During the past 20 years, modern treatments have dramatically changed the prognosis for symptomatic patients with type 1 Gaucher's disease (GD). Since 1991, therapy has shifted from an approach primarily directed at symptom control to the actual reduction of glucocerebroside cellular burden. The latter therapeutic option has been realized through enzyme replacement therapy (ERT) and, more recently, with the use of miglustat, an oral substrate synthesis inhibitor (an approach referred to as substrate reduction therapy, SRT).
However, certain problems (e.g. pulmonary hypertension, bone involvement) may persist even with treatment directed at the underlying biochemical basis of GD. Response to treatment in patients with these two complications is not entirely predictable, and there are no clinical or biochemical markers that can reliably predict treatment outcome. Indeed, an otherwise good haematological and visceral (liver/spleen) response to ERT does not preclude progression of pulmonary hypertension or the appearance of new bone crises.
We present a patient with a stable type 1 GD, treated with ERT for >10 years, who developed a new bone crisis.
A 31-year-old White woman had been diagnosed at the age of 4 with non-neuronopathic (type 1) GD. Her genotype was N370S/W-4X. At presentation, she had mild pancytopenia, hepatosplenomegaly and bone pain. She started receiving ERT with alglucerase 60 U/kg every 2 weeks in 1992, aged 18 years, and was switched to the recombinant formulation (imiglucerase) in 1995. After 8 years of treatment, and following normalization of her haematological and other clinical parameters, the initial enzyme therapy dose was reduced to a maintenance regimen of 30 U/kg every 2 weeks.
Soon after diagnosis, she suffered a bone crisis in the legs. A skeletal MRI in 1995 confirmed residual lesions compatible with a previous bone crisis, and showed generalized bone marrow infiltration. In 2003, her enzyme dose was increased to 60 U/kg every 2 weeks due to an episode of bone pain (no MRI was performed). Despite this increased dose, in April 2005 the patient experienced an acute and severe bout of pain on the right hip and knee. Her right knee was swollen and was warm to the touch. The patient improved after 1 month on NSAIDs, steroids and opioids. One month after the first symptoms, she was referred to our centre, where a skeletal MRI showed focal hypointense signal on T1 TSE and hyperintense signal on SET2 and FS (Dp Spir) (Figure 1) in both femoral heads and extended marrow oedema in both distal diaphyses, characteristic of an acute bone crisis. Some sclerotic foci corresponding to old lesions were also seen. Vertebral bodies had an entirely normal signal, with no changes suggestive of marrow infiltration by Gaucher cells.
This case represents a clinical challenge. Despite treatment with ERT (and based on a more limited experience, using SRT) to reduce Gaucher-cell burden and ameliorate clinical symptoms, disease-related complications may remain a threat in some patients. Progressive bone disease may be a source of disabling complications in GD.
Coronal SET1: hypointensity signal in femoral heads and diaphisis.
The pathophysiology of bone crisis is not fully understood. It is thought that intravascular activation of coagulation, possibly due to inflammatory factors, may trigger an ischaemic insult to the bone, leading to acute crisis. Whatever the mechanism, bone crises may occur in treated and stable patients. Unfortunately, there are no markers that reliably predict bone crisis in GD. Some studies have suggested that residual enzymic activity1 (associated with less deleterious mutant alleles) correlates inversely with severity of bone involvement.2 The present case may be viewed as supportive of this hypothesis, since one of the alleles (W-4X) give rises to a truncated protein with no activity.
The second question that arises from this unusual case is how to treat the patient. Resumption of a higher ERT dose did not mitigate the severity of the episode or prevent its occurrence. As the patient had no signs of osteopenia, bisphosphonates were not indicated. Furthermore, the effect of miglustat on prevention of bone crisis is as yet unknown. These observations require further studies.
As more effective treatments prolong the lifespan of patients with type 1 GD, new perspectives on this clinical entity are being revealed.
Torralba MA, Pérez-Calvo JI, Pastores GM, Cenarro A, Giraldo P, Pocoví M. Identification and characterization of a novel mutation c.1090G>T (G325W) and nine common mutant alleles leading to Gaucher disease in Spanish patients. Blood Cells Mol Dis2001; 27:89–95.
Torralba-Cabeza MA. Análisis molecular de 20 familias españolas afectadas por la enfermedad de Gaucher. Identificación y caracterización de las mutaciones responsables de la enfermedad y estudio de la relación genotipo/fenotipo mediante mutagénesis dirigida y expresión de las proteínas mutantes en células COS-1. Doctoral thesis, Universidad de Zaragoza, 1999.