Ching Yin Wan, Jack Davis, Manveer Chauhan, Josie Gleeson, Yair D J Prawer, Ricardo De Paoli-Iseppi, Christine A Wells, Jarny Choi, Michael B Clark
IsoVis - a webserver for visualization and annotation of alternative RNA isoforms
Nucleic acids research
metachromatic leukodystrophy mld devastating rare neurodegenerative disease typically loss motor cognitive skills precedes early death disease characterised deficient lysosomal arylsulphatase arsa activity accumulation undegraded sulphatide due pathogenic variants arsa gene atidarsagene autotemcel arsacel ex vivo haematopoietic stem cell gene therapy approved use uk 2021 treat earlyonset forms pre earlysymptomatic mld optimal outcomes require early diagnosis absence family history difficult achieve without newborn screening nbs prepilot mld nbs study conducted feasibility study manchester uk using twotiered screening test algorithm preestablished cutoff values cov firsttier c160 sulphatide c160s secondtier arsa tests evaluated prepilot study initial test validation using nonneonatal diagnostic bloodspots demonstrated arsa pseudodeficiency status associated normal c160s results age n 43 hence expected cause false positive results firsttier test instability arsa bloodspot required transfer nbs bloodspots ambient temperature 20c storage within 78 days heel prick earliest possible uk prepilot study eleven 3687 deidentified nbs samples prepilot positive c160s based preestablished cov 170 nmoll 18 multiples median mom 11 samples subsequently tested negative determined arsa cov 20 mean negative controls however two 20 nbs samples mld patients would missed c160s cov suspected false negative case displayed 4 mean arsa activity single arsa analysis initial test validation confirmed genotyping nbs bloodspot severe late infantile mld phenotype predicted led urgent assessment child authority approval timely commencement arsacel gene therapy 11 months old secondary c160s analysis nbs bloodspot 150 nmoll 167 mom lowest result reported thus far new cov 165 mom recommended future pilot studies furthermore preliminary data study showed c161oh sulphatide specific mld c160s conclusion prepilot study adds international evidence recommends newborn screening mld making possible patients benefit fully treatment early diagnosis