Prolidase deficiency

Prolidase deficiency (PD) is an autosomal recessive disease that is extremely uncommon and is associated with collagen metabolism^[1] and affects the connective tissues. This rare condition affects assorted systems because of an error on an enzyme, which is affiliated with the creation of collagen. Collagen is a powerful protein that is observed in the bones, tissues, and the skin. Collagen causes the degradation of iminodipeptides. Iminodipeptides are compounds, which break down to form amino acids. Prolidase is an enzyme responsible for the breaking down of iminodipeptides. In this condition there is a defect, which causes a lack of prolidase. Those affected by PD eliminate large quantities of iminodipeptides in their urine because of a deficiency in the prolidase enzyme.^[2] When the function of prolidase operates incorrectly it results in this recessive connective tissue condition (PD).

Prolidase splits dipeptides that contain C-terminal proline or hydroxyproline. When the amount of prolidase is insufficient, the typical recycling of the residues of proline, acquired from the degrading of collagen, is not functioning properly. As a result, there is an accumulation of iminodipeptides causes disruptions in the connective tissue metabolism and elimination of an excessive volume of iminodipeptides in the urine.

It is estimated that about 70 people with this condition have been recorded in medical literature. Those who have researched this disorder predict that this condition exists in about 1 in 1 million to 1 in 2 million newborns/infants.^[3] The characteristics of this disorder are extremely inconsistent in their expression.

Characteristics and Symptoms

Prolidase deficiency generally becomes evident throughout infancy, but the initial symptoms can appear from the time of birth to young adulthood. This condition results in very diverse symptoms.^[3] The seriousness of the symptoms exhibited in PD can be significantly inconsistent between those who are affected. It is possible for individuals who are affected by this condition to be asymptomatic. In those people who exhibit no symptoms, this disorder can be identified through laboratory testing. For instance, newborn screening testing or testing extended to the family members of those who are influenced by this condition.

One of the primary features of prolidase deficiency is the passing of high quantities of proteins (peptides) through urine. In addition, most of those affected exhibit skin lesions or ulcers on the skin that are persistent. The majority of these ulcers are seen on the legs and feet. The severity of these skin lesions normally begins during childhood, and may span from a mild rash to skin ulcers that are more severe.^[3] The skin ulcers particularly on the legs could possibly not entirely heal, which can cause difficulties that could lead to infection and amputation. Those affected by PD can also suffer from intellectual disabilities that can range from mild to more serious. The development of children who are affected could progress more slowly and approximately 75% of those who have PD have an intellectual disability. These individuals also have an elevated vulnerability to infections, particularly the infections of the respiratory system. Some who suffer from PD acquire recurrent lung disease.

Clinically, the distinguishing feature that is seen most frequently, and exists in the majority of those affected is the appearance of dermatological problems.^[4] The abundant amounts of those who suffer from this condition exhibit abnormal facial characteristics. The distinguishing facial appearance in those who have PD consist of, pronounced eyes which are spaced far apart (hypertelorism), a high forehead, a compressed bridge of the nose or saddle nose, and a small lower jaw and chin (micrognathia).^[3]

In addition to the symptoms stated, those with prolidase deficiency are also vulnerable to serious skin or ear infections and possibly respiratory tract infections that could risk their lives. Affected individuals may also have an enlarged spleen (splenomegaly), and on some occasions the spleen and liver may both be enlarged (hepatosplenomegaly).^[3]

Causes and Genetics

The mutations on the PEPD (peptidase-D) gene result the development of prolidase deficiency.^[3] The location of this gene is on chromosome 19 and it contains the instructions on how to make the enzyme prolidase. Prolidase plays a part in destroying and recycling proteins, like collagen. This gene presents information for the creation of prolidase, an enzyme, which is known as peptidase-D. Prolidase assists in the division of specific dipeptides. Dipeptides are molecules that are made up of two components that are, protein building blocks (amino acids). Exclusively, prolidase separates dipeptides that contain proline of hydroxyproline, which are both amino acids. By releasing those amino acids, prolidase can help to prepare them for use in generating proteins which are essential to the body.

Prolidase is associated with the last part of in the breaking down of some proteins that are acquired via diet and the proteins which the body does not find necessary anymore. Prolidase is essential for collagen biosynthesis and its inadequacy causes deterioration in the connective tissue of the skin, capillaries, and lymphatic tissue. Mutations of the prolidase gene results in the activity of prolidase being decreased or completely lost, which causes PD.

It has been proposed that the buildup of dipeptides which have not yet been broken down, can induce the death of cells. After cells die, the volume of the cell is expelled within the neighboring tissue and that may result in inflammation and give rise to problems of the skin as seen in PD. Also said that if the breaking down of collagen is defective while the extracellular matrix (ECM) is undergoing alteration, that it could cause problems with the skin as well. Collagen is a protein that is widely scattered throughout the body and it serves to support the structure of internal organs and connective tissues. The mental impairment that can develop in those with PD might arise from complications involving the management of neuropeptides. Neuropeptides are the proteins that have an abundance of proline and help with communication in the brain.

At least 19 mutations in the PEPD gene have been identified in individuals with prolidase deficiency. The mutations on the PEPD gene seen in individuals affected by PD, result in the prolidase enzyme action being lost.^[5]

This condition is inherited in an autosomal recessive fashion, meaning that the two copies of the gene in every cell contain mutations. Each of the parents of the person who suffers from an autosomal recessive disorder possesses one copy of the mutant gene, but they usually do not exhibit the signs and symptoms of the disorder.^[3]

Diagnosis

The diagnosis of prolidase deficiency is based on whether there is a presence of ulcers on the skin, and if there is, the position at which they are located and also the identifying particular proteins in urine. In order to confirm the diagnosis, a blood test is required to measure the action of the prolidase enzyme.

Treatment

There is not a definitive treatment available for prolidase deficiency. Although there is no treatment, it is possible to try to keep the condition under control. The management is restricted to treating the skin ulcers. They can be treated with an oral ascorbate, manganese (cofactor of prolidase), suppression of collagenase, and local applications of ointments that contain L-glycine and L-proline can be used to help to manage the irritation of the skin. The response to the treatment is inconsistent between affected individuals.^[6]

References

External links

• Prolidase deficiency on OrphaNet