Lessons Learned from Inherited Metabolic Disorders of Sulfur-Containing Amino Acids Metabolism.
Study Goal
The researchers aimed to evaluate the role of N-Acetylcysteine as part of treatment strategies for disorders of sulfur-containing amino acid metabolism.
Results Summary
The study suggests N-Acetylcysteine may be beneficial in treating certain metabolic disorders by addressing deficiencies in cysteine or glutathione, but it does not provide specific efficacy data.
Population
Patients with disorders of sulfur-containing amino acid metabolism (e.g., defects in methionine demethylation, homocysteine remethylation, or cysteine catabolism).
Effective Dosage
Not specified
Duration
Not specified
Interactions
None mentioned
| Intervention | Direction | Endpoint | Population | Dosage | Impact | Claim # |
|---|---|---|---|---|---|---|
low-protein/low-Met diet with Cys-enriched amino acid supplements | neutral | disorders of sulfur-containing amino acid metabolism | patients with human genetic disorders of sulfur-containing amino acid metabolism | - | Treatment should be started as early as possible and may include | #1 |
pharmacological doses of B vitamins | neutral | disorders of sulfur-containing amino acid metabolism | patients with human genetic disorders of sulfur-containing amino acid metabolism | - | Treatment should be started as early as possible and may include | #2 |
betaine | increase | Hcy remethylation | patients with human genetic disorders of sulfur-containing amino acid metabolism | - | to stimulate Hcy remethylation | #3 |
N-acetylcysteine or AdoMet | neutral | disorders of sulfur-containing amino acid metabolism | patients with human genetic disorders of sulfur-containing amino acid metabolism | - | the provision of | #4 |
liver transplantation or enzyme replacement therapy | neutral | disorders of sulfur-containing amino acid metabolism | patients with human genetic disorders of sulfur-containing amino acid metabolism | - | experimental approaches such as | #5 |
long-term markedly elevated Met concentrations | increase | Met concentrations | patients in several disorders of sulfur-containing amino acid metabolism | markedly elevated | exposed to | #6 |
very high blood Met concentrations (typically >800 μmol/L) | increase | risk of demyelination | patients with Met adenosyltransferase I/III (MATI/III) deficiency due to biallelic mutations in the MATIA gene | >800 μmol/L | An increased risk of demyelination has been attributed to | #7 |
decreased liver AdoMet synthesis | increase | risk of demyelination | patients with Met adenosyltransferase I/III (MATI/III) deficiency due to biallelic mutations in the MATIA gene | - | An increased risk of demyelination has been attributed to possibly also | #8 |
excessively high Met concentration | increase | encephalopathy and brain edema | some patients with cystathionine β-synthase deficiency | excessively high | has been associated with | #9 |
Met | increase | toxicity | some patients with cystathionine β-synthase deficiency | - | direct toxicity of Met has been postulated | #10 |
The metabolism of sulfur-containing amino acids (SAAs) requires an orchestrated interplay among several dozen enzymes and transporters, and an adequate dietary intake of methionine (Met), cysteine (Cys), and B vitamins. Known human genetic disorders are due to defects in Met demethylation, homocysteine (Hcy) remethylation, or cobalamin and folate metabolism, in Hcy transsulfuration, and Cys and hydrogen sulfide (H2S) catabolism. These disorders may manifest between the newborn period and late adulthood by a combination of neuropsychiatric abnormalities, thromboembolism, megaloblastic anemia, hepatopathy, myopathy, and bone and connective tissue abnormalities. Biochemical features include metabolite deficiencies (e.g. Met, S-adenosylmethionine (AdoMet), intermediates in 1-carbon metabolism, Cys, or glutathione) and/or their accumulation (e.g. S-adenosylhomocysteine, Hcy, H2S, or sulfite). Treatment should be started as early as possible and may include a low-protein/low-Met diet with Cys-enriched amino acid supplements, pharmacological doses of B vitamins, betaine to stimulate Hcy remethylation, the provision of N-acetylcysteine or AdoMet, or experimental approaches such as liver transplantation or enzyme replacement therapy. In several disorders, patients are exposed to long-term markedly elevated Met concentrations. Although these conditions may inform on Met toxicity, interpretation is difficult due to the presence of additional metabolic changes. Two disorders seem to exhibit Met-associated toxicity in the brain. An increased risk of demyelination in patients with Met adenosyltransferase I/III (MATI/III) deficiency due to biallelic mutations in the MATIA gene has been attributed to very high blood Met concentrations (typically >800 μmol/L) and possibly also to decreased liver AdoMet synthesis. An excessively high Met concentration in some patients with cystathionine β-synthase deficiency has been associated with encephalopathy and brain edema, and direct toxicity of Met has been postulated. In summary, studies in patients with various disorders of SAA metabolism showed complex metabolic changes with distant cellular consequences, most of which are not attributable to direct Met toxicity.