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Gaucher's disease (GD)

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Gaucher disease (GD) is a lysosomal storage disorder (LSD) which is inherited as an autosomal recessive condition with an estimated birth frequency of 1:50,000 to 1:100,000 in the European population with a higher incidence of 1:500 to 1:1000 live births in the Ashkenazi Jewish population

  • characterized by a deficiency of glucocerebrosidase, the usual function of which is to cleave glucose residues from ceramide. As a result, glucocerebroside accumulates, principally in the phagocytic cells of the body but also sometimes in the central nervous system neurones
    • the Gauchers Association in the UK report that in 2016 they knew of 310 people with Gaucher disease in the UK and Ireland (293 adults and children in Scotland England and Wales and 17 in all of Ireland)

  • GD is caused by mutations of the GBA1 gene which encodes for the enzyme glucocerebrosidase. Reduced enzyme function results in the over storage of glucosylceramide in white blood cells known as macrophages that accumulate primarily in the bone marrow, liver, spleen, and secondarily in the lungs and brain
    • the different sites of accumulation result in multi-system disease and diverse clinical symptoms
    • tphenotypic presentation of the condition ranges from almost asymptomatic to severe, life-threatening and fatal
    • there are 3 different types of GD with type 1 affecting 95% of those diagnosed in Europe, the US and Canada

  • Type 1 GD is the non-neuronopathic form of the condition with phenotypic presentation ranging from mild to severe and life threatening. The onset of symptoms may occur at any time from childhood into adulthood with people with identical mutations manifesting as variations in overall severity and organ involvement. Patients who present in early childhood generally go on to have more severe symptoms than those who present later in adulthood.

  • Type 2 GD accounts for 1% of GD cases and is a fatal neuronopathic form of the condition with neonatal-infantile onset which is rapidly progressive, leading to death typically by the age of 2

  • Type 3 GD (also known as the chronic neuronopathic form), accounts for 4% of GD cases. Symptoms develop in childhood with progressive neurological deterioration that may result in death during the second decade, although some patients with non-progressive disease have survived into their fourth decade

  • Enzyme replacement therapy (ERT) and substrate reduction therapy (SRT) are used to reduce the severity of symptoms in children with type 1 GD

Characteristics of Gaucher disease subtypes

  Type 1 Type 2 Type 3
Phenotype

Accounts for 95% of GD cases.

Diverse phenotypes among patients with identical GBA mutations manifests as variations in the overall severity of the disease, as well as in the pattern of organ involvement

Childhood or adult onset varying from asymptomatic to life threatening symptoms.

Accounts for 1% of GD cases.

Typically neonatal-infantile onset with a rapidly progressive fatal course.

The median age of death is 9 months

Accounts for 4% of GD cases.

Typically infantile-childhood onset; sub-acute and slowly progressive may result in death during the second decade although some have survived to their 4th decade

Visceral symptoms Hepatomegaly (>80% of patients), splenomegaly (>90% of patients), interstitial lung disease and pulmonary hypertension Hepatomegaly, splenomegaly, hydrops fetalis (neonatal presentation) and interstitial lung disease Hepatomegaly, splenomegaly and interstitial lung disease
Hematopoietic symptoms Anaemia and thrombocytopenia Anaemia and thrombocytopenia Anaemia and thrombocytopenia
Orthopaedic symptoms Bony pain crisis, osteopenia, aseptic necrosis of femoral head, bony lytic lesions, bony infarctions and pathological fractures Arthrogryposis in severe cases, and generally death before bony abnormality Bony pain crisis, osteopenia, aseptic necrosis of femoral head, bony lytic lesions, bony infarctions and pathological fractures
Neurologic symptoms No CNS involvement and no cognitive regression except for an increased risk in Parkinson's disease Bulbar palsies, hypertonicity, abnormal ocular saccades and cognitive impairment Oculomotor apraxia, myoclonic epilepsy, generalized tonic-clonic seizures, and cognitive impairment

 

Notes:

  • reduced glucocerebrosidase enzyme function results in the over storage of glucosylceramide in white blood cells known as macrophages, that accumulate primarily in the bone marrow, liver, spleen, and secondarily in the lungs and brain. The different sites of accumulation result in multi-system disease and diverse clinical symptoms. The phenotypic presentation of the condition ranges from almost asymptomatic to severe, life-threatening and fatal

  • the development of enzyme replacement therapy (ERT) and substrate reduction therapy (SRT) have made GD treatable with the exception of the neurological deterioration associated with types 2 and 3
    • ERT aims to replace the defective or missing enzyme with a functional protein that is infused into the bloodstream and taken up into cellular lysosomes
    • ERT targets the underlying metabolic deficit rather than providing symptomatic management
    • SRT targets the failure of the lysosomal metabolic pathway by inhibiting the production of glucosylceramide and thereby reducing its accumulation in the lysosomes and the likelihood of subsequent multi organ dysfunction

  • identification of deficient glucocerebrosidase activity in amniotic fluid cells permits prenatal diagnosis

Reference:

  • Solutions for Public Health, Screening for Gaucher Disease, A report for the UK National Screening Committee. December 2013
  • UK National Screening Committee. Briefing note: Screening for Gaucher disease in newborns. June 2018
  • Giraldo P, Alfonso P, Iruin P Gort L et al Mapping the genetic and clinical characteristics of Gaucher disease in the Iberian Peninsula. Orphanet Journal of Rare Diseases 2012 7:17
  • Goker-Alpan O, Hruska KS, Orvisky E, et al Divergent phenotypes in Gaucher disease implicate the role of modifiers Journal of Medical Genetics 2005;42:e37.
  • Biegstraaten M., Cox T. M., Belmatoug N, Berger M, Collin-Histed T, Vom Dahl S., Di Rocco M, Fraga C,. Giona F, Giraldo P, 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.

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