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Homocystinuria
Homocystinuria
Homocystinuria
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Homocystinuria
Other namesCystathionine beta synthase deficiency or CBS deficiency[1]
Homocysteine
SpecialtyEndocrinology, medical genetics Edit this on Wikidata

Homocystinuria (HCU)[2] is an inherited disorder of the metabolism of the amino acid methionine due to a deficiency of cystathionine beta synthase or methionine synthase.[3] It is an inherited autosomal recessive trait, which means a child needs to inherit a copy of the defective gene from both parents to be affected. Symptoms of homocystinuria can also be caused by a deficiency of vitamins B6, B12, or folate.[3]

Signs and symptoms

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This defect leads to a multi-systemic disorder of the connective tissue, muscles, central nervous system (CNS), and cardiovascular system. Homocystinuria represents a group of hereditary metabolic disorders characterized by an accumulation of the amino acid homocysteine in the serum and an increased excretion of homocysteine in the urine. Infants appear to be normal and early symptoms, if any are present, are vague.[citation needed]

Signs and symptoms of homocystinuria that may be seen include the following:

Cause

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It is usually caused by the deficiency of the enzyme cystathionine beta synthase,[3] mutations of other related enzymes such as methionine synthase,[3] or the deficiency of folic acid, vitamin B12 and/or pyridoxine (vitamin B6).[3]

Diagnosis

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The term homocystinuria describes an increased excretion of the thiol amino acid homocysteine in urine (and incidentally, also an increased concentration in plasma). The source of this increase may be one of many metabolic factors, only one of which is CBS deficiency. Others include the re-methylation defects (cobalamin defects, methionine synthase deficiency, MTHFR) and vitamin deficiencies including riboflavin (vitamin B2), pyridoxal phosphate (vitamin B6), folate (vitamin B9), and cobalamin (vitamin B12). In light of this, a combined approach to laboratory diagnosis is required to reach a differential diagnosis.[citation needed]

CBS deficiency may be diagnosed by routine metabolic biochemistry. Genetic testing may be used to screen for known SNPs (mutations). In the first instance, plasma or urine amino acid analysis will frequently show an elevation of methionine and the presence of homocysteine. Many neonatal screening programs include methionine as a metabolite. The disorder may be distinguished from the re-methylation defects (e.g., MTHFR, methionine synthase deficiency, or the cobalamin defects) in lieu of the elevated methionine concentration.[7] Additionally, organic acid analysis or quantitative determination of methylmalonic acid should help to exclude cobalamin (vitamin B12) defects and vitamin B12 deficiency giving a differential diagnosis.[8]

The laboratory analysis of homocysteine itself is complicated because most homocysteine (possibly above 85%) is bound to other thiol amino acids and proteins in the form of disulphides (e.g., cysteine in cystine-homocysteine, homocysteine in homocysteine-homocysteine) via disulfide bonds. Since as an equilibrium process the proportion of free homocysteine is variable a true value of total homocysteine (free + bound) is useful for confirming diagnosis and particularly for monitoring of treatment efficacy. To this end it is prudent to perform total homocyst(e)ine analysis in which all disulphide bonds are subject to reduction prior to analysis, traditionally by HPLC after derivatisation with a fluorescent agent, thus giving a true reflection of the quantity of homocysteine in a plasma sample.[9]

Treatment

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No specific cure has been discovered for homocystinuria; however, many people are treated using high doses of vitamin B6 (also known as pyridoxine).[10] Slightly less than 50% respond to this treatment and need to take supplemental vitamin B6 for the rest of their lives. Those who do not respond usually respond to supplementation with folic acid and trimethylglycine (betaine).[10] Typically this is mediated by cystathionine beta-synthase activity, i.e. those who have adequate CBS activity typically respond to B6 . Occasionally adding cysteine[citation needed]to the diet can be helpful, as glutathione is synthesized from cysteine (so adding cysteine can be important to reduce oxidative stress). Riboflavin, a cofactor for the MTHFR enzyme pathway and multiple glutathione-related pathways, may also be used.[citation needed]

Betaine (N,N,N-trimethylglycine) is used to reduce concentrations of homocysteine by promoting the conversion of homocysteine back to methionine, i.e., increasing flux through the re-methylation pathway independent of folate derivatives (which is mainly active in the liver and in the kidneys). The re-formed methionine is then gradually removed by incorporation into body protein. The methionine that is not converted into protein is converted to S-adenosyl-methionine which goes on to form homocysteine again. Betaine is, therefore, only effective if the quantity of methionine to be removed is small. Hence treatment includes both betaine and a diet low in methionine. In classical homocystinuria (CBS, or cystathione beta synthase deficiency), the plasma methionine level usually increases above the normal range of 30 micromoles/L and the concentrations should be monitored as potentially toxic levels (more than 400 micromoles/L) may be reached.[citation needed]

[edit]

For the subset of patients whose homocystinuria is caused by cystathionine beta-synthase deficiency (i.e. those that do not respond to B6 supplementation), low-protein food is recommended for this disorder, which requires food products low in particular types of amino acids (e.g., methionine) in addition to supplementation.[11]

Prognosis

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The life expectancy of patients with homocystinuria is reduced only if untreated. It is known that before the age of 30, almost one quarter of patients die as a result of thrombotic complications (e.g., heart attack).[citation needed]

Society and culture

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One theory suggests that Akhenaten, a pharaoh of the eighteenth dynasty of Egypt, may have had homocystinuria.[12]

See also

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References

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Further reading

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Revisions and contributorsEdit on WikipediaRead on Wikipedia

Homocystinuria

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from Grokipedia
Homocystinuria is a rare group of inherited metabolic disorders characterized by the inability to properly metabolize the , leading to the accumulation of (and often ) in the blood and urine. The most common form, classical homocystinuria due to cystathionine beta-synthase () deficiency, results from biallelic pathogenic variants in the CBS gene, which encodes the enzyme responsible for converting to cystathionine in the transsulfuration pathway. Rarer forms arise from defects in the remethylation pathway (e.g., 5,10-methylenetetrahydrofolate reductase [MTHFR] deficiency or cobalamin C [cblC] disorder), which have distinct clinical features and are discussed in the Classification section. This autosomal recessive condition has an estimated incidence of 1 in 200,000 to 1 in 335,000 births worldwide, though prevalence may vary by population due to founder effects in certain ethnic groups. In CBS deficiency, clinical manifestations affect multiple organ systems, with thromboembolism representing the primary cause of morbidity and early mortality, often occurring in the second or third decade of life if untreated. Ocular involvement is prominent, including (dislocation of the eye's lens) typically by age 8 in untreated individuals, severe , and increased risk of or . Skeletal abnormalities contribute to a habitus, featuring tall stature, long limbs (dolichostenomelia), , pectus deformities, , and , which can lead to fractures. Central nervous system effects may include developmental delay or (affecting approximately 50% of untreated cases), seizures, and psychiatric disturbances such as behavioral issues or . Diagnosis of CBS deficiency is established through elevated plasma total homocysteine levels (typically >100 µmol/L) and methionine, often detected via newborn screening or clinical evaluation prompted by symptoms; confirmation involves molecular genetic testing to identify CBS variants. Management focuses on reducing homocysteine levels through pyridoxine (vitamin B6) supplementation for responsive cases (about 50% of patients), a methionine-restricted diet with cysteine supplementation, betaine to promote remethylation of homocysteine, and adjunctive folate and vitamin B12. Multidisciplinary care addresses complications, including antithrombotic prophylaxis and orthopedic interventions. Early diagnosis and treatment significantly improve prognosis, potentially allowing normal lifespan and function, though lifelong monitoring is essential to mitigate vascular risks.

Definition and Epidemiology

Definition and Classification

Homocystinuria is an inherited characterized by markedly elevated levels of in the blood () and urine (homocystinuria), resulting from genetic defects in the metabolism of , an essential sulfur-containing . This condition arises from disruptions in the biochemical pathways that process , leading to its accumulation and potential toxicity to multiple organ systems. Homocysteine serves as a key intermediate in methionine metabolism, participating in two primary pathways: transsulfuration, where it is converted to cystathionine and eventually , and remethylation, where it is recycled back to using and derivatives as cofactors. Defects in enzymes or cofactors involved in these pathways underlie the various forms of homocystinuria. The disorder is classified into several major types based on the specific metabolic defect. Classical homocystinuria, the most common form, results from cystathionine beta-synthase (CBS) deficiency, an autosomal recessive condition caused by biallelic pathogenic variants in the CBS gene; it is further subdivided into pyridoxine-responsive (vitamin B6-responsive) and non-responsive variants, with the former showing partial or complete normalization of homocysteine levels upon pyridoxine supplementation. Remethylation defects, which impair the conversion of homocysteine to methionine, include methylene tetrahydrofolate reductase (MTHFR) deficiency due to MTHFR gene variants, as well as cobalamin C (cblC) and cobalamin G (cblG) defects arising from mutations in MMACHC and MTR genes, respectively; these often present with low or normal methionine levels, distinguishing them biochemically from CBS deficiency. Rare forms encompass isolated methionine synthase deficiency (cblE, due to MTRR variants) and other cobalamin processing errors like cblF or cblJ. Homocystinuria specifically denotes the severe genetic forms of this elevation, in contrast to , which encompasses milder elevations often acquired through nutritional deficiencies (e.g., of , , or B12), renal impairment, or other non-genetic factors, typically without the extreme levels seen in inherited defects.

Prevalence and Risk Factors

Homocystinuria due to cystathionine beta-synthase (CBS) deficiency, the classical form, has a global estimated at approximately 1 in 200,000 to 1 in 335,000 live births. A 2020 analysis using genetic databases estimated a worldwide of about 0.38 per 100,000 (1 in 263,000), with variations by ancestry such as 0.72 per 100,000 in non-Finnish Europeans and 0.02 per 100,000 in Asians. This rate reflects data from clinical records and programs across diverse populations, though ascertainment methods can influence reported figures. Prevalence varies significantly by geography and ethnicity, often due to founder effects and population-specific genetic variants. Higher incidences are observed in certain regions, such as (1 in 1,800 newborns), (1 in 6,400), (1 in 65,000), and (1 in 17,800). In contrast, rates are lower in many African and Asian populations, exemplified by 1 in 800,000 to 1 in 1,000,000 in . The primary risk factor for CBS deficiency is its autosomal recessive inheritance pattern, requiring both parents to be carriers of pathogenic variants in the gene. substantially elevates risk in isolated or endogamous communities, contributing to elevated prevalence in areas like the . for homocystinuria is implemented in numerous countries, including all U.S. states since the early following federal recommendations, enabling early detection and intervention. Similar programs exist in parts of Europe and the , such as and , where high baseline rates justify routine testing. However, underreporting persists due to variable in milder forms, which may evade detection until later in life or remain .

Pathophysiology

Homocysteine Metabolism

is an intermediate in the of sulfur-containing , primarily derived from the demethylation of dietary in a process catalyzed by S-adenosylmethionine-dependent methyltransferases. Under normal conditions, is cleared through two main intersecting pathways: remethylation and transsulfuration, which prevent its accumulation and maintain metabolic . The remethylation pathway recycles back to , occurring ubiquitously in tissues and involving two primary enzymes. transfers a from 5-methyltetrahydrofolate to , regenerating and tetrahydrofolate, with (cobalamin) serving as a cofactor in the form of . Alternatively, betaine-homocysteine methyltransferase (BHMT), active mainly in the liver and kidneys, uses betaine (derived from choline oxidation) as the methyl donor to convert to , producing as a byproduct. , in the form of 5-methyltetrahydrofolate, is essential for the reaction, linking to the one-carbon pool. The transsulfuration pathway, predominantly active in the liver, , , and , directs toward synthesis for protein incorporation, production, and other sulfur-containing compounds. This pathway begins with the of and serine to form cystathionine, catalyzed by the pyridoxal 5'-phosphate (PLP)-dependent enzyme cystathionine β-synthase (), followed by cleavage of cystathionine to , α-ketobutyrate, and ammonia by cystathionine γ-lyase (CSE), also PLP-dependent. (), the precursor to PLP, is the key cofactor for both enzymes, facilitating the β-replacement and γ-elimination reactions. The reaction can be represented as: serine + [homocysteine](/page/Homocysteine)→[CBS](/page/CBS), PLPcystathionine + H2O\text{serine + [homocysteine](/page/Homocysteine)} \xrightarrow{\text{[CBS](/page/CBS), PLP}} \text{cystathionine + H}_2\text{O}
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