Homocystinuria due to Deficiency of N(5,10)-Methylenetetrahydrofolate Reductase Activity

CLINICAL CHARACTERISTICS

Homocystinuria due to deficiency of N(5,10)-methylenetetrahydrofolate reductase (MTHFR) activity can present in the neonatal period, adolescence, or adulthood. Neonatal onset is typically characterized by postnatal microcephaly, developmental delays, feeding difficulties, growth deficiency, seizures, intellectual disability, neonatal apneas, motor and gait abnormalities, psychiatric manifestations, a history of stroke, and progressive neurologic deterioration. Individuals with adolescent or adult onset may present with milder clinical manifestations, which may include thromboembolic events, lens dislocation, and less commonly cognitive decline, psychiatric manifestations, seizures, and/or motor and gait abnormalities.

DIAGNOSIS/TESTING: The diagnosis of homocystinuria due to deficiency of N(5,10)-MTHFR activity is established in a proband with characteristic clinical and laboratory findings (low plasma methionine, increased plasma and urine homocysteine, low plasma and CSF 5-methyltetrahydrofolate [MTHF]) and biallelic pathogenic variants in identified by molecular genetic testing.

MANAGEMENT

Betaine, methionine, vitamin B, and L-5-MTHF can reduce risk of neurologic manifestations and increase life span. Respiratory support as needed; sleep study for those with suspected apnea and respiratory compromise; feeding therapy as needed; standard treatment for seizures by neurologist; developmental and educational support; treatment of motor and gait abnormalities per orthopedist, physical medicine and rehabilitation specialist, and physical and occupational therapists; treatment for neurovascular manifestations to prevent stroke; social work and family support. Plasma homocysteine and plasma amino acids to assess methionine concentration every three to four months; assess for respiratory issues annually or as needed; assess growth, nutrition, oral intake, seizures, changes in tone, movement disorders, and family needs at each visit; behavioral assessment annually or as needed; assessment of motor and gait abnormalities at each visit; neurovascular assessment annually or as needed. High-protein diet; medications impacting folate metabolism (e.g., methotrexate); certain anti-seizure medications (e.g., valproic acid) that may increase homocysteine levels; inadequate monitoring of vitamin levels. Testing of all at-risk sibs is warranted to allow early detection and timely intervention. If prenatal testing has not been performed, a newborn with an older sib with homocystinuria due to deficiency of N(5,10)-MTHFR activity should receive immediate nutritional and metabolic management pending results of biochemical testing (e.g., plasma homocysteine and methionine concentration) and/or molecular genetic testing for the familial pathogenic variants.

GENETIC COUNSELING

Homocystinuria due to deficiency of N(5,10)-MTHFR activity is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for an pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Once the pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives and prenatal/preimplantation genetic testing are possible.