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

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

Most rare clinical missense variants cannot currently be classified as pathogenic or benign. Deficiency in human 5,10-methylenetetrahydrofolate reductase (MTHFR), the most common inherited disorder of folate metabolism, is caused primarily by rare missense variants. Further complicating variant interpretation, variant impacts often depend on environment. An important example of this phenomenon is the MTHFR variant p.Ala222Val (c.665C>T), which is carried by half of all humans and has a phenotypic impact that depends on dietary folate. Here we describe the results of 98,336 variant functional-impact assays, covering nearly all possible MTHFR amino acid substitutions in four folinate environments, each in the presence and absence of p.Ala222Val. The resulting atlas of MTHFR variant effects reveals many complex dependencies on both folinate and p.Ala222Val. MTHFR atlas scores can distinguish pathogenic from benign variants and, among individuals with severe MTHFR deficiency, correlate with age of disease onset. Providing a powerful tool for understanding structure-function relationships, the atlas suggests a role for a disordered loop in retaining cofactor at the active site and identifies variants that enable escape of inhibition by S-adenosylmethionine. Thus, a model based on eight MTHFR variant effect maps illustrates how shifting landscapes of environment- and genetic-background-dependent missense variation can inform our clinical, structural, and functional understanding of MTHFR deficiency.

• Keywords
• clinical variant interpretation, cystathionine beta synthase, deep mutational scanning, folate, gene- environment interaction, homocystinuria, methylenetetrahydrofolate reductase, molecular dynamics, mthfr, variant effect mapping,
• MeSH
• Diploidy MeSH
• Genotype MeSH
• Gene Library MeSH
• Humans MeSH
• Methylenetetrahydrofolate Reductase (NADPH2) deficiency   genetics   physiology   MeSH
• Mutation, Missense * MeSH
• DNA Mutational Analysis MeSH
• Saccharomyces cerevisiae genetics   MeSH
• Amino Acid Substitution MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Research Support, N.I.H., Extramural MeSH
• Names of Substances
• Methylenetetrahydrofolate Reductase (NADPH2) MeSH
• MTHFR protein, human MeSH Browser

Cystathionine β-synthase (CBS) deficiency has a wide clinical spectrum, ranging from neurodevelopmental problems, lens dislocation and marfanoid features in early childhood to adult onset disease with predominantly thromboembolic complications. We have analysed clinical and laboratory data at the time of diagnosis in 328 patients with CBS deficiency from the E-HOD (European network and registry for Homocystinurias and methylation Defects) registry. We developed comprehensive criteria to classify patients into four groups of pyridoxine responsivity: non-responders (NR), partial, full and extreme responders (PR, FR and ER, respectively). All groups showed overlapping concentrations of plasma total homocysteine while pyridoxine responsiveness inversely correlated with plasma/serum methionine concentrations. The FR and ER groups had a later age of onset and diagnosis and a longer diagnostic delay than NR and PR patients. Lens dislocation was common in all groups except ER but the age of dislocation increased with increasing responsiveness. Developmental delay was commonest in the NR group while no ER patient had cognitive impairment. Thromboembolism was the commonest presenting feature in ER patients, whereas it was least likely at presentation in the NR group. This probably is due to the differences in ages at presentation: all groups had a similar number of thromboembolic events per 1000 patient-years. Clinical severity of CBS deficiency depends on the degree of pyridoxine responsiveness. Therefore, a standardised pyridoxine-responsiveness test in newly diagnosed patients and a critical review of previous assessments is indispensable to ensure adequate therapy and to prevent or reduce long-term complications.

• Keywords
• developmental delay, homocystinuria, methionine, natural history, patient registry, thromboembolism,
• MeSH
• Cystathionine beta-Synthase deficiency   MeSH
• Child MeSH
• Adult MeSH
• Phenotype MeSH
• Homocystinuria diagnosis   drug therapy   enzymology   MeSH
• Infant MeSH
• Middle Aged MeSH
• Humans MeSH
• Linear Models MeSH
• Methionine blood   MeSH
• Adolescent MeSH
• Young Adult MeSH
• Delayed Diagnosis MeSH
• Child, Preschool MeSH
• Pyridoxine therapeutic use   MeSH
• Registries MeSH
• Aged MeSH
• Severity of Illness Index MeSH
• Check Tag
• Child MeSH
• Adult MeSH
• Infant MeSH
• Middle Aged MeSH
• Humans MeSH
• Adolescent MeSH
• Young Adult MeSH
• Male MeSH
• Child, Preschool MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Geographicals
• Europe MeSH
• Names of Substances
• Cystathionine beta-Synthase MeSH
• Methionine MeSH
• Pyridoxine 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

BACKGROUND: For the majority of rare clinical missense variants, pathogenicity status cannot currently be classified. Classical homocystinuria, characterized by elevated homocysteine in plasma and urine, is caused by variants in the cystathionine beta-synthase (CBS) gene, most of which are rare. With early detection, existing therapies are highly effective. METHODS: Damaging CBS variants can be detected based on their failure to restore growth in yeast cells lacking the yeast ortholog CYS4. This assay has only been applied reactively, after first observing a variant in patients. Using saturation codon-mutagenesis, en masse growth selection, and sequencing, we generated a comprehensive, proactive map of CBS missense variant function. RESULTS: Our CBS variant effect map far exceeds the performance of computational predictors of disease variants. Map scores correlated strongly with both disease severity (Spearman's ϱ = 0.9) and human clinical response to vitamin B6 (ϱ = 0.93). CONCLUSIONS: We demonstrate that highly multiplexed cell-based assays can yield proactive maps of variant function and patient response to therapy, even for rare variants not previously seen in the clinic.

• MeSH
• Cystathionine beta-Synthase genetics   metabolism   MeSH
• Phenotype MeSH
• Genetic Testing methods   MeSH
• Genotype MeSH
• Homocystinuria genetics   MeSH
• Humans MeSH
• Mutation, Missense * MeSH
• Saccharomyces cerevisiae Proteins genetics   MeSH
• Saccharomyces cerevisiae MeSH
• Genetic Complementation Test methods   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Research Support, N.I.H., Extramural MeSH
• Names of Substances
• Cystathionine beta-Synthase MeSH
• Saccharomyces cerevisiae Proteins MeSH