Abstract Objectives 5,10-Methenyltetrahydrofolate synthetase (MTHFS) deficiency is an ultra-rare autosomal recessive inborn error of folate metabolism caused by biallelic pathogenic variants in the MTHFS gene and associated with a severe neurodevelopmental disorder. Methods Patients with molecularly confirmed MTHFS deficiency were identified through a comprehensive search of the PubMed database. A total of 12 patients from 10 unrelated families, including our patient, were analyzed. Demographic data, clinical features, biochemical findings, neuroimaging and electrophysiological results, molecular genetic characteristics, treatment responses, and outcomes were systematically compared. Results The disorder showed a pan-ethnic distribution. All patients presented with symptoms during the neonatal and/or infantile period. Clinical features included severe global developmental delay, microcephaly, hypotonia, growth retardation, mild dysmorphic features, and epilepsy. The male-to-female ratio was 1:1, and parental consanguinity was reported in 30 % of families. Laboratory findings revealed macrocytic anemia, hyperhomocysteinemia, and mildly reduced or low–normal cerebrospinal fluid 5-methyltetrahydrofolate levels. Brain magnetic resonance imaging demonstrated cerebral hypomyelination, thinning of the corpus callosum, cerebellar atrophy, vermian hypoplasia, and T2 hypointensity of the basal ganglia. Homozygous variants were identified in 60 % of patients, and missense variants accounted for 50 % of all detected variants. A total of 12 distinct pathogenic variants were reported, with c.434G>A p.(Arg145Gln) being the most recurrent (4/20 alleles, 20 %). Despite metabolic treatment, no significant clinical improvement was observed. Two patients (17 %) died at an early age, while the remaining patients exhibited severe neurodevelopmental impairment. Conclusions MTHFS deficiency should be considered in the differential diagnosis of patients presenting with severe developmental delay and microcephaly accompanied by isolated hyperhomocysteinemia.
Kılıç et al. (Tue,) studied this question.