Clinical Presentation

Gaucher disease type 1 (non-neuronopathic)

Gaucher disease type 1 has the widest variability in age of onset, rate of progression, and combination of organs affected.1 Although it is common for the first manifestations to appear in childhood, onset can occur at any age. At least half of all patients experience onset before the age of 20, but onset has been observed as late as the eighth decade of life.2

Patients may present with any combination of visceral, haematological, and skeletal manifestations. The severity of disease may differ between affected organ systems.3 A patient may have significant visceral and haematologic manifestations but mild or no skeletal manifestations, and vice versa.3

Primary central nervous system (CNS) involvement is absent and defines Gaucher disease type 1. However, neurological signs and symptoms secondary to bone disease do occur. Neurological manifestations in Gaucher disease type 1 are always distinct from those seen in neuronopathic Gaucher disease (see more in Clinical manifestations by organ system).4

Gaucher disease type 1 is usually clearly distinct from neuronopathic forms when CNS involvement has been excluded using an appropriate array of assessments. However, when Gaucher disease presents in childhood, type 3 may be misdiagnosed at type 1. This is because the same systemic manifestations occur in both subtypes and the neurological manifestations of Gaucher disease type 3 may not be apparent early in the disease course. Beyond childhood, most patients with type 3 disease will have developed neurological manifestations and therefore the designation of Gaucher disease type 1 is clearer.2

 In general, rapidly progressive disease with severe involvement of visceral organs is more likely to occur in patients with earlier onset than in patients with later onset of signs and symptoms that become overt in adulthood.5 Disease-specific treatment can be effective in slowing down the visceral and haematologic manifestations of the disease.1

Comorbidities in Gaucher disease type 1

Cancer

Gaucher disease has been linked to the development of haematological malignancies including multiple myeloma, acute lymphoblastic leukaemia, chronic lymphocytic leukaemia, acute myelogenous leukaemia, chronic myelogenous leukaemia, Hodgkin’s disease, and non-Hodgkin’s lymphoma.6 Multiple myeloma and monoclonal gammopathies of undetermined significance, a precursor to multiple myeloma, are particularly prevalent.6 In a registry study of 2742 Gaucher disease type 1 patients, the incidence of multiple myeloma was 6 times higher than in an age- and gender-matched general population.7 The increased risk of cancer appears to become significant after age 40. The contribution of multiple myeloma  to mortality in Gaucher disease type 1 patients is unclear.8

With the exception of multiple myeloma, current data suggests that patients with Gaucher disease type 1 do not have an increased risk of developing other cancers such as breast, prostate, colon and rectum, lung, and haematologic malignancies.6,7

Parkinsonism

Glucocerebrosidase (GBA) gene mutations are an accepted risk factor for Parkinson’s disease.8 Patients with Gaucher disease type 1 are at increased risk of developing Parkinson’s disease, with a registry study showing that Parkinsonism is 6 to 17 times higher in Gaucher disease type 1 patients than in reference populations.9 The study also reported that the likelihood of an individual patient with Gaucher disease developing Parkinsonism before age 70 years is 5% to 7%.

Gaucher disease type 2

Gaucher disease type 2 is the rarest and bleakest diagnosis.10 This neuronopathic form of Gaucher disease is characterised by early onset of primary central nervous system (CNS) involvement and a drastic reduction of lifespan to a maximum of 2 years. It is the only form of Gaucher disease for which there is no consensus as to the indication of disease-specific treatment. Management is focused on supportive and palliative care.11,12  

Gaucher disease type 2 classically presents between 3 and 6 months after birth with visceral, haematologic and neurologic manifestations. Neurological decline is rapid but the manifestations vary. The neurologic manifestations are consistent with brainstem involvement and include bulbar signs and fine motor dysfunction. Oculomotor involvement is characteristic.10,12,13

An absence of bone manifestations is sometimes considered characteristic of Gaucher disease type 2.14 It is possible that bone manifestations are not appreciated in this severe form of the disease because skeletal complications of Gaucher disease are primarily long term.10,15

Gaucher disease type 3

Gaucher disease type 3 is defined by primary CNS involvement. It is distinguished from type 2 disease by a later onset of CNS involvement and slower progression of CNS manifestations.2 This is reflected in the longer lifespan (5 to 50 years) compared with patients with type 2 disease. Neurologic manifestations include abnormalities in eye movements, seizures, and intellectual deterioration.4

The same visceral, haematologic and skeletal manifestations of type 1 disease occur in Gaucher disease type 3.4

Variants of Gaucher disease subtypes

Gaucher disease represents a continuum of phenotypes arising from heterogeneous mutations of GBA gene. Thus sometimes the disease may have a clinical presentation that is not accurately described by any of the three broad subtype classifications. An example is patients with neurologic disease that is more severe than that associated with type 3 disease but with later onset than is typical of type 2 disease.4 Such presentations have been referred to as an intermediate phenotype.

Another example is a distinctive phenotype characterised by homozygosity for the D409H allele featuring impaired horizontal ocular sacchades, corneal opacities, and cardiac/aortic valvular calcification. This phenotype is consistent with type 3 disease in all other respects and has been referred to as type 3c. Other variants referred to as type 3a and type 3b have been described but the utility of these sub-classifications is limited due to overlapping presentations.4

The severest form of Gaucher disease described is lethal in utero or within hours to days after birth. Designated the classification ‘perinatal-lethal’, this phenotype is distinguished by prematurity, in utero death, nonimmune hydrops fetalis, hepatosplenomegaly, ichthyosis, arthrogryposis, and facial dysmorphy.16

Summary of Gaucher disease subtypes2,5,14

 

  Non-neuronopathic Neuronopathic
Characteristic Type 1 Type 2 Type 3
Cases > 95% 1% 2% to 3%
Age at onset Childhood/adulthood Infancy Childhood/adolescence
Hepatosplenomegaly Mild to severe Mild to severe Mild to very severe
Skeletal abnormalities Mild to severe Absent Mild to very severe
Primary CNS disease Absent Very severe Mild to severe
Haematologic abnormalities Mild to severe Severe Mild to severe
Lifespan (years) <5 to >80 Up to 2 (median 9-11 months) 5 to 50
Ethnic predilection Panethnic/Ashkenazi Jews Panethnic Panethnic/ Norrbottnian Sweden

Adapted with permission from Grabowski, G. A., Petsko GA, Kolodny EH. Gaucher Disease. In: Valle D, Beaudet AL,Vogelstein B, Kinzler KW, Antonarakis SE, Ballabio A, et al., editors. The Online Metabolic and Molecular Bases of Inherited Disease. New York, NY: McGraw-Hill; 2014.

 

 

References

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  2. 2.Grabowski GA, Zimran A, Ida H. (2015) Gaucher disease types 1 and 3: Phenotypic characterization of large populations from the ICGG Gaucher Registry. Am J Hematol 90 Suppl 1: S12-18.
  3. 3.Mistry PK, Belmatoug N, vom Dahl S, Giugliani R. (2015) Understanding the natural history of Gaucher disease. Am J Hematol 90 Suppl 1: S6-11.
  4. 4.Grabowski GA, Kolodny EH, Weinreb NJ, et al. Gaucher Disease: Phenotypic and Genetic Variation. . In: Valle D, Beaudet AL, Vogelstein B, Kinzler KW, Antonarakis SE, Ballabio A, et al., editors. New York, NY: McGraw-Hill; 2014.
  5. 5.Grabowski GA. (2004) Gaucher disease: lessons from a decade of therapy. J Pediatr 144(5 Suppl): S15-19.
  6. 6.Mistry PK, Taddei T, vom Dahl S, Rosenbloom BE. (2013) Gaucher disease and malignancy: a model for cancer pathogenesis in an inborn error of metabolism. Crit Rev Oncog 18(3): 235-246.
  7. 7.Rosenbloom BE, Weinreb NJ, Zimran A, Kacena KA, Charrow J, Ward E. (2005) Gaucher disease and cancer incidence: a study from the Gaucher Registry. Blood 105(12): 4569-4572.
  8. 8.Cox TM, Rosenbloom BE, Barker RA. (2015) Gaucher disease and comorbidities: B-cell malignancy and parkinsonism. Am J Hematol 90 Suppl 1: S25-28.
  1. 9.Rosenbloom B, Balwani M, Bronstein JM, et al. (2011) The incidence of Parkinsonism in patients with type 1 Gaucher disease: data from the ICGG Gaucher Registry. Blood Cells Mol Dis 46(1): 95-102.
  2. 10.Gupta N, Oppenheim IM, Kauvar EF, Tayebi N, Sidransky E. (2011) Type 2 Gaucher disease: phenotypic variation and genotypic heterogeneity. Blood Cells Mol Dis 46(1): 75-84.
  3. 11.Kaplan P, Baris H, De Meirleir L, et al. (2013) Revised recommendations for the management of Gaucher disease in children. Eur J Pediatr 172(4): 447-458.
  4. 12.Weiss K, Gonzalez AN, Lopez G, Pedoeim L, Groden C, Sidransky E. (2015) The clinical management of Type 2 Gaucher disease. Mol Genet Metab 114(2): 110-122.
  5. 13.Tylki-Szymanska A, Vellodi A, El-Beshlawy A, Cole JA, Kolodny E. (2010) Neuronopathic Gaucher disease: demographic and clinical features of 131 patients enrolled in the International Collaborative Gaucher Group Neurological Outcomes Subregistry. J Inherit Metab Dis 33(4): 339-346.
  6. 14.Grabowski GA. (2008) Phenotype, diagnosis, and treatment of Gaucher's disease. Lancet 372(9645): 1263-1271.
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  8. 16.Grabowski, G. A., Petsko GA, Kolodny EH. Gaucher Disease. In: Valle D, Beaudet AL, Vogelstein B, Kinzler KW, Antonarakis SE, Ballabio A, et al., editors. The Online Metabolic and Molecular Bases of Inherited Disease. New York, NY: McGraw-Hill; 2014.