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Internal Medicine

Gaucher disease (GD)

Deficiency of the lysosomal enzyme glucocerebrosidase (β-glucosidase), leading to the accumulation of glucocerebroside within tissue macrophages in multiple organs.

  • M/C lysosomal storage disease (in India & worldwide)
    • Subgroup, sphingolipidosis as it involves dysfunctional metabolism of sphingolipids
  • Autosomal recessive inheritance (GBA gene on chromosome 1)

History

Philippe Charles Ernest Gaucher
Philippe Charles Ernest Gaucher (July 26, 1854 – January 25, 1918), physician and scientist from France
348px-philippe_charles_ernest_gaucher
Philippe Charles Ernest Gaucher (July 26, 1854 – January 25, 1918), physician and scientist from France

The disease was first recognized by the French doctor Philippe Gaucher, who originally described it in 1882 and lent his name to the condition. In 1902, its mode of inheritance was discovered by Nathan Brill. The neuronal damage associated with the disease was discovered in the 1920s, and the biochemical basis for the disease was elucidated in the 1960s by Roscoe Brady. The first effective treatment for the disease, the drug alglucerase (Ceredase), was approved by the FDA in April 1991. An improved drug, imiglucerase (Cerezyme), was approved by the FDA in May 1994 and has replaced the use of Ceredase. October is National Gaucher’s Disease Awareness Month in the United States.


Pathophysiology

GBA gene (Chromosome 1)
Autosomal recessive inheritance

↓ glucocerebrosidase/acid β-glucosidase (GBA)

Glucocerebroside
(component of cell membrane)
Cannot be broken → accumulates in macrophage lysosomes

Gaucher cells
(crumpled-tissue paper appearance)

Lysosomal enzymes & inflammatory cytokines
(released by gaucher cells & nearby macrophages d/t unclear mechanism)

Immune response

Scar tissue

Hydrolysis of glucosylceramide (GlcCer) by glucocerebrosidase (GCase) in the lysosome (A).
Hydrolysis of glucosylceramide (GlcCer) by glucocerebrosidase (GCase) in the lysosome (A). GCase is activated by saposin C. In lysosomal storage diseases, an enzyme deficiency is responsible for the accumulation of its substrate in the cell lysosome (overload disease). Gaucher disease is caused by a deficiency in glucocerebrosidase (GCase) (or β-glucosidase), which leads to an accumulation of GlcCer. GlcCer forms fibrillar aggregates that accumulate in macrophages and result in the cell cytoplasm presenting a characteristic “crumpled tissue paper” appearance (B), personal pictures, with the courtesy of Fabrice Camou and Rachid Seddik). These cells, known as Gaucher cells, infiltrate various organs (e.g., bone marrow, spleen, and liver) and are responsible for the major signs of the disease. | Stirnemann, J., Belmatoug, N., Camou, F., Serratrice, C., Froissart, R., Caillaud, C., … Berger, M. G. (2017). A Review of Gaucher Disease Pathophysiology, Clinical Presentation and Treatments. International Journal of Molecular Sciences, 18(2), 441. https://doi.org/10.3390/ijms18020441

Gaucher cells localised in:

  • Bone marrow
  • Liver
  • Spleen

Histopathology:

No role for histological examination of the bone marrow, liver or spleen for diagnosis of the disease.
  • Gaucher cells (lipid-laden macrophages resembling crumpled tissue paper)

Presentation

Presentation

Clinical spectrum:

  • Type 1 GD (GD1): Non-neuronopathic GD (M/C)
  • Type 2 GD (GD2): Acute neuronopathic/infantile cerebral GD (1% cases)
  • Type 3 GD (GD3): Chronic neuronopathic GD (5% cases)
Clinical classification of the forms of GD
Clinical classification of the forms of GD. Recently the classic categories of types 1, 2 and 3 have blurry edges along a phenotypic continuum. Patients with GD can have a spectrum of symptoms, ranging from mild to severe neurological effects. | Linari, S., & Castaman, G. (2015). Clinical manifestations and management of Gaucher disease. Clinical Cases in Mineral and Bone Metabolism : The Official Journal of the Italian Society of Osteoporosis, Mineral Metabolism, and Skeletal Diseases, 12(2), 157–164. https://doi.org/10.11138/ccmbm/2015.12.2.157
 Type 1Type 2Type 3
Disease onsetChildhood/adulthoodInfancyChildhood/adolescence
SplenohepatomegalyPresentPresentPresent
High prevalenceAshkenazi Jews?Swedish province of Norrbotten
Bone involvementPresentAbsentPresent
Ocular signsAbsentPresentPresent
Neurological involvementAbsentPresent, severePresent, mild
Other organ involvementLiver cirrhosis Pulmonary hypertensionHydrops Congenital ichthyosisCardiac and vascular calcifications
Lifespan with or without therapyEarly childhood to late adulthoodLess than 2 yearsVariable—up to early adulthood
Response to ERTGoodPoor, not indicatedVariable

Haematological (classical) symptoms:

  • Painless hepatosplenomegaly
  • Hypersplenism & pancytopenia
  • Osteoporosis (75% cases)
    • Erlenmeyer flask deformity of femur (aseptic necrosis of the femur head)
  • Bone pain (mild-to-moderate intermittent pain)

Severe acute “bone crises”

Accompanied by periosteal elevation, leukocytosis, and fever and can cause debilitation for several days and require narcotic analgesics

Neurological symptoms:

  • GD1: Impaired olfaction and cognition
  • GD2: Serious convulsions, hypertonia, intellectual disability, and apnea
  • GD3: Myoclonus, convulsions, dementia, and ocular muscle apraxia
Prevalence of affected organ involvement in Gaucher disease
Prevalence of affected organ involvement in Gaucher disease among children at diagnosis. Growth retardation refers to patients below the fifth percentile for height. Radiologic evidence of bone disease may indicate Erlenmeyer flask deformity, marrow infiltration, osteopenia, avascular necrosis, infarction, and/or new fractures. Anemia is defined according to age and sex references for hemoglobin concentrations as follows: less than 11 g/dL for boys 12 years and older; less than 10 g/dL for girls 12 years and older; less than 9.5 g/dL for children aged 2 to younger than 12 years; less than 8.5 for children aged 6 months to younger than 2 years; and less than 9.1 g/dL for infants younger than 6 months. Hepatomegaly (liver volume in multiples of normal size predicted for body weight [MN]) is defined as moderate (>1.25 to 2.5 MN) to severe (>2.5 MN). Splenomegaly (spleen volume in multiples of normal) is defined as moderate (>5 to 15 MN) to severe (>15 MN). Thrombocytopenia is defined as moderate (platelet count, 60 × 103/μL to >120 × 103/μL) to severe (platelet count, <60 × 103/μL). | Kaplan, P., HC, A., KA, K., & JD, Y. (2006). The clinical and demographic characteristics of nonneuronopathic gaucher disease in 887 children at diagnosis. Archives of Pediatrics & Adolescent Medicine, 160(6), 603–608. Retrieved from http://dx.doi.org/10.1001/archpedi.160.6.603

Diagnosis

Glucocerebrosidase assay (GOLD STANDARD):

  • Measures glucocerebrosidase activity in leukocytes (or fibroblasts)

CT-scan:

X-ray:

X-ray of the Erlenmeyer Flask deformity of the femora
X-ray of the Erlenmeyer Flask deformity of the femora—showing lack of curve at the dia-metaphyseal junction resembling a conical flask (picture to the right) along with cortical thinning. | Nagral, A. (2014). Gaucher disease. Journal of Clinical and Experimental Hepatology, 4(1), 37–50. https://doi.org/10.1016/j.jceh.2014.02.005

MRI:

T1 and T2W1 images of the lumbar spine reveals generalized decrease in marrow signal (arrows) in the vertebral bodies representing changes of osteosclerosis.
T1 and T2W1 images of the lumbar spine reveals generalized decrease in marrow signal (arrows) in the vertebral bodies representing changes of osteosclerosis. | Nagral, A. (2014). Gaucher disease. Journal of Clinical and Experimental Hepatology, 4(1), 37–50. https://doi.org/10.1016/j.jceh.2014.02.005

Management

Treatment strategies in a patient with Gaucher disease
Treatment strategies in a patient with Gaucher disease | Modified from: Ho M.W., Seck J., Schmidt D. Adult Gaucher’s disease: kindred studies and demonstration of a deficiency of acid beta-glucosidase in cultured fibroblasts. Am J Hum Genet. 1972;24:37–45.

Recombinant glucocerebrosidase therapy:

  • Imiglucerase (approved in 1995)
  • Velaglucerase (approved in 2010)
  • Taliglucerase alfa (Elelyso) (approved in 2012)

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