Signs & Symptoms

• Early Signs:
  • Developmental delay
  • Global failure to thrive
  • Microcephaly
• Progression:
  • Rigidity and spasticity
  • Seizures and epilepsy (various types)
  • Cerebral hypomyelination (visible on MRI)
• Variability: Severity of disabilities varies among patients.

Causes

• Genetic Basis:
  • Caused by disease-causing variants in the MTHFS gene.
  • MTHFS gene produces the 5-MTHF protein, essential for metabolizing folinic acid into L-methyl folate.
  • Variants affect folinic acid breakdown, leading to its buildup and preventing myelin formation.
• Inheritance:
  • Autosomal recessive disorder.
  • Each parent carries one normal and one disease-causing gene variant.
  • Affected child risk: 25% with each pregnancy.
  • Carrier child risk: 50% with each pregnancy.
  • Child receiving normal genes from both parents: 25% chance.
  • Risk is equal for males and females.

Affected Populations

• Prevalence:
  • Rare disorder with unknown frequency.
  • Reported cases globally (e.g., Iran, Haiti, United States; ancestries include British Isles, France, Portugal, Italy, Austria, Czech Republic).
• Age of Diagnosis:
  • Youngest diagnosed child was 4 years old.
  • No adult diagnoses, possibly due to lack of testing or recognition.
  • Affects males and females equally.

Disorders with Similar Symptoms

• Other neurodevelopmental disorders can present with similar signs and symptoms.

Diagnosis

• Clinical Suspicion:
  • Based on symptoms such as failure to thrive, developmental delay, and microcephaly.
• Imaging:
  • MRI shows cerebral hypomyelination.
  • MRI before 18 months shows slowed myelin development.
  • MRI after 2 years shows little to no progress in myelination.
• Cerebral Spinal Fluid Study:
  • Low 5-MTHF level may be found.
• Genetic Testing:
  • Confirmed through whole exome sequencing or whole genome sequencing.
  • Single gene testing for family members if a variant is identified.

Standard Therapies

• Current Treatments:
  • Restricting vitamin B-9 (folate; folic acid) in the diet.
  • Supplementing with L-methyl folate orally.
  • Intramuscular methyl cobalamin.
  • Nutrition advice to avoid fortified foods and supplements with folate/folinic acid.
• Multidisciplinary Care:
  • Essential for addressing physical and neurodevelopmental symptoms.
  • Includes physical, occupational, and speech therapies.
  • Neurologist for seizures, epilepsy, developmental delays, and muscle tone management.
  • Palliative care for coordinated care and treatment.
• Genetic Counseling:
  • Recommended for families with an affected child.

References

• 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