OP1 – 2527: Phenotypic variation between siblings with metachromatic leukodystrophy

Abstract

Objective Metachromatic Leukodystrophy (MLD) is a rare autosomal-recessive disorder caused by mutations in the Arylsulfatase A gene. Although over 160 mutations have been characterized, the genotype-phenotype correlation is only partly understood, and the variability in siblings is unclear with some evidence for a discrepant clinical course in juvenile patients. The aim of this study was to systematically investigate the phenotypic variation in MLD siblings in comparison to a large MLD cohort. Methods Patients with MLD of late-infantile and juvenile onset were recruited within the national research network LEUKONET. In order to increase the number of siblings, clinical data from the Netherlands were included. Data about disease onset and dynamic were obtained using a questionnaire; gross motor deterioration, cognitive decline and MRI changes were described. Results Detailed clinical information was available from 11 sibling-pairs (2 late-infantile) and 61 single patients (44 late-infantile). Variability of age at onset was similar between the siblings and randomly chosen pairs of the remaining cohort (euclidean distances). This was even more marked in late-infantile than in juvenile patients. First symptoms and disease dynamic, also, were as variable in late-infantile patients as in the whole cohort. In juvenile patients, however, both the type of first symptoms and the dynamic of the disease course were more homogeneous within siblings compared to the variability in the whole cohort. Conclusions For the first time, a systematic analysis of phenotypic variation in siblings with MLD is reported. Late-infantile patients showed a similar variability between siblings as in the whole cohort, whereas siblings with juvenile MLD showed a more homogeneous course regarding type of first symptoms and dynamic of the disease (not regarding age at onset). These results seem of high relevance especially with respect to the evaluation of therapeutic effects, where non-treated siblings are often used as controls.