Pulmonary vascular disease in Gaucher disease: clinical spectrum, determinants of phenotype and long-term outcomes of therapy
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Pulmonary arterial hypertension (PAH) and hepatopulmonary syndrome (HPS) are rare pulmonary vascular complications of type 1 Gaucher disease (GD1). We examined GBA1 genotype, spleen status, Severity Score Index (SSI), and other patient characteristics as determinants of GD/PAH-HPS phenotype. We also examined the long-term outcomes of imiglucerase enzyme replacement therapy (ERT) +/− adjuvant therapies in 14 consecutive patients. We hypothesized a role of BMPR2 and ALK1 as genetic modifiers underlying GD/PAH-HPS phenotype. Median age at diagnosis of GD1 was 5 yrs (2–22); PAH was diagnosed at median 36 yrs (22–63). There was a preponderance of females (ratio 5:2). ERT was commenced at median 36.5 yrs (16–53) and adjuvant therapy at 36 yrs (24–57). GBA1 genotype was N370S homozygous in two patients, N370S heteroallelic in 12. Median SSI was 15 (7–20). All patients had undergone splenectomy at median age 12 yrs (2–30). In three patients, HPS was the initial presentation, and PAH developed after its resolution; in these three, HPS responded dramatically to ERT. In seven patients, sequencing of the coding regions of BMPR2 and ALK1 was undertaken: 3/7 were heterozygous for BMPR2 polymorphisms; none harbored ALK1 variants. With ERT (± adjuvant therapy), 5/14 improved dramatically, five remained stable, two worsened, and two died prematurely. In this largest series of GD/PAH-HPS patients, there is preponderance of females and N370S heteroallelic GBA1 genotype. Splenectomy appears essential to development of this phenotype. In some patients, HPS precedes PAH. BMPR2 and ALK1 appear not be modifier genes for this rare phenotype of GD. ERT +/− adjuvant therapy improves prognosis of this devastating GD phenotype.
KeywordsPulmonary Arterial Hypertension Genetic Modifier Enzyme Replacement Therapy Gauche Disease Hereditary Hemorrhagic Telangiectasia
Enzyme replacement therapy
Type 1 Gaucher disease
Pulmonary arterial hypertension
Right ventricular systolic pressure
Severity Score Index
We would like to thank the patients for participating in these studies. We thank colleagues from around the US who have referred patients to us.
Contract grant sponsor
NIH T32 post-doctoral training program in investigative hematology (T32-HL07262) supported SML. PKM is supported by NIDDK K24DK066306 mid-career clinical investigator award and research support from Genzyme Corporation. The study was supported in part by a pilot project grant from the Yale Liver Center (NIDDK 3P30DK034989).
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