Stage II: Summary Report Secondary Findings in Adults Non-diagnostic, excludes newborn screening & prenatal testing/screening Stage I Survey Update History Stage 2 Status (Adult):Complete (Actionability curation complete.)

Condition: Gaucher Disease
GENEDISEASE PAIRS: GBA230800 GBA230900 GBA231000 GBA231005 GBA608013
Narrative Description of Evidence
1. What is the nature of the threat to health for an individual carrying a deleterious allele?
Prevalence of the Genetic Disorder
Gaucher disease (GD) has a frequency of 1/40,000 in the US. Type 1 is the most common form of GC and affects 1/40,000 to 1/100,000 in the population worldwide. The disorder is panethnic, though it is most common among the Ashkenazi Jewish population, with a prevalence of 1/400 to 1/850. Types 2 and 3 are more rare and occur in less than 1/100,000 live births.
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Clinical Features
(Signs / symptoms)
GD is a lysosomal storage disorder caused by a deficiency of glucocerebrosidase which results in the multisystemic accumulation of glucosylceramide-laden macrophages (Gaucher cells) in various tissues: spleen, liver, bone marrow, bone mineral, and less often the lungs, skin, eyes, kidneys, lymphatic system, and heart. Clinical manifestations and symptoms include hepatosplenomegaly, abdominal discomfort, bone pain, anemia, fatigue, thrombocytopenia, excessive bleeding, increased risk of infections, cardiovascular complications, and pulmonary disease. Some forms of GD include neuronal involvement. GD consists of a continuum of clinical findings from a perinatal lethal disorder to an asymptomatic type. However, there are three broad clinical types:
• Type 1 (non-neuronopathic form) accounts for 95% of cases. It is characterized by bone disease, hepatosplenomegaly, thrombocytopenia, anemia, and pulmonary disease.
• Type 2 (acute neuropathic form) accounts for 1% of cases. It is the most severe form and is associated with systemic toxicity, hepatosplenomegaly, thrombocytopenia, anemia, pulmonary disease, and dermatologic changes. Primary neurological involvement is severe and can include bulbar signs, pyramidal signs, and cognitive impairment. A perinatal-lethal subtype is associated with ichthyosiform or collodion skin abnormalities and nonimmune hydrops fetalis.
• Type 3 (chronic neuropathic form) accounts for 4% of cases. It is associated with bone disease, hepatosplenomegaly, thrombocytopenia, anemia, and pulmonary disease. Primary neurological involvement is minimal and can include oculomotor apraxia, seizures, and progressive myoclonic epilepsy. A cardiovascular subtype is characterized by calcification of the aortic and mitral valves, mild splenomegaly, corneal opacities, and supranuclear ophthalmoplegia.
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Natural History
(Important subgroups & survival / recovery)
GD is a progressive disorder whose natural course and extent of disease is highly variable. Clinical presentation, age at onset, and disease course can vary by clinical type:
• Type 1 affects children and adults at any age, with an average age of diagnosis of 20. Some patients are asymptomatic. Clinical presentation and disease progression vary and survival may be normal depending on the severity of complications. In general, clinical manifestations presenting in the 1st or 2nd decades of life are typically more aggressive and progress to greater severity than those manifesting at a later stage in life. Bone disease is typically the most painful and debilitating aspect of Type 1. Among a cohort of 2876 patients with Type 1 GD, life expectancy was estimated as 68 years, 9 years earlier than the reference population. Splenectomized patients had a life expectancy of 64 years, earlier than nonsplenectomized at 72 years.
• Type 2 typically has onset before age 2 years (sometimes in utero) and a rapidly progressive course with death by age 2 to 4 years, typically due to lung failure.
• Type 3 typically has onset before age 2 for systemic involvement, but the neurological involvement may manifest at any age. It has a more slowly progressive course than Type 2 with survival into the 3rd or 4th decade.
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2. How effective are interventions for preventing harm?
Information on the effectiveness of the recommendations below was not provided unless otherwise stated.
Patient Management
Patients with GD should be regularly monitored and treated by a multidisciplinary team with expertise in treating GD to assess disease course and effects of therapy. (Tier 2)
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Enzyme replacement therapy (ERT) with recombinant glucocerebrosidase (e.g., imiglucerase) is the current standard of care for symptomatic patients with GD Types 1 and 3, but has little effect on the course of patients with Type 2 disease and is not recommended.
• To initiate ERT in Type 1, at least 2 of the following manifestations must be present: hepatic, splenic (or prior splenectomy), cardiac, pulmonary, or renal compromise; anemia; low levels of platelets; pain or bone crisis; active bone disease; and impaired quality of life.
• All patients with Type 3 GD should be given ERT as soon as possible after diagnosis.
• ERT is effective in improving hematological and visceral manifestations, reducing bone marrow burden, and improvement in overall quality of life. Clinical improvement of asthenia, abdominal pain, and bone pain occurs after 3 to 6 months. Reduction in hepatomegaly and splenomegaly is noted after 1-2 years and continues to be stabilized for 3-4 years. Response of bone anomalies occurs after 3-4 years.
• Some manifestations are irreversible and do not respond to ERT: fibrous splenomegaly, secondary osteoarthritis, osteofibrosis, osteonecrosis, deformities due to vertebral compression, hepatic fibrosis, lung fibrosis, and lytic lesions. However, timely initiation of ERT can prevent these manifestations.
• There is currently no evidence that ERT reverses, prevents, or slows neurological progression in patients with Type 3 GD. (Tier 2)
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Pregnancy can exacerbate GD by worsening of thrombocytopenia and coagulation disorders and the onset of bone pain, especially for women who have not yet received ERT or whose manifestations are not controlled by treatment. The question of pregnancy and its possible outcomes should be discussed with women of childbearing age and, whenever possible, pregnancy in women with GD must be anticipated. Therapeutic goals should be achieved before considering a pregnancy. After delivery, women should be monitored for infection, bleeding, appearance of bone crises, and bone rarefaction. (Tier 2)
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Following the initial diagnosis, all patients with GD (from asymptomatic to severely affected) should undergo the following assessments to establish the baseline disease characteristics, determine candidacy for treatment, and develop therapeutic goals and a monitoring strategy. Patients should continue to undergo regular monitoring to assess the course of the disease. The frequency of assessments varies by guideline and may be adjusted according to disease progression.:
• Comprehensive medical history of patient and family, including a family pedigree
• Comprehensive physical examination
• Clinical evaluations: assessment for anemia/thrombocytopenia; hepatosplenomegaly ocular, pulmonary, cardiac, and skeletal pathology; and asthenia
• Biochemical markers: glucocerebrosidase, chitotriosidase, ACE, and TRAP
• Laboratory evaluations: general hematology and coagulation screens; liver function tests; thyroid/parathyroid panel; vitamin D level; inflammation, HIV, and hepatitis; baseline for antibodies to ERT
• Patients predicted to have neuronopathic GD should also undergo assessment of neurological impairment
• Quality of life questionnaire. (Tier 2)
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Family Management
Genetic counseling and carrier testing is important for families with a history of GD and should include patients and their parents, siblings, children, and spouses. Screening for GD in spouses may only useful in the case of consanguinity or if the spouse is of Ashkenazi origin. (Tier 2)
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Circumstances to Avoid
Nonsteroidal anti-inflammatory drugs (NSAIDs) should be avoided in individuals with moderate to severe thrombocytopenia. (Tier 3)
3. What is the chance that this threat will materialize?
Mode of Inheritance
Autosomal Recessive
Prevalence of Genetic Mutations
The Ashkenazi Jewish population is estimated to have a carrier frequency of 1/18. Estimates of prevalence in other populations were not available. Given that a GBA mutation is detected in 99% of clinically diagnosed patients with GD and the prevalence of GD is 1/40,000 in the US, then the carrier frequency can be estimated as 1/100. (Tier 4)
Relative Risk
(Include any high risk racial or ethnic subgroups)
Type 1:
Splenomegaly: 90-95%
Hepatomegaly: 80%
Bone disease: 70-100%. (Tier 4)
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Information on relative risk was not available.
GD is characterized by variable clinical expression and severity. Even patients with the same genotype, including siblings and monozygotic twins, may show distinct patterns of disease. (Tier 3)
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4. What is the Nature of the Intervention?
Nature of Intervention
Surveillance recommendations are extensive and likely involve multiple providers, which could be burdensome to the patient. ERT with imiglucerase has demonstrated an excellent safety profile in patients with GD, and is generally well tolerated. Adverse reactions are generally mild to moderate and do not prevent ongoing treatment. Roughly 15% of patients develop antibodies to imiglucerase, increasing the risk of hypersensitivity to the product. Significant events that result in the discontinuation of treatment (e.g., anaphylaxis) are rare. (Tier 3)
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5. Would the underlying risk or condition escape detection prior to harm in the settting of recommended care?
Chance to Escape Clinical Detection
Almost 25% of patients with Type 1 GD do not gain timely access to therapy because of delays in diagnosis after the onset of symptoms. The rarity of the disease and nonspecific and heterogeneous nature of GD symptoms may impede consideration of this disease in the differential diagnosis. (Tier 4)

Final Consensus Scores
Outcome / Intervention Pair
Nature of the
Prevention of major manifestations (including hepatosplenomegaly, pancytopenia, and bone disease) / Surveillance and initiation of ERT
To see the scoring key, please go to:
Description of sources of evidence:
Tier 1: Evidence from a systematic review, or a meta-analysis or clinical practice guideline clearly based on a systematic review.
Tier 2: Evidence from clinical practice guidelines or broad-based expert consensus with non-systematic evidence review.
Tier 3: Evidence from another source with non-systematic review of evidence with primary literature cited.
Tier 4: Evidence from another source with non-systematic review of evidence with no citations to primary data sources.
Tier 5: Evidence from a non-systematically identified source.
Reference List
1. Cox TM, Aerts JM, Belmatoug N, Cappellini MD, vom Dahl S, Goldblatt J, Grabowski GA, Hollak CE, Hwu P, Maas M, Martins AM, Mistry PK, Pastores GM, Tylki-Szymanska A, Yee J, Weinreb N. 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. (2008) 31(3):319-36.
2. Mistry PK, Cappellini MD, Lukina E, Ozsan H, Mach Pascual S, Rosenbaum H, Helena Solano M, Spigelman Z, Villarrubia J, Watman NP, Massenkeil G. A reappraisal of gaucher disease-diagnosis and disease management algorithms. Am J Hematol. (2011) 86(1):110-5.
3. Vellodi A, Tylki-Szymanska A, Davies EH, Kolodny E, Bembi B, Collin-Histed T, Mengel E, Erikson A, Schiffmann R. Management of neuronopathic gaucher disease: revised recommendations. J Inherit Metab Dis. (2009) 32(5):660-4.
4. Martins AM, Valadares ER, Porta G, Coelho J, Semionato Filho J, Pianovski MA, Kerstenetzky MS, Montoril Mde F, Aranda PC, Pires RF, Mota RM, Bortolheiro TC. Recommendations on diagnosis, treatment, and monitoring for gaucher disease. J Pediatr. (2009) 155(4 Suppl):S10-8.
5. GM Pastores, DA Hughes. Gaucher disease. 2000 Jul 27 [Updated 2015 Feb 26]. In: RA Pagon, MP Adam, HH Ardinger, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2018. Available from:
6. Wang RY, Bodamer OA, Watson MS, Wilcox WR. Lysosomal storage diseases: diagnostic confirmation and management of presymptomatic individuals. Genet Med. (2011) 13(5):457-84.
7. Bhengu L, Davidson A, du Toit P, Gerntholtz T, Govendragaloo K, Heitner R, Henderson B, Mubaiwa L, Varughese S. South african guidelines for the management of gaucher disease, 2011. S Afr Med J. (2012) 102(8):697-702.
8. Gaucher disease national diagnosis and treatment protocol. Publisher: Haute Autorite de Sante.. (2007) Website:
9. Weinreb NJ, Aggio MC, Andersson HC, Andria G, Charrow J, Clarke JT, Erikson A, Giraldo P, Goldblatt J, Hollak C, Ida H, Kaplan P, Kolodny EH, Mistry P, Pastores GM, Pires R, Prakash-Cheng A, Rosenbloom BE, Scott CR, Sobreira E, Tylki-Szymanska A, Vellodi A, vom Dahl S, Wappner RS, Zimran A. Gaucher disease type 1: revised recommendations on evaluations and monitoring for adult patients. Semin Hematol. (2004) 41(4 Suppl 5):15-22.
10. Weinreb NJ, Deegan P, Kacena KA, Mistry P, Pastores GM, Velentgas P, vom Dahl S. Life expectancy in gaucher disease type 1. Am J Hematol. (2008) 83(12):896-900.
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