Causes of Methylenetetrahydrofolate Reductase (MTHFR) Deficiency
MTHFR deficiency is primarily caused by mutations in the MTHFR gene, with over 109 different mutations identified across 171 families, most of which are "private" mutations occurring in individual families rather than being common in the population. 1
Genetic Causes
Types of Mutations
- Gene mutations: 109 different MTHFR mutations have been documented, including:
- 70 missense mutations (64%)
- 17 splicing mutations (16%)
- 11 nonsense mutations (10%)
- 7 small deletions (6%)
- 2 no-stop mutations
- 1 small duplication
- 1 large duplication 1
Most Common Mutations
- The most frequent mutation is c.1530A>G (p.Lys510=), a splicing defect found in 13 families
- The most common missense mutation is c.1129C>T (p.Arg377Cys), identified in 10 families 1
- C677T polymorphism creates a thermolabile variant with reduced enzyme activity 2
- A1298C polymorphism results in an E to A substitution that decreases enzyme activity 3
Inheritance Pattern
- Autosomal recessive inheritance
- Homozygosity for C677T occurs in approximately 10% of North Americans 3
- Homozygosity for A1298C is observed in approximately 10% of Canadian individuals 3
- Compound heterozygosity (C677T + A1298C) occurs in approximately 15% of individuals 3
Relationship Between Enzyme Activity and Clinical Presentation
Severe Deficiency
- Patients with very low enzyme activity (<1.5% of control values) present earlier in life (median age 5 weeks) 4
- Early-onset symptoms include:
- Feeding problems
- Encephalopathy
- Muscular hypotonia
- Neurocognitive impairment
- Apnea
- Hydrocephalus
- Microcephaly
- Epilepsy 4
Moderate Deficiency
- Patients with higher residual enzyme activity (>1.7-34.8%) present later in life 4
- Late-onset symptoms include:
- Psychiatric symptoms
- Mental retardation
- Myelopathy
- Ataxia
- Spasticity 4
Biochemical Mechanisms
Folate Metabolism Disruption
- MTHFR is essential for converting 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate (the bioactive form of folate) 5
- At least 90 polymorphisms have been found in the MTHFR gene locus 5
- The C677T polymorphism greatly reduces enzyme activity or renders the enzyme inactive 5
Homocysteine Elevation
- MTHFR deficiency results in hyperhomocysteinemia 1
- Homocysteine is maintained within a narrow range through reactions involving several enzymes and cofactors (vitamin B6, vitamin B12, and folic acid) 6
- Elevated homocysteine levels increase risk for neural tube defects and vascular disease 3
Risk Factors and Associated Conditions
- Folate deficiency exacerbates the effects of MTHFR mutations 7
- Vitamin B2 (Riboflavin) deficiency can worsen symptoms 7
- Homozygosity for the 677C-->T polymorphism is associated with a 7.2-fold increased risk for neural tube defects 2
- Severe MTHFR deficiency can cause vascular thrombosis, developmental delay, and neurological disorders 8
Diagnostic Considerations
- Measurement of enzyme activity in fibroblasts can determine the severity of deficiency 4
- Genetic testing can identify specific mutations 1
- Plasma homocysteine levels are typically elevated 7
- Homocysteine levels >10 μmol/L are considered elevated and may warrant intervention 7
MTHFR deficiency represents a spectrum of disease severity directly correlated with the degree of enzyme activity impairment, which is determined by the specific genetic mutations present in each individual.