The NCS‐LSD cohort study: a description of the methods and analyses used to assess the long‐term effectiveness of enzyme replacement therapy and substrate reduction therapy in patients with lysosomal storage disorders

Abstract

Lysosomal storage disorders (LSDs) comprise more than 50 extremely rare, inherited metabolic diseases resulting from a deficiency of specific lysosomal enzymes required for normal macromolecular metabolism. The National Collaborative Study for Lysosomal Storage Disorders (NCS-LSD), was a longitudinal cohort study which collected prospective and retrospective clinical data, and patient-reported data from adults and children with a confirmed diagnosis of Gaucher disease, Fabry disease, mucopolysaccharidosis type I (MPS I), mucopolysaccharidosis type II (MPS II), Pompe disease and Niemann Pick disease type C (NPC) in the UK. The study aimed to determine the natural history of these conditions and estimate the effectiveness and cost of therapies. Clinical outcomes were chosen to reflect disease progression. Age- and gender-adjusted treatment effects were estimated using generalised linear mixed models. Treated patients contributed data before and during treatment while untreated patients contributed natural history data. A total of 711 adults and children were recruited to this study from the seven LSD treatment centres in England. Data was collected from 2008 to 2011. This paper describes the methods used to collect and analyse clinical data for this study. The clinical findings are reported separately in a series of condition-specific articles in this issue.

Long‐term effectiveness of enzyme replacement therapy in adults with Gaucher disease: results from the NCS‐LSD cohort study

“…Finally, although the collection of historical data allowed us to examine the natural history of treated and untreated conditions, it is likely that there have been changes over time in which tests are carried out and how they are performed. These limitations are discussed in more detail in our companion Methods paper (Henley et al 2014).…”

“…Simulated power calculations (see Henley et al 2014) for details of the approach) showed that a sample size of 150 adults provides 80 % power to detect an effect of time on treatment of at least 0.01 standard deviations (SD) per year based on cross-sectional data sampled from a mean of 11 years follow-up (i.e. an expected change of 0.11 SD over the course of 11 years on ERT, assuming a linear effect of time on therapy).…”

Lacritin and other autophagy associated proteins in ocular surface health

“…When mutated, autophagic flux becomes suboptimal and cholesterol accumulates giving rise to the lysosomal storage disease Niemann-Pick type C associated with neurodegeneration, retinal degeneration (Claudepierre et al, 2010) and slow vertical eye movements (Salsano et al, 2012). Lysosomal substrate reduction therapy is available for Niemann-Pick type C disease that is mild to moderate (Henley et al, 2014). Although corneal involvement is uncommon, cornea of NPC1 −/− mice display inclusions (Hovakimyan et al, 2011).…”

Progress and potential of non-inhibitory small molecule chaperones for the treatment of Gaucher disease and its implications for Parkinson disease

“…So far, substrate reduction therapy has primarily been used in patients with type 1 GD with moderate symptoms. Despite its discrete approach, SRT is limited in its applicability for type 2 and 3 GD due to pharmacokinetics limitations (40). …”