Pulmonary vascular disease in Gaucher disease: clinical spectrum, determinants of phenotype and long‐term outcomes of therapy

Abstract

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.

Gaucher Disease

“…Splenectomy has been associated with a higher risk of cholesterol gall stones, pulmonary complications including pulmonary hypertension, avascular necrosis of bone and iron overload states. [88][89][90][91] Neuronopathic disease-This is best managed by a pediatric Neurologist and specific drugs for myoclonus or epilepsy are needed.…”

Phenotype diversity in type 1 Gaucher disease: discovering the genetic basis of Gaucher disease/hematologic malignancy phenotype by individual genome analysis

“…4,5 Phenotype diversity manifests as variations in the overall severity of the disease, as well as in the pattern of organ involvement (eg, visceral/hematologic vs skeletal vs pulmonary involvement). 2,[6][7][8] Another category of phenotype variation in GD1 is exemplified by the occurrence of unusual manifestations such as Parkinson disease, 9 pulmonary hypertension, 10 and cancers, [11][12][13][14][15][16] which, despite their potentially life-threatening nature, appear to show imperfect correlation with the overall severity of the classic manifestations. 11,12 These observations are consistent with the notion that modifier genes may underlie these phenotypes.…”

Gaucher’s Disease, Myoclonic Seizures after Splenectomy: A Case Report

“…Splenectomy is rarely indicated for palliation for more than 15 years in Western with a higher risk of cholesterol gall stones, pulmonary complications including pulmonary hypertension, avascular necrosis of bone and iron overload states. [7][8][9][10] The patient here didn't have enough money to receive ERT at the beginning and had splenectomy 3 years ago to relieve pain. Then the disease progressed and developed myoclonic epilepsy.…”