Genetic Testing Leads to Improved Prognosis for Woman With Rare PAH

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by Vanda Pinto, PhD |

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Identification of mutations in the ATP13A3 gene, which are associated with a severe form of pulmonary arterial hypertension (PAH), led doctors to select a riskier treatment approach for a 21-year-old woman to prevent her symptoms from worsening, according to a case study.

“Short-term follow-up is encouraging, and the patient remains the only known surviving pediatric PAH patient with an associated biallelic ATP13A3 mutation in the literature,” the researchers wrote.

The findings support the benefits of genetic testing in helping clinicians choose the right care for distinct groups of patients.

The report, “Genetics Dictating Therapeutic Decisions in Pediatric Pulmonary Hypertension? A Case Report Suggesting We Are Getting Closer,” was published in the journal Pulmonary Circulation.

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PAH is a type of pulmonary hypertension (PH) characterized by the narrowing of the pulmonary arteries (the vessels that transport blood through the lungs) and high blood pressure. Studies have shown that genetic factors contribute to about 12.5% of PAH cases in adults, compared to about 42% of childhood-onset PH.

At least 26 genes have been associated with PAH, including the ATP13A3 gene, which contains instructions to produce a protein responsible for the transport of compounds necessary for cell growth. A recent case study of three families showed that mutations in ATP13A3 resulted in a severe inherited form of childhood-onset PAH, or cPAH. Rare mutations in both ATP13A3 gene copies (biallelic), each inherited from the mother and the father, were found to be the cause of this type of cPAH.

Now, a team of researchers at the University of California, San Francisco, and Columbia University Irving Medical Center reported a case of a woman with PAH with previously unidentified ATP13A3 mutations.

The patient had a long history of shortness of breath, or dyspnea, and also reported an episode of fainting. An echocardiogram showed enlargement of her heart’s right ventricle. Since the underlying causes were not identified, the clinicians made the diagnosis of idiopathic PAH.

Further tests confirmed severe pulmonary hypertension. Based on her clinical findings, the researchers decided to perform a balloon dilation of the patent foramen ovale, a small opening that leads to abnormal blood flow between the two upper chambers of the heart. An aggressive treatment plan was also started with several medications, such as treprostinil, bosentan (sold as Tracleer, among others), sildenafil (sold as Revatio), aspirin, as well as oxygen.

The patient’s overall health improved dramatically, reflected as a drop in the World Health Organization functional classification (WHO-FC) from IV to II (the higher the classification, the worse the patient’s condition). One year after treatment initiation, her pulmonary artery pressure and systemic arterial pressure had decreased.

However, in the following six months, her health status began to decline gradually with an increase to WHO-FC III. Pulmonary artery pressure and systemic arterial pressure values also started to rise.

Genetic screening revealed that the patient had different mutations in the two ATP13A3 gene copies. The researchers were aware of four children with biallelic ATP13A3 gene mutations who were unresponsive to aggressive PH treatments and had died. Worried that the same outcome could occur for their patient, the doctors decided to change strategy and perform a Potts procedure, a historically high-risk surgery.

During this surgery, a Potts shunt is strategically placed to connect the descending aorta, the large artery that carries blood to the body, and the left pulmonary artery. This decompresses the right ventricle and is expected to preserve its function.

“Despite her young age, the only mild worsening in her clinical status, and the normal [blood flow and heart function markers], our PH team saw this as a ‘window of opportunity’ and recommended a Potts shunt to the family,” the researchers wrote.

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The patient recovered well and at a 12-month follow-up visit, her health status was classified as WHO-FC II. However, her indexed pulmonary vascular resistance values, a measure of the resistance that blood must overcome to flow through lung vessels, was still high, as well as her pulmonary artery pressure and systemic arterial pressure.

Although the researchers suspect she may ultimately need a lung transplant evaluation, they consider her short-term follow-up encouraging.

“We speculate that an increased use of comprehensive genetic testing can aid in identifying the underlying [processes] and the expected natural history, and guide treatment plans among PAH patients,” they concluded.