Mutation Frequency of Three Neurodegenerative Lysosomal Storage Diseases: From Screening to Treatment?

The ascertainment of mutation frequencies in the general population may have impact on the population's wellbeing and respective healthcare services. Furthermore, it may help define which approaches will be more effective for certain patients based on the genetic cause of disease.

Determine the frequency of three mutations, known to be a major cause of three distinct Lysosomal Storage Diseases (LSDs).

The following pre-requisites were met: each mutation accounted for over 55% of the disease alleles among previously reported unrelated patients, all three diseases were among the most prevalent LSDs in the population under study, they all involved devastating deterioration of the nervous system, lacked curative treatment and may be fatal in childhood or adolescence. The anonymous samples used in this study were representative of the whole population; mutations were tested by PCR based methods, positive results were further confirmed. The diseases studied were Mucopolysaccharidosis type I (Hurler, MIM 607014), Tay Sachs disease variant B1 (TS, MIM 272800) and Metachromatic Leukodystrophy (MLD, MIM 250100); the mutations were, respectively, p.W402X, p.R178C and c.465+1G>A.

Increased carrier frequencies were found for Tay Sachs disease variant B1 HEXA p.R178C mutation (1:340) and for the infantile MLD ARSA c.465+1G> A mutation (1:350) denoting higher risk for these sub-types of disease in Portugal and possibly in individuals of Iberian ancestry. Carrier screening in target populations may provide the foundations for more effective approaches to precision medicine.