., Plecko, Barbara ORCID: 0000-0002-3203-1325, Parini, Rossella ORCID: 0000-0003-4505-1306, Rokicki, Dariusz ORCID: 0000-0002-9736-2838, Schiff, Manuel ORCID: 0000-0001-8272-232X, Schimmel, Mareike, Sewell, Adrian C., Sperl, Wolfgang, Spiekerkoetter, Ute, Steinmann, Beat, Taddeucci, Grazia, Trejo-Gabriel-Galan, Jose M., Trefz, Friedrich, Tsuji, Megumi, Antonia Vilaseca, Maria, von Kleist-Retzow, Juergen-Christoph, Walker, Valerie, Zeman, Jiri ORCID: 0000-0002-2678-7919, Baumgartner, Matthias R. and Fowler, Brian (2016). Clinical pattern, mutations and in vitro residual activity in 33 patients with severe 5, 10 methylenetetrahydrofolate reductase (MTHFR) deficiency. J. Inherit. Metab. Dis., 39 (1). S. 115 - 125. HOBOKEN: WILEY. ISSN 1573-2665

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Abstract

Background Severe methylenetetrahydrofolate reductase (MTHFR) deficiency is a rare inborn defect disturbing the remethylation of homocysteine to methionine (<200 reported cases). This retrospective study evaluates clinical, biochemical genetic and in vitro enzymatic data in a cohort of 33 patients. Methods Clinical, biochemical and treatment data was obtained from physicians by using a questionnaire. MTHFR activity was measured in primary fibroblasts; genomic DNA was extracted from cultured fibroblasts. Results Thirty-three patients (mean age at follow-up 11.4 years; four deceased; median age at first presentation 5 weeks; 17 females) were included. Patients with very low (<1.5 %) mean control values of enzyme activity (n=14) presented earlier and with a pattern of feeding problems, encephalopathy, muscular hypotonia, neurocognitive impairment, apnoea, hydrocephalus, microcephaly and epilepsy. Patients with higher (>1.7-34.8 %) residual enzyme activity had mainly psychiatric symptoms, mental retardation, myelopathy, ataxia and spasticity. Treatment with various combinations of betaine, methionine, folate and cobalamin improved the biochemical and clinical phenotype. During the disease course, patients with very low enzyme activity showed a progression of feeding problems, neurological symptoms, mental retardation, and psychiatric disease while in patients with higher residual enzyme activity, myelopathy, ataxia and spasticity increased. All other symptoms remained stable or improved in both groups upon treatment as did brain imaging in some cases. No clear genotype-phenotype correlation was obvious. Discussion MTHFR deficiency is a severe disease primarily affecting the central nervous system. Age at presentation and clinical pattern are correlated with residual enzyme activity. Treatment alleviates biochemical abnormalities and clinical symptoms partially.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Huemer, MartinaUNSPECIFIEDorcid.org/0000-0002-0590-678XUNSPECIFIED
Mulder-Bleile, ReginaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Burda, PatricieUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Froese, D. SeanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Suormala, TerttuUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ben Zeev, BruriaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Chinnery, Patrick F.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Dionisi-Vici, CarloUNSPECIFIEDorcid.org/0000-0002-0007-3379UNSPECIFIED
Dobbelaere, DriesUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gokcay, GuldenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Demirkol, MuebeccelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Haeberle, JohannesUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lossos, AlexanderUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mengel, EugenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Morris, Andrew A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Niezen-Koning, Klary E.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Plecko, BarbaraUNSPECIFIEDorcid.org/0000-0002-3203-1325UNSPECIFIED
Parini, RossellaUNSPECIFIEDorcid.org/0000-0003-4505-1306UNSPECIFIED
Rokicki, DariuszUNSPECIFIEDorcid.org/0000-0002-9736-2838UNSPECIFIED
Schiff, ManuelUNSPECIFIEDorcid.org/0000-0001-8272-232XUNSPECIFIED
Schimmel, MareikeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sewell, Adrian C.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sperl, WolfgangUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Spiekerkoetter, UteUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Steinmann, BeatUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Taddeucci, GraziaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Trejo-Gabriel-Galan, Jose M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Trefz, FriedrichUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tsuji, MegumiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Antonia Vilaseca, MariaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
von Kleist-Retzow, Juergen-ChristophUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Walker, ValerieUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Zeman, JiriUNSPECIFIEDorcid.org/0000-0002-2678-7919UNSPECIFIED
Baumgartner, Matthias R.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Fowler, BrianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-292881
DOI: 10.1007/s10545-015-9860-6
Journal or Publication Title: J. Inherit. Metab. Dis.
Volume: 39
Number: 1
Page Range: S. 115 - 125
Date: 2016
Publisher: WILEY
Place of Publication: HOBOKEN
ISSN: 1573-2665
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
S-ADENOSYLMETHIONINE; CEREBROSPINAL-FLUID; MR SPECTROSCOPY; HOMOCYSTINURIA; BETAINE; FOLATE; BRAIN; PSYCHOSIS; GENEMultiple languages
Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & ExperimentalMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/29288

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