Are You Confident of the Diagnosis?
What you should be alert for in the history
Gaucher disease (GD), an autosomal recessive lysosomal storage disorder, is classified into three major clinical subtypes: type1 GD (non-neuronopathic), type 2 GD (acute neuronopathic), and type 3 GD (subacute neuronopathic).
Type 1 GD is differentiated from types 2 and 3 by the absence of primary neurologic involvement. The presentation of type 1 GD varies greatly, with some patients developing symptoms and coming to medical attention in early childhood, while other patients remain asymptomatic throughout life.
Characteristic findings on physical examination
Commonly reported symptoms of GD include easy bruising or bleeding, bone or joint pain, and fatigue. Types 2 and 3 GD have neurological involvement as well, and may present with psychomotor retardation, oculomotor apraxia, and hypertonia.
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Characteristic findings are summarized in Table I.
Table I.
| System | Manifestation |
| Skeletal | Marrow infiltration, Erlenmeyer flask deformity, lytic lesions, bone infarcts, avascular necrosis and low bone density |
| Visceral | Hepatosplenomegaly |
| Hematologic | Cytopenias and acquired coagulation factor abnormalities |
| Pulmonary | Pulmonary hypertension, alveolar and interstitial lung disease |
| Immunologic | Polyclonal or monoclonal gammopathy |
| Metabolic | Low total and high-density lipoprotein (HDL) cholesterol, high ferritin, elevated chitotriosidase and angiotensin converting enzyme levels* |
| Neurologic | Types 2 and 3 disease: Psychomotor retardation, opisthotonus, oculomotor apraxia, retroflexion, spasticity |
| Cardiovascular | Homozygosity for the D409H mutation confers an atypical phenotype with valvular calcification |
| Dermatological | Petechiae, easy bruising, brownish pigmented spots; ichthyosis or collodion skin in acute neuronopathic cases |
*Biomarkers for GD
Dermatological symptoms of GD are rare and non-specific, but can include brown or yellowish-brown pigmented spots on the skin or eyes, and a tendency for easy tanning. Polyps may be present in the colon or maxillary sinus. Perinatal or neonatal cases of acute neuronopathic GD may present with severe neonatal ichthyosis or collodion skin, arthrogryposis, and facial dysmorphy.
Expected results of diagnostic studies
A diagnosis of Gaucher disease can be made through enzyme analysis of acid β-glucosidase activity. Affected individuals will have activity that is markedly decreased to less than 10% of normal mean activity. Enzyme activity does not differentiate the subtypes or predict disease severity.
Genetic testing of five common mutations of the GBA gene (N370S, L444P, 84GG, IVS2+1, R496H) detects GD mutations in over 95% of affected patients of Ashkenazi Jewish (AJ) descent, and approximately 50%-60% of GD patients of other ancestry. Sequencing of the GBA gene is available, with a 98% mutation detection rate.
Diagnosis confirmation
The differential diagnosis includes:
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-Lysosomal storage diseases and mucopolysaccharidosis: hepatosplenomegaly, which is seen in Gaucher disease, is present in other lysosomal storage diseases, including types A and B Niemann-Pick disease and the mucopolysaccharidoses types I, II, III, VI, and VII. The presence of other clinical features, as well as biochemical testing, distinguishes these.
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-Saposin C deficiency: Patients with saposin C deficiency can present with symptoms similar to severe neuronopathic Gaucher disease. They have normal acid β-glucosidase activity.
Who is at Risk for Developing this Disease?
Gaucher disease can affect individuals of any ethnic background, although type 1 GD is most prevalent in the AJ population, with a carrier frequency of approximately 1 in 15 and disease prevalence in that population of about 1 in 900. There is less data available on the frequency of GD in non-AJ populations, but estimates range from approximately 1 in 60,000 to 1 in 100,000. Founder mutations have been identified in Spanish, Portuguese, Swedish, Arab, Greek, and Albanian populations.
The three forms of Gaucher disease are summarized in Table II.
Table II.
| Clinical features | Non-neuronopathic (type 1) | Acute neuronopathic (type 2) | Sub-acute neuronopathic (type 3) |
| Onset | Childhood/adulthood | Infancy | Childhood |
| Visceral involvement | + | + | + |
| Hematological abnormalities | + | + | + |
| Bone disease | + | _ | + |
| Neurodegenerative course | _ | +++ | ++ (progressive) |
| Survival (years) | 6-80 | <2 | 20-40 |
| Frequency | 1:40,000-60,000 | <1:100,000 | <1:100,000 |
| Ethnicity (ethnic predilection) | Pan-ethnic (Ashkenazi Jewish) | Pan-ethnic | Pan-ethnic (Norbottnian, Polish, Jenin Arab population) |
What is the Cause of the Disease?
Etiology
GD is an autosomal recessive disorder caused by mutations in the GBA gene. These mutations result in deficient activity of acid-β-glucosidase, a lysosomal enzyme responsible for the breakdown of glucosylceramide (GL-1) into glucose and ceramide. This deficiency leads to a buildup of GL-1, primarily in the monocyte-macrophage cells of the liver, spleen and bone marrow.
Pathophysiology
Clinical manifestations include hepatosplenomegaly, anemia, thrombocytopenia, and bone disease. Types 2 and 3 GD also exhibit neurologic involvement. Type 2 is characterized by onset of neurologic involvement before age two, and a rapid disease progression with death usually occurring by age four, while type 3 is characterized by a slower neuronopathic disease progression with individuals living into their thirties or forties .
Dermatologic manifestations may be caused by insufficient levels of ceramide as a result of deficient acid-β-glucosidase, leading to abnormalities in the epidermal permeability barrier.
Systemic Implications and Complications
GD can result in anemia, thrombocytopenia, splenomegaly, and bone disease including osteopenia and osteoporosis. Thrombocytopenia may result from hypersplenism or marrow infiltration and may be associated with easy bruising or bleeding. Anemia results from hypersplenism, or iron or B12 deficiency. GD patients can also have acquired coagulation factor abnormalities and abnormal platelet aggregation.
Splenomegaly is commonly seen in GD patients and the spleen can be significantly enlarged. Massive splenomegaly may result in abdominal discomfort or fullness. Hepatomegaly is commonly seen, although cirrhosis or liver failure is rare.
Bone disease in Gaucher is often debilitating and can result in acute or chronic bone pain, avascular necrosis, pathologic fractures, and joint collapse. Patients may be asymptomatic and still have osteopenia or osteoporosis. Growth retardation can be seen in symptomatic children with GD.
GD patients may have lung involvement, primarily in the form of interstitial lung disease or pulmonary hypertension. Severe pulmonary hypertension is more commonly seen in splenectomized patients.
Patients may also have polyclonal or monocloncal gammopathy and other immunoglobulin abnormalities. GD can also result in elevation of angiotensin-converting enzyme, chitotriosidase, CCL18, ferritin, and tartrate-resistant acid phosphotase. HDL cholesterol levels are typically low. Patients also have an increased risk for multiple myeloma and hematologic malignancies. Although the pathophysiology is still unclear, GD patients appear to be at increased risk for Parkinson disease.
Treatment Options
SYMPTOMATIC TREATMENT
Joint replacement may be required to address joint damage or limited range of motion. Analgesics may be used for pain management. Osteopenia or osteoporosis may be treated with bisphosphonates and calcium and vitamin D supplementation. Anemia and thrombocytopenia may be treated with transfusion of blood products; in the past, partial or total splenectomy may have been used for severe pancytopenia, but currently available treatment options have made it rare.
Current standard of care is enzyme replacement therapy, as described below.
SYSTEMIC TREATMENT OPTIONS
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– Enzyme replacement therapy
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– Substrate reduction therapy
Optimal Therapeutic Approach for this Disease
ENZYME REPLACEMENT THERAPY (ERT)
Administration of exogenous recombinant enzyme provides safe and effective therapy. ERT, available as either imiglucerase or velaglucerase, acts by reducing the accumulated GL-1 substrate.
Imiglucerase, FDA-approved since 1993, has been shown to reduce hepatosplenomegaly, improve hematologic counts, and increase bone density, as well as decrease the frequency of bone pain and bone crises. Velaglucerase was FDA-approved in 2010, and there is less data on long-term effects. Both imiglucerase and velaglucerase are administered intravenously, with a recommended dose ranging from 15-60 units/kg every two weeks.
Taliglucerase, another form of ERT, is available through clinical trials and is not yet FDA-approved.
SUBSTRATE REDUCTION THERAPY (SRT)
The principle of substrate reduction therapy is to reduce the rate of GL-1 synthesis to offset the catabolic defect and to restore metabolic balance. Miglustat is the only FDA-approved form of SRT currently available, and it is recommended only for those patients with type 1 GD in whom ERT is not an option. Other forms of SRT are currently in clinical trials.
Patient Management
Once the diagnosis of GD has been made, type 1 and type 3 GD patients should receive a baseline exam, followed by annual evaluations to monitor disease severity and progression, regardless of symptoms. Type 2 GD should be evaluated monthly, or as otherwise required.
Baseline examination should include a physical exam and detailed family history.
Laboratory tests should be performed to measure hematologic indices, cholesterol profile, liver function , iron indices, and GD biomarkers (chitotriosidase, angiotensin-converting enzyme, tartrate-resistant acid phosphatase, and CCL18).
Radiologic studies such as magnetic resonance imaging (MRI) or computed tomography (CT) of the abdomen should be performed to estimate liver and spleen volumes, and MRI of the femurs should be done to detect infarcts and monitor bone marrow infiltration.
X-rays should be taken to measure children’s bone age, and to detect lytic lesions or Erlenmeyer flask deformity, and dual-emission x-ray absorptiometry (DXA) should be used to assess bone mineral density.
Older patients should also be monitored for manifestations of Parkinson disease. For patients with type 2 or type 3 GD, neurological evaluation including electroencephalogram, MRI of the brain, and neuropsychometric testing are also recommended.
GD is a progressive disease that requires a “watchful waiting” approach to monitoring. Many patients report no symptoms, and disease manifestations may be apparent only through laboratory or imaging studies, underscoring the importance of regular evaluation. While ERT can reverse many of the effects of GD (e.g. hematologic and visceral involvement), certain skeletal manifestations are irreversible, and it is thus important to begin treatment before such conditions develop.
The question of when to initiate treatment depends upon the results of annual evaluations and the impact of symptoms on a patient’s quality of life. While ERT, requiring biweekly infusions, can have a large impact on a patient’s lifestyle, the risks involved are otherwise small, limited mainly to the possibility of infusion-related reactions. Because the neurodegenerative course of type 2 GD is so severe, dermatologic manifestations are typically not treated. Dermatologic symptoms in type 1 GD are benign and require no specialized therapy.
Unusual Clinical Scenarios to Consider in Patient Management
Because GD is a genetic disease, there are implications for a patient’s family. Parents of an affected patient are obligate carriers of a GBA mutation; likewise, all children of an affected patient will carry at least one GBA mutation. Siblings of an affected patient have a 25% chance of being affected themselves; if not affected, they have a 67% chance of being a GD carrier.
Partners of GD patients planning a pregnancy should be screened for GD mutations to determine carrier status. Because of the high carrier frequency of GD, it is not uncommon to see affected individuals in multiple generations of a family (unusual for an autosomal recessive disease), giving the inheritance pattern a pseudodominant appearance.
What is the Evidence?
Grabowski, G, Petsko, G, Kolodny, E, Scriver, CR, Sly, WS, Childs, B, Beaudet, AL, Valle, D, Kinzler, KW. “Gaucher disease”. The online metabolic and molecular bases of inherited disease. 2000. (Overview of Gaucher disease, including molecular basis, mutations and prevalence, symptoms, and treatment.)
Charrow, J, Andersson, HC, Kaplan, P. “The Gaucher registry: demographics and disease characteristics of 1698 patients with Gaucher disease”. Arch Intern Med. vol. 160. 2000. pp. 2835-43. (Describes the demographic and clinical characteristics of Gaucher disease patients prior to receiving enzyme replacement therapy)
Weinreb, NJ. “International collaborative Gaucher group (ICGG)”. vol. 5. 2004. pp. 15-22. (Updated consensus on minimum recommendations for effective monitoring of adult type 1 GD patients)
Vellodi. “Management of neuronopathic Gaucher disease: revised recommendations”. J Inherit Metab Dis. vol. 32. 2009. pp. 660-4. (Review of recommendations for evaluation of type 2 and type 3 GD patients)
Weinreb, NJ. “Effectiveness of enzyme replacement therapy in 1028 patients with type 1 Gaucher disease after 2 to 5 years of treatment: a report from the Gaucher registry”. Am J Med. vol. 113. 2002. pp. 112-9. (Effectiveness of imiglucerase in treatment of GD)
Platt, FM, Jeyakumar, M. “Substrate reduction therapy”. Acta Paediatr Suppl. vol. 97. 2008. pp. 88-93. (Substrate reduction therapy in treatment of GD)
Elstein, D. “Early achievement and maintenance of the therapeutic goals using velaglucerase alfa in type 1 Gaucher disease”. Blood Cells Mol Dis. vol. 46. 2010. pp. 119-23. (Effectiveness of velaglucerase in treatment of GD)
Pastores, G, Hughes, D. “Gaucher disease”. (Review of Gaucher disease, including availability of genetic testing and enzyme analysis)
Holleran, W, Ziegler, S, Goker-Alpan, O, Eblan, M, Elias, P, Schiffman, R, Sidransky, E. “Skin abnormalities as an early predictor of neurologic outcome in Gaucher disease”. Clin Genet. vol. 69. 2006. pp. 355-7. (Case report of infant with type 2 GD presenting prenatally with skin abnormalities)
Stone, D, Carey, W, Christodoulou, J, Sillence, D, Nelson, P, Callahan, M. “Type 2 Gaucher disease: the collodion baby phenotype revisited”. Arch Dis Child Fetal Neonatal Ed. vol. 82. 2000. pp. F163-6. (Review of case reports of type 2 GD presenting with congenital ichthyosis)
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