Gaucher disease

From Ganfyd

Gaucher's disease is an autosomal recessive lysosomal storage disease caused by any one of 300 odd mutations of the GBA gene that codes for lysosomal enzyme acid Β glucosidase^[1]. These result in excess accumulation of glucosylceramide.

Presentation

There are three clinical phenotypes:

1. Type 1
   • Child or adult onset - 60% diagnosed before 20 years, very rarely in 9th decade.
   • Hepatosplenomegaly - more marked in early onset patients
     • Anaemia or thrombocytopenia in less than half (perhaps more common in adult onset)
   • Bone involvement
     • Erlenmeyer's flask derfomity of distal femur
     • Lytic lesions
     • Osteopenia
     • Bone pain
   • No neurodegeneration
   • Death can be in adult life
   • Classically in Ashkenazi Jews
   • Child onset can have growth retardation
   • N370S allele if present is predictive of this type
2. Type 2
   • Infant onset
   • Prognosis about 9 months but can present at birth as fetal hydrops which is rapidly lethal
   • No bone manifestations
   • Neurogeneration
     • Bulbar signs
     • Oculomotor paresis
   • Hepatosplenomegaly
   • L444P hetrozygotes with other GBA mutations predictive
3. Type 3
   • Up to adolescence onset
   • Full features: ie hepatosplenomegaly, bone involvement and neurodegeneration
     • A variant termed Type 3a can have myoclonic seizures within weeks of birth but mild visceral involvement
     • A variant termed Type 3b can have marked hepatosplenomegaly but only slowly progressive nerve involvement
   • Deaf by early adulthood
   • Classically in Swedish kindred
   • Genotype D409H/D409H
   • L444P homozygosity strongly predictive
     • Hydrocephalus
     • Corneal opacities
     • Aortic valve and ascending aorta calcification

There is a relationship in carrier's with Lewy body formation and Parkinsonism which is poorly understood.

Diagnosis

• Enzyme activity in leukocytes or fibroblasts if phenotype
• DNA testing in families

Treatment

Main issue is individual cost

• Enzyme therapy
  • Mannose terminated glucocerebrosidase iv
  • Imiglucerase
• Miglustat
• Velaglucerase alfa

Future

• ? Short chain ceramide analogues.
• ? competitive inhibitors/conformational modifiers that redirect dysfunctional enzyme
• ? Gene therapy

References