Metachromatic leukodystrophy genotypes in The Netherlands reveal novel pathogenic ARSA variants in non-Caucasian patients

Beerepoot, Shanice; Dooren, Silvy J.M. van; Salomons, Gajja S.; Boelens, Jaap Jan; Jacobs, Edwin H.; Knaap, Marjo S. van der; Kuilenburg, André B. P.; Wolf, Nicole I.

doi:10.1007/s10048-020-00621-6

Cited by 13 publications

(24 citation statements)

References 31 publications

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“…Thus, we could substantiate our earlier findings that in late‐infantile MLD MRI abnormalities gradually evolve after symptom onset while in juvenile MLD MRI abnormalities are already present at symptom onset, in a larger cohort and describe early signs in more detail 14 . Part of the present cohort was previously published 4,6,7,14–16,20,25–32 . Fumagalli et al.…”

Section: Discussionsupporting

confidence: 90%

Recognizing early MRI signs (or their absence) is crucial in diagnosing metachromatic leukodystrophy

Schoenmakers

Beerepoot

Krägeloh‐Mann

et al. 2022

Ann Clin Transl Neurol

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Objectives Metachromatic leukodystrophy (MLD) has characteristic white matter (WM) changes on brain MRI, which often trigger biochemical and genetic confirmation of the diagnosis. In early or pre‐symptomatic disease stages, these typical MRI changes might be absent, hampering early diagnosis. This study aims to describe the characteristics of MRI WM abnormalities at diagnosis, related to clinical presentation. Methods We retrospectively reviewed brain MRIs of MLD patients followed in 2 centers at the time of diagnosis regarding MLD MRI score and presence of tigroid pattern. In addition, MLD subtype, symptom status, CNS/PNS phenotype, motor/cognitive/mixed phenotype, and the presence of CNS symptoms were evaluated. Results We included 104 brain MRIs from patients with late‐infantile (n = 43), early‐juvenile (n = 24), late‐juvenile (n = 20) and adult (n = 17) onset. Involvement of the corpus callosum was a characteristic early MRI sign and was present in 71% of the symptomatic late‐infantile patients, 94% of the symptomatic early‐juvenile patients and 100% of the symptomatic late‐juvenile and adult patients. Symptomatic early‐juvenile, late‐juvenile and adult patients generally had WM abnormalities on MRI suggestive of MLD. By contrast, 47% of the early‐symptomatic late‐infantile patients had no or only mild WM abnormalities on MRI, even in the presence of CNS symptoms including pyramidal signs. Interpretation Patients with late‐infantile MLD may have no or only mild, nonspecific abnormalities at brain MRI, partly suggestive of ‘delayed myelination’, even with clear clinical symptoms. This may lead to significant diagnostic delay. Knowledge of these early MRI signs (or their absence) is important for fast diagnosis.

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Section: Discussionsupporting

confidence: 90%

Recognizing early MRI signs (or their absence) is crucial in diagnosing metachromatic leukodystrophy

Schoenmakers

Beerepoot

Krägeloh‐Mann

et al. 2022

Ann Clin Transl Neurol

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“…In this retrospective study, we included 27 subjects from the MLD cohort (total n = 90) of the Amsterdam Leukodystrophy Center, a Dutch nationwide expertise centre, with a confirmed diagnosis of MLD 26 ; available data on the age of symptom onset and loss of gross motor function over time and at least one available CSF, plasma or serum sample. In addition, we included 13 patients from the same cohort with an already performed NfL measurement during clinical assessment in our centre, resulting in a total inclusion of 40 study participants.…”

Section: Methodsmentioning

confidence: 99%

Neurofilament light chain and glial fibrillary acidic protein levels in metachromatic leukodystrophy

Beerepoot

Heijst

Roos

et al. 2021

Brain

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Metachromatic leukodystrophy is a lethal metabolic leukodystrophy, with emerging treatments for early disease stages. Biomarkers to measure disease activity are required for clinical assessment and treatment follow-up. This retrospective study compared neurofilament light chain and glial fibrillary acidic protein levels in CSF (n = 11) and blood (n = 92) samples of 40 patients with metachromatic leukodystrophy (aged 0–42 years) with 38 neurologically healthy children (aged 0–17 years) and 38 healthy adults (aged 18–45 years), and analyzed the associations between these levels with clinical phenotype and disease evolution in untreated and transplanted patients. Metachromatic leukodystrophy subtype was determined based on the (expected) age of symptom onset. Disease activity was assessed by measuring gross motor function deterioration and brain MRI. Longitudinal analyses with measurements up to 23 years after diagnosis were performed using linear mixed models. CSF and blood neurofilament light chain and glial fibrillary acidic protein levels in pediatric controls were negatively associated with age (all P < 0.001). Blood neurofilament light chain level at diagnosis (median, interquartile range; picogram per milliliter) was significantly increased in both pre-symptomatic (14.7, 10.6–56.7) and symptomatic patients (136, 40.8–445) compared to controls (5.6, 4.5–7.1), and highest amongst patients with late-infantile (456, 201–854) or early-juvenile MLD (291.0, 104–445) and those ineligible for treatment based on best practice (291, 57.4–472). Glial fibrillary acidic protein level (median, interquartile range; picogram per milliliter) was only increased in symptomatic patients (591, 224–1150) compared to controls (119, 78.2–338) and not significantly associated with treatment eligibility (P = 0.093). Higher blood neurofilament light chain and glial fibrillary acidic protein levels at diagnosis were associated with rapid disease progression in late-infantile (P = 0.006 and P = 0.051, respectively) and early-juvenile patients (P = 0.048 and P = 0.039, respectively). Finally, blood neurofilament light chain and glial fibrillary acidic protein levels decreased during follow-up in untreated and transplanted patients but remained elevated compared with controls. Only neurofilament light chain levels were associated with MRI deterioration (P < 0.001). This study indicates that both proteins may be considered as non-invasive biomarkers for clinical phenotype and disease stage at clinical assessment, and that neurofilament light chain might enable neurologists to make better informed treatment decisions. In addition, neurofilament light chain holds promise assessing treatment response. Importantly, both biomarkers require pediatric reference values, given that their levels first decrease before increasing with advancing age.

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“…Genotype‐phenotype correlation has been variably reported 7‐10 . Three main clinical phenotypes have been described: the late‐infantile (LI, onset 0‐2.5 years) form (40‐60% of cases), 10 usually associated with two 0 alleles, and characterized by early motor impairment, rapid psychomotor regression, and premature death 11 ; the juvenile (J, onset 2.6‐16 years) variant (20‐40% of cases, with a higher prevalence in specific geographic areas 12 ), characterized by a combination of motor and cognitive deficits at onset and a more heterogenous progression than LI 13 ; the adult (AD, onset >16 years) form (18‐20% of cases), frequently presenting with cognitive decline, behavioral and psychiatric disturbances, and with variable outcomes 14 . The J and AD variants are either heterozygous or homozygous for R alleles 12 .…”

Section: Introductionmentioning

confidence: 99%

Metachromatic leukodystrophy: A single‐center longitudinal study of 45 patients

Fumagalli

Zambon

Rancoita

et al. 2021

J of Inher Metab Disea

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In this study, we characterize the natural course of metachromatic leukodystrophy (MLD), explore intra/inter group differences, and identify biomarkers to monitor disease progression. This is a longitudinal observational study. Genotype and characteristics at disease onset were recorded. Time‐to‐event analyses were performed to assess time to major disease‐related milestones in different subgroups. Longitudinal trajectories of nerve conduction velocities (NCV), brain MRI score, and brainstem auditory evoked responses (BAERs) were described. We recruited 22 late‐infantile, 14 early‐juvenile, 5 late‐juvenile, and 4 adult MLD patients. Thirty‐four were prospectively evaluated (median FU time 43 months). In late‐infantile patients, the attainment of independent walking was associated with a later age at dysphagia. In early‐juvenile, the presence of isolated cognitive impairment at onset was not a favorable prognostic factor. Late‐infantile and early‐juvenile subjects showed similar rapid loss of ambulation and onset of seizures, but late‐infantile displayed earlier loss of trunk control, dysphagia, and death. We found significant differences in all major disease‐related milestones (except death) between early‐juvenile and late‐juvenile patients. Late‐juvenile and adult patients both presented with a predominant cognitive impairment, mild/no peripheral neuropathy, lower brain MRI score at plateau compared to LI/EJ, and later cerebellar involvement. NCV and BAER were consistently severely abnormal in late‐infantile but not in older subjects, in whom both NCV and BAER were variably affected, with no deterioration over time in some cases. This study clarifies intra/inter group differences between MLD subtypes and provides additional indications regarding reliable clinical and instrumental tools to monitor disease progression and to serve as areference to evaluate the efficacy of future therapeutic interventions inthe different MLD variants.

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Metachromatic leukodystrophy genotypes in The Netherlands reveal novel pathogenic ARSA variants in non-Caucasian patients

Cited by 13 publications

References 31 publications

Recognizing early MRI signs (or their absence) is crucial in diagnosing metachromatic leukodystrophy

Recognizing early MRI signs (or their absence) is crucial in diagnosing metachromatic leukodystrophy

Neurofilament light chain and glial fibrillary acidic protein levels in metachromatic leukodystrophy

Metachromatic leukodystrophy: A single‐center longitudinal study of 45 patients

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