A model of neuronopathic Gaucher disease.

Gaucher disease (GD) is a lysosomal disorder involving the accumulation of glucocerebroside in the liver, spleen, bones and brain. Some patients exhibit only systemic disease (type I), but others have additional neurological signs which may lead to rapid neurodegeneration in infancy (type II) or take a more intermediate course (type III). Types II and III are collectively known as neuronopathic Gaucher disease (NGD). Systemic disease can now be treated by enzyme replacement therapy (ERT), but its efficacy in NGD is limited. Two infants who presented with bulbar palsy and failure to thrive were enzymatically diagnosed at 8 months with NGD. They were started on high-dose ERT (120 IU/kg every 2 weeks). Both underwent serial oculomotor assessment and an audiological battery, including visual reinforcement audiometry, otoacoustic emissions, and the auditory brain stem response (ABR). Biochemical markers showed an incomplete systemic response to ERT, but neurological deterioration was relentless, leading to death at 16 and 25 months. Oculomotor testing revealed a complete absence of saccadic eye movements and progressive bilateral sixth nerve palsy in one. Audiological assessment revealed progressive deterioration of ABRs, but with normal peripheral hearing and otoacoustic emissions. Both infants showed neurological deterioration in spite of high-dose ERT. The audiological findings suggested a loss of inner hair cell pathway function with preserved outer hair function, similar to what is seen in auditory neuropathy. The unusual pattern of audiological and oculomotor abnormalities is consistent with an excitotoxic mechanism predisposing nerve cells to glucocerebroside toxicity. Such excitotoxic damage may be amenable to direct therapeutic intervention.