Intrafamilial Variability of Natural Disease Course in Metachromatic Leukodystrophy

Aims: Metachromatic leukodystrophy (MLD) is caused by mutations in the Arylsulfatase A gene. Today over 160 mutations have been characterized. The genotype–phenotype correlation is only partly understood, especially juvenile patients are thought to have a heterogeneous clinical cause. The aim of this study was to systematically investigate the intrafamilial variability of disease courses in MLD.

Methods: Patients with late-infantile and juvenile MLD were recruited within the national research network LEUKONET. To increase the number of siblings, clinical data from the Netherlands were included. Data about disease onset and dynamic were obtained using a questionnaire.

Results: Detailed clinical information was available from 83 patients (48 late infantile), among them 11 were sibling pairs (two late infantile). Age of onset was similarly variable between the siblings and randomly chosen pairs of the remaining cohort (euclidean distances). This was more obvious in the late-infantile group than in the juvenile patients. In addition, the variability of the first symptoms and disease dynamic was similar in the late-infantile patients compared with the whole cohort. However, in juvenile patients both the types of first symptoms and the dynamic of the disease course was more homogeneous within families compared with the variability in the whole cohort.

Conclusion: This is the first study that systematically analyzes data of intrafamilial disease variability in MLD. While the disease course in late-infantile patients was as variable between siblings as in the whole cohort, siblings with juvenile MLD showed a more homogeneous course regarding type of first symptoms and dynamic of the disease (not regarding age of onset). As nontreated siblings are often used as controls in the evaluation of therapeutic effects, these results seem of high relevance.