A female case of 5,10-methenyltetrahydrofolate synthetase deficiency with novel neuro-imaging abnormalities

Çavuşoğlu, Dilek; Köse, Melis; Er, Esra; Elmas, Muhsin; Gençpınar, Pınar; Dündar, Nihal Olgaç; Aydın, Kürşad

doi:10.1016/j.braindev.2022.05.008

Cited by 2 publications

(9 citation statements)

References 7 publications

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“…Seven cases with MTHFS deficiency have been described before with a comparable but not very specific neurometabolic phenotype. [1][2][3][4][5] Folate serves as cofactor in the provision of one-carbon units for the synthesis of purines, thymidine, and the remethylation of homocysteine to methionine (Figure 1). [8][9][10][11] MTHFS (5,10-methenyltetrahydrofolate synthetase or the systematic name 5-formyltetrahydrofolate cyclo-ligase) catalyzes the irreversible conversion of 5FTHF to 5,10-methenyltetrahydrofolate.…”

Section: Discussionmentioning

confidence: 99%

“…Seven cases with MTHFS deficiency have been described before with a comparable but not very specific neurometabolic phenotype. 1 , 2 , 3 , 4 , 5 …”

Section: Discussionmentioning

confidence: 99%

“…5,10‐Methenyltetrahydrofolate synthetase (MTHFS) deficiency (OMIM# 618367) is an extremely rare defect of folate metabolism (Figure 1). Seven patients with MTHFS deficiency have been published 1–5 . Core clinical features are microcephaly, severe global development delay, cerebral hypomyelination, epilepsy, and failure‐to‐thrive.…”

Section: Introductionmentioning

confidence: 99%

“…Seven patients with MTHFS deficiency have been published. 1 , 2 , 3 , 4 , 5 Core clinical features are microcephaly, severe global development delay, cerebral hypomyelination, epilepsy, and failure‐to‐thrive. Anemia has also been reported.…”

Section: Introductionmentioning

confidence: 99%

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5,10‐methenyltetrahydrofolate synthetase deficiency: An extreme rare defect of folate metabolism in two Dutch siblings

Liepina,

Smith,

Huidekoper

et al. 2024

JIMD Reports

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Two siblings, presenting with a neurometabolic phenotype, were identified with 5, 10‐methenyltetrahydrofolate synthetase (MTHFS) deficiency. Whole genome sequencing in both patients demonstrated an homozygous MTHFS variant NM_006441.3(MTHFS):c.434G > A, p.Arg145Gin, which has been described before. At baseline, both patients showed moderate hyperhomocysteinemia, decreased 5‐methyltetrahydrofolate (5MTHF), and increased 5‐formyltetrahydrofolate (5‐FTHF) in whole blood. In CSF, 5MTHF levels were in the low‐normal range and 5‐FTHF was strongly increased. In our novel enzyme assay, MTHFS activity was deficient in cultured fibroblasts in both sisters. Oral treatment was initiated with escalating dose of 5‐methyltetrahydrofolate (5MTHF) up to 12 mg and hydroxycobalamin 5 mg daily. Plasma homocysteine normalized and 5MTHF became elevated in the blood of both patients. The elevated 5FTHF levels increased further on treatment in blood and CSF. This regimen resulted in some clinical improvement of patient 1. In patient 2, the clinical benefits of 5MTHF supplementation were less obvious. It seems plausible that the alleviation of the deficient 5MTHF levels and normalization of homocysteine in blood are of some clinical benefit. On the other hand, the very high levels of 5FTHF may well be detrimental and may prompt us to decrease the dose of 5MTHF. In addition, we hypothesize that the crippled MTHFS enzyme may destabilize the purinosome, which is presumably not ameliorated by 5MTHF.

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Section: Discussionmentioning

confidence: 99%

“…Seven cases with MTHFS deficiency have been described before with a comparable but not very specific neurometabolic phenotype. 1 , 2 , 3 , 4 , 5 …”

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

5,10‐methenyltetrahydrofolate synthetase deficiency: An extreme rare defect of folate metabolism in two Dutch siblings

Liepina,

Smith,

Huidekoper

et al. 2024

JIMD Reports

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“…The level of 5, 10-MTHF in cerebrospinal fluid is decreased due to MTHFS impairment, whereas peripheral folate levels are normal. The clinical features mainly include global developmental delay (GDD), hypotonia, epilepsy, microcephaly, delayed myelination or hypomyelination and other cerebral dysplasia ( Rodan et al, 2018 ; Romero et al, 2019 ; Sakthivel et al, 2020 ; Cavusoglu et al, 2022 ; Vafaee-Shahi et al, 2022 ). However, as an extremely rare disorder, there is very limited understanding of this disease.…”

Section: Introductionmentioning

confidence: 99%

Exome sequencing identified novel variants in three Chinese patients with 5,10-methenyltetrahydrofolate synthetase deficiency

Xu,

Zhu,

Fang

et al. 2023

Front. Genet.

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5,10-methenyltetrahydrofolate synthetase (MTHFS) deficiency is a folate metabolism disorder known as a rare autosomal recessive neurodevelopmental disorder (MIM: #618367). With central nervous system involvements, it is mainly characterized by developmental delay, epilepsy, microcephaly, hypertonia, and cranial nerves involvement. Here, we report three new cases with MTHFS deficiency from two non-consanguineous Chinese families. All patients showed white matter dysplasia and global developmental delay, of which only patient 1 and 2 manifested tonic-clonic seizures. Moreover, patient 2 had severe eczema and patient 3 had recurrent diarrhea. Both phenotypic features are firstly found in MTHFS deficiency. Trio whole-exome sequencing and sanger sequencing were used to identify four novel variants, p.Y169Tfs*17, p.S53F, c.117+1delG, and p.E61G in the MTHFS gene. The identification of four novel pathogenic variants and varied clinical features in three affected patients expands the genotype and phenotype spectrum of MTHFS deficiency. We also reviewed all cases of MTHFS deficiency that had previously been reported. The experience of diagnosis and treatment from these cases provides us a more comprehensive understanding of this rare disease.

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A female case of 5,10-methenyltetrahydrofolate synthetase deficiency with novel neuro-imaging abnormalities

Cited by 2 publications

References 7 publications

5,10‐methenyltetrahydrofolate synthetase deficiency: An extreme rare defect of folate metabolism in two Dutch siblings

5,10‐methenyltetrahydrofolate synthetase deficiency: An extreme rare defect of folate metabolism in two Dutch siblings

Exome sequencing identified novel variants in three Chinese patients with 5,10-methenyltetrahydrofolate synthetase deficiency

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