J Med Genet 42:e37 doi:10.1136/jmg.2004.028019
  • Electronic letters

Divergent phenotypes in Gaucher disease implicate the role of modifiers

  1. O Goker-Alpan1,
  2. K S Hruska1,
  3. E Orvisky1,
  4. P S Kishnani2,
  5. B K Stubblefield1,
  6. R Schiffmann3,
  7. E Sidransky1
  1. 1NSB/NIMH and MGB/NGHRI, National Institutes of Health, Bethesda, MD, USA
  2. 2Duke University Medical Center, Division of Medical Genetics, Durham, NC, USA
  3. 3DMNB/NINDS, National Institutes of Health, Bethesda, MD, USA
  1. Correspondence to:
 Dr Ellen Sidransky
 Section on Molecular Neurogenetics, NSB/NIMH/NIH, 35 Convent Drive 1A100, Bethesda, MD 20892, USA;
  • Accepted 12 January 2005
  • Revised 11 January 2005


Background: Gaucher disease is classified into neuronopathic and non-neuronopathic forms with wide phenotypic variation among patients sharing the same genotype. While homozygosity for the common L444P allele usually correlates with the neuronopathic forms, how a defined genotype leads to a phenotype remains unknown.

Methods: The genetic and epigenetic factors causing phenotypic differences were approached by a clinical association study in 32 children homozygous for the point mutation L444P. Direct sequencing and Southern blots were utilised to establish the genotype and exclude recombinant alleles. Glucocerebrosidase activity was measured in lymphoblast and fibroblast cell lines.

Results: Residual enzyme activity was highly variable and did not correlate with the observed clinical course. There was also a wide spectrum of phenotypes. Average age at diagnosis was 15 months, and slowed saccadic eye movements were the most prevalent finding. The most severe systemic complications and highest mortality occurred in splenectomised patients before the advent of enzyme replacement therapy (ERT). On ERT, as morbidity and mortality decreased, developmental and language deficits emerged as a major issue. Some trends related to ethnic background were observed.

Conclusion: The wide clinical spectrum observed in the L444P homozygotes implicates the contribution of genetic modifiers in defining the phenotype in Gaucher disease.


  • Competing interests: Dr PS Kishnani has received research and grant support from Genzyme Corporation for work on some lysosomal storage disorders including Gaucher disease. Dr Kishnani is also a member of the Pompe disease advisory board for Genzyme Corporation.

  • Consents to publish the photographs shown in figure 1 were provided by the patients and/or parents.