Pulmonary Alveolar Microlithiasis (PAM) is a rare lung disorder where small stones form and accumulate in the air sacs of the lung. These stones cause inflammation, scarring of lung tissue and reduced respiratory ability resulting in the patient requiring supplemental oxygen.
New research from a team at the University of Cincinnati has uncovered and identified key bio-markers and a potential new therapeutic approach that could be the key in treating this rare lung disease.
A few years ago a team discovered that DNA mutations in the gene SLC34A2 caused a loss of a cellular pump which would normally remove phosphate from the air spaces in the lungs. As a result calcium and phosphate levels rise in the alveolar sacs and cause the formation of stones or microliths that invoke inflammation. Patients find that by middle-age this chronic inflammation has caused scarring and damage to the lungs and experience respiratory failure.
The team collected samples from people all over the world with help from the RDCRN programme who’s goals are to advance medical research on rare diseases by providing support for clinical studies and to facilitate collaboration and data sharing. This enables scientists from multiple disciplines at hundreds of clinical sites around the world to work together to help study more than 200 rare diseases.
They found that those with mutations in this specific gene also had elevated levels of certain serum markers. Certain cytokines and surfactant proteins were raised in line with the presence of stones in the lung, suggesting that by testing and monitoring these levels it could be a useful tool in following the disease progression and treatment responses in patients.
They also discovered that the stones dissolved easily in EDTA, a molecule used in many detergents as it binds to calcium. “Washing the lungs with an EDTA-containing solution reduced the burden of stones in air spaces,” says Dr McCormack. “This finding could translate into a therapy for humans if toxicity studies demonstrate that the approach is safe.”
A low-phosphate diet was found to prevent stone development and to even reverse lung calcification. However low phosphate levels can cause other medical problems and this approach will need to be tested in clinical trials first. Although another strategy is to utilise gene therapy and to insert a gene for a working phosphate pump back into the cells using viral vectors.
“This study demonstrates how discovering the causes of these rare lung diseases not only can inform us how the lung normally functions, but can also lead us to potential therapeutic interventions for these rare and often lethal lung diseases,” says James Kiley, PhD, Director of the Division of Lung Diseases at NHLBI.
McCormack says rare disease research can reveal surprising insights into the fundamental biology of the lung. “Studies of the PAM.. model have already revealed a potential role for phosphate in the regulation of surfactant balance in the lung and have attracted the interest of cystic fibrosis scientists interested in exploring the possible interaction between [the phosphate pump] and the defective chloride channel in that disease,” explains McCormack.
Although human trials are a few years way, UC’s research offers some hope to patients who suffer from this rare disease. Kathleen Falco, 65 from Riverhead in America shares a similar story with other patients. She was misdiagnosed with Sarcoidosis in 1977 until 2000 when they diagnosed PAM. It started to take its toll in her 40’s and a few years ago her symptoms intensified and she has shortness of breath, reduced mobility and dependency on supplemental oxygen. She cant walk, take part in outdoor activities, has lost weight and finds it hard to breathe when its hot or cold. She felt isolated, with little information and no support network or forums and eventually sort out help through the internet and was put into contact with Dr McCormack. She’s hoping that the trials will be a success and that she may be able to live out her retirement years being able to breathe a bit easier and enjoy a much improved quality of life.