Cystathioninuria, also called cystathionase deficiency, is an

autosomal An autosome is any chromosome that is not a sex chromosome. The members of an autosome pair in a diploid cell have the same morphology, unlike those in allosomal (sex chromosome) pairs, which may have different structures. The DNA in autosom ...

recessive In genetics, dominance is the phenomenon of one variant (allele) of a gene on a chromosome masking or overriding the effect of a different variant of the same gene on the other copy of the chromosome. The first variant is termed dominant and t ...

metabolic disorder A metabolic disorder is a disorder that negatively alters the body's processing and distribution of macronutrients, such as proteins, fats, and carbohydrates. Metabolic disorders can happen when abnormal chemical reactions in the body alter t ...

. It is characterized by an abnormal accumulation of plasma cystathionine leading to excess cystathionine in the urine. Hereditary cystathioninuria is associated with the reduced activity of the enzyme

cystathionine gamma-lyase The enzyme cystathionine γ-lyase (EC 4.4.1.1, CTH or CSE; also cystathionase; systematic name L-cystathionine cysteine-lyase (deaminating; 2-oxobutanoate-forming)) breaks down cystathionine into cysteine, 2-oxobutanoate ( α-ketobutyrate), and ...

. It is considered a biochemical anomaly. This is because it associated with a wide range of diseases and its inconsistency. Cystathionase catalyzes cystathionine to cysteine and α-ketobutyrate. Cysteine is an essential amino acid and its conversion from cystathionine occurs in the trans-sulfuration pathway. The availability of cysteine is necessary for the synthesis of an important anti-oxidant, glutathione. Cystathionase has a co-enzyme, pyridoxal phosphate, which is the active form the vitamin B6. This means that vitamin B6 is essential for the function of cystathionase. Cystathioninuria can be broken down into two main categories. Primary cystathioninuria is caused by the recessive inherited deficiency of cystathionase enzyme. Secondary cystathioninuria is described by non-genetic conditions of excess cystathionine. Secondary cystathioninuria includes temporary excess cystathionine of premature infants, severe generalized liver damage, thyrotoxicosis, hepatoblastoma, or neuroblastoma. Cases of secondary cystathioninuria are not responsive to vitamin B6 administration.

Types

Under primary cystathioninuria, the inherited mutation of CTH gene, there are two forms. There is ''vitamin B6 – unresponsive'' and ''vitamin B6 – responsive'' cystathioninuria. The vitamin B6 – unresponsive form is thought to be from a lack of the synthesis of cystathionase. This means that the mutation in CTH from this form of cystathioninuria, results in the absence of cystathionase. It could also result from the synthesis of a cystathionase that is so greatly mutated it cannot function at all. On the other hand, vitamin B6 – responsive form still has synthesis of cystathionase. However, the cystathionase has an altered ability to bind to vitamin B6, its coenzyme. This changed interaction lowers the efficiency of cystathionase, so it cannot convert cystathionine as well.

Genetics

Cystathioninuria is inherited in an autosomal recessive manner. This means the defective gene responsible for the disorder is located on an autosome, and two copies of the defective gene (one inherited from each parent) are required in order to be born with the disorder. The parents of an individual with an autosomal recessive disorder both

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one copy of the defective gene, but usually do not experience any signs or symptoms of the disorder. Interestingly,

homozygotes Zygosity (the noun, zygote, is from the Greek "yoked," from "yoke") () is the degree to which both copies of a chromosome or gene have the same genetic sequence. In other words, it is the degree of similarity of the alleles in an organism. Mo ...

and

heterozygotes Zygosity (the noun, zygote, is from the Greek "yoked," from "yoke") () is the degree to which both copies of a chromosome or gene have the same genetic sequence. In other words, it is the degree of similarity of the alleles in an organism. Mo ...

were able to be distinguished in one study through both plasma and urinary levels of cystathionine. The homozygote individuals had cystathionine levels greater than 0.5 moles per milligram of

creatinine Creatinine (; ) is a breakdown product of creatine phosphate from muscle and protein metabolism. It is released at a constant rate by the body (depending on muscle mass). Biological relevance Serum creatinine (a blood measurement) is an importa ...

. Each of the homozygote individuals had a significant amount of cystathionine in the plasma as well. In contrast, the heterozygote individuals excreted approximately one tenth the amount of cystathionine as the homozygote individuals. The heterozygote individuals also had no detectable amounts of cystathionine in their plasma. The gene for cystathionase, CTH, has been sequenced and multiple mutations have been shown to be associated with the development of cystathioninuria. Two

nonsense Nonsense is a communication, via speech, writing, or any other symbolic system, that lacks any coherent meaning. Sometimes in ordinary usage, nonsense is synonymous with absurdity or the ridiculous. Many poets, novelists and songwriters have u ...

mutations were found in exon 8 and exon 11 of CTH. Two

missense In genetics, a missense mutation is a point mutation in which a single nucleotide change results in a codon that codes for a different amino acid. It is a type of nonsynonymous substitution. Substitution of protein from DNA mutations Missense mu ...

mutations were also found, mainly in exon 2 and exon 7. In addition, a common non-synonymous single nucleotide polymorphism in exon 12 was also identified. The presence of various CTH mutations is consistent with the various categories associated with cystathioninuria.

Diagnosis

The main way to diagnosis cystathioninuria is simply through increased urinary excretion of cystathionine. In some cases, a genetic test is employed.

Treatment

The treatment, if any is available, varies depending on the category of cystathioninuria a patient has. The vitamin B6 – responsive form is best treated by an increased consumption of vitamin B6. This increased consumption helps with cystathionase's altered ability to bind to the active form of vitamin B6.

References

External links

Amino acid metabolism disorders Autosomal recessive disorders {{genetic-disorder-stub