Quantitative analysis of the natural history of prolidase deficiency: description of 17 families and systematic review of published cases

Rossignol, Francis; Moreno, Marvid S. Duarte; Benoist, Jean‐François; Boehm, Manfred; Bourrat, E.; Cano, Aline; Chabrol, B.; Cosson, Claudine; Díaz, José Luís Dapena; D'Harlingue, Arthur E.; Dimmock, David; Freeman, Alexandra F.; García, María Tallón; Garganta, Cheryl; Goerge, Tobias; Halbach, Sara; Laffolie, Jan de; Lam, Christina; Martin, Ludovic; Martins, Esmeralda; Meinhardt, Andrea; Melki, Isabelle; Ombrello, Amanda K.; Pérez, Noémie; Quelhas, Dulce; Scott, Anna I.; Slavotinek, Anne; Soares, Ana Rita; Stein, Sarah L.; Süßmuth, Kira; Thies, Jenny; Ferreira, Carlos R.; Schiff, Manuel

doi:10.1038/s41436-021-01200-2

Cited by 14 publications

(32 citation statements)

References 133 publications

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“…The role of the metallopeptidase prolidase in regulating immune tolerance has previously been suggested by the variable autoimmune syndrome seen in some prolidase-deficient human patients. The incidence of ANAs in humans with PD is estimated at 21% ( 7 ); consistent with this, and with the expected sexual dimorphism, we observed positive ANAs in 42.9% of Pepd −/− mice on initial screening, and 22.5% when these animals were rederived at our institution. Because WT ANA frequency was also lower in the second location, this likely to be due to environmental differences between the two animal facilities.…”

Section: Discussionsupporting

confidence: 89%

“…Prolidase-deficient mice also demonstrate an activated T cell phenotype and elevated serum IgA, with glomerular immune complex deposition reminiscent of early human lupus nephritis ( 44 ), mimicking the phenotype in a subset of PD patients ( 7 , 8 , 11 , 45 ) and confirming, to our knowledge, for the first time, the direct association of autoimmunity and PD. However, loss of prolidase did not result in impaired renal function, nor did we detect immune complex deposition in other organs.…”

Section: Discussionsupporting

confidence: 69%

“…Initial screening of male and female Pepd −/− mice demonstrated increased incidence of ANAs compared with WT controls at 12 wk (WT 67/386, 17.36% positive versus Pepd −/− 6/14, 42.9% positive, p = 0.0267, two-tailed Fisher’s exact test), and a similar trend toward ANA positivity was recapitulated on rederivation of the mice in a separate facility ( Fig. 1A ; WT 3/38, 7.9% positive versus Pepd −/− 9/40, 22.5% positive, p = 0.0739, two-tailed Fisher’s exact test), mirroring the rate of ANAs seen in humans with PD (21%) ( 7 ). SLE has a 9:1 female-to-male incidence ( 20 ).…”

Section: Resultssupporting

confidence: 63%

“…Curiously, autoimmune and inflammatory features are also common in PD patients ( 8–11 ), including hypergammaglobulinemia with high titers of IgE and IgA, positivity for antinuclear Abs (ANAs) (21%), and splenomegaly (45%). Fifteen percent of PD patients are diagnosed with an autoimmune disorder, and 6% meet the formal diagnostic criteria for systemic lupus erythematosus (SLE) ( 7 ). However, it is unclear whether the loss of immunological tolerance is triggered by direct effects of PD on immune function or by exposure to self-antigens in the context of chronic skin or respiratory infections.…”

Section: Introductionmentioning

confidence: 99%

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Prolidase Deficiency Causes Spontaneous T Cell Activation and Lupus-like Autoimmunity

Hodgson

Crockford

Bhandari

et al. 2023

The Journal of Immunology

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Prolidase deficiency (PD) is a multisystem disorder caused by mutations in the PEPD gene, which encodes a ubiquitously expressed metallopeptidase essential for the hydrolysis of dipeptides containing C-terminal proline or hydroxyproline. PD typically presents in childhood with developmental delay, skin ulcers, recurrent infections, and, in some patients, autoimmune features that can mimic systemic lupus erythematosus. The basis for the autoimmune association is uncertain, but might be due to self-antigen exposure with tissue damage, or indirectly driven by chronic infection and microbial burden. In this study, we address the question of causation and show that Pepd-null mice have increased antinuclear autoantibodies and raised serum IgA, accompanied by kidney immune complex deposition, consistent with a systemic lupus erythematosus–like disease. These features are associated with an accumulation of CD4 and CD8 effector T cells in the spleen and liver. Pepd deficiency leads to spontaneous T cell activation and proliferation into the effector subset, which is cell intrinsic and independent of Ag receptor specificity or antigenic stimulation. However, an increase in KLRG1+ effector CD8 cells is not observed in mixed chimeras, in which the autoimmune phenotype is also absent. Our findings link autoimmune susceptibility in PD to spontaneous T cell dysfunction, likely to be acting in combination with immune activators that lie outside the hemopoietic system but result from the abnormal metabolism or loss of nonenzymatic prolidase function. This knowledge provides insight into the role of prolidase in the maintenance of self-tolerance and highlights the importance of treatment to control T cell activation.

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Section: Discussionsupporting

confidence: 89%

Section: Discussionsupporting

confidence: 69%

Section: Resultssupporting

confidence: 63%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Prolidase Deficiency Causes Spontaneous T Cell Activation and Lupus-like Autoimmunity

Hodgson

Crockford

Bhandari

et al. 2023

The Journal of Immunology

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“…Disorders of lipid metabolism such as glutaric aciduria type IIC and long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency ( 13 ) or disorders of organic acid metabolism such as lysinuric protein intolerance (LPI) ( 19 , 20 , 35 ), methylmalonic acidemia ( 17 ), propionic acidemia ( 17 , 18 ) may be complicated by HLH. There are many other rare IEMs complicated by HLH that are also reported such as biotinidase deficiency ( 12 ), hepatolenticular degeneration ( 33 ), mevalonate kinase deficiency ( 30 , 31 ), pyrimidine deficiency ( 32 ), disorder of glycogen metabolism ( 14 , 15 ), prolidase deficiency ( 16 ) and cobalamin C disease ( 34 ).…”

Section: Discussionmentioning

confidence: 99%

Case Report: Hemophagocytic Lymphocytosis in a Patient With Glutaric Aciduria Type IIC

Huang

Zhu

et al. 2022

Front. Immunol.

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Hemophagocytic lymphocytosis (HLH) is a rare disease caused by inborn errors of immunity (IEI), secondary to infection, lymphoma or autoimmune disorders, but we often overlook the fact that HLH can be secondary to inborn errors of metabolism (IEM). Here, we describe a patient who was diagnosed with glutaric aciduria type IIC complicated by features suggestive of possible HLH. The diagnosis of glutaric aciduria type IIC, a IEM, was confirmed by whole exome sequencing. The patient was treated with coenzyme Q10 and riboflavin which effectively improved her liver function. During treatment, the patient developed severe anemia and thrombocytopenia. Persistent fever, splenomegaly, cytopenias, increased ferritin, hypertriglyceridemia, hypofibrinogenemia, and hemophagocytosis in the bone marrow pointed to the diagnosis of HLH; however, the patient eventually died of gastrointestinal bleeding. After other potential causes were ruled out, the patient was diagnosed with glutaric aciduria type IIC complicated by features suggestive of possible HLH. When cytopenias occurs in IEM patients, HLH is a possible complication that cannot be ignored. This case suggests a possible relationship between IEM and risk for immune dysregulation.

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Prolidase deficiency: A novel PEPD missense variant in exon 2

Ido

Tessier

Yoder

et al. 2023

American J of Med Genetics Pt A

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Prolidase deficiency is an autosomal recessive disease that causes impaired collagen degradation. Altered collagen homeostasis results in the intracellular accumulation of imidodipeptides, which contain proline and hydroxyproline. The many clinical manifestations of prolidase deficiency include dysmorphic facial features, skeletal deformities, hepatosplenomegaly, necrotizing skin ulcers, and recurrent infections. Current clinical knowledge of this genetic disease relies upon few case reports due to its extreme rarity. Diagnosis is dependent on the detection of a pathologic gene variant. Additional diagnostic confirmation may be provided by urine amino acid quantification or reduced in vitro prolidase activity. We present a case of prolidase deficiency caused by a novel variant manifested by skeletal malformations and lifelong multisystemic infections. Genetic testing revealed a homozygous missense variant in the PEPD gene at nucleotide position 200, whereby adenine was replaced by guanine (c.200A > G). The corresponding amino acid change replaced glutamine with arginine at codon 67 (p.Gln67Arg). After boiling the urine sample for hydrolysis, quantitative urine amino acids demonstrated a markedly elevated proline level, confirming the diagnosis. We also provide a discussion of the pathophysiology, clinical manifestations, diagnostic testing, and clinical management of this disease.

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Quantitative analysis of the natural history of prolidase deficiency: description of 17 families and systematic review of published cases

Cited by 14 publications

References 133 publications

Prolidase Deficiency Causes Spontaneous T Cell Activation and Lupus-like Autoimmunity

Prolidase Deficiency Causes Spontaneous T Cell Activation and Lupus-like Autoimmunity

Case Report: Hemophagocytic Lymphocytosis in a Patient With Glutaric Aciduria Type IIC

Prolidase deficiency: A novel PEPD missense variant in exon 2

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