Prolidase Deficiency

A number sign (#) is used with this entry because prolidase deficiency is caused by homozygous or compound heterozygous mutation in the PEPD gene (613230) on chromosome 19q13.

Description

Prolidase deficiency is a rare autosomal recessive multisystem disorder associated with massive imidodipeptiduria and lack of or reduced prolidase activity in erythrocytes, leukocytes, or cultured fibroblasts. The disorder is clinically heterogeneous and severity varies widely. Features include chronic, slowly healing ulcerations, mainly on the legs and feet. The ulcers are often preceded by other dermatologic manifestations that may occur anywhere and include erythematous papular eruptions, telangiectases with pruritus and photosensitivity, impetigo-like eruptions, pruritic eczematous lesions, and necrotic papules. Mild to severe mental retardation is often a feature, and recurrent respiratory tract infections, sometimes fatal, are common. Facial dysmorphism may include low hairline and hirsutism, saddle nose, ocular hypertelorism, micrognathia, a high-arched palate, mandibular protrusion, and exophthalmos. Clinical manifestations are usually detectable after birth or in early childhood, but late-onset cases have been reported (summary by Lupi et al., 2008).

Clinical Features

Powell et al. (1974) described a patient who excreted massive amounts of glycyl-L-proline and other di- and tri-peptides containing proline. Prolidase, the enzyme known to cleave the bond between the other amino acid and proline (which is carboxyl-terminal), was found to be absent or markedly decreased in the patient's red and white cells. The mother and maternal grandfather had intermediate levels. The father was not available for study. The parents were not known to be related. The proband was a 7-year-old white male with dry, cracked erythematous palms and soles and with obesity from an early age. Mild mental retardation and 'mild diffuse demineralization' of long bones were described.

Powell et al. (1975) studied 2 children with prolidase deficiency. Clinical features included chronic dermatitis, frequent infections, splenomegaly, and massive imidodipeptiduria. Powell et al. (1977) reported that chronic ear and sinus infections, chronic skin lesions, and splenomegaly were features.

Sheffield et al. (1977) described an 11-year-old boy who was born of consanguineous parents and presented distinctive clinical features of recurrent skin ulceration, lymphedema, hepatosplenomegaly, and mild mental retardation. Massive amounts of dipeptides, most of which had proline or hydroxyproline as the carboxyl residue, were excreted in the urine. Glycylproline predominated. Prolidase deficiency was demonstrable in red cells, fibroblasts, and continuous lymphocyte cultures.

Myara et al. (1984) stated that about 20 cases of prolidase deficiency had been reported. Dermatologic features, particularly severe leg ulcers, and mental retardation of variable severity were the main manifestations (Der Kaloustian et al., 1982). Recurrent infections might be due to a disturbance of complement component C1q, which contains a large amount of iminoacids. Most patients have an unusual facial appearance as well as splenomegaly. After gelatin ingestion, excretion of iminoacids in the urine is increased, indicating that iminoacid absorption in the intestine is not modified even though prolidase is deficient in the intestine. Freij et al. (1984) described affected brothers.

Leoni et al. (1987) described prolidase deficiency in 2 sisters who suffered from recurrent leg ulcers, which first appeared in early childhood. Milligan et al. (1989) described a patient in whom chronic leg ulceration was due to prolidase deficiency. They added erosive cystitis as a feature of the disorder.

Shrinath et al. (1997) described 2 children with prolidase deficiency who developed clinical and immunologic abnormalities consistent with a diagnosis of systemic lupus erythematosus (SLE; 152700). The first child died from septicemia, and SLE was diagnosed only during his terminal illness. As a result of this diagnosis, his cousin, who was already known to have prolidase deficiency, was investigated further and a diagnosis of SLE was confirmed. Following treatment with oral prednisolone, her clinical condition improved, although she had a persistently raised erythrocyte sedimentation rate and florid facial rash. Both prolidase deficiency and SLE are associated with disturbances in immune function and have clinical features in common. Prolidase deficiency may be a risk factor for SLE. Shrinath et al. (1997) suggested that patients with SLE should be specifically investigated for prolidase deficiency, especially where there is a family history of SLE or presentation of SLE in childhood, since standard immunologic or hematologic investigations will not identify the biochemical abnormalities characteristic of prolidase deficiency.

Falik-Zaccai et al. (2010) reported 20 patients from 10 kindreds with prolidase deficiency in northern Israel. There were 7 Druze and 3 Arab Muslim families. All presented with some degree of developmental delay, most with moderate cognitive or speech delay. All also had some degree of facial dysmorphism, including ocular hypertelorism, exophthalmos, upward or downward slanting palpebral fissures, small-beaked nose, low posterior hairline, facial hirsutism, and a slender upper lip. Dermatologic manifestations included erythematous papular eruptions, impetigo-like eruptions, pseudo-psoriasis skin lesions, and pruritic eczematous lesions. Other more variable features included splenomegaly, hepatitis-like symptoms, osteomyelitis, recurrent lung infections, and asthma. One patient had chronic lung disease resembling cystic fibrosis (CF; 219700), and 2 developed SLE. The phenotype was highly heterogeneous, and there was great inter- and intrafamilial variability. In 1 family, the severity ranged from death in infancy to an essentially asymptomatic adult with minor facial dysmorphism and mental deficits.

Biochemical Features

Endo et al. (1987) found absence of a subunit of prolidase in red cells in a patient with prolidase deficiency.

Wysocki et al. (1988) described a 17-year-old girl with recurrent ulceration, initially covering most of her body but later in life confined mainly to her legs. Although she had an almost complete absence of prolidase in plasma and erythrocytes, this patient did not excrete hydroxyproline-containing dipeptides in her urine. One or more of the symptoms of prolidase deficiency may reflect a tissue deficiency of L-proline, which is not reclaimed in the absence of prolidase. Excretion of this amino acid, in bound form, can be as high as 20 to 30 mmol/day. Against the proposition that the failure of recovery of proline from iminodipeptides has a major role in the pathogenesis of prolidase deficiency is the fact that oral administration of L-proline does not relieve the dermatologic lesions. Attempts at enzyme replacement with normal matched erythrocytes have had no effect on iminodipeptiduria and this appears to be due to the fact that prolidase occurs in erythrocytes in an inactive form. Hechtman et al. (1988) found that brief exposure of intact erythrocytes to low concentrations of manganese ion activated intracellular prolidase without causing hemolysis. Hechtman et al. (1988) showed that erythrocytes so treated retained high levels of enzymatic activity for at least 2 weeks.

Ohhashi et al. (1988) reported prolidase serum activities against 6 different substrates from 2 patients with prolidase deficiency, their mother, and controls.

Boright et al. (1988) demonstrated 3 classes of mutant prolidase alleles. In 6 prolidase-deficient cell strains, Boright et al. (1989) identified 3 types of mutations: half the cell lines showed a mutation that conferred a CRM-negative phenotype, while the other 3 showed CRM-positive mutations of 2 types, 1 mutation encoding an enlarged subunit (60 kD as contrasted with the normal 58-kD polypeptide) and the others associated with subunits of normal size. Complementation analysis indicated that the mutations mapped to the same locus. Normal subjects and obligate heterozygotes expressing CRM-negative mutations had thermostable prolidase activity at 50 degrees C in cell extracts, whereas heterozygotes expressing CRM-positive mutations had thermolabile activity under the same conditions, implying negative allelic complementation in the putative heterodimer. Alternative enzymatic activity not encoded at the prolidase locus was indicated by the occurrence of prolidase-like activity about 5% of normal in amount but with a preference for substrate different from normal, in cells homozygous (or compound) for CRM-negative mutations. Allelic heterogeneity at the major locus and the amount of alternative peptidase activity encoded elsewhere appeared to be determinants of the associated and heterogeneous clinical phenotype.

Endo et al. (1990) demonstrated great biochemical heterogeneity in prolidase deficiency. There was no apparent relation between the clinical symptoms and the biochemical phenotypes, except that mental retardation was present in the polypeptide-negative (CRM-negative) patients. Berardesca et al. (1992) reported the case of a 15-year-old boy with prolidase deficiency and marked urinary excretion of the iminodipeptide gly-pro. After blood transfusion, prolidase activity in erythrocytes against substrate glycyl-proline increased to 15.7% of donor activity and declined to 12% and 3.4% of normal activity after 8 and 45 days, respectively. Urinary iminodipeptide levels following transfusion remained unaltered. Transfusions of concentrated erythrocytes led to at least partial healing of ulcers of the skin but these recurred by 18 months after the last transfusion.

Diagnosis

Kurien et al. (2006) described the biochemical diagnostic techniques for prolidase deficiency.

Inheritance

Complementation studies indicated that a single genetic locus is involved in prolidase deficiency (Boright et al., 1988).

Reports of multiple affected sibs, parental consanguinity, and equal sex distribution indicate that prolidase deficiency is an autosomal recessive disorder (Milligan et al., 1989).

Molecular Genetics

In 2 unrelated patients with prolidase deficiency, Tanoue et al. (1990) identified homozygosity for a mutation in the PEPD gene (613230.0001).

Ledoux et al. (1994) described 4 mutant PEPD alleles associated with prolidase deficiency and Ledoux et al. (1996) reported 2 additional ones. Ledoux et al. (1996) developed a novel expression system to study mutant PEPD alleles by using COS-1 cells and demonstrated that 4 of these mutations were responsible for the enzyme deficiency (613230.0003-613230.0006).

In 5 cases of prolidase deficiency, Forlino et al. (2002) provided molecular characterization of 3 mutations, all of which resulted in loss of prolidase activity. Long-term cultured fibroblasts from the patients were used to develop an in vitro model that allowed investigation of the affected cells. Light and electron microscopy revealed that prolidase-deficient cells were more round and branched out than controls, and had increased cytosolic vacuolization, interruptions of the plasma membrane, mitochondrial swelling, and modifications of the mitochondrial matrix and cristae. Forlino et al. (2002) interpreted these findings as evidence that absence of prolidase activity causes the activation of a necrosis-like cellular death, which could be responsible for the skin lesions typical of prolidase deficiency.

Wang et al. (2006) reported 4 Geauga Amish children with prolidase deficiency, born of consanguineous parents whose ancestry could be traced to common ascendants 7 or 8 generations back, in whom they identified a homozygous nonsense mutation in the PEPD gene (613230.0008). All 4 patients had massive imidodipeptiduria and clinically similar multisystem involvement, with typical facial features of prominent forehead, low nasal root, ocular hypertelorism, and proptosis. Splenomegaly and elevated immunoglobulins, especially of IgE, were observed in 3 patients, who also had asthma-like chronic reactive airway disease. There was neonatal jaundice and hepatomegaly in all 4 patients, and 3 had anemia, thrombocytopenia, and petechiae. Wang et al. (2006) stated that this was the first report of prolidase deficiency in the Amish as well as in the United States.

Population Genetics

Falik-Zaccai et al. (2010) identified the same PEPD mutation (S202F; 613230.0011) in 17 patients from northern Israel with prolidase deficiency. The patients were from 6 Druze kindreds living in 4 different villages and from 2 Arab Muslim kindreds living in 2 different villages. The separate practices of consanguinity and endogamy reduce the likelihood of genetic interchange between these 2 groups, but haplotype analysis indicated a founder effect. The findings refuted the possibility of the Druze being a homogeneous population, and suggested that the mutation arose before the establishment of the Druze community.