Quantitative longitudinal natural history of eight gangliosidoses - conceptual framework and baseline data of the German 8-in-1 disease registry. A cross-sectional analysis.

Abstract

PurposeGangliosidoses are a group of inherited neurogenetic autosomal recessive lysosomal storage disorders usually presenting with progressive macrocephaly, developmental delay and regression, leading to significant morbidity, and premature death. A quantitative definition of the natural history would support and enable clinical development of specific therapies. MethodsSingle disease registry of eight gangliosidoses (NCT04624789). Cross-sectional analysis of baseline data in N= 26 patients. Primary endpoint: disease severity assessed by the 8-in-1 score. Secondary endpoints: first neurological sign or symptom observed a. by parents and b. by physicians, diagnostic delay, as well as phenotypical characterization. Tertiary endpoints: Neurological outcomes (development, ataxia, dexterity) and disability. ResultsThe 8-in-1 score quantitatively captured severity of disease. Parents recognized initial manifestations (startle reactions) earlier than physicians (motor developmental delay and hypotonia). Median diagnostic delay was 3.16 [IQR 0.69 ... 6.25] years. Eight patients presented with late-infantile phenotypes. ConclusionData in this registry raise awareness of these rare and fatal conditions in order to accelerate diagnosis, inform counselling of afflicted families, define quantitative endpoints for clinical trials, and can serve as historical controls for future therapeutic studies. The characterization of a late-infantile phenotype is novel. Longitudinal follow-up is planned.