Lysosomal storage diseases (LSDs) are metabolic disorders caused by mutations in genes encoding for the proteins involved in lysosomal homeostasis. Collectively affecting 1:5000 live births and often present as pediatric neurodegenerative diseases.

Over 70 different LSDs have been identified, most being autosomal recessive.  I.e. two copies of mutated genes are required from each parent for a child to show symptoms. With a smaller number of LSDs X-linked, such as Fabry disease and MPSII (Hunter Syndrome), hence more common in males.

Suspicion of an LSD is typically triggered by evidence of visceral disease in the bodies soft internal organs, such as the lungs, the heart, and the organs of the digestive, excretory, reproductive, and circulatory. For example swelling of the spleen (hepatosplenomegaly) in Gaucher and Niemann-Pick B; Liver disease in Niemann-Pick type C or developmental issues in Tay-Sachs disease.

LSDs often manifests with a combination of symptoms that help define a particular disease. However these symptoms are usually not unique to the LSD in question. The most serious and difficult to treat symptoms are neurological.

Studies on lysosomal dysfunction in neurological autoimmune diseases indicate the potential importance of lysosomal homeostasis in managing more common diseases, including: Rheumatoid arthritis, Multiple Sclerosis and ALS.  Neurodegenerative diseases, such as Alzheimer’s, Parkinson’s and Huntington’s disease are also associated with lysosomal imbalances. A clear genetic link between Gaucher’s disease has been shown for a number of year.

Therapeutic approaches include enzyme replacement therapy (ERT)  which involves administration of a functional version of the defective enzyme to the target and ‘chaperone therapy where small molecules active site inhibitors aim to stabilise the conformation of the mutant enzyme .ERT is typically administered by intravenous injection which are not able to cross the blood–brain barrier, and have limited effective neurological manifestations.

Trialing new approaches can be hindered through challenges in identifying and subsequently recruiting patients at an early stage. Whilst some countries have adopted large scale newborn screening (NBS) initiatives to help identify patients this can be expensive. Due to both the large number of false positives as well as limited and relatively expensive treatment options for those children who are identified.

Detailed health economic analysis of such large scale screening for LSDs is limited though most European countries consider it to be of undemonstrated cost effectiveness. In the US universal NBS for Pompe disease followed by confirmatory testing was estimated to cost an additional $26 million annually. With infants with screened and treated for infantile-onset disease experiencing lifetime increase of over 11 QALYs for a corresponding ICER of $379,000/QALY, from a societal perspective.

NBS was pioneered in the 1960s with Guthrie’s test for phenylketonuria (PKU), collecting capillary blood via a pin prick on the heel. In Fabry disease, one of the earliest reported NBS trials was in 2006 for 37,104 Italian male neonates. The study determined that the incidence of late-onset Fabry disease was eleven times higher than the classic phenotype. (1 in 3,1000 v’s 1 in 50,000).

In the US, Fabry disease is not included on the Recommended Uniform Screening Panel (RUSP). This is due to its variable disease onset and limited data demonstrating positive impact of early preventive treatment early. Neiman Pick disease type C and Krabbe disease, were also considered but ultimately rejected for inclusion around 2010. Pompe disease was eventually approved in 2013. More recently mucopolysaccharidoses type II (MPS II) was included in 2022. However despite improvements in the treatment options for Krabbe disease the panel decided not to include following a review that same year.

Some US states have continued to study real world results of screening. A 4 year study of  65,605 infants from New York (a 73% consent rate), screening 69 infants positive for either Pompe, Gaucher, Niemann–Pick A/B, Fabry, and MPS 1. With 23 were confirmed true positives, all of whom were predicted to have late-onset phenotypes with a further six of the 69 with undetermined disease status.

HCD Economics has already conducted research into Gaucher Type III, and  Phenylketonuria (PKU). For an informal chat about how we can support your  access and health economic strategies in LSDs, please contact: