Recognising a rare condition that mimics common blood disorders: a case study of Gaucher disease

Thursday, 6 May 2021

Gaucher disease (GD) is a condition where fat-laden cells accumulate in the spleen, liver, and bone marrow, resulting in a progressive multisystem disorder.1 GD is treatable, and many patients can achieve a normal life, especially when therapy is initiated early.2 However, its status as a rare disease means that GD is not on most physicians’ radar, even when they encounter patients with typical symptoms. Factors that further delay the diagnosis of GD include the variability of clinical presentation, the presence of nonspecific symptoms, and the overlap of common presenting symptoms with acute blood disorders or malignancies.2,3 In this article, Professor Jeff Szer, a well-known Australian GD physician and researcher, presents a case study to highlight key signs that can help to identify patients with GD and demonstrate the importance of ongoing management.

What is Gaucher disease?

Although designated a rare disease, GD is one of the most common lysosomal storage disorders, affecting approximately 1 in 40 000 to 1 in 80 000 in the general population. It has a higher prevalence in Ashkenazi Jewish populations of around 1 in 850.4,5 In Australia, there are around 100 patients with diagnosed GD being treated by a handful of specialists, with most physicians treating only one patient.

Autosomal recessive mutations in the GBA1 gene cause deficient activity of the lysosomal enzyme glucocerebrosidase, resulting in the accumulation of lipids in lysosomes of macrophages. These lipid-laden macrophages, called ‘Gaucher cells’, build up in visceral organs, primarily the spleen and liver, and in bone marrow, causing multisystem disease with diverse clinical manifestations.1,6

Complex genetics lead to diverse and variable clinical phenotypes

The genetics of GD is highly complex, with over 400 mutations identified to date, including recombination events with a highly homologous pseudogene.6,7 While some mutations are associated with neurologic involvement and disease severity, the genotypic-phenotypic correlations are not reliably prognostic, as even siblings who share a common genotype can exhibit different presenting symptoms, disease course, and treatment response.6,7 Despite this limitation, identifying a patient’s genotype is important for helping to guide therapeutic decisions and disease monitoring intervals.2

The clinical presentation of GD encompasses a broad range of signs and symptoms, with GD usually classified into 3 subtypes according to age of onset and whether neurologic involvement is present.1,5,6 Type 1 (GD1) accounts for >90% of cases and is the least severe form, presenting at any age with typical visceral and bone manifestations but without neurologic involvement.1,5,6 Neurologic manifestations are present in type 2 (GD2) and type 3 (GD3) and are termed the neuronopathic forms of GD. GD3 typically presents in early childhood with a milder neurologic phenotype and variable systemic symptoms, which slowly progress over time. GD type 2 is the rarest and most severe form, presenting in newborns or in early infancy with rapidly progressing and fatal neurologic and systemic disease.1,6

Identifying patients for diagnostic testing is challenging but important

The heterogeneity of clinical presentation, as well as the substantial overlap of early disease-specific symptoms with haematologic disorders or malignancies, make identifying patients with GD challenging.3 Many patients with GD are referred to haematologists or oncologists, but only 1 in 5 of these specialists would consider GD type 1 in their differential diagnosis of a patient presenting with the typical visceral and haematologic manifestations of GD1.8 Delays between symptom onset and diagnosis are common, with a definitive diagnosis taking at least 5 to 7 years in 1 in 6 patients and up to 26 years in some patients.3,8,9 Early diagnosis is vital to ensure timely initiation of disease-specific treatment.10 Delayed treatment can lead to irreversible but preventable complications (e.g., avascular necrosis, bone pain, liver abnormalities, life-threatening bleeding) that result in worse outcomes and prognosis, and reduced quality of life.3,8,9 Preventing irreversible bone complications is particularly important, as these manifestations have the greatest effect on patients’ quality of life.2,11



Diagnosis and early disease course

A 7-year-old  boy, born in 1975 to European Ashkenazi Jewish parents, presented with bone pain. Upon evaluation, splenomegaly was identified, and he was diagnosed with Gaucher disease type 1.

From ages 10 to 18 years, he experienced episodes of severe bone pain in his legs about once a year. These episodes impaired his mobility for about 3 days and required hospitalisation and opiates.

At age 22 years, he was referred to a specialist for treatment after splenomegaly and hepatomegaly were identified. His spleen and liver were both palpable 7 cm below the costal margins, with splenic volume estimated to be approximately 10 times greater than normal and liver volume 2.5 times greater. Laboratory tests showed the presence of thrombocytopenia but not anaemia. Radiography revealed bone changes in the lower limbs. Disease-specific treatment was not initiated at this stage.

At age 24 years, disease progression was evident, with worsening splenomegaly (spleen now palpable 10 cm below costal margins), low platelet count, and severe bone changes. Genetic analysis was performed, identifying a compound heterozygote N370S/84GG mutation. The patient met the eligibility criteria for reimbursed treatment via the Life Saving Drugs Program, and  enzyme replacement therapy (ERT) was initiated at a dose of 30 units/kg/2 weeks.

Initial response to treatment

After 2 years of treatment, the patient’s  hepatomegaly was completely resolved. Spleen size was greatly reduced, with splenomegaly resolving completely after 4 years of treatment. Platelet count normalised within 1.5 years of ERT. Glucosylsphingosine (a GD-specific biomarker) was reduced from 1230 nmol/mL before starting ERT to 160 nmol/mL at 1.5 years; however, levels remained over 10 times the upper limit of normal (10 nmol/mL) throughout the patient’s treatment. Routine annual MRI showed slow improvement in the bone manifestations in his lumbar spine and femur.

Ongoing monitoring and management

ERT dose reduction to 15 units/kg/2 weeks was required in 2009 to 2010 for about 12 months. No change in the patient’s biomarkers, platelet count, or MRI findings occurred.

At age 40, the patient’s ERT dose was increased to 60 units/kg/2 weeks, due to his glucosylsphingosine level remaining high at 170 nmol/mL.

In 2016 (aged 41), asymptomatic avascular necrosis of the femoral head was detected by routine annual MRI, and treated successfully with a core decompression procedure. At this time, his glucosylsphingosine level had decreased to 100 nmol/mL.

Current status

In 2020, the patient was asymptomatic with a glucosylsphingosine level of 70 nmol/mL, and continuing on high-dose ERT.


Recognising key features of early GD

The most common presenting symptoms of GD1 are splenomegaly, hepatomegaly, thrombocytopenia, anaemia, and bone pain, with patients most frequently reporting abdominal distension, moderate to severe bleeding, and bone pain as their first symptoms,3,6 as demonstrated by the case study presented. Children with GD often experience growth retardation and delayed puberty, while other manifestations of GD can include hyperferritinaemia, gammopathy, and less commonly, pulmonary disease.3,6 While bone manifestations can be asymptomatic, they often present as diffuse bone pain with intermittent bone crises that can cause avascular necrosis and joint collapse,6,11 as in the case study presented. Low bone mineral density resulting from Gaucher cells infiltrating the bone marrow can lead to osteolytic lesions, bony infarctions, and increased risk for fractures.6,11

The Gaucher Earlier Diagnosis Consensus initiative recently published major clinical signs and contributing variables suggestive of early GD to help guide physicians identify patients with possible GD.4 As well as recognising the key clinical signs, physicians should also consider GD in patients with Ashkenazi Jewish ancestry or a family history of GD or Parkinson disease (PD).4,10



Major clinical signs

  • Splenomegaly
  • Thrombocytopenia
  • Anaemia
  • Hepatomegaly
  • Bone pain, crises, avascular necrosis, or fractures
  • Hyperferritinaemia
  • Gammopathy

Neurologic signs in patients with GD3

  • Disturbed oculomotor function
  • Myoclonus epilepsy
  • Disturbed motor function

Other contributing factors

  • Ashkenazi Jewish ancestry
  • Family history of GD or PD


Diagnosing GD

Diagnosis of GD requires demonstration of reduced glucocerebrosidase enzyme activity, typically in leukocytes, mononuclear cells, or fibroblasts, which is then confirmed through molecular analysis of the GBA1 gene. Dried blood spots (DBS) have recently been validated as a reliable and convenient source to perform enzymatic and molecular diagnostic testing.2,5,10 A recent study has demonstrated the utility of a DBS enzyme test to screen adults presenting with unexplained splenomegaly and/or thrombocytopenia associated with other haematologic signs, diagnosing GD in over 3% of the study population of 455, and identifying that lower platelet counts and higher serum ferritin levels could reliably differentiate those patients with GD.12

Treatment of GD

The introduction of enzyme replacement therapy (ERT) has made GD a highly treatable condition, particularly when initiated early, improving clinical outcomes, prognosis, and quality of life for patients with GD1 and GD3.7 ERT infusions contain an enzyme with glucocerebrosidase activity (imiglucerase, velaglucerase alfa and taliglucerase are available in Australia via the Life saving Drugs Program) to increase the breakdown of lipids that have accumulated in the macrophage lysosomes.1 ERT typically results in significant decreases in spleen and liver size and improvements in platelet counts and haemoglobin levels after 6 months of treatment.1,2 While ERT improves growth rate in children and some bone manifestations, it does not help treat more progressive bone complications, nor any neurologic features present in patients with GD2 or GD3.2,11

For adults with GD1 unable or unwilling to receive ERT infusions, orally administered substrate reduction therapy (SRT) improves visceral and haematologic symptoms by reducing the production of the lipid targeted by the deficient enzyme.1,2,5

When managing patients with GD, treatment goals focus on normalising haematologic values, eliminating or reducing signs and symptoms and preventing complications of visceral and bone disease, as well as improving patients’ quality of life and general well-being.1 Early detection of common long-term complications or associated diseases, such as malignancies, PD, insulin resistance, and diabetes, is also a key part of management.1

Ongoing monitoring is essential

Regular ongoing monitoring of haematologic, visceral, and bone parameters, as well as evaluating quality of life, are necessary to assess response to treatment and identify any progression or complications early.5,10 As demonstrated in the case study presented, routine imaging is essential, as progression of bone disease can often occur despite effective control of other disease manifestations, and may be completely asymptomatic.11 In addition, patients can often maintain stable disease activity even when they experience significant manifestations.10 In Australia, routine annual monitoring is also a requirement for continued subsidisation of treatment costs through the Life Saving Drugs Program.

While a number of plasma biomarkers are used to diagnose GD and monitor disease activity, glucosylsphingosine has emerged as the most sensitive and specific.2 Levels of glucosylsphingosine are highly elevated in plasma and visceral tissues from all patients with GD, and are particularly high in patients with neuronopathic disease.6 Evidence shows that glucosylsphingosine is a reliable biomarker for diagnosis and disease monitoring, and perhaps for prognostication. It can be reliably quantified in plasma and DBS and reflects therapeutic responses.13

Awareness is key to timely diagnosis of GD

When evaluating patients with symptoms of splenomegaly, thrombocytopenia, or bone pain, always include GD in your differential diagnosis.4 Timely diagnosis of GD leads to improved management of patients. Treating patients with GD is immensely gratifying because ERT can be highly effective, particularly when initiated before irreversible bone manifestations develop. Treatment is limited to fortnightly infusions, allowing these patients to live a normal life.2 A DBS is a simple first step to identify possible GD, potentially saving your patient years of misdiagnoses, a multitude of specialist visits and unnecessary invasive tests, and delays in accessing the appropriate treatment to help reduce systemic manifestations and prevent irreversible complications.3,8



  1. Biegstraaten M, et al. Management goals for type 1 Gaucher disease: An expert consensus document from the European working group on Gaucher disease. Blood Cells Mol Dis. 2018;68:203-208.
  2. Revel-Vilk S, et al. How we manage Gaucher Disease in the era of choices. Br J Haematol. 2018;182(4):467-480.
  3. Mehta A, et al. Exploring the patient journey to diagnosis of Gaucher disease from the perspective of 212 patients with Gaucher disease and 16 Gaucher expert physicians. Mol Genet Metab. 2017;122(3):122-129.
  4. Mehta A, et al. Presenting signs and patient co-variables in Gaucher disease: outcome of the Gaucher Earlier Diagnosis Consensus (GED-C) Delphi initiative. Intern Med J. 2019;49(5):578-591.
  5. Peters H, et al. Treatable lysosomal storage diseases in the advent of disease-specific therapy. Intern Med J. 2020;50 Suppl 4:5-27.
  6. Hughes D, Sidransky E. Gaucher disease: Pathogenesis, clinical manifestations, and diagnosis. In: UpToDate. Hahn S (Ed). UpToDate, Waltham, MA, 2021.
  7. Gary SE, et al. Recent advances in the diagnosis and management of Gaucher disease. Expert Rev Endocrinol Metab. 2018;13(2):107-118.
  8. Mistry PK, et al. 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.
  9. Thomas AS, et al. Diagnosing Gaucher disease: an on-going need for increased awareness amongst haematologists. Blood Cells Mol Dis. 2013;50(3):212-217.
  10. Zimran A, et al. A patient with Gaucher disease and plasma cell dyscrasia: bidirectional impact. Hematology Am Soc Hematol Educ Program. 2020;2020(1):389-394.
  11. Hughes D, et al. Gaucher Disease in bone: from pathophysiology to practice. J Bone Miner Res. 2019;34(6):996-1013.
  12. Motta I, et al. Predicting the probability of Gaucher disease in subjects with splenomegaly and thrombocytopenia. Sci Rep. 2021;11(1):2594.
  13. Revel-Vilk S, et al. Value of glucosylsphingosine (Lyso-Gb1) as a biomarker in Gaucher disease: A systematic literature review. Int J Mol Sci. 2020;21(19):7159.

Sponsored by sanofi-aventis australia pty ltd trading as Sanofi Genzyme,  Macquarie Park, NSW 2113. MAT-AU-2100341. April 2021.

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