Cystathionine β-synthase (CBS) deficiency (classical homocystinuria) has a wide range of severity. Mildly affected patients typically present as adults with thromboembolism and respond to treatment with pyridoxine. Severely affected patients usually present during childhood with learning difficulties, ectopia lentis and skeletal abnormalities; they are pyridoxine non-responders (NR) or partial responders (PR) and require treatment with a low-methionine diet and/or betaine. The European network and registry for Homocystinurias and methylation Defects (E-HOD) has published management guidelines for CBS deficiency and recommended keeping plasma total homocysteine (tHcy) concentrations below 100 μmol/L. We have now analysed data from 311 patients in the registry to see how closely treatment follows the guidelines. Pyridoxine-responsive patients generally achieved tHcy concentrations below 50 μmol/L, but many NRs and PRs had a mean tHcy considerably above 100 μmol/L. Most NRs were managed with betaine and a special diet. This usually involved severe protein restriction and a methionine-free amino acid mixture, but some patients had a natural protein intake substantially above the WHO safe minimum. Work is needed on the methionine content of dietary protein as estimates vary widely. Contrary to the guidelines, most NRs were on pyridoxine, sometimes at dangerously high doses. tHcy concentrations were similar in groups prescribed high or low betaine doses and natural protein intakes. High tHcy levels were probably often due to poor compliance. Comparing time-to-event graphs for NR patients detected by newborn screening and those ascertained clinically showed that treatment could prevent thromboembolism (risk ratio 0.073) and lens dislocation (risk ratio 0.069).

• Keywords
• betaine, homocystinuria, methionine, newborn screening, protein restriction, pyridoxine,
• MeSH
• Betaine therapeutic use   MeSH
• Cystathionine beta-Synthase * deficiency   genetics   MeSH
• Child MeSH
• Adult MeSH
• Homocysteine blood   MeSH
• Homocystinuria * diet therapy   drug therapy   diagnosis   blood   MeSH
• Infant MeSH
• Humans MeSH
• Methionine MeSH
• Adolescent MeSH
• Young Adult MeSH
• Infant, Newborn MeSH
• Child, Preschool MeSH
• Pyridoxine * therapeutic use   MeSH
• Registries MeSH
• Check Tag
• Child MeSH
• Adult MeSH
• Infant MeSH
• Humans MeSH
• Adolescent MeSH
• Young Adult MeSH
• Male MeSH
• Infant, Newborn MeSH
• Child, Preschool MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Betaine MeSH
• Cystathionine beta-Synthase * MeSH
• Homocysteine MeSH
• Methionine MeSH
• Pyridoxine * MeSH

BACKGROUND: Cystathionine β-synthase (CBS)-deficient homocystinuria (HCU) is an inherited disorder of sulfur amino acid metabolism with varying severity and organ complications, and a limited knowledge about underlying pathophysiological processes. Here we aimed at getting an in-depth insight into disease mechanisms using a transgenic mouse model of HCU (I278T). METHODS: We assessed metabolic, proteomic and sphingolipidomic changes, and mitochondrial function in tissues and body fluids of I278T mice and WT controls. Furthermore, we evaluated the efficacy of methionine-restricted diet (MRD) in I278T mice. RESULTS: In WT mice, we observed a distinct tissue/body fluid compartmentalization of metabolites with up to six-orders of magnitude differences in concentrations among various organs. The I278T mice exhibited the anticipated metabolic imbalance with signs of an increased production of hydrogen sulfide and disturbed persulfidation of free aminothiols. HCU resulted in a significant dysregulation of liver proteome affecting biological oxidations, conjugation of compounds, and metabolism of amino acids, vitamins, cofactors and lipids. Liver sphingolipidomics indicated upregulation of the pro-proliferative sphingosine-1-phosphate signaling pathway. Liver mitochondrial function of HCU mice did not seem to be impaired compared to controls. MRD in I278T mice improved metabolic balance in all tissues and substantially reduced dysregulation of liver proteome. CONCLUSION: The study highlights distinct tissue compartmentalization of sulfur-related metabolites in normal mice, extensive metabolome, proteome and sphingolipidome disruptions in I278T mice, and the efficacy of MRD to alleviate some of the HCU-related biochemical abnormalities.

• Keywords
• Cystathionine beta-synthase, Homocystinuria, Metabolomics, Methionine restriction, Proteomics,
• MeSH
• Cystathionine beta-Synthase * metabolism   deficiency   genetics   MeSH
• Homocystinuria * metabolism   genetics   MeSH
• Liver * metabolism   MeSH
• Lipidomics methods   MeSH
• Metabolomics * methods   MeSH
• Mitochondria metabolism   MeSH
• Disease Models, Animal * MeSH
• Mice, Transgenic * MeSH
• Mice MeSH
• Proteome metabolism   MeSH
• Proteomics * methods   MeSH
• Sphingolipids * metabolism   MeSH
• Animals MeSH
• Check Tag
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Cystathionine beta-Synthase * MeSH
• Proteome MeSH
• Sphingolipids * MeSH

Cystathionine beta-synthase (CBS)-deficient homocystinuria (HCU) is the most common inborn error of sulfur amino acid metabolism. The pyridoxine non-responsive form of the disease manifests itself by massively increasing plasma and tissue concentrations of homocysteine, a toxic intermediate of methionine metabolism that is thought to be the major cause of clinical complications including skeletal deformities, connective tissue defects, thromboembolism and cognitive impairment. The current standard of care involves significant dietary interventions that, despite being effective, often adversely affect quality of life of HCU patients, leading to poor adherence to therapy and inadequate biochemical control with clinical complications. In recent years, the unmet need for better therapeutic options has resulted in development of novel enzyme and gene therapies and exploration of pharmacological approaches to rescue CBS folding defects caused by missense pathogenic mutations. Here, we review scientific evidence and current state of affairs in development of recent approaches to treat HCU.

• Keywords
• chaperones, cystathionine beta-synthase, enzyme therapy, gene therapy, homocystinuria, pegtibatinase, proteasome inhibitors,
• MeSH
• Cystathionine beta-Synthase genetics   metabolism   MeSH
• Homocystinuria * drug therapy   genetics   metabolism   MeSH
• Quality of Life MeSH
• Humans MeSH
• Mutation, Missense MeSH
• Thromboembolism * MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Review MeSH
• Research Support, N.I.H., Extramural MeSH
• Names of Substances
• Cystathionine beta-Synthase MeSH

BACKGROUND: The main genetic causes of homocystinuria are cystathionine beta-synthase (CBS) deficiency and the remethylation defects. Many patients present in childhood but milder forms may present later in life. Some countries have newborn screening programs for the homocystinurias but these do not detect all patients. RESULTS: HCU Network Australia is one of the very few support groups for patients with homocystinurias. Here we report the results of its survey of 143 patients and caregivers from 22 countries, evaluating current diagnostic pathways and management for the homocystinurias. Most (110) of the responses related to patients with CBS deficiency. The diagnosis was made by newborn screening in 20% of patients and in 50% of the others within 1 year of the initial symptom but in 12.5% it took over 15 years. The delay was attributed mainly to ignorance of the disease. Physicians need to learn to measure homocysteine concentrations in children with neurodevelopmental problems, and in patients with heterogeneous symptoms such as thromboembolism, dislocation of the optic lens, haemolytic uraemic syndrome, and psychiatric disease. Even when the diagnosis is made, the way it is communicated is sometimes poor. Early-onset CBS deficiency usually requires a low-protein diet with amino acid supplements. More than a third of the participants reported problems with the availability or cost of treatment. Only half of the patients always took their amino acid mixture. In contrast, good adherence to the protein restriction was reported in 98% but 80% said it was hard, time-consuming and caused unhappiness. CONCLUSIONS: There is often a long delay in diagnosing the homocystinurias unless this is achieved by newborn screening; this survey also highlights problems with the availability and cost of treatment and the palatability of protein substitutes.

• Keywords
• Cystathionine beta-synthase deficiency, Delay in diagnosis, Patient reported outcome, Patient support groups, Remethylation disorders,
• MeSH
• Cystathionine beta-Synthase MeSH
• Child MeSH
• Homocystinuria * diagnosis   MeSH
• Humans MeSH
• Infant, Newborn MeSH
• Caregivers MeSH
• Patient Satisfaction MeSH
• Check Tag
• Child MeSH
• Humans MeSH
• Infant, Newborn MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Geographicals
• Australia MeSH
• Names of Substances
• Cystathionine beta-Synthase MeSH