Gaucher Disease


Article Author:
William Stone
Hajira Basit


Article Editor:
Samip Master


Editors In Chief:
Kranthi Sitammagari
Mayank Singhal


Managing Editors:
Avais Raja
Orawan Chaigasame
Carrie Smith
Abdul Waheed
Khalid Alsayouri
Trevor Nezwek
Radia Jamil
Patrick Le
Anoosh Zafar Gondal
Saad Nazir
William Gossman
Hassam Zulfiqar
Hussain Sajjad
Steve Bhimji
Muhammad Hashmi
John Shell
Matthew Varacallo
Heba Mahdy
Ahmad Malik
Sarosh Vaqar
Mark Pellegrini
James Hughes
Beata Beatty
Beenish Sohail
Nazia Sadiq
Hajira Basit
Phillip Hynes


Updated:
5/11/2019 2:29:40 PM

Introduction

Gaucher disease (pronounced as GO-SHEY) is an autosomal recessive inborn error of metabolism caused by mutations in the glucocerebrosidase (GBA1) gene [1]. GBA1 is an enzyme that cleaves beta-glucosidic linkage of glucocerebroside lipids. Inborn errors of metabolism are particularly relevant in pediatrics since their presentation is very often (but not always) in the neonatal period of infancy. There are five known types of Gaucher disease: type 1, type 2, type 3, perinatal lethal and cardiovascular. The perinatal lethal form is the most severe and its complications can begin before birth or in early infancy.

Knowing the major manifestations of any inborn error of metabolism is the key to making a diagnosis. Inborn errors of metabolism primarily result from the lack (or insufficient levels) of specific enzymes needed: (1) convert fat or carbohydrates to energy or to; (2) breakdown amino acids or other metabolites, allowing them to accumulate and become toxic if not treated. Gaucher disease is a “toxic accumulation” inborn error of metabolism due to the accumulation of glucocerebroside lipids. It is the most common cause of lysosomal storage diseases. Lysosomes are subcellular organelles responsible for the physiological turnover of cell constituents. Toxic accumulation inborn errors of metabolism fall into three major categories, localized toxicity, circulating toxicity or a combination of both. Gaucher disease is an example of localized toxicity.

Etiology

The underlying cause of all forms of Gaucher disease is mutations in the GBA1 gene resulting in a lysosomal deficiency of glucocerebrosidase activity. All forms of Gaucher disease lead to the toxic accumulation of glucocerebroside lipids, primarily in the liver, spleen, and bone marrow. A glucocerebroside is composed of a glucose molecule linked to the oxygen atom on carbon atom 1 of the sphingosine moiety of ceramide. All forms of Gaucher disease are also classified as lysosomal storage disorders. There are at least 40 other lysosomal storage disorders including mucopolysaccharidosis, Tay-Sachs disease, and Fabry disease [2]. All lysosomal storage disorders tend to get worse over time, in other words, they are progressive. Lysosomes are spherical intracellular organelles where many lipids and macromolecules are delivered for degradation by hydrolytic enzymes. Lysosomes are abundant in macrophages. The lysosomes in the macrophages of patients with Gaucher disease become progressively enlarged and filled with undigested glucocerebroside. The lysosomes can eventually be filled with undigested lipids that resemble “crumpled tissue paper” when visualized by electron microscopy. In the absence of appropriate treatment, the liver can expand two-fold to three-fold its normal size and the spleen by 15-fold.

Despite knowing the precise genetic causes of most forms of Gaucher disease, the exact cause remains unknown. It is possible for patients with the same mutation to have very different signs and symptoms. It is also possible for patients with similar signs and symptoms to have very different genetic mutations. Environmental factors, as well as an individual's particular genetic makeup, most likely influence the phenotypic expression of Gaucher disease.

Epidemiology

Gaucher disease is the most common autosomal recessive disease in the Ashkenazi (Eastern European) Jewish population with a carrier frequency of 6% compared to 0.7% to 0.8% of the non-Jewish population. Cystic fibrosis (4% carrier frequency) and Tay-Sachs Disease (3.7% carrier frequency) are also common in the Ashkenazi population.

The most common form of Gaucher disease is type 1 which has a very variable phenotype ranging from early childhood symptoms to no symptoms throughout life but typically does not have a neurological component. In contrast to type 1, both type 2 and 3 are rare and do affect the central nervous system. Both type 2 and the perinatal lethal typically result in neonatal death whereas type 3 results in mid to early adulthood death.

Pathophysiology

The signs and symptoms of Gaucher disease can be classified into visceral, hematologic, skeletal, and metabolic components. The visceral components include enlarged liver and spleen (hepatosplenomegaly).

Hematological components can include thrombocytopenia, anemia, and leukopenia. Cerebroside accumulation in the bone marrow is thought to decrease platelet production resulting in low platelet count. Similarly, cerebroside accumulation in the spleen is thought to result in an excessive break down of red blood cells resulting in anemia as well as more active removal of white blood cells (WBC) resulting in a low WBC count. The rapid and premature destruction of blood cells can lead to an increased risk of bleeding and infections.

The skeletal components can include bone crisis, the death of bone cells (called avascular necrosis or osteonecrosis), a low bone density compared to normal peak density, pathological bone fracture, and Erlenmeyer flask deformity. Much of these skeletal abnormalities are attributed to the buildup of glucocerebroside-laden macrophages in the bone-marrow where they restrict blood flow and the delivery nutrients and oxygen which can result in intense pain, bone cell necrosis, low bone density, and growth abnormalities.

Histopathology

Classic glycolipid-laden macrophages are found in liver biopsy and bone marrow samples.

Liver biopsy samples typically reveal glycolipid-laden Gaucher cells evident in the sinusoids, but the hepatocytes do not manifest overt glycolipid storage because of biliary excretion of glucocerebroside and because exogenous glycolipid turnover is typically handled by the mononuclear phagocytes. As hepatocytes are spared, there is a very low incidence of liver failure in individuals with Gaucher disease.

The pathologic hallmark of Gaucher disease is Gaucher cells in the macrophage-monocyte system typically found in the bone marrow. These cells have a characteristic wrinkled-paper appearance, resulting from intracytoplasmic substrate deposition, and stain positive with periodic acid–Schiff. Histologic evaluation should not be used as a primary diagnostic tool.

History and Physical

Gaucher disease can present with several signs and symptoms, depending on the underlying type. Commonly seen presenting symptoms are as follows:

  • Painless hepatomegaly and splenomegaly
  • Hypersplenism and pancytopenia
  • Severe joint pains, most frequently affecting hips and knees.
  • Impaired olfaction and cognition (Type I)
  • Serious convulsions, hypertonia, intellectual disability, and apnea (Type II)
  • Myoclonus, seizures, dementia, and ocular muscle apraxia (Type III)
  • Parkinsonism
  • Osteoporosis
  • Yellowish-brown skin pigmentation

The diagnosis of Gaucher disease depends upon finding a low GBA1 enzyme level in peripheral blood leukocytes as well as establishing the presence of mutant alleles in the GBA1 gene. Despite the fact that only a blood sample is needed to diagnosis Gaucher disease, some patients undergo unnecessary invasive bone marrow or liver biopsy before making a correct diagnosis. Physician awareness of the signs and symptoms of Gaucher disease can help avoid such mishaps. Moreover, before an accurate diagnosis is made, many patients with an enlarged liver or spleen are told they could have cancer.

Evaluation

Laboratory Studies

CBC Count

  • CBC and platelet count will access the degree of cytopenia.

Liver Function Enzyme Testing

  • Mild elevation of liver enzyme levels is common; the presence of jaundice or abnormal hepatocellular synthetic function merits further study.

Coagulation

  • Regular monitoring should be performed.

Enzyme Activity

  • Diagnosis is confirmed through measurement of glucocerebrosidase activity in peripheral blood leukocytes. Less than 15% of mean normal activity is diagnostic.

Genotype Testing

  • Molecular diagnosis is often helpful in Ashkenazi patients, in whom 6 GBA1 mutations (c.84insG, L444P, N370S,  IVS2+1g>a, V394L, and R496H) account for most disease alleles.
  • In some ethnicities, sequencing of the exons of GBA1 may be necessary in order to establish the genotype.
  • Mutation analysis has limited predictive value with respect to Gaucher disease progression. Avoid relying on PCR-based tests for individual mutations because they do not reveal the presence of recombinant alleles associated with greater severity of the disease.

Associated Marker Testing

  • Angiotensin-converting enzyme, total acid phosphatase, and ferritin levels are usually elevated. These levels may normalize with treatment.
  • Monitoring chitotriosidase enzyme is useful except in the 10% of the population that has a deficiency in this protein.
  • Monitoring glucosylsphingosine levels may be useful, as the level has been shown to correlate with response to therapy.

Imaging

  • Ultrasonography - may reveal abdominal organomegaly.
  • MRI - may be useful in revealing early skeletal involvement (avascular necrosis, spinal degradation, and degree of bone marrow infiltration.
  • Radiography - may reveal skeletal manifestations and pulmonary involvement.
  • Dual-energy x-ray absorptiometry - may evaluate osteopenia and bone crises.
  • Echocardiograms are helpful in evaluating the possibility of pulmonary hypertension.
  • In neuronopathic Gaucher disease, monitoring of EEG, brainstem-evoked potential, swallowing studies, and neuro-ophthalmologic evaluation should be done at regular intervals.

Bone Marrow Aspiration

  • In the past, the diagnosis was made by finding classic glycolipid-laden macrophages in bone marrow aspirate. Today, aspiration is not typically needed due to alternative less invasive tests.
  • Bone marrow aspiration is not the initial diagnostic test because the blood enzyme test is more sensitive, specific, less invasive.

Liver Biopsy

  • Liver biopsy may be performed to evaluate unexplained hepatomegaly. However, a biopsy is rarely needed because a specific diagnostic test is available.

Treatment / Management

Treatment for Gaucher disease falls into two categories, enzyme replacement therapy and substrate reduction therapy [3].  In general, enzyme replacement therapy provides an intravenous infusion containing the enzyme that is deficient or absent in the body. In the case of Gaucher disease, this would be the GBA1 enzyme (also called beta-glucosylceramidase or beta-glucocerebrosidase). The FDA has approved both Cerezyme (imiglucerase) and VPRIV (velaglucerase alfa) for Gaucher disease type 1 and 3 enzyme replacement therapy. Enzyme replacement therapy typically cannot replace an enzyme deficient in the brain due to the blood-brain barrier and therefore is not effective for the treating the central nervous systems problems associated with type 2 and 3 Gaucher disease. Enzyme replacement therapy will help with the “non-brain” signs and symptoms associated with type 3 Gaucher disease, e.g., enlarged organs and skeletal issues.

Enzyme replacement therapy does not correct the underlying genetic defect and acts only to relieve signs, symptoms and ongoing damage caused by the accumulation of toxins. Moreover, it is possible to develop antibodies to the replacement enzyme.

Substrate reduction therapy is an orally administered small-molecule drug (not protein) that relies on a strategy distinct from that of enzyme replacement therapy. In substrate reduction therapy the goal is to reduce the levels of a substrate such that toxic accumulation of the substrate’s subsequent degradative product is diminished to a level that is clinically less toxic. In the case of Gaucher disease, the goal is to use substrate reduction therapies that can inhibit the first committed step in glycosphingolipid biosynthesis. There are two FDA-approved substrate reduction therapy drugs to treat patients with Gaucher disease, i.e., Cerdelga (eliglustat) and Zavesca (miglustat). Cerdelga, a glucosylceramide synthase inhibitor, does not effectively cross the blood-brain barrier is indicated only for type 1 Gaucher disease [4]. It is not yet known if Cerdelga is safe or effective in children. Miglustat can cross the blood-brain barrier and could, therefore, be potentially beneficial for type 2 and 3 Gaucher disease. Nevertheless, miglustat is currently indicated only for the treatment mild to moderate type 1 Gaucher disease only in adults.

Enhancing Healthcare Team Outcomes

Evaluation and treatment of Gaucher disease is difficult and requires a coordinated team approach of physicians, nurse practitioners, and physician assistants to maintain the health of the patient. [Level V]


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Gaucher Disease - Questions

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A 2-year-old female is brought to the emergency department for petechiae on her legs. Initial bloodwork reveals anemia and thrombocytopenia. Physical examination is suggestive of splenomegaly. She has had multiple infections in the past year. Further evaluation reveals decreased activity of glucocerebrosidase. Which of the following is the most likely diagnosis?



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A pathology researcher is investigating a blood sample from a patient with Gaucher disease. He notices multiple macrophages that have abnormal cytoplasm, giving them the appearance of "crumpled tissue paper". Which of the following substances is most likely accumulated in these cells?



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A 4-year-old boy is being evaluated for anemia and thrombocytopenia. Bone marrow aspirate reveals large multinucleated macrophage-like cells that are engorged with cytoplasmic fibrils. His parents are of Ashkenazi Jewish descent. Which of the following enzymes is most likely deficient enzyme in this patient?



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A 5-year-old male is brought to the clinic by his parents for tiring easily. He recently started going to school and his teacher is concerned he doesn't play well with the other children. If he tries to run, he stops quickly after a few steps. Physical examination shows significantly pale conjunctivae and yellow sclerae. A smooth notched viscus is palpated 3 cm below the left costal margin. A blood test reveals decreased beta-glucocerebrosidase activity. Which of the following is the best initial therapy for this patient?



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A Jewish couple of Eastern European presents to the clinic for advice. They are planning on having a child but have learned their child may be at risk of developing errors of metabolism. They inquire about which diseases they should be most concerned. Epidemiologically speaking, which of the following best answers their question?



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An 8-year-old boy is brought to the clinic for generalized weakness. He has a history of Gaucher disease. Physical examination reveals conjunctival pallor and yellow sclerae. There is also suspicion for hepatosplenomegaly. Which of the following enzymes is most likely deficient in this patient?



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A 4-year-old boy is brought to the emergency department with a witnessed seizure. He has never had similar episodes in the past, except for a febrile seizure at two years of age. His parents are of Ashkenazi Jewish descent. The child has been lagging in cognitive milestones as well. A blood test demonstrates decreased glucosylceramidase activity. Which of the following is the most likely diagnosis?



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A 9-month old female infant is brought to the clinic for worsening difficulty with swallowing, spasticity, and head retraction. Her parents belong to the Ashkenazi Jew population. After an extensive workup, she is diagnosed with a deficiency of glucocerebrosidase. Which of the following accumulates abnormally in such patients?



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A 9-year-old boy is brought to the clinic with left hip pain that has been bothering him for about four months. He has used acetaminophen and ibuprofen without much benefit. An x-ray is highly suggestive of avascular necrosis of the head of the femur. His parents of Ashkenazi Jewish descent. Which of the following is the inheritance pattern of the patient's underlying diagnosis?



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A 13-year-old girl is brought to the clinic after being treated for a dizzy spell at a hospital. She has no significant past medical history. A complete blood count shows white blood cells of 5000/microL, hematocrit of 24%, and platelets of 96,000/microL. On physical examination, he has a notched smooth surface palpable 4 cm below the left costal margin. A femur x-ray shows expansion of the bone marrow in the shape of an Erlenmeyer flask. Which of the following is the best initial test for this patient?



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A pathology researcher is investigating different liver biopsies from patients with inborn errors of metabolism. He comes across a particular sample that has some cells' cytoplasm giving the appearance of "crumpled tissue paper." Which of the following is the most likely underlying diagnosis of the patient?



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A 6-year-old boy is brought to the clinic with six months' history of right hip pain. He has been prescribed acetaminophen and ibuprofen several times, but symptoms persist. An x-ray is performed which shows bony sclerosis, multiple areas of subchondral radiolucent lines (crescent sign), and flattening of the head of the femur. Which of the following is the most likely diagnosis?



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A 3-year-old female is brought to the clinic by her parents for "not keeping up other kids." She does not like running and can never keep up when playing with other children. She appears to get easily tired with minor activity. Physical examination suggests hepatosplenomegaly. Both her parents are of Ashkenazi Jewish descent. Which of the following is the most appropriate test to perform in this patient?



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A three-year-old girl is being evaluated for severe neurologic abnormalities and splenomegaly. Bone marrow aspirate reveals reticulum cell hyperplasia. Which of the following enzyme's will have decreased/absent activity?



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A 9-year-old boy presents after he fell from the bed and injured his leg. He is crying and inconsolable. Past medical history reveals a fracture of his left tibia a year ago. His mother reports that he has a congenital disease for which he takes Miglustat. Which of the following is the correct enzyme deficiency for the patient's underlying condition?



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Gaucher Disease - References

References

Stirnemann J,Belmatoug N,Camou F,Serratrice C,Froissart R,Caillaud C,Levade T,Astudillo L,Serratrice J,Brassier A,Rose C,Billette de Villemeur T,Berger MG, A Review of Gaucher Disease Pathophysiology, Clinical Presentation and Treatments. International journal of molecular sciences. 2017 Feb 17;     [PubMed]
Ferreira CR,Gahl WA, Lysosomal storage diseases. Translational science of rare diseases. 2017 May 25;     [PubMed]
Mistry PK,Lopez G,Schiffmann R,Barton NW,Weinreb NJ,Sidransky E, Gaucher disease: Progress and ongoing challenges. Molecular genetics and metabolism. 2017 Jan - Feb;     [PubMed]
Mistry PK,Lukina E,Ben Turkia H,Shankar SP,Baris H,Ghosn M,Mehta A,Packman S,Pastores G,Petakov M,Assouline S,Balwani M,Danda S,Hadjiev E,Ortega A,Gaemers SJM,Tayag R,Peterschmitt MJ, Outcomes after 18 months of eliglustat therapy in treatment-naïve adults with Gaucher disease type 1: The phase 3 ENGAGE trial. American journal of hematology. 2017 Nov;     [PubMed]

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