Prolidase Deficiency May Cause Combined Pulmonary Fibrosis and Emphysema Syndrome in Adulthood, Case Study Suggests

Prolidase deficiency, an inherited enzymatic disease, may cause combined pulmonary fibrosis and emphysema (CPFE) syndrome in adulthood, a case study suggests.

The report, “Prolidase deficiency: a new genetic cause of combined pulmonary fibrosis and emphysema syndrome in the adult,” was published in the European Respiratory Journal.

CPFE is a clinical syndrome characterized by pulmonary fibrosis and emphysema (damage of the air sacs, causing shortness of breath), which usually affects male smokers. The disorder is associated with poorer outcomes, and a higher mortality risk than either disease alone.

People with CPFE typically have impaired diffusing capacity of the lung for carbon monoxide (%DLCO) — a test of the lungs’ capacity to transfer oxygen from the air sacs into the blood — but preserved forced expiratory volume in one second (FEV1) and forced vital capacity (FVC), two measures of the air volume that can be forcefully exhaled. However, results of these lung function tests may vary in these patients, challenging the CFPE diagnosis process.

While its underlying mechanisms remain largely unknown, CPFE may be the result of predisposing genetic factors and environmental triggers (such as smoking), research suggests.

In the study, researchers in France report the case of a Portuguese man with prolidase deficiency who developed CPFE later in his adulthood, suggesting a potential association between the two disorders.

Prolidase deficiency is a rare metabolic disorder caused by mutations in the PEPD gene, which lead to an impaired production of the prolidase enzyme. Prolidase is responsible for dividing dipeptides (molecules composed of two amino acids, the building blocks of proteins) containing the amino acid proline, freeing it and making it available for producing proteins needed by the body.

Disease symptoms, which can vary greatly among patients, usually appear during infancy. Symptoms may include skin lesions, recurrent respiratory infections, unusual facial features, intellectual disability, and enlargement of the spleen and/or liver (with elevated levels of liver enzymes).

The study reports the case of a 22-year-old man who was first referred to the hospital due to digital clubbing — a condition in which the finger and nail take on the appearance of an upside-down spoon — since he was 12. He smoked 20 cigarettes a day since age 13, and had no history of inherited diseases in his family.

The patient had enlargement of the liver and spleen, and showed signs of lung disease, mildly impaired lung function, and shortness of breath when exercising.

One year later, his lung function had declined, and a lung biopsy showed a non-usual interstitial pneumonia pattern of pulmonary fibrosis, inflammation, and signs of potential emphysema.

After some misdiagnoses (including overlapping rheumatoid arthritis and systemic lupus), the presence of high levels of dipeptides suggested prolidase deficiency, which was confirmed by the detection of a previously reported disease-causing PEPD mutation. The patient also showed symptoms consistent with the disease, including skin lesions, facial dysmorphism, intellectual problems, and enlargement of liver and spleen.

The man was advised to quit smoking, and was treated with corticosteroids (to manage lung inflammation), along with oral supplementation with vitamin C, proline, and essential amino acids (to control his prolidase deficiency).

However, he continued smoking for 11 years and his lung function declined further, with severe airflow obstruction and air trapping. During this period, the patient was admitted to the hospital several times for lower airway infections.

He then started supplemental oxygen therapy and non-invasive ventilation.

At the last follow-up, 17 years after the first visit (16 years after his lung biopsy), the patient’s lung function was profoundly impaired, with low values on DLCO, FEV1, and FVC.

Chest computed tomography scans showed progression of pulmonary fibrosis over the first 10 years of follow-up. After that, fibrosis became less pronounced, while emphysema progressed considerably, which the researchers noted was likely the cause of the patient’s chronic respiratory insufficiency.

The imaging features were consistent with CPFE, but the patient’s lung function progression was not characteristic of the syndrome, the researchers said. While the mechanisms behind pulmonary fibrosis and emphysema in prolidase deficiency remain unclear, tobacco smoking may have contributed to their development.

Overall, the researchers suggested “that prolidase deficiency is a genetic factor that may contribute to pulmonary fibrosis and potentially emphysema.”