Is Fabry disease associated with leukaemia?
2006-08-31

Fabry disease is an X-linked hereditary storage disorder caused by deficient activity of the lysosomal enzyme α-galactosidase A. This results in a progressive accumulation of the glycosphingolipid globotriaosylceramide (Gb3) in many organ systems. Typical clinical symptoms include angiokeratomas, hypohidrosis, acroparaesthesias, corneal and lenticular opacities, cardiac insufficiency, cerebrovascular manifestations and renal dysfunction. With an estimated prevalence ranging from 1:40 000 to 1:117 000, Fabry disease often remains undetected. Evidence suggests that attenuation of levels of ceramide, the central molecule in sphingolipid metabolism, is involved in cancer pathogenesis and may contribute to malignant tumour transformation, including development of acute leukaemia (Ogretmen & Hannun, 2004). Here, we present two patients with acute leukaemia who were subsequently found to have Fabry disease. We postulate that the progressive accumulation of Gb3 due to deficiency of α-galactosidase A may have damaged haematopoietic cells, leading to excessive proliferation and, eventually, the development of cancer. Patient 1 was a male who died at the age of 32 years, 2 years after being diagnosed with acute myeloid leukaemia. At diagnosis, histological analysis of bone marrow revealed dense blast cells without signs of maturation, with round to oval nuclei and inconspicuous nucleoli. Immunohistochemistry using the CD34 antibody showed that blast cells were intensely and specifically positive for membrane-associated CD34. At diagnosis, the patient presented with chronic renal failure and proteinuria. Kidney function did not improve during 1 year of treatment with prednisolone. Fabry disease was later diagnosed in a brother of this patient (who also presented with chronic renal failure; Cybulla et al, 2005). Further investigation revealed six more family members with the condition (Fig 1A). Histological re-analysis of the kidney and myocardium of patient 1 revealed prominent Gb3 deposits, indicating that he had suffered from Fabry disease. (A) Pedigree of family of patient 1. (B) Pedigree of family of patient 2. Squares represent males; circles represent females. Black areas represent patients carrying the GAL gene mutation and white areas represent patients without the GAL gene mutation. Arrows indicate patients 1 and 2. Patient 2 was a 43-year-old male who was diagnosed with acute lymphatic leukaemia at the age of 3 years. It was not possible to determine retrospectively whether Gb3 deposits were present at this age. Following treatment for leukaemia he entered and remains incomplete remission. The patient was not diagnosed with Fabry disease until the age of 40 years, when he developed chronic renal failure and Gb3 deposits were identified in his kidneys. The patient had a kidney transplant and is receiving enzyme replacement therapy. Three family members were also found to have Fabry disease (Fig 1B). We speculate that haematopoietic progenitor cells, with their excessive proliferative potential, are susceptible to damage in patients with Fabry disease, particularly in those in whom diagnosis is significantly delayed. This induces chromosomal aberrations and malignant transformation, which may lead to cancer development (potentially by additional mutation events). This would assume that underlying, but undetected Anderson–Fabry disease, smouldering for years in patients, might lead to a vulnerability of haematopoietic and other cells and finally the evolution of cancer. To our knowledge, this is the first report of leukaemia in patients with Fabry disease. However, solid tumours and Fabry disease have been observed in four individuals worldwide: one with colon cancer (Kusama et al, 1993), two with nevocarcinoma (Vidmar et al, 1977) and one with bilateral renal cell carcinoma (Blanco et al, 2005). The authors suggest that the presence of both a solid tumour and Fabry disease in the same patient may be coincidence. A predisposition to cancer in patients with Fabry disease, however, should not be excluded. There may, therefore, be unknown or misdiagnosed cases of Fabry disease among cancer patients. If Fabry disease is found to increase susceptibility to cancer, there will be implications for planning individual therapeutic strategies and for preventing tumour onset. We are currently performing a prospective epidemiological trial of the relationship between Fabry disease and cancer.