A case report of ‘Two-Hit’ digenic mutations in PAH: role of PADN in management

TL;DR

A 47-year-old woman with PAH caused by two rare gene mutations showed significant improvement after targeted therapy and pulmonary artery denervation.

Contribution

This is one of the rare cases of PAH caused by digenic mutations in FLNA and MMACHC, with successful treatment using PAH-specific therapy and PADN.

Findings

The patient had digenic mutations in FLNA and MMACHC, contributing to PAH.

Symptoms improved significantly over 2 years with targeted therapy and PADN.

The case emphasizes the value of genetic screening and personalized treatment in PAH.

Abstract

Pulmonary arterial hypertension (PAH) is a severe cardiopulmonary disorder characterized by progressive elevation of pulmonary vascular resistance, resulting to right ventricular dysfunction and premature mortality. Although genetic mutations are increasingly recognized in PAH pathogenesis, cases involving digenic mutations remain exceptionally rare.

We report the case of a 47-year-old female presenting with a 5-year history of exertional dyspnea, which progressively worsened over the preceding 2 months. Diagnostic imaging revealed pulmonary artery dilatation and right heart enlargement, and right heart catheterization confirmed PAH with a mean pulmonary arterial pressure of 43 mmHg. Whole exome sequencing identified a novel heterozygous mutation in FLNA (c.4754C>T, p.Thr1585Met) and a known heterozygous mutation in MMACHC (c.609G>A, p.Trp203Ter). The patient was initiated on PAH-specific therapy and pulmonary artery denervation (PADN) treatment. Over a 2-year follow-up period, her symptoms significantly improved, with no evidence of heart failure progression.

This case highlights a rare instance of PAH associated with digenic mutations in FLNA and MMACHC. The patient demonstrated a favorable response to targeted PAH therapy and PADN treatment, highlighting the importance of genetic screening and personalized treatment strategies in PAH management.

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