Association of Age at Onset and First Symptoms With Disease Progression in Patients With Metachromatic Leukodystrophy

Abstract

Objective:To compare disease progression between different onset forms of Metachromatic Leukodystrophy (MLD) and to investigate the influence of the type of first symptoms on the natural course and dynamic of disease progression.Methods:Clinical, genetic and biochemical parameters were analyzed within a nationwide study of patients with late-infantile (LI, onset ≤ 2.5 years), early-juvenile (EJ, onset 2.6 - < 6 years), late-juvenile (LJ, onset 6 – < 16 years), and adult (onset ≥ 16 years) forms of MLD. First symptoms were categorized as motor symptoms only, cognitive symptoms only, or both.. Standardized clinical endpoints included loss of motor and language functions, as well as dysphagia/tube feeding.Results:97 Patients with MLD were enrolled. Patients with LI (n=35) and EJ (n=18) MLD exhibited similarly rapid disease progression, all starting with motor symptoms (with or without additional cognitive symptoms). In LJ (n=38) and adult-onset (n=6) patients, the course of the disease was as rapid as in the early-onset forms, when motor symptoms were present at disease onset, while patients with only cognitive symptoms at disease onset exhibited significantly milder disease progression, independent of their age at onset. A certain genotype-phenotype correlation was observed.Conclusions:In addition to age at onset, the type of first symptoms predicts the rate of disease progression in MLD. These findings are important for counselling and therapy.Classification of Evidence:This study provides Class II evidence that in patients with MLD, age at onset and the type of first symptoms predict the rate of disease progression.

Long‐term disease course of two patients with multiple sulfatase deficiency differs from metachromatic leukodystrophy in a broad cohort

“…This might support the idea that language decline is not only due to motor discoordination but also might indicate disabled speech‐concept in line with mental decline. Relevant swallowing problems (EDACS 2) in patient 2 occurred about 3 years after onset, corresponding to early cases of juvenile MLD (median 13 years after onset, range 2‐18 years) 19 , but did not yet occur in patient 1.…”

“…To investigate whether dynamics in disease course may serve as an early clue for MSD in children presenting with symptoms of ARSA deficiency, we compared the clinical course of our two MSD patients (Supplementary Material S1) to a cohort of 59 (21 late‐infantile, 28 juvenile) patients with MLD regarding gross motor‐, speech‐, and swallowing decline by the use of standardized tools 16‐18,29 . This approach was shown as essential describing natural history of neurodegenerative diseases 7,16,18‐21 …”

“…This illustrates that the disease dynamics of the two MSD patients, despite of their earlier onset, was differently protracted in comparison to the well‐known disease dynamics in juvenile MLD (Figure 2). 18,19 …”

“…Disease onset before the age of 30 months was defined as “late‐infantile”, and between 30 months and 15 years as “juvenile” 18 . Dynamics of motor and language decline in the MLD patients was previously published 16,18,19 …”

“…17,18 It can be used retrospectively, indispensably for data acquisition in rare diseases. It has been used for natural history studies, 7,16,[18][19][20][21] and studies evaluating therapy. [22][23][24][25][26][27] 2 | MATERIAL AND METHODS…”