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Last updated: 4/29/2024
Years published: 2024
NORD gratefully acknowledges Ian Rossman, MD, PhD, Akron Children’s Hospital and AnnMarie Papik for the preparation of this report.
Summary
5,10 – methenyltetrahydrofolate synthetase deficiency is a neurodevelopmental genetic disorder characterized by developmental delay, difficulty growing and gaining weight (failure to thrive), lack of myelin production in the brain (cerebral hypomyelination), short stature, seizures (epilepsy), small head (microcephaly), spasticity and rigidity. Symptoms may be present at birth, but not recognized until later in infancy or childhood when developmental delays and growth problems become more obvious. This disorder is caused by changes (disease-causing variants) in the MTHFS gene. This gene is involved in processing folate which is known to be a vital part of brain development.
Introduction
Early diagnosis of MTHFS deficiency is important in order to make dietary changes to reduce folate/folic acid and start treatment with oral L-meth folate supplements and intramuscular methyl cobalamin. This may help to improve symptoms and development.
The first signs of MTHFS deficiency are developmental delay, global failure to thrive and microcephaly. Affected children start to show signs of rigidity and spasticity as they develop. Seizures may not be noticeable right away but affected children will eventually be diagnosed with different types of epilepsy. An MRI will show cerebral hypomyelination. Some patients have more severe disabilities than others.
5,10-methenyltetrahydrofolate synthetase deficiency is caused by changes (disease-causing variants) in the MTHFS gene. This gene is responsible for producing the 5-MTHF protein. This protein plays an essential role in metabolizing the carbon chains of folinic acid and turning them into L-methyl folate. Disease-causing variants in the MTHFS gene affect the breakdown of folinic acid, causing folinic acid to build up and preventing the formation of myelin.
MTHFS deficiency follows autosomal recessive inheritance. Recessive genetic disorders occur when an individual inherits a disease-causing gene variant from each parent. If an individual receives one normal gene and one disease-causing gene variant, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the gene variant and have an affected child is 25% with each pregnancy. The risk of having a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females.
MTHFS deficiency is a rare disorder, but the frequency is not known. Rare disorders often go misdiagnosed or undiagnosed, making it difficult to determine their true frequency in the general population. This disorder has been reported around the globe (Iran, Haiti, United States; with ancestry from the British Isles, France, Portugal, Italy, Austria, Czech Republic).
The youngest child diagnosed to date was 4 years old. No adults have been diagnosed, this may be due to lack of testing or recognition of the disorder. Males and Females are equally likely to be affected.
MTHFS deficiency may be suspected based on symptoms including failure to thrive, global developmental delay and microcephaly.
An MRI will show cerebral hypomyelination. If an MRI is done at or before 18 months of age the MRI will show slowed development of myelin. MRIs completed from 2 years on will show little to no progress in myelination from previous MRIs. A cerebral spinal fluid study (CSF) can be done to look for a low 5-MTHF level.
A diagnosis is confirmed with genetic testing. To date, all reported cases have been diagnosed through whole exome sequencing or whole genome sequencing that look for variants in many different genes. If a MTHFS gene variant is identified, single gene testing for that variant can be considered for other family members.
Treatment
There are currently no standard therapies. Treatment includes restricting vitamin B-9 (folate; folic acid) in the diet and supplementing with L-methyl folate orally. Intramuscular methyl cobalamin is another method of treatment. A nutritionist may also provide advice about avoiding fortified foods and supplements that contain folate/folinic acid.
Children with MTHFS gene variants have several physical and neurodevelopmental symptoms that require multidisciplinary care. Multidisciplinary care should start as soon as a diagnosis is confirmed to support development and lower the risk of life-limiting conditions (i.e. epilepsy and failure to thrive). This includes but is not limited to physical, occupational and speech therapies.
A neurologist can address seizures and epilepsy, developmental delays, muscle tone management, and order testing such as magnetic resonance imaging (MRI) and electroencephalograms (EEGs).
A palliative care program may also be helpful to coordinate care and treatment.
Genetic counseling is recommended for families with an affected child.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]
Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/
For information about clinical trials sponsored by private sources, contact:
www.centerwatch.com
For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/
JOURNAL ARTICLES
Romero JA, Abdelmoumen I, Hasbani D, Khurana DS, Schneider MC. A case of 5,10-methenyltetrahydrofolate synthetase deficiency due to biallelic null mutations with novel findings of elevated neopterin and macrocytic anemia. Mol Genet Metab Rep. 2019;21:100545. Published 2019 Nov 21. doi:10.1016/j.ymgmr.2019.100545
Rodan LH, Qi W, Ducker GS, et al. 5,10-methenyltetrahydrofolate synthetase deficiency causes a neurometabolic disorder associated with microcephaly, epilepsy, and cerebral hypomyelination. Mol Genet Metab. 2018;125(1-2):118-126. doi:10.1016/j.ymgme.2018.06.006
Misselbeck K, Marchetti L, Priami C, Stover PJ, Field MS. The 5-formyltetrahydrofolate futile cycle reduces pathway stochasticity in an extended hybrid-stochastic model of folate-mediated one-carbon metabolism. Sci Rep. 2019;9(1):4322. Published 2019 Mar 13. doi:10.1038/s41598-019-40230-4
INTERNET
MTHFS-related developmental delay-microcephaly-short stature-epilepsy syndrome. Orphanet. https://www.orpha.net/en/disease/detail/597874?name=MTHFS&mode=name Accessed March 25, 2024.
NEDMEHM. Online Mendelian Inheritance in Man (OMIM). Updated 03/28/2019. https://omim.org/entry/618367 Accessed March 25, 2024.
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