Homocystinuria without methylmalonic aciduria

Homocystinuria without methylmalonic aciduria is a group of inherited metabolic disorders characterized by elevated levels of homocysteine in the blood and urine without an accompanying increase in methylmalonic acid. This distinguishes it from combined homocystinuria with methylmalonic aciduria (cobalamin defects such as cblC, cblD, and cblF). The condition encompasses several distinct subtypes, including classical homocystinuria due to cystathionine beta-synthase (CBS) deficiency (the most common form), as well as disorders of methionine remethylation such as methylenetetrahydrofolate reductase (MTHFR) deficiency, and defects in cobalamin metabolism affecting only the methylation pathway (cblE and cblG types). These conditions share the common biochemical finding of hyperhomocysteinemia but differ in their underlying genetic causes and specific clinical presentations. The body systems most commonly affected include the eyes, skeletal system, vascular system, and central nervous system. In classical CBS deficiency, key clinical features include ectopia lentis (lens dislocation), marfanoid habitus (tall and thin body build with long limbs), osteoporosis, intellectual disability of variable severity, and a significantly increased risk of thromboembolic events such as stroke, deep vein thrombosis, and pulmonary embolism. Thromboembolism is the major cause of morbidity and early mortality. In MTHFR deficiency, neurological manifestations predominate, including developmental delay, seizures, and psychiatric disturbances, while lens dislocation is typically absent. The cblE and cblG defects present with megaloblastic anemia and neurological dysfunction. Treatment depends on the specific subtype. For CBS deficiency, approximately half of patients respond to high-dose pyridoxine (vitamin B6) supplementation, which can substantially reduce homocysteine levels. Non-responsive patients are managed with a methionine-restricted diet supplemented with betaine and cystine, along with folate and vitamin B12. Betaine (trimethylglycine) is used across subtypes to promote alternative remethylation of homocysteine to methionine. For MTHFR deficiency, treatment may include betaine, methionine supplementation, folate (as methyltetrahydrofolate), and vitamin B12. For cblE and cblG defects, hydroxocobalamin injections are the primary treatment. Early detection through newborn screening and prompt initiation of treatment significantly improve outcomes.

Data sourced from FDA regulatory filings and ClinicalTrials.gov. Updated periodically.

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