Table 4 Studies reporting progression-related outcomes in untreated (natural history) cohorts
Author(s), year, country | Number of patients with MLD | Association between GMFC-MLD at baseline and progression | Gross motor function | Cognitive function | Eating, drinking, and breathing | Key finding(s) |
|---|---|---|---|---|---|---|
Artigalas et al. 2010 [9] Brazil | 22 late-infantile MLD; 4 juvenile MLD | ✔ | Reports the age of acquisition and loss of neuropsychomotor developmental milestones in patients with late-infantile and juvenile MLD | |||
Biffi et al. 2008 [76] Italy | 16 late-infantile MLD; 9 juvenile MLD | ✔ | ✔ | Patients with the 0/0 genotype had the most rapid decline in gross motor function and the most severe cognitive impairment. Patients with the 0/R genotype had progressive and severe motor and cognitive deficit, while patients with the R/R genotype were relatively less impaired, and cognitive function remained stable | ||
Brown et al. 2018 [39] USA | 11 juvenile MLD | ✔ | ✔ | Caregivers reported impairments in physical functioning related to activities of daily living in patients with juvenile MLD | ||
Chen et al. 2016 [42] Australia | 5 juvenile MLD in total; 2 untreateda | ✔ | Describes age (or time after diagnosis) at which patients with juvenile MLD were gastrostomy-fed | |||
Eichler et al. 2016 [81] USA, France, Germany, and Colombia | 14 late-infantile MLD; 6 juvenile MLD; 3 adult MLD; 30 caregivers | ✔ | Across all clinical subtypes of MLD, 50% of caregivers reported that their dependents had difficulty swallowing, and 43% reported breathing/respiratory difficulties | |||
Elgun et al. 2019 [45] Germany | 12 sibling pairs (3 late-infantile MLD, 9 juvenile MLD) compared with 61 unrelated children (29 late-infantile MLD, 32 juvenile MLD) | ✔ | ✔ | All children in the late-infantile MLD group had rapid and uniform progression of motor function decline In the juvenile MLD group, the course of motor decline was significantly different between siblings and unrelated patients | ||
Fumagalli et al. 2021 [49] Italy | 22 late-infantile MLD; 19 juvenile MLD (14 early-juvenile, 5 late-juvenile) | ✔ | ✔ | Significant differences in all major disease-related milestones (except death) were observed between the early-juvenile and late-juvenile MLD groups. The late-infantile MLD group displayed earlier loss of trunk control, dysphagia, and death from the time of symptom onset when compared with the early-juvenile group, but loss of ambulation and the start of seizures were similarly rapid between both groups | ||
Groeschel et al. 2011 [51] Germany | 33 late-infantile MLD; 35 juvenile MLD | ✔ | ✔ | Eichler MLD MRI severity scores were significantly correlated with GMFC-MLD level in both late-infantile and juvenile MLD, but this was less remarkable in the juvenile form | ||
Groeschel et al. 2012 [50] Germany | 18 late-infantile MLD | ✔ | Demyelination load was associated with decline in gross motor function assessed using GMFC-MLD in patients with late-infantile MLD, and was correlated with disease duration | |||
Groeschel et al. 2016 [52] Germany | 65 juvenile MLD (24 treated with HSCT; 41 untreated) | ✔ | ✔ | Ten years after disease onset, 28 of 41 patients (68%) in the untreated cohort had progressed to GMFC-MLD level 5 and had experienced loss of language, and untreated patients’ Eichler MLD MRI severity scores significantly increased from their early to late disease stagesb | ||
Harrington et al. 2019 [53] USA | 16 late-infantile MLD; 16 juvenile MLD | ✔ | ✔ | ✔ | Caregivers reported that patients with late-infantile MLD experienced rapid disease progression; mean time from first symptom to either complete loss of a gross motor function, a fine motor function, or speech was only 1.0 year (range: 0.2–4.0 years) | |
Jabbehdari et al. 2015 [55] Iran | 12 late-infantile MLD; 6 juvenile MLD | ✔ | ✔ | Patients with late-infantile MLD had difficulties with swallowing and eating 2 years after disease onset, and the mental and motor regression process lasted about 10.5 months The progression of juvenile MLD was slower than the late-infantile form | ||
Kehrer et al. 2011 [56] Germany | 21 late-infantile MLD; 38 juvenile MLD | ✔ | ✔ | Three-quarters of the patients with late-infantile MLD showed their first motor symptoms before the age of 18 months The time to move from GMFC-MLD level 1 to level 6 was significantly longer in patients with juvenile MLD than in patients with late-infantile MLD | ||
Kehrer et al. 2014 [57] Germany | 23 late-infantile MLD; 36 juvenile MLD | ✔ | In the late-infantile MLD group, the median age when language decline occurred was 30 months (range: 17–42 months); almost half (48%) never learned to speak complete sentences. In the juvenile MLD group, the median age when language decline occurred was 8 years There were significant differences between the late-infantile and juvenile MLD groups in terms of problems in concentration and behavioral problems appearing as the first symptoms of disease | |||
Kehre et al. 2021 [5] Germany | 35 late-infantile MLD; 56 juvenile MLD (18 early-juvenile, 38 late-juvenile) | ✔ | ✔ | ✔ | For all clinical endpoints, patients with cognitive onset only had significantly slower progression in the course of their disease than patients with either motor onset only or motor and cognitive onset Patients with late-infantile MLD had significantly shorter time from disease onset to their first swallowing difficulties than patients with early-juvenile MLD; however, time from disease onset to tube feeding was similar | |
Kim et al. 1997 [58] South Korea | 7 late-infantile MLD | ✔ | All children displayed normal development until the onset of symptoms (ranging from 9 to 28 months) | |||
Koto et al. 2021 [16] Japan | 15 late-infantile MLD | ✔ | Most patients (60.0%) had enteral nutrition and 20.0% had a tracheostomy; 6.7% had nasal nutrition | |||
Liaw et al. 2015 [61] Taiwan | 5 late-infantile MLD | ✔ | ✔ | ✔ | All children had rapid psychomotor regression after disease onset and became bedridden at a median age of 2 years and 5 months The median age at which language function regressed to “unable to speak” in four patients was 2 years and 6 months, while the median age at which social function deteriorated to “loss of eye contact” in three patients was 3 years and 5 months Of four patients who had data available on support with feeding and breathing, all had a gastric tube fitted (at ages ranging from 2.5 to 3.7 years), and one patient had home BiPAP respiratory support at the age of 5.1 years | |
Mahmood et al. 2010 [63] USA | 98 late-infantile MLDc; 78 juvenile MLDc | ✔ | Three triplets with a diagnosis of late-infantile MLD had normal initial development; at approximately 16 months of age, a rapid change in their development was noticed | |||
Martin et al. 2012 [104] France | 10 late-infantile MLD; 3 juvenile MLD | ✔ | In the five late-infantile and three early-juvenile MLD patients with baseline and follow-up data available, changes in mean MRI severity scores over time indicated a more rapid decline in the late-infantile patients | |||
Strolin et al. 2017 [71] Germany | 46 juvenile MLD | ✔ | A significant positive correlation between demyelination load and higher GMFC-MLD level in patients with juvenile MLD was reported | |||
van Rappard et al. 2016 [101] Netherlands | 8 late-infantile MLD; 18 juvenile MLD | ✔ | Most evaluable untreated patients needed feeding via gastrostomy | |||
van Rappard et al. 2018 [87] Netherlands | 12 juvenile MLD | ✔ | A strong correlation between NAA concentration at baseline and GMFC-MLD score at latest follow-up was reported in untreated patients 2 years after diagnosis | |||
Zlotogora et al. 1981 [103] Israel | 6 late-infantile MLD | ✔ | Children with late-infantile MLD showed a significant delay in walking compared with unaffected children |