Diagnosis of Gaucher disease commonly delayed despite effective treatments to prevent complications

Despite being the most common lysosomal storage disorder, prolonged diagnostic delays may occur in Gaucher disease resulting in disabling and life-threatening complications that are preventable or reversible when given appropriate treatment.1

Classic symptoms of Gaucher disease include cytopenia, hepatosplenomegaly and bone pain. However, few haematologist–oncologists consider Gaucher disease in their list of differential diagnoses. Instead, they favour conditions such as leukaemia, lymphoma and multiple myeloma. As a result, Gaucher disease may go undiagnosed for many years – one study reported an average of over four years elapsed from first onset of symptoms to diagnosis. A delay in diagnosing Gaucher disease can result in the development of complications, including avascular necrosis, severe bleeding, chronic bone pain, life-threatening sepsis, pathologic fractures, growth failure and/or liver pathology, which are preventable or reversible by appropriate treatment with enzyme replacement therapy.¹

Case in point

Recently, a case was presented of a 55 year old female with a history of general weakness for some months. Other than a history of longstanding effort bruising following physical work or intensive training and intermittent bilateral knee pain from the age of 15, she was otherwise well and had no significant family history.²

Physical examination did not reveal organomegaly or lymphadenopathy.²

Several investigations were ordered, including a full blood count, which revealed Hb 114 g/L, WBC 3.27 x10⁹/L and platelet count 69 x10⁹/L. Liver function tests were normal, as was the APTT result; however, INR (1.3; normal range 0.9–1.2) and ferritin (817 mg/L; normal range 20–300) values were outside the normal range. Subsequently, an abdominal CT (CT) identified a slightly enlarged spleen (13.58 x 7.95 cm) without focal lesions.²

Among the differential diagnoses were chronic idiopathic thrombocytopenic purpura and other haematological disorders, including lymphoma. Bone marrow examination revealed the presence of large cells with slightly basophilic, fibrillary cytoplasm (described as ‘crumpled tissue paper’ appearance) and eccentrically placed nuclei, which were identified as Gaucher cells.²

Gaucher cells are distended lipid-laden macrophages, which stain positive with Periofic acid-Schiff (PAS).These are the prototypical cell type of Gaucher disease.³

Gaucher disease is an autosomal recessive lysosomal storage disorder. It is characterised by a mutation in a gene encoding a lysosomal enzyme, glucocerebrosidase, required for the hydrolysis and breakdown of glycolipids.^3,4 The loss of function mutation results in the accumulation of glycolipids, primarily within the monocyte/macrophage cell lineage of the reticuloendothelial system.⁴

Clinically, there are three major subtypes of Gaucher disease, distinguished by neurological involvement and time course of the disease.⁵ Type 1 is the most frequent, affecting between 1:40,000 and 1:75,000 people worldwide. The prevalence in Australia is estimated at 1:57,000 live births.^6,7 The incidence of type 1 Gaucher disease is highest in Ashkenazi Jews, who have a disease prevalence of 1 in 855 and an estimated carrier rate of 1:14 to 1:18.^7-10 This subtype is non-neuronopathic. Symptoms typically appear in adulthood and are associated with splenomegaly and haematological complications. Typically disease progression is slow;¹¹ however, a recent study identified an association with malignant complications, in particular multiple myeloma.¹²

Subtypes 2 and 3 are rarer forms of the disease, accounting for only 10% of cases, with a disease prevalence of 1:100,000 to 1: 150,000.^7,13 Both subtypes are neuronopathic; however, type 2 Gaucher disease symptoms typically appear before the age of two, with the disease following a rapidly progressive course.¹³ Symptoms include impaired neurological development and progressive cognitive dysfunction, reflecting the extensive central nervous system involvement. Often oculomotor dysfunction presents as the first clinical symptom.⁸ Life expectancy is typically 2–4 years.¹³ In a study involving 104 infants, the average age of death reported was 11.7 months.¹⁴

Subtype 3 clinically lies between type 1 and type 2. It presents later with a more variable course than type 2, but is more severe and aggressive than type 1.⁴ Clinical signs can include progressive dementia, ataxia, myoclonus,¹⁵ supranuclear gaze palsy, corneal opacification and cardiovascular calcification.¹⁶

Over 300 mutations localised to 1q21 have been described to date. N370S, the cause of type 1 Gaucher disease, is by far the most frequent, accounting for 81% of mutant alleles in the Gaucher registry.¹⁴

Diagnostic investigations include microsopy, to identify the Gaucher cell, and biochemistry. Enzyme analysis of leukocytes for β-glucosidase activity is the definitive diagnostic investigation for Gaucher disease. β-glucocerebrosidase enzyme activity in peripheral blood leukocytes or other nucleated cells is assayed. Enzyme activity is reduced to 10–15% of normal function in the case of type 1 Gaucher disease, and 0–9% of normal function in types 2 and 3 Gaucher disease.¹⁷

In this case, a diagnosis of Gaucher disease was confirmed with low activity of glucocerebrosidase in peripheral blood leukocytes (0.02 mkat/kg protein; normal range 0.2–0.7). DNA sequencing identified a c.1226A>G (N370S) mutation in the GBA1 gene.²

Gaucher Disease Identification Tool

1. Medical History

Is the patient experiencing:

Yes	No
		Bone pain
		Fatigue
		Adynamia (lethargy, weakness)

2. Abdominal Ultrasound

Are the following pathologies present:

Yes	No
		Hepatosplenomegaly

3. Haematology review

Is there evidence of:

Yes	No
		Anaemia
		Thrombocytopaenia

4. Clinical Chemistry

Is there pathological evidence of:

Yes	No
		Elevated ferritin
		Elevated tartrate resistant acid phosphatase
		Elevated angiotensin converting enzyme

5. MRI of lower limbs

Are the following pathologies present:

Yes	No
		Is there displacement of the yellow marrow in the T1 weighted sequences?

6. Special tests

Is there pathological evidence of:

Yes	No
		Reduced β-glucocerebrosidase activity
		Elevated chitotriosidase activity

Results

If clinical suspicion persists despite an absence of symptoms related to Gaucher disease, it is important to implement a surveillance program including a regular three monthly review of symptoms.

If a patient is complaining of bone pain, fatigue and adynamia, but there is no ultrasound evidence of hepatosplenomegaly, a GP referral is required to assess alternative causes of these symptoms. A 6 monthly abdominal ultrasound review would be appropriate, unless symptomatic.

Review other causes of hepatosplenomegaly.

Review other causes of hepatosplenomegaly with cytopaenia.

Diagnosis of Gaucher disease suspected, repeat test immediately. If still negative, consider other causes of hepatosplenomegaly with cytopaenia and bone marrow involvement.

Diagnosis of Gaucher disease confirmed – begin treatment.

References:

1. Genzyme Australasia Pty Ltd.: Gaucher Disease Diagnostic Algorithm.
2. Pastores GM, Hughes DA. Gaucher Disease [online]. GeneReviews, University of Washington, Seattle. 13 March 2008 [cited 27 April 2009]. Available from URL: http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=gaucher
3. Grabowski GA, Andria G, Baldellou A, Campbell PE, Charrow J, Cohen IJ, et al. Pediatric non-neuronopathic Gaucher disease: Presentation, diagnosis and assessment. Consensus statements. Eur J Pediatr. 2004; 163(2): 58-66.
4. Zimran A, Altarescu G, Rudensky B, Abrahamov A, Elstein D. Survey of hematological aspects of Gaucher disease. Hematology. 2005; 10: 1516.
5. Cohen IJ. Bone crises in Gaucher disease. Isr Med Assoc J. 2003;5:8389.

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Go through the following questionnaire with your patient.

Treatment of Gaucher disease is based on each individual’s clinical findings. Common goals of treatment include: ^18-20

1. Reduction of symptoms;
2. Preventing irreversible damage;
3. Improved quality of life;
4. Optimisation of growth and development in children.

Enzyme replacement therapy with recombinant glucocerebrosidase, imiglucerase (Cerezyme) is indicated for patients with a confirmed diagnosis of type 1 Gaucher disease that results in one or more of the following conditions:³²

• Anaemia;
• Thrombocytopenia;
• Bone disease;
• Hepatomegaly or splenomegaly.

In Australia, reimbursed therapy is available for children who are symptomatic and adults meeting the following criteria:^19,21-22

• Haemoglobin < 105 g/L for females, and < 115 g/L for males; 
• Platelet count < 120 x 10⁹/mm³ on at least two occasions more than one month apart;
• Liver > 1.25 times normal size;
• Spleen > 5 times normal size;
• Radiologic evidence of skeletal disease beyond mild osteopenia or Erlenmeyer flask deformity.

In type 1 disease in adults, imiglucerase has the potential to correct haematological abnormalities within 6–12 months, resolve bone pain in a large numbers of patients, and can reduce organomegaly by up to 60%.^23-25 In children, its use prevents a number of complications including skeletal abnormalities later in life.¹⁸ Whilst not approved for use in type 2 and 3 disease,³² enzyme replacement has been shown to be beneficial for the alleviation of non-neurological symptoms; however, as it is unable to cross the blood–brain barrier, it has little effect on neurological disease.^8,24-26

The benefits of enzyme replacement therapy have been shown with ten year results from the International Collaborative Gaucher Group (ICGG) Gaucher Registry. The Registry was assembled in 1991 and is the largest existing source of information on the natural history of Gaucher disease and the effect of disease-specific treatment. Clinical status following ten years of treatment was available for over 750 patients with type 1 Gaucher disease. Mean haemoglobin levels and mean platelet counts rose to within normal limits after 12 months and remained steady over the ten-year period. Spleen size was reduced from a mean of 16.7 MN at treatment initiation to 10.5 MN at 12 months, and 5.4 MN at ten years. Mean liver volume was also reduced to near normal levels by the third year of treatment, and was normal at year ten.²⁵

The safety profile of imiglucerase is excellent, allowing patients the freedom of home therapy and use during pregnancy. Anti-glucocerebrosidase antibodies develop in approximately 15% of patients.²⁴

Other treatments include substrate reduction therapy,^28-29 bone marrow transplantation³⁰ and gene therapy.³¹

For more information, see Gaucher Disease.

References

1. Mistry PK, Sadan S, Yang R, Yee J, Yang M. Consequences of diagnostic delays in type 1 Gaucher disease: The need for greater awareness among hematologists-oncologists and an opportunity for early diagnosis and intervention. Am J Hematol 2007; 82(8): 697-701.
2. Machaczka M, Klimkowska M, Hägglund H. Effort bruising disclosing Gaucher disease in a 55-year-old non-Jewish woman. J Inherit Metab Dis. 2009; 32(6): 758-61.
3. Kumar V, Abbas A, Fausto N. Robbins and Cotran Pathologic Basis of Disease (7th edition). Philadelphia: Elsevier Saunders; 2005, pp 158-91.
4. Elstein D, Abrahamov A, Hadas-Halpern I, Zimran A. Gaucher’s disease. Lancet. 2001; 358(9278): 324-7.
5. Charrow J, Andersson HC, Kaplan P, Kolodny EH, Mistry P, Pastores G, et al. The Gaucher registry: Demographics and disease characteristics of 1698 patients with Gaucher disease. Arch Intern Med. 2000; 160(18): 2835-43.
6. Meikle PJ, Hopwood JJ, Clague AE, Carey WF. Prevalence of lysosomal storage disorders. JAMA. 1999; 281(3): 249-54.
7. Mehta A. Epidemiology and natural history of Gaucher’s disease. Eur J Int Med. 2006; 17(Suppl): S2-5.
8. Grabowski GA. Gaucher disease: Gene frequencies and genotype/phenotype correlations. Genet Test. 1997; 1(1): 5-12.
9. Grabowski GA. Recent clinical progress in Gaucher disease. Curr Opin Pediatr. 2005; 17(4): 519-24.
10. Zuckerman S, Lahad A, Shmueli A, Zimran A, Peleg L, Orr-Urtreger A, et al. Carrier screening for Gaucher disease: Lessons for low-penetrance, treatable diseases. JAMA. 2007; 298(11): 1329-31.
11. Beutler E. Commentary: The natural history of Gaucher disease. Blood Cells Mol Dis. 1998; 24(1): 82.
12. Taddei T, Kacena K, Yang M, Yang R, Malhotra A, Boxer M, et al. The underrecognized progressive nature of N370S Gaucher disease and assessment of cancer risk in 403 patients. Am J Hematol. 2009; 84: 208-14.
13. Sidransky E. New perspectives in type 2 Gaucher disease. Adv Pediatr. 1997; 44: 73-107.
14. Cooper D, Ball E, Stenson P, Phillips A, Howells K, Mort M. The Human Gene Mutation Database at the Institute of Medical Genetics in Cardiff [online]. Cardiff University. 2008 [cited 27 April 2009]. Available from URL: http://www.hgmd.cf.ac.uk/ac/index.php
15. Blom S, Erikson A. Gaucher disease – Norrbottnian type. Neurodevelopmental, neurological, and neurophysiological aspects. Eur J Pediatr. 1983; 140(4): 316-22.
16. Bohlega S, Kambouris M, Shahid M, Al Homsi M, Al Sous W. Gaucher disease with oculomotor apraxia and cardiovascular calcification (Gaucher type IIIC). Neurology. 2000; 54(1): 261-3.
17. Pastores GM, Hughes DA. Gaucher Disease [online]. GeneReviews, University of Washington, Seattle. 13 March 2008 [cited 27 April 2009]. Available from URL: http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=gaucher
18. Grabowski GA, Andria G, Baldellou A, Campbell PE, Charrow J, Cohen IJ, et al. Pediatric non-neuronopathic Gaucher disease: Presentation, diagnosis and assessment. Consensus statements. Eur J Pediatr. 2004; 163(2): 58-66. 
19. NIH Technology Assessment Panel on Gaucher Disease. Gaucher disease. Current issues in diagnosis and treatment. JAMA. 1996; 275(7): 548-53.
20. Pastores GM, Weinreb NJ, Aerts H, Andria G, Cox TM, Giralt M, et al. Therapeutic goals in the treatment of Gaucher disease. Semin Hematol. 2004; 41(4 Suppl 5): 4-14.
21. Weinreb NJ, Aggio MC, Andersson HC, Andria G, Charrow J, Clarke JT, et al. Gaucher disease type 1: Revised recommendations on evaluations and monitoring for adult patients. Semin Hematol. 2004; 41(4 Suppl 5): 15-22.
22. Pharmaceutical Benefits Advisory Committee. Public Summary Document: Guidelines for Treatment of Gaucher Disease by Enzyme Replacement with Imiglucerase [online]. Department of Health and Ageing, Australian Government. 13 February 2006 [cited 18 May 2009]. Available from: http://www.health.gov.au/internet/main/publishing.nsf/Content/71D15BD1EE4A4A8DCA256F85007A7F66/$File/gguidelines.pdf
23. Weinreb NJ, Charrow J, Andersson HC, Kaplan P, Kolodny EH, Mistry P, et al. 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. 2002; 113(2): 112-9.
24. Elstein D, Zimran A. Review of the safety and efficacy of imiglucerase treatment of Gaucher disease. Biologics: Targets & Therapy 2009; 407-417.
25. Weinreb NJ, vom Dahl S, Domenica M. Long-term data from the ICGC Gaucher registry: clinical parameters after ten years of treatment with Imiglucerase. Blood (ASH Annual Meeting Abstracts). 2009; 114: Abstract 3590.
26. Prows CA, Sanchez N, Daugherty C, Grabowski GA. Gaucher disease: Enzyme therapy in the acute neuronopathic variant. Am J Med Genet. 1997; 71(1): 16-21.
27. Altarescu G, Hill S, Wiggs E, Jeffries N, Kreps C, Parker CC, et al. The efficacy of enzyme replacement therapy in patients with chronic neuronopathic Gaucher’s disease. J Pediatr. 2001; 138(4): 539-47.
28. Public Summary Document: Miglustat, capsule 100 mg, Zavesca® [online]. Department of Health and Ageing, Australian Government. 18 July 2008 [cited 28 April 2009]. Available from URL: http://www.health.gov.au/internet/main/publishing.nsf/Content/pbac-psd-miglustat-mar08
29. Elstein D, Dweck A, Attias D, Hadas-Halpern I, Zevin S, Altarescu G, et al. Oral maintenance clinical trial with miglustat for type I Gaucher disease: Switch from or combination with intravenous enzyme replacement. Blood. 2007; 110(7): 2296-301.
30. Steward CG, Jarisch A. Haemopoietic stem cell transplantation for genetic disorders. Arch Dis Child. 2005; 90(12): 1259-63.
31. Enquist IB, Nilsson E, Ooka A, Månsson JE, Olsson K, Ehinger M, et al. Effective cell and gene therapy in a murine model of Gaucher disease. Proc Natl Acad Sci USA. 2006; 103(37): 13819-24.
32. Genzyme Australasia Pty Ltd. Product Information: Cerezyme Powder for Injection. North Ryde, NSW: Genzyme Australasia Pty Ltd; 14 September 2006.