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Intellectual disability


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MTHFS (methenyltetrahydrofolate synthetase)
EnsemblGeneIds (GRCh38): ENSG00000136371
EnsemblGeneIds (GRCh37): ENSG00000136371
OMIM: 604197, Gene2Phenotype
MTHFS is in 2 panels

2 reviews

Zornitza Stark (Australian Genomics)

Green List (high evidence)

Three unrelated individuals reported with supporting biochemical evidence.
Created: 10 Mar 2020, 4:26 a.m. | Last Modified: 10 Mar 2020, 4:26 a.m.
Panel Version: 3.3

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Neurodevelopmental disorder with microcephaly, epilepsy, and hypomyelination, 618367


Variants in this GENE are reported as part of current diagnostic practice

Konstantinos Varvagiannis (Other)

Green List (high evidence)

Biallelic pathogenic MTHFS variants cause Neurodevelopmental disorder with microcephaly, epilepsy, and hypomyelination (# 618367).

The gene encodes 5,10-Methenyltetrahydrofolate synthetase which catalyzes conversion of 5-formyltetrahydrofolate (5-FTHF or folinic acid) to 5,10-methenyltetrahydrofolate (5,10-MTHF).

At least 3 unrelated individuals have been reported. The phenotype appears to be relevant to both epilepsy and ID gene panels and the role of variants/the gene supported by enzymatic activity studies, 5-FTHF accumulation, 5,10-MTHF levels (low/low-normal), the role of folate metabolism pathway overall and some supporting (metabolic) evidence from the mouse model.
Rodan et al (2018 - PMID: 30031689) reported on 2 individuals both presenting with microcephaly, severe global DD, epilepsy, progressive spasticity and cerebral hypomyelination upon MRI imaging. Short stature was also feature in both.

The 1st patient was an 8-year-old male who following exome sequencing was found to harbor 2 missense variants each inherited from a carrier parent. (NM_006441.3:c.434G>A / p.R145Q and c.107T>C / p.L36P). A further AFG3L2 indel was not felt to fit with his phenotype (and the onset of the related disorder appears to occur later).

Previous investigations included extensive metabolic testing, CMA, Angelman syndrome methylation analysis, GFAP, POLG1, TYMP sequencing, mitochondrial genome analysis and an XL-ID gene panel (further suggesting relevance of this gene to the current panel) were all non-diagnostic.

CSF 5-MTHF levels were initially on the low-normal range, subsequently found to be decreased (upon folinic acid supplementation) and later normalized upon use of another regimen.

MTHFS activity was measured in control fibroblasts as well as fibroblasts from this individual, with the latter demonstrating no enzyme activity. Accumulation (30x elevation) of 5-FTHF (the substrate of MTHFS) was demonstrated in patient fibroblasts.

The 2nd patient was a 11-year-old male with similar features incl. global DD (standing/walking/single words at/after 4 years of age, limited vocabulary and articulation upon last examination).

Extensive metabolic work-up as well as genetic testing for an epilepsy panel, vanishing white matter disease gene panel, mitochondrial genome as well as specific gene sequencing (LAMA2, POLR3A, POLR3B) were all non-diagnostic. Trio exome revealed 2 MTHFS variants in trans configuration (c.484C>T / p.Q162X and c.434G>A / p.R145Q).
Romero et al (2019 - PMID: 31844630) reported on a 4-year-old female with congenital microcephaly, severe global DD (nonverbal/nonambulatory at the age of 4), spasticity, epilepsy and cerebral hypomyelination.

Extensive investigations prior to exome sequencing revealed macrocytic anemia, decreased CSF 5-MTHF and elevated neopterin, 2 CNVs of uncertain significance upon CMA with additional long ROH on chr15. Methylation studies were negative. The child was homozygous for c.220C>T / p.R74X (RefSeq is probably NM_006441.3. MTHFS lies on chr15. The parents were unrelated but came from the same town). There were no other candidate variants from the exome analysis.

Both articles discuss extensively the role of the folate metabolism pathway overall in nucleic acid synthesis, AA metabolism, neurotransmitter synthesis, methylation as well as 5-FTHF / 5,10-MTHF in particular in myelin stabilization and DNA synthesis (eg. according to Romero et al. a defect in MTHFS would impair myelin production and also lead to decreased myelin stability).
A book chapter cited by Rodan et al (in N. Blau et al. (eds.), Physician’s Guide to the Diagnosis, Treatment, and Follow-Up of Inherited Metabolic Diseases - DOI: 10.1007/978-3-642-40337-8_10) included limited details on a patient with 'MTHFS gene mutation'. This individual had early speech delay, seizures beginning in infancy, ID, autistic features, recurrent infections and was found to have very low CSF 5-MTHF levels. [Details in p169 and table 10.6 - p173].
In a mouse model reported by Field et al (2011 - PMID: 22303332), Mthfs was disrupted through insertion of a gene trap vector between the first 2 exons. Heterozygous [Mthfs(gt/+)] mice were fertile and viable. Mthfs protein levels were slightly but not statistically significantly reduced in tissues measured. No homozygous embryos were recovered following intercrosses of heterozygous mice, suggesting that Mthfs is an essential gene. Mouse embryonic fibroblasts from heterozygous mice [Mthfs (gt/+)] exhibited reduced de novo purine biosynthesis, but did not exhibit altered de novo thymidylate biosynthesis. Plasma folate levels were altered in heterozygous mice on a standard (/control) diet.

[Please consider inclusion in other possibly relevant panels e.g. for metabolic disorders]
Sources: Literature
Created: 2 Jan 2020, 11:41 p.m. | Last Modified: 2 Jan 2020, 11:43 p.m.
Panel Version: 3.0

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Neurodevelopmental disorder with microcephaly, epilepsy, and hypomyelination, 618367



Mode of Inheritance
BIALLELIC, autosomal or pseudoautosomal
  • Neurodevelopmental disorder with microcephaly, epilepsy, and hypomyelination, 618367
Clinvar variants
Variants in MTHFS
Panels with this gene

History Filter Activity

2 Jan 2020, Gel status: 0

Created, Added New Source, Set mode of inheritance, Set publications, Set Phenotypes, Set penetrance

Konstantinos Varvagiannis (Other)

gene: MTHFS was added gene: MTHFS was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: MTHFS was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: MTHFS were set to 30031689; 31844630; 22303332; Phenotypes for gene: MTHFS were set to Neurodevelopmental disorder with microcephaly, epilepsy, and hypomyelination, 618367 Penetrance for gene: MTHFS were set to Complete Review for gene: MTHFS was set to GREEN