Advertisement

Journal of Inherited Metabolic Disease

, Volume 34, Issue 3, pp 643–650 | Cite as

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

  • Sarah Michelman Lo
  • Jun Liu
  • F. Chen
  • G. M. Pastores
  • J. Knowles
  • M. Boxer
  • Kirk Aleck
  • Pramod K. Mistry
Rapid Communication

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.

Keywords

Pulmonary Arterial Hypertension Genetic Modifier Enzyme Replacement Therapy Gauche Disease Hereditary Hemorrhagic Telangiectasia 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Abbreviations

ERT

Enzyme replacement therapy

GD

Gaucher disease

GD1

Type 1 Gaucher disease

HPS

Hepatopulmonary syndrome

PAH

Pulmonary arterial hypertension

RVSP

Right ventricular systolic pressure

SSI

Severity Score Index

Notes

Acknowledgments

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).

References

  1. Austin ED, Loyd JE (2007) Genetics and mediators in pulmonary arterial hypertension. Clin Chest Med 28(1):43–57, vii-viiiPubMedCrossRefGoogle Scholar
  2. Choi M, Scholl UI, Ji W et al. (2009) Genetic diagnosis by whole exome capture and massively parallel DNA sequencing. Proc Natl Acad Sci USA 106(45):19096–19101PubMedCrossRefGoogle Scholar
  3. Cox TM, Aerts JM, Belmatoug N et al. (2008) Management of non-neuronopathic Gaucher disease with special reference to pregnancy, splenectomy, bisphosphonate therapy, use of biomarkers and bone disease monitoring. J Inherit Metab Dis 31(3):319–36, Epub 2008 May 23. ReviewPubMedCrossRefGoogle Scholar
  4. Dawson A, Elias DJ, Rubenson D et al. (1996) Pulmonary hypertension developing after alglucerase therapy in two patients with type 1 Gaucher disease complicated by the hepatopulmonary syndrome. Ann Intern Med 125(11):901–904PubMedGoogle Scholar
  5. Elleder M (2006) Glucosylceramide transfer from lysosomes–the missing link in molecular pathology of glucosylceramidase deficiency: a hypothesis based on existing data. J Inherit Metab Dis 29(6):707–715PubMedCrossRefGoogle Scholar
  6. Elstein D, Klutstein MW, Lahad A et al. (1998) Echocardiographic assessment of pulmonary hypertension in Gaucher’s disease. Lancet 351:1544–1546PubMedCrossRefGoogle Scholar
  7. Grabowski GA (2008) Phenotype, diagnosis, and treatment of Gaucher’s disease. Lancet 372(9645):1263–1271PubMedCrossRefGoogle Scholar
  8. Grabowski GA, Kolodyny EH, Weinreb NJ, et al. (2006) Gaucher disease: phenotypic and genetic variation. In: Schriver CR, Beaudet AL, Sly WS, et al. (eds.) The Online Metabolic and Molecular Basis of Inherited Diseases (ww.ommbid.com). McGraw-Hill, New York, Ch 146.1Google Scholar
  9. Hůlková H, Poupetová H, Harzer K et al. (2010) Abnormal nonstoring capillary endothelium: a novel feature of Gaucher disease. Ultrastructural study of dermal capillaries. J Inherit Metab Dis 33(1):69–78PubMedCrossRefGoogle Scholar
  10. Humbert M, Morrell N, Archer S et al. (2004) Cellular and molecular pathobiology of pulmonary arterial hypertension. J Am Coll Cardiol 43(12 Suppl S):13S–24SPubMedCrossRefGoogle Scholar
  11. Lachmann RH, Wight DG, Lomas DJ et al. (2000) Massive hepatic fibrosis in Gaucher’s disease: clinico-pathological and radiological features. QJM 93(4):237–244PubMedCrossRefGoogle Scholar
  12. Lee RE, Yousem SA (1988) The frequency and type of lung involvement in patients with Gaucher’s disease. Lab Invest 58:54AGoogle Scholar
  13. Lee S, Shroyer K, Markham N, Cool C, Voelkel N, Tuder R (1998) Monoclonal endothelial cell proliferation is present in primary but not secondary pulmonary hypertension. J Clin Invest 101:927–934PubMedCrossRefGoogle Scholar
  14. Lo SM, Stein P, Mullaly S et al. (2010) Expanding spectrum of the association between Type 1 Gaucher disease and cancers: a series of patients with up to 3 sequential cancers of multiple types–correlation with genotype and phenotype. Am J Hematol 85(5):340–5PubMedGoogle Scholar
  15. Loyd JE, Atkinson JB, Pietra GG et al. (1988) Heterogeneity of pathologic lesions in familial primary pulmonary hypertension. Am Rev Respir Dis 138(4):952–957PubMedGoogle Scholar
  16. Loyd JE, Butler MD, Foroud TM et al. (1998) Genetic anticipation and abnormal gender ratio at birth in familial primary pulmonary hypertension. Am J Respir Crit Care Med 152:93–97Google Scholar
  17. Mistry PK, Wraight EP, Cox TM (1996) Therapeutic delivery of proteins to macrophages: implications for treatment of Gaucher’s disease. Lancet 348(9041):1555–1559PubMedCrossRefGoogle Scholar
  18. Mistry PK, Sirrs S, Chan A et al. (2002) Pulmonary hypertension in type 1 Gaucher’s disease: genetic and epigenetic determinants of phenotype and response to therapy. Mol Genet Metab 77:91–98PubMedCrossRefGoogle Scholar
  19. Mistry PK, Cappellini MD, Lukina E et al. (2010) A reappraisal of Gaucher disease-diagnosis and disease management algorithms. Am J HematolGoogle Scholar
  20. Mistry PK, Liu J, Yang M et al. (2010b) Glucocerebrosidase gene-deficient mouse recapitulates Gaucher disease displaying cellular and molecular dysregulation beyond the macrophage. Proc Natl Acad Sci USA 107(45):19473–19478PubMedCrossRefGoogle Scholar
  21. Möller T, Leren TP, Eiklid KL et al. (2010) A novel BMPR2 gene mutation associated with exercise-induced pulmonary hypertension in septal defects. Scand Cardiovasc J 44(6):331–336PubMedCrossRefGoogle Scholar
  22. Morse JH (2002) Bone morphogenetic protein receptor 2 mutations in pulmonary hypertension. Chest 121(3 Suppl):50S–53SPubMedCrossRefGoogle Scholar
  23. Newman JH, Phillips JA 3rd, Loyd JE (2008) Narrative review: the enigma of pulmonary arterial hypertension: new insights from genetic studies. Ann Intern Med 148(4):278–283PubMedGoogle Scholar
  24. Roberts WC, Fredrickson DS (1967) Gaucher’s disease of the lung causing severe pulmonary hypertension with associated acute recurrent pericarditis. Circulation 35:783–789PubMedGoogle Scholar
  25. Rodriguez-Roisin R, Krowka MJ (1994) Is severe arterial hypoxaemia due to hepatic disease an indication for liver transplantation? A new therapeutic approach. Eur Respir J 7:839–842PubMedGoogle Scholar
  26. Ross DJ, Spira S, Buchbinder NA (1997) Gaucher Cells in pulmonary-capillary blood in association with pulmonary hypertension. N Engl J Med 336:379–381PubMedCrossRefGoogle Scholar
  27. Smith RL, Hutchins GM, Sack GH Jr, Ridolfi RL (1978) Unusual cardiac, renal and pulmonary involvement in Gaucher’s disease. Interstitial glucocerebroside accumulation, pulmonary hypertension and fatal bone marrow embolization. Am J Med 65:352–360PubMedCrossRefGoogle Scholar
  28. Taddei TH, Kacena KA, Yang M et al. (2009) The underrecognized progressive nature of N370S Gaucher disease and assessment of cancer risk. Am J Hematol 84(4):208–214PubMedCrossRefGoogle Scholar
  29. Tayebi N, Cushner S, Sidransky E (1996) Differentiation of the glucocerebrosidase gene from pseudogene by long-template PCR: implications for Gaucher disease. Am J Hum Genet 59:740–741PubMedGoogle Scholar
  30. Thachil J (2009) The enigma of pulmonary hypertension after splenectomy – does the megakaryocyte provide a clue? QJM 102(10):743–5, Epub 2009 Jul 21PubMedCrossRefGoogle Scholar
  31. Theise ND, Ursell PC (1990) Pulmonary hypertension and Gaucher’s disease: logical association or mere coincidence? Am J Pediatr Hematol Oncol 12:74–76PubMedCrossRefGoogle Scholar
  32. Yeager M, Halley G, Golpon H, Voelkel N, Tuder R (2001) Microsatellite instability of endothelial cell growth and apoptosis genes within plexiform lesions in primary pulmonary hypertension. Circ Res 88:E2–E11PubMedGoogle Scholar
  33. Zimran A, Kay A, Gelbart T et al. (1992) Gaucher disease: clinical, laboratory radiologic and genetic features of 53 patients. Medicine 71:337–353PubMedCrossRefGoogle Scholar

Copyright information

© SSIEM and Springer 2011

Authors and Affiliations

  • Sarah Michelman Lo
    • 1
  • Jun Liu
    • 2
  • F. Chen
    • 3
  • G. M. Pastores
    • 4
  • J. Knowles
    • 5
  • M. Boxer
    • 6
  • Kirk Aleck
    • 7
  • Pramod K. Mistry
    • 8
  1. 1.Section of Hematology-Oncology, Department of PediatricsYale University School of MedicineNew HavenUSA
  2. 2.Department of Pediatrics, Section of Gastroenterology and HepatologyYale University School of MedicineNew HavenUSA
  3. 3.Section of Digestive Diseases, Department of Internal MedicineYale University School of MedicineNew HavenUSA
  4. 4.Department of NeurologyNew York University School of MedicineNew YorkUSA
  5. 5.Department of Psychiatry, Keck School of MedicineUniversity of Southern CaliforniaLos AngelesUSA
  6. 6.U.S. OncologyTucsonUSA
  7. 7.St. Joseph’s Hospital and Medical CenterPhoenixUSA
  8. 8.Departments of Pediatrics and Internal Medicine, Section of Pediatric Hepatology and GastroenterologyYale University School of MedicineNew HavenUSA

Personalised recommendations