Partial Rescue of Biochemical Parameters After Hematopoietic Stem Cell Transplantation in a Patient with Prolidase Deficiency Due to Two Novel PEPD Mutations

Abstract

Prolidase deficiency (PD) is a rare recessive disorder resulting from mutations in the prolidase gene (PEPD); only 17 causative mutant alleles had been so far characterized. Prolidase is a ubiquitous enzyme that hydrolyses dipeptides with C-terminal proline or hydroxyproline residues and indeed, lack of this enzyme activity causes massive urine excretion of undigested iminodipeptides. The clinical manifestations of PD are widely variable, and include intractable skin ulcers, unusual face, different degree of mental retardation, and recurrent infections. No definitive treatment is at present available.

We report an 8-year girl with a typical PD facies, normal intelligence, and recurrent deep ulcerations complicated by infections. She was found to be compound heterozygous for two novel mutations in PEPD, c.1133delACG and c.1301delT, affecting the C-terminal end of the enzyme where the active site is located. Given her life-threatening course, she underwent allogeneic hematopoietic stem cell transplantation (HSCT) from her HLA-identical brother, confirmed heterozygous for the c.1133delACG allele. Successful engraftment was documented by full-donor chimerism. Posttransplant monitoring of erythrocyte prolidase activity showed that the child had converted to a heterozygous pattern. Reduction of excreted urine dipeptides, evaluated by capillary electrophoresis, supported the effectiveness of the treatment. Unfortunately the patient died on day +92 of invasive fungal infection.

Despite the unfavorable outcome, we provide the first evidence that HSCT has the potential to reverse some of the biochemical features of PD patients. The indication to transplant must be balanced against the clinical manifestation of individual patients.

Competing interests: None declared.

Appendices

Short Summary

Two novel causative mutations were documented in a patient with Prolidase Deficiency (PD), a rare autosomal recessive disease of connective tissue for which only 17 mutant causative alleles had been reported. No therapies with curative potential are available for PD patients; this is the first report of HSCT with at least partial rescue of this disease. Reversal of enzyme activity and urine dipeptides excretion suggested that PD could be added to the disorders treatable by transplantation.

Accession Codes: OMIM: 170100 (Prolidase Deficiency); E.C.: 3.4.13.9 (Prolidase); HUGO: PEPD (Proliase); GeneBank: NM_000285.3 (Prolidase mRNA)

Contributions of Individual Authors

• Rolando Cimaz made initial diagnosis and designed therapeutic approach

• Maurizio Aricò Désirée Caselli: took care of the evaluation of the feasibility and then of performing HSCT transplantation

• Silvia Riva Marco Spada: provided expert clinical care during the phase of severe liver failure

• Luca Cantarini: performed the molecular characterization of the patient and her family

• Antonella Forlino Roberta Besio, Antonio Rossi performed the molecular and biochemical characterization of the patient and determined prolidase activity at the different pre and posttransplantation time

• Ersilia De Lorenzi Raffaella Colombo: performed the capillary electrophoresis experiments to evaluate urine dipeptide excretion following transplantation

• Maurizio Aricò and Antonella Forlino: planned the study analyzed the data and wrote the manuscript

The guarantor for the present article is Maurizio Aricò.

All authors declare that the answers to all questions on the JMDI competing interest questionnaire are No and therefore they have nothing to declare.

Funding

This work was supported by MIUR 2008 (2008XA48SC) by Fondazione Cariplo 2007 to A.F. and by Progetto Regione Lombardia (cod. SAL/45) “Dalla scienza dei materiali alla medicina molecolare” to A.F., A.R. and E.D.L.

The authors confirm independence from the sponsors the content of the article has not been influenced by the sponsor. Informed consent for all the laboratory and genetic studies, and for treatment including HSCT was obtained from both parents.