Homocystinuria · HCY

Description

Classic homocystinuria is an autosomal recessive disorder of sulfur amino acid metabolism. Pathogenic variants in CBS reduce or abolish cystathionine beta-synthase activity. The enzyme normally condenses homocysteine and serine to form cystathionine, the committed step toward cysteine. With the enzyme impaired, homocysteine and methionine accumulate in blood and tissues, while cystathionine and cysteine fall. Inheritance is autosomal recessive. The causative gene is CBS on chromosome 21.

Untreated children develop ectopia lentis, often by the first decade, along with progressive myopia. Skeletal findings include marfanoid habitus, scoliosis, and osteoporosis. Thromboembolism, including stroke and pulmonary embolism in young people, is the leading cause of early death. Intellectual disability and psychiatric symptoms are reported across cohorts when treatment is delayed.

Detection is by newborn screening on the dried blood spot, using tandem mass spectrometry to measure methionine. Confirmation uses plasma total homocysteine, plasma amino acids, and CBS gene sequencing. Methionine elevation can be subtle in pyridoxine-responsive disease, and some affected newborns are missed by methionine-only screening protocols, a limitation discussed by Huemer et al. (Journal of Inherited Metabolic Disease, 2015) and in the E-HOD registry.

Reported worldwide birth incidence is approximately 1 in 200,000 to 1 in 350,000, with regional variation. Founder effects are documented in Qatar, where Zschocke et al. (Human Mutation, 2009) reported an estimated incidence near 1 in 1,800 births tied to a CBS founder variant.

A clinically important distinction is the response to pyridoxine, vitamin B6. Pyridoxine-responsive disease usually carries residual enzyme activity and responds to oral B6 with a fall in homocysteine. Pyridoxine-non-responsive disease requires aggressive dietary management. Response status is established by a supervised B6 trial and shapes the rest of treatment.

Treatments to date

Treatment is started as soon as classic homocystinuria is suspected after newborn screening or clinical presentation, and continues for life. Goals are to lower plasma total homocysteine into a safe range and to prevent thromboembolism, lens dislocation, and skeletal disease.

Pyridoxine-responsive disease is treated with oral pyridoxine, often combined with folate and vitamin B12 to support remethylation. Many B6 responders maintain control with vitamin therapy and a moderate methionine restriction.

Pyridoxine-non-responsive disease is treated with lifelong dietary methionine restriction. Natural protein is limited and replaced with methionine-free medical formula that supplies cystine, since cysteine becomes a conditionally essential amino acid when CBS activity is lost. A metabolic dietitian monitors growth, plasma methionine, plasma total homocysteine, and cystine status.

Betaine anhydrous, marketed as Cystadane, was approved by the FDA in October 1996 for homocystinuria. Betaine donates a methyl group to remethylate homocysteine to methionine through betaine-homocysteine methyltransferase, lowering plasma homocysteine. It is used as adjunctive therapy in non-responsive disease and in responsive disease that is incompletely controlled. Plasma methionine is monitored because betaine raises it.

Antithrombotic management and ophthalmology follow-up are part of standard care. Lens subluxation may require surgery. Bone density and cardiovascular risk are tracked into adulthood.

No approved enzyme replacement therapy or gene therapy restores normal CBS activity. Investigational approaches in development include enzyme substitution with pegylated human truncated CBS (OT-58, Travere) and earlier-stage gene therapy programs.