Pre-sulfo and sulfite oxidase deficiency

What is the effect of sulfite oxidase deficiency on the body and what consequences can it have at the neurological level?

Sulfite oxidase deficiency is an inherited disorder of sulfur-containing amino acid metabolism that results in accumulation of sulfite in tissues and body fluids. This condition can arise due to a lack of the enzyme sulfite oxidase or a defect in the synthesis of the necessary cofactor for this enzyme, known as molybdenum (MoCo).

In both cases, severe neurological disease occurs.

What are sulfur amino acids and how are they removed?

Amino acids are molecules found in proteins and play an important role in the body. Some amino acids, such as methionine and cystine, contain sulfur in their structure. These amino acids are formed and broken down through a specific metabolic pathway, in which the last step involves the transformation of sulfites into sulfates, which are eliminated through the urine.

What is the function of sulfite oxidase?

The enzyme sulfite oxidase, with the help of the cofactor molybdenum (MoCo), converts sulfites to sulfates. This cofactor is also essential for the functioning of the xanthine oxidase and aldehyde oxidase enzymes.

When there is a defect in the MoCo cofactor, a deficiency occurs in all three enzymes, which has clinical and biochemical consequences.

A metabolic error of sulfite oxidase implies an alteration in metabolism, where certain enzymatic processes do not occur efficiently, which can lead to the accumulation of toxic compounds such as sulfites, which are probably neurotoxic. These alterations have pathological consequences.

What are the consequences of sulfite buildup due to sulfite oxidase deficiency?

In cases of sulfite oxidase deficiency, sulfites accumulate in the body without being able to be converted into sulfates for elimination through urine.

If there is a deficiency of the cofactor MoCo, the three enzymes that depend on it do not function properly, leading to a buildup of xanthine and hypoxanthine, as well as uric acid deficiency.

What causes sulfite oxidase deficiency and how is this genetic disorder inherited?

Sulfite oxidase deficiency occurs due to genetic changes (mutations) in the SUOX gene, which is responsible for encoding this enzyme. It can also occur due to mutations in other genes involved in the synthesis of the MoCo cofactor, such as MOCS1 (type A deficiency), MOCS2 (type B deficiency) and GPHN.

These deficiencies are inherited genetic disorders of autosomal recessive inheritance. This means that the parents carry the mutations in these genes, although they do not experience the effects of the enzyme deficiency themselves.

What are the possible neurological symptoms and clinical manifestations that a child may experience in case of sulfite oxidase deficiency?

The first signs of both deficiencies may appear in the first days of life or during the first year.

In the case of sulfite oxidase deficiency, clinical symptoms are primarily central to the nervous system and may include impaired muscle tone, seizures, movement disorders, and, in patients who survive into infancy, failure to thrive and displacement. of the crystalline Brain injury develops early.

In general, the disease has a rapid and fatal course, although there are exceptions.

In MoCo deficiency, xanthine accumulation can also cause kidney stone formation due to the presence of xanthinuria.

How is Sulfite Oxidase deficiency diagnosed?

The diagnosis of sulfite oxidase deficiency is made by analyzing the plasma and urine of patients.

In plasma, an increase in sulfocysteine and taurine levels is observed, as well as an absence of total cystine and homocysteine. In freshly collected urine, an increase in sulfites is detected and the same alterations observed in plasma are present.

In the case of MoCo deficiency, in addition to these findings, a deficiency of uric acid in the serum and urine is observed, as well as an elevated excretion of xanthine and hypoxanthine in the urine.

To confirm the diagnosis of the disease, enzymatic and genetic studies are required, which makes it possible to provide genetic counseling and perform prenatal diagnosis.

What are the therapeutic options available to treat sulfite oxidase deficiency and MoCo deficiency?

In the case of isolated sulfite oxidase deficiency, therapeutic options are limited. However, in the case of MoCo deficiency, the therapeutic response appears to be more promising.

Therapeutic possibilities include:

1. Protein restriction by means of a diet low in methionine and supplemented with cystine.
2. Use of dextromethorphan, an NMDA receptor inhibitor, to reduce neuronal excitotoxicity.
3. Treatment of MoCo deficiency.
4. In adults, the protein restriction diet (1) can be supplemented with the Naturlider Pre-sulfo food supplement.

An effective replacement therapy for type A MoCo deficiency (caused by mutations in the MOCS1 gene) has recently been discovered. This substrate replacement therapy makes it possible to restore MoCo-dependent enzymatic activities by reintroducing cyclic pyranopterin monophosphate (cPMP), the first intermediate in the MoCo synthesis pathway. This helps stop the associated neurodegeneration.

Both sulfite oxidase deficiency and MoCo deficiency are serious neurometabolic diseases, but early diagnosis and replacement or symptomatic treatment can help patients.

Fountain:

https://www.sanidad.gob.es/biblioPublic/publicaciones/docs/vol29_4TtoDieteticoEnfMetabolicas.pdf

https://metabolicas.sjdhospitalbarcelona.org/ecm/deficiencia-sulfito-oxidasa-cofactor-molibdeno/info/cuales-posibilidades-terapeuticas