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RARE DISEASE

Homocystinuria due to cystathionine beta-synthase deficiency

Synonyms: CBS-deficient HCU, Cystathionine beta-synthase deficiency, Cystathionine beta-synthase-deficient homocystinuria, Homocystinuria due to CBS deficiency

Drug discovery

drugs

With orphan designations

Overview

Homocystinuria due to cystathionine beta-synthase (CBS) deficiency is an autosomal recessive disorder of methionine metabolism caused by pathogenic variants in the CBS gene. This results in elevated homocysteine and methionine levels, leading to multisystem complications including ectopia lentis, thromboembolism, osteoporosis, marfanoid habitus, and neurodevelopmental impairment. Early diagnosis via newborn screening and prompt treatment (e.g., vitamin B6, methionine restriction) can prevent severe outcomes, though clinical heterogeneity persists based on residual enzyme activity and therapeutic responsiveness [1][2][4][6].

Population

Global prevalence ranges from 1:200,000 to 1:335,000 with higher incidence in specific populations (e.g., ~1:1,800 in Qatar, 1:17,800 in Germany) [1][2][10].
Approximately 50% of patients are pyridoxine-responsive, with milder phenotypes [6][12].

Burden

Untreated patients face high morbidity: 30–50% risk of thromboembolic events, progressive lens dislocation, and intellectual disability [5][6][12].
Even treated individuals with total homocysteine ≥50 µM exhibit elevated risks of vascular, skeletal, and ocular complications [5][10].
Late diagnosis correlates with irreversible damage, emphasizing the critical role of neonatal screening and lifelong biochemical monitoring [2][6][12].

Therapies

Pyridoxine (vitamin B6): High doses (100–500 mg/day) for responsive patients, combined with folate/B12 supplementation [2][3][6].
Dietary management: Methionine-restricted diet with cysteine supplementation for non-responders; protein substitutes (e.g., methionine-free formulas) are often required [2][12].
Adjunctive therapies: Betaine (6–9 g/day) to enhance homocysteine remethylation, alongside anticoagulation (e.g., aspirin) for thromboprophylaxis [3][6][12].

Categories: rare developmental anomalies during embryogenesis, rare genetic diseases, rare inborn errors of metabolism, rare neurological diseases, rare ophthalmic disorders

Research Papers

494 drug discovery papers about Homocystinuria due to cystathionine beta-synthase deficiency, with 2 first-in-class and 2 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:

2026-07-06 | Homocystinuria presenting with cerebral venous thrombosis: a case report highlighting progressive thrombosis.

Homocystinuria is a hereditary metabolic disorder primarily caused by defects in enzymes involved in methionine metabolism, resulting in excessive accumulation of homocysteine and its metabolites in the blood and urine. Cerebral venous sinus thrombosis (CVST), premature atherosclerosis, and other thromboembolic events are among the most serious clinical manifestations of homocystinuria. We report a 13-year-old boy who initially presented with headache, followed by progressive disturbance of consciousness and status epilepticus. Cranial magnetic resonance imaging (MRI) revealed superior sagittal sinus thrombosis. He was transferred to a tertiary hospital, where he underwent emergency thrombus aspiration under digital subtraction angiography (DSA) guidance and received low-molecular-weight heparin (LMWH) anticoagulation. Although endovascular aspiration combined with LMWH controlled the seizures, his venous thrombosis continued to progress. He subsequently developed lower-extremity deep vein thrombosis, acute pulmonary embolism, and ventricular fibrillation. Clinical biochemical evaluation and genetic testing confirmed classic homocystinuria. Targeted therapy with warfarin, aspirin, vitamin B6, folic acid, and betaine resulted in a favorable prognosis. Early etiological screening, including genetic testing, should be prioritized in young patients with unexplained or recurrent thrombosis to optimize treatment and prognosis. Rational use of anticoagulants combined with targeted metabolic therapy (vitamin B6, folic acid, betaine) and antiplatelet therapy is critical for improving outcomes in such patients.

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2026-05-11 | Homocystinuria in a consanguineous indigenous family from rural Honduras: a ten-year follow up and literature review of familial cases.

Homocystinuria (HCU) is a rare autosomal recessive metabolic disorder, characterized by a mutation in the enzyme cystathionine beta-synthase and abnormally high levels of homocysteine in the blood. HCU that runs in a family is rare; prior to this report, there have been only 150 familial cases described in the literature. Here, we describe a familial cluster of HCU in four children in "Family V," a consanguineous indigenous family from rural Honduras with a 10-year clinical follow up. We describe the diagnosis, presentation and progression of three patients who were diagnosed in 2015; critical findings include substantial vision loss in Patients 1 and 2, and a significant decline in language ability in Patient 3. We also describe the presentation of Patient 4, a grandchild who we diagnosed with probable HCU based on symptoms very similar to his siblings and highly suspicious for HCU. Additionally, we completed a narrative review of previously published familial HCU cases, using PubMed and Google Scholar, to highlight common phenotypic trends in familial HCU patients. In the reported familial cases, 57% had CNS complications, 48% had ocular complications, and 30% had cardiovascular complications.

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2026-04-14 | Liver-Targeted AAV-DJ-hCBS Therapy Achieves Long-Term Correction of Metabolic Imbalance in CBS-Deficient Mice.

Cystathionine β-synthase (CBS) deficiency causes classical homocystinuria with severe hyperhomocysteinemia (HHcy) that is inadequately controlled by current therapies. We tested whether liver-targeted CBS gene therapy provides durable biochemical and phenotypic rescue. Using a Cre-inducible adult mouse model of whole-body CBS loss, a single intravenous dose of AAV-DJ-hCBS (3 × 1012 or 3 × 1013 vg/kg) was administered, and the animals were followed for 12 months. Vector biodistribution showed ~100-fold hepatic enrichment over the kidney and spleen. Both doses rapidly normalized plasma homocysteine (<8 µM), maintaining correction throughout the study while preventing alopecia, weight loss, and loss of adiposity. Liver histology showed resolution of inflammation, and only 2 of 19 mice developed anti-hCBS antibodies. Liver proteomics (3998 proteins quantified) revealed CBS deficiency-associated suppression of tRNA aminoacylation and dysregulation of lipid and carbon metabolism with an HNF4A transcriptional signature, all normalized by therapy. Liver metabolomics demonstrated accumulation of S-adenosylmethionine and S-adenosylhomocysteine and disruption of phosphatidylcholine synthesis, also corrected by treatment. Plasma metabolomics revealed systemic disturbances fully normalized by hepatic CBS restoration. These findings identify the liver as the central metabolic control point in CBS deficiency and support liver-targeted gene therapy as a durable corrective strategy.

Open article ↗

2026-07-06 | Homocystinuria presenting with cerebral venous thrombosis: a case report highlighting progressive thrombosis.

Open article ↗

2026-05-11 | Homocystinuria in a consanguineous indigenous family from rural Honduras: a ten-year follow up and literature review of familial cases.

Open article ↗

2026-04-14 | Liver-Targeted AAV-DJ-hCBS Therapy Achieves Long-Term Correction of Metabolic Imbalance in CBS-Deficient Mice.

Open article ↗

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Drug Discovery Landscape

9 orphan drug designations for Homocystinuria due to cystathionine beta-synthase deficiency, including 1 approved therapy.

Drug	Therapy type	Regulator	Orphan designation	Approval	Sponsor
betaine	small molecules	FDA	2026-07-17	—	Cycle Pharmaceuticals Ltd.
Modified human cystathionine beta synthase messenger ribonucleic acid encapsulated in a lipid nanoparticle	RNAs	FDA	2024-07-18	—	INNORNA USA INC.
live biotherapeutic consisting of metP and metDC genes which are incorporated into the genome of a probiotic strain of E. coli Nissie 1917	other	FDA	2022-11-22	—	Synlogic Operating Company, Inc.
Poly(oxy-1,2-ethanediyl), alpha-(carboxymethyl)-omega-methoxy-, amide with cystathionine γ-lyase [Pyridoxal 5’-phosphate cofactor] (synthetic engineered human), tetramer	proteins	EMA	2020-10-19	—	Aeglea Ireland Limited
Polyethylene glycol-modified human recombinant truncated cystathionine beta-synthase	proteins	EMA	2016-05-30	—	Travere Therapeutics Ireland Limited
polyethylene glycol modified recombinant C-terminal truncate of human cystathionine beta-synthase	proteins	FDA	2015-03-17	—	Travere Therapeutics Switzerland GmbH
taurine	small molecules	FDA	2010-03-22	—	Johan L. Van Hove, MD, PhD
Betaine [Cystadane]	small molecules	EMA	2001-07-09	—	Recordati Rare Diseases
Betaine [Cystadane]	small molecules	FDA	1994-05-16	1996-10-25	Orphan Europe SARL

Homocystinuria due to cystathionine beta-synthase deficiency

Homocystinuria due to cystathionine beta-synthase deficiency

Homocystinuria due to cystathionine beta-synthase deficiency

Overview

Population

Burden

Therapies

Categories: rare developmental anomalies during embryogenesis, rare genetic diseases, rare inborn errors of metabolism, rare neurological diseases, rare ophthalmic disorders

Research Papers

2026-07-06 | Homocystinuria presenting with cerebral venous thrombosis: a case report highlighting progressive thrombosis.

2026-05-11 | Homocystinuria in a consanguineous indigenous family from rural Honduras: a ten-year follow up and literature review of familial cases.

2026-04-14 | Liver-Targeted AAV-DJ-hCBS Therapy Achieves Long-Term Correction of Metabolic Imbalance in CBS-Deficient Mice.

2026-07-06 | Homocystinuria presenting with cerebral venous thrombosis: a case report highlighting progressive thrombosis.

2026-05-11 | Homocystinuria in a consanguineous indigenous family from rural Honduras: a ten-year follow up and literature review of familial cases.

2026-04-14 | Liver-Targeted AAV-DJ-hCBS Therapy Achieves Long-Term Correction of Metabolic Imbalance in CBS-Deficient Mice.

Drug Discovery Landscape

Updated: Aug 30, 2026