Elin Haf Davies

Randomized, controlled trial of miglustat in Gaucher's disease type 3.

To evaluate the efficacy and safety of miglustat, concomitant with enzyme replacement therapy (ERT), in patients with Gauchers disease type 3 (GD3).

Outcome of type III Gaucher disease on enzyme replacement therapy: review of 55 cases.

SummaryThe European Task Force for Neuronopathic Gaucher Disease (NGD) met in 2006 to review its 2001 guidelines. Fifty-five patients from five European countries were reviewed; 29 were male and 26 female. The majority of the patients were homozygous for the L444P mutation. All had been on enzyme replacement therapy (ERT). However, there was considerable variation in the dose of ERT, as well as an uneven distribution of risk factors. Thus, the oldest patients were on the lowest doses, and several had had a total splenectomy, while the youngest patients had a high proportion of compound heterozygosity and were on the highest doses, and very few had had a splenectomy. This heterogeneity rendered analysis very difficult. However, some observations were possible. The older patients appeared to remain relatively stable despite a low dose of ERT. In the younger patients, there was no clear effect of high-dose ERT. However, the period of follow-up was too short in many patients to draw valid conclusions. These data will be used to draw up revised guidelines.

A severity scoring tool to assess the neurological features of neuronopathic Gaucher disease

SummaryType III Gaucher disease is one of the three recognized subtypes of Gaucher disease, an inherited deficiency of lysosomal glucocerebrosidase. Phenotypically there is a wide spectrum of visceral and neurological manifestations. Enzyme replacement is effective in managing the visceral disease; however, the neurological manifestations remain a more challenging obstacle. There is an unfulfilled need to reliably monitor neurological disease and its response to treatment. A severity scoring tool was developed through neurological domain identification, item generation and tool formation. Domain identification was established based on a retrospective single centre study (n=15) and a systematic review of publications. Forty-seven patients with neuronopathic Gaucher disease were then assessed using the tool to establish the clinical and statistical reliability of each domain. Judgement quantification of the tool was established through a process of content validity involving five European experts. Content validity is considered to be most effective when undertaken systematically. Concurrent validity and feasibility of the tool was also highlighted. This process allowed a revised and validated version of the tool to be developed.

Brain white matter abnormalities in paediatric Gaucher Type I and Type III using diffusion tensor imaging

ObjectiveBiomarkers to monitor neurological dysfunction in Neuronopathic Gaucher disease (NGD) are lacking. Diffusion tensor imaging (DTI) is a technique which allows us to probe the microstructure of the white-matter of the brain, in-vivo. The aim of this study was to investigate the value of DTI to visualise and quantify white matter integrity in children with NGD and Type I Gaucher.DesignDTI was performed and fractional anisotropy (FA), mean diffusivity (MD), axial (λaxial) diffusivity and radial (λradial) diffusivity maps calculated. Tract-based spatial statistics (TBSS) was used to perform a voxel-wise statistical analysis of the main white matter structures compared to age-sex matched control groups.SettingThe study was performed at Great Ormond Street Children’s Hospital NHS TrustPatientsFour NGD and three Type I Gaucher paediatric patients were recruitedResultsThe findings suggest the presence of microstructural white matter changes in NGD patients primarily in the middle cerebellar peduncles compared to an age-sex matched control group. This finding is relevant to the clinical manifestation of ataxia seen in NGD. Diffuse non-specific changes were seen in the Type I patients, but without a focal point.ConclusionsThis study is the first to use DTI to examine the Gaucher brain. While the numbers studied are small, the results suggest that DTI may be an attractive surrogate marker of NGD, worthy of further exploration for use in clinical studies.

Paediatric investigation plans for pain: painfully slow!

PurposeTo examine the early impact of the Paediatric Regulation, which entered into force in Europe on 27 January 2007, on the development of pharmaceutical drugs in the therapeutic field of pain submitted to the Paediatric Committee (PDCO) and to the European Medicines Agency (EMA).MethodsPaediatric Investigations Plans (PIPs) submitted with a Decision (outcome) reached between September 2007 and March 2010 were included in the analysis.ResultsOf the 17 Paediatric Investigation Plans submitted, 14 have resulted in an EMA Decision, 3 were withdrawn by the applicants, 8 were granted a full waiver from development, and 1 resulted in a negative opinion. Decisions as issued included 15 clinical trials, with at least 1,282 children to be recruited into studies across five different products. Neonates were included in four of the products.ConclusionsThe small number of submissions indicates a lack of new drugs being developed for the management of pain. Ethical concerns that too many vulnerable children will be recruited into clinical trials must be balanced against limiting the number of off-label prescribing and obtaining age-appropriate information on paediatric use. Now is an opportune time for clinicians, academics, learned societies and industry to collaborate for the benefit of children in pain.

Four-year follow-up of chronic neuronopathic Gaucher disease in Europeans using a modified severity scoring tool

In 2007, the European Task Force for neuronopathic Gaucher disease (NGD) published a review of 55 patients across four countries. Although some observations were possible, analysis was difficult due to the absence of a systematic way of assessing patients. In response to this, a Severity Scoring Tool (SST) was devised to offer a systematic means of assessing the neurological presentation seen. The SST has been modified (mSST) and is a valid tool for monitoring neurological progression. This review describes disease status and progression of neurological manifestations in a cohort of 39 chronic NGD patients across three European countries over a period of 4 years, using the mSST.