Influence of Age and Type of First Symptoms on Disease Progression in Metachromatic Leukodystrophy

Background: Metachromatic leukodystrophy (MLD) is a lysosomal storage disorder due to ARSA-Gene mutations leading to deficiency of arylsulfatase A (ARSA). The disease results in progressive loss of motor, cognitive and behavioural function. While disease course in the late-infantile form shows rapid and uniform decline, it is more variable and protracted in later-onset forms. Aim of the study was to compare disease progression between the different onset forms and to investigate the influence of type of first symptoms on the natural course.

Methods: Gross motor and cognitive (including behavioural) parameters were retrieved within this retrospective nationwide study of 92 patients with MLD (35 late-infantile, 19 early-juvenile (2.6 – 5.9 years) and 38 late-juvenile (6 – 15.9 years)). Three patterns of first symptoms were defined [gross motor symptoms only, cognitive symptoms only, or both (mixed)]. Standardized clinical endpoints included loss of gross motor and language functions as well as dysphagia/PEG. Rate of progression was compared using survival analyses and log-rank test.

Results: Patients with late-infantile and early-juvenile MLD showed a similarly rapid disease progression, most of them starting with motor symptoms only (39% of early-juvenile patients had mixed onset). Late-juvenile patients had on average a slower disease course (p < 0.05) in relation to late-infantile and/or early-juvenile patients in all observed parameters. However, when only patients with motor and mixed type of onset were analyzed, their disease progression was not different to those with the early onset forms. Patients with only cognitive symptoms at age of onset had a milder disease progression, independent of their age of onset.

Discussion: These results show that not only the age at onset, but also the types of first symptoms have a significant influence on disease progression. Late-infantile and early-juvenile patients showed a gross motor or mixed symptom constellation at onset and a rapidly progressive disease. And patients with late-juvenile MLD had a similarly rapid disease progression, when their first symptoms included abnormalities in gross motor function. In contrast, the disease progresses more slowly when only cognitive symptoms characterize the onset of disease.

Conclusions: Up to date, age at onset is considered the main prognostic parameter for progression in MLD. We provide evidence that type of first symptoms is the relevant parameter, and that gross motor abnormalities as first symptoms – with or without cognitive signs – indicate a more rapid progression whereas pure cognitive signs are related to a slower course.

No conflict of interest has been declared by the author(s).