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Pediatr Endocrinol Rev. Author manuscript; available in PMC 2015 July 30. Published in final edited form as: Pediatr Endocrinol Rev. 2014 September ; 12(0 1): 72–81.
Gaucher Disease: The Metabolic Defect, Pathophysiology, Phenotypes And Natural History Hagit N. Baris, M.D.1, Ian J. Cohen, M.B., Ch.B.1, and Pramod K. Mistry, M.B., B.S., Ph.D., F.R.C.P.2 1Gaucher
Clinic, Raphael Recanati Genetic Institute, Rabin Medical Center, Beilinson Hospital, Petah Tikva, Israel, and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
Author Manuscript
2Department
of Medicine and Pediatrics, Yale Lysosomal Disease Center, Yale School of Medicine, New Haven, Connecticut, USA
Abstract
Author Manuscript
Gaucher disease (GD), a prototype lysosomal storage disorder, results from inherited deficiency of lysosomal glucocerebrosidase due to biallelic mutations in GBA. The result is widespread accumulation of macrophages engorged with predominantly lysosomal glucocerebroside. A complex multisystem phenotype arises involving the liver, spleen, bone marrow and occasionally the lungs in type 1 Gaucher disease; in neuronopathic fulminant type 2 and chronic type 3 disease there is in addition progressive neurodegenerative disease. Manifestations of Gaucher disease type 1 (GD1) include hepatosplenomegaly, cytopenia, a complex pattern of bone involvement with avascular osteonecrosis (AVN), osteoporosis, fractures and lytic lesions. Enzyme replacement therapy became the standard of care in 1991, and this has transformed the natural history of GD1. This article reviews the clinical phenotypes of GD, diagnosis, pathophysiology and its natural history. A subsequent chapter discusses the treatment options.
Keywords Gaucher disease; Lysosomal storage disorder; GBA; neuronopathic Gaucher disease; Ashkenazi Jews; bone disease; enzyme therapy
Introduction Author Manuscript
Gaucher disease (GD) is one of the most frequent lysosomal disorders with a prevalence of 1:50,000 in the general population, but as high as 1 in 850 in the Ashkenazi Jewish (AJ) population.(1,2) Philippe Charles Ernest Gaucher’s MD thesis of 1882 annotated a previously unreported disorder in which he described abnormal histiocytes in the tissues of a
Corresponding author: Hagit Baris, M.D., The Raphael Recanati Genetic Institute Rabin Medical Center, Beilinson Hospital, Petah Tikva, 49100, Israel; Tel: +972-3-9377659; [email protected]. Disclosure The authors declare no conflict of interest. Hagit N. Baris Ian J. Cohen Pramod K. Mistry
Baris et al.
Page 2
Author Manuscript
32 year-old woman who died of cachexia and massive hepatosplenomegaly. (3) Gaucher concluded that his patient suffered from a neoplasm of the spleen. To this day, malignancy is often the first diagnosis considered when a patient presents with the classic clinical signs of Gaucher disease.(4)
Author Manuscript
The eponym “Gaucher Disease” was introduced by Mandlebaum.(5) It was recognized as a multi-systemic chronic disease involving the liver, spleen, bone marrow and lymph nodes with familial aggregation. A similar systemic disease associated with rapidly progressive neurodegenerative disease (Gaucher disease Type 2) was first described in 1927, (6) followed, in 1959, by a report of a less rapidly progressive neurodegenerative disease (Gaucher disease type 3) in the Norrbottnian region of Northern Sweden.(7) In 1965 Roscoe Brady and his colleagues at the NIH unraveled the metabolic defect in Gaucher disease as an inherited deficiency of lysosomal glucocerebrosidase,(8) followed more than a quarter of a century later by the ultimate realization of enzyme replacement therapy by the same group. (9)
Author Manuscript
Three forms of the disease have been recognized based on age of onset, clinical signs and presence and rate of progression or absence of neurological disease. These are classified as Gaucher disease type 1 (GD1), which is characterized by splenomegaly, blood disorders, orthopedic complications and lack of neurological symptoms; Gaucher disease type 2 (GD2), characterized by hepatosplenomegaly and central nervous system involvement within the first year of life, and Gaucher disease type 3 (GD3), with nervous system involvement in childhood. These three forms of the disease share the same defect in the enzyme glucocerebrosidase and present a continuum of clinical picture; however, the distinct subtypes help in treatment decision-making.(10,11) It also became apparent that GD1 is especially prevalent in people of Ashkenazi Jewish (AJ) ancestry.(12)
The Pathogenetic Basis of GD
Author Manuscript
The eponymous Gaucher cells (foamy macrophages) seen on bone marrow aspirate and in other tissues represent macrophages engorged with glucosylceramide (GL1)-laden lysosomes.(13,14) They are characteristic of, but not exclusive to, Gaucher disease since many lipid-laden macrophages have a similar appearance that can sometimes be misleading in making the diagnosis. Gaucher cells have the appearance of signet rings with ‘wrinkled tissue paper’ because the nucleus is pushed to the periphery of the cells by the massive accumulation of glucocerebroside structures in the lysosomal system.(Figure 1) Widespread accumulation of these storage cells underlies the multisystemic manifestations of Gaucher disease involving the liver, spleen, bone marrow, and occasionally the lungs.(15) Lysosomal lipids spill over into the cytoplasm. By pathways that are not fully understood, but which may involve ceramidase, glucosylceramide is converted into glucosylsphingosine (Lyso GL1). Serum levels of glucosylceramide are elevated some 5 to 10 -fold, but there is massive elevation of glucosylsphingosine to >100 fold and lyso GL1 is by far the most prevalent plasma sphingolipid. There is accumulating evidence that Lyso GL1 and its downstream lipids mediate the widespread cellular dysfunction seen in Gaucher disease.(16) Massive generation of these bioactive lipids from the macrophage system engages other cell types in the pathophysiology; in particular, there is prominent involvement of the immune
Pediatr Endocrinol Rev. Author manuscript; available in PMC 2015 July 30.
Baris et al.
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system indicated by hypercytokinemia, reflecting both the innate and adaptive immune systems as well as osteoblast dysfunction that may contribute to osteopenia by osteoblastosteoclast regulation uncoupling.(17) Mesenchymal stem cells in Gaucher disease have a decreased capacity to differentiate into osteoclasts.(18) Although the Gaucher cell is the epicenter of disease pathophysiology and generator of bioactive lipids, the amount of GL1 that accumulates in massively enlarged organs such as the spleen of GD patients is
Pediatr Endocrinol Rev. Author manuscript; available in PMC 2015 July 30. Published in final edited form as: Pediatr Endocrinol Rev. 2014 September ; 12(0 1): 72–81.
Gaucher Disease: The Metabolic Defect, Pathophysiology, Phenotypes And Natural History Hagit N. Baris, M.D.1, Ian J. Cohen, M.B., Ch.B.1, and Pramod K. Mistry, M.B., B.S., Ph.D., F.R.C.P.2 1Gaucher
Clinic, Raphael Recanati Genetic Institute, Rabin Medical Center, Beilinson Hospital, Petah Tikva, Israel, and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
Author Manuscript
2Department
of Medicine and Pediatrics, Yale Lysosomal Disease Center, Yale School of Medicine, New Haven, Connecticut, USA
Abstract
Author Manuscript
Gaucher disease (GD), a prototype lysosomal storage disorder, results from inherited deficiency of lysosomal glucocerebrosidase due to biallelic mutations in GBA. The result is widespread accumulation of macrophages engorged with predominantly lysosomal glucocerebroside. A complex multisystem phenotype arises involving the liver, spleen, bone marrow and occasionally the lungs in type 1 Gaucher disease; in neuronopathic fulminant type 2 and chronic type 3 disease there is in addition progressive neurodegenerative disease. Manifestations of Gaucher disease type 1 (GD1) include hepatosplenomegaly, cytopenia, a complex pattern of bone involvement with avascular osteonecrosis (AVN), osteoporosis, fractures and lytic lesions. Enzyme replacement therapy became the standard of care in 1991, and this has transformed the natural history of GD1. This article reviews the clinical phenotypes of GD, diagnosis, pathophysiology and its natural history. A subsequent chapter discusses the treatment options.
Keywords Gaucher disease; Lysosomal storage disorder; GBA; neuronopathic Gaucher disease; Ashkenazi Jews; bone disease; enzyme therapy
Introduction Author Manuscript
Gaucher disease (GD) is one of the most frequent lysosomal disorders with a prevalence of 1:50,000 in the general population, but as high as 1 in 850 in the Ashkenazi Jewish (AJ) population.(1,2) Philippe Charles Ernest Gaucher’s MD thesis of 1882 annotated a previously unreported disorder in which he described abnormal histiocytes in the tissues of a
Corresponding author: Hagit Baris, M.D., The Raphael Recanati Genetic Institute Rabin Medical Center, Beilinson Hospital, Petah Tikva, 49100, Israel; Tel: +972-3-9377659; [email protected]. Disclosure The authors declare no conflict of interest. Hagit N. Baris Ian J. Cohen Pramod K. Mistry
Baris et al.
Page 2
Author Manuscript
32 year-old woman who died of cachexia and massive hepatosplenomegaly. (3) Gaucher concluded that his patient suffered from a neoplasm of the spleen. To this day, malignancy is often the first diagnosis considered when a patient presents with the classic clinical signs of Gaucher disease.(4)
Author Manuscript
The eponym “Gaucher Disease” was introduced by Mandlebaum.(5) It was recognized as a multi-systemic chronic disease involving the liver, spleen, bone marrow and lymph nodes with familial aggregation. A similar systemic disease associated with rapidly progressive neurodegenerative disease (Gaucher disease Type 2) was first described in 1927, (6) followed, in 1959, by a report of a less rapidly progressive neurodegenerative disease (Gaucher disease type 3) in the Norrbottnian region of Northern Sweden.(7) In 1965 Roscoe Brady and his colleagues at the NIH unraveled the metabolic defect in Gaucher disease as an inherited deficiency of lysosomal glucocerebrosidase,(8) followed more than a quarter of a century later by the ultimate realization of enzyme replacement therapy by the same group. (9)
Author Manuscript
Three forms of the disease have been recognized based on age of onset, clinical signs and presence and rate of progression or absence of neurological disease. These are classified as Gaucher disease type 1 (GD1), which is characterized by splenomegaly, blood disorders, orthopedic complications and lack of neurological symptoms; Gaucher disease type 2 (GD2), characterized by hepatosplenomegaly and central nervous system involvement within the first year of life, and Gaucher disease type 3 (GD3), with nervous system involvement in childhood. These three forms of the disease share the same defect in the enzyme glucocerebrosidase and present a continuum of clinical picture; however, the distinct subtypes help in treatment decision-making.(10,11) It also became apparent that GD1 is especially prevalent in people of Ashkenazi Jewish (AJ) ancestry.(12)
The Pathogenetic Basis of GD
Author Manuscript
The eponymous Gaucher cells (foamy macrophages) seen on bone marrow aspirate and in other tissues represent macrophages engorged with glucosylceramide (GL1)-laden lysosomes.(13,14) They are characteristic of, but not exclusive to, Gaucher disease since many lipid-laden macrophages have a similar appearance that can sometimes be misleading in making the diagnosis. Gaucher cells have the appearance of signet rings with ‘wrinkled tissue paper’ because the nucleus is pushed to the periphery of the cells by the massive accumulation of glucocerebroside structures in the lysosomal system.(Figure 1) Widespread accumulation of these storage cells underlies the multisystemic manifestations of Gaucher disease involving the liver, spleen, bone marrow, and occasionally the lungs.(15) Lysosomal lipids spill over into the cytoplasm. By pathways that are not fully understood, but which may involve ceramidase, glucosylceramide is converted into glucosylsphingosine (Lyso GL1). Serum levels of glucosylceramide are elevated some 5 to 10 -fold, but there is massive elevation of glucosylsphingosine to >100 fold and lyso GL1 is by far the most prevalent plasma sphingolipid. There is accumulating evidence that Lyso GL1 and its downstream lipids mediate the widespread cellular dysfunction seen in Gaucher disease.(16) Massive generation of these bioactive lipids from the macrophage system engages other cell types in the pathophysiology; in particular, there is prominent involvement of the immune
Pediatr Endocrinol Rev. Author manuscript; available in PMC 2015 July 30.
Baris et al.
Page 3
Author Manuscript
system indicated by hypercytokinemia, reflecting both the innate and adaptive immune systems as well as osteoblast dysfunction that may contribute to osteopenia by osteoblastosteoclast regulation uncoupling.(17) Mesenchymal stem cells in Gaucher disease have a decreased capacity to differentiate into osteoclasts.(18) Although the Gaucher cell is the epicenter of disease pathophysiology and generator of bioactive lipids, the amount of GL1 that accumulates in massively enlarged organs such as the spleen of GD patients is
