Extremely low arylsulfatase A enzyme activity does not necessarily cause symptoms: A long‐term follow‐up and review of the literature

Laugwitz, Lucia; Santhanakumaran, Vidiyaah; Spieker, Mareike; Boehringer, Judith; Bender, Benjamín; Gieselmann, Volkmar; Beck‐Woedl, Stefanie; Bruchelt, Gernot; Harzer, K.; Kraegeloh‐Mann, Ingeborg; Groeschel, Samuel

doi:10.1002/jmd2.12293

Cited by 8 publications

(3 citation statements)

References 45 publications

(129 reference statements)

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“…For example, when screening for MLD by quantification of ASA in dried blood spots via immunoassay, there is a risk of false-negative results due to the presence of conformationally normal ASA that is deficient in enzyme activity [ 64 , 65 ]. Low ASA activity itself does not necessarily result in symptomatic disease, so it is recommended that NBS strategies combine measurement of ASA activity, quantification of sulfatide and genetic testing [ 66 ]. An ongoing study of a pilot scheme in Northern Germany, for example, has offered proof of concept of a high-throughput method for MLD NBS incorporating testing for ASA activity, sulfatide levels and genetic confirmation [ 57 ].…”

Section: Discussionmentioning

confidence: 99%

A systematic review on the birth prevalence of metachromatic leukodystrophy

Chang,

Bergamasco,

Bonnin

et al. 2024

Orphanet J Rare Dis

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Background Metachromatic leukodystrophy (MLD) is an autosomal recessive lysosomal storage disease caused by deficiency in arylsulfatase A (ASA) activity arising primarily from ASA gene (ARSA) variants. Late-infantile, juvenile and adult clinical subtypes are defined by symptom onset at ≤ 2.5, > 2.5 to < 16 and ≥ 16 years, respectively. Epidemiological data were sought to address knowledge gaps and to inform decisions regarding the clinical development of an investigational drug. Methods To synthesize all available estimates of MLD incidence and birth prevalence worldwide and in selected countries, Ovid MEDLINE and Embase were searched systematically (March 11, 2022) using a population, intervention, comparator, outcome, time and setting framework, complemented by pragmatic searching to reduce publication bias. Where possible, results were stratified by clinical subtype. Data were extracted from non-interventional studies (clinical trials, non-clinical studies and case reports were excluded; reviews were used for snowballing only). Results Of the 31 studies included, 14 reported birth prevalence (13 countries in Asia–Pacific, Europe, the Middle East, North America and South America), one reported prevalence and none reported incidence. Birth prevalence per 100,000 live births ranged from 0.16 (Japan) to 1.85 (Portugal). In the three European studies with estimates stratified by clinical subtypes, birth prevalence was highest for late-infantile cases (0.31–1.12 per 100,000 live births). The distribution of clinical subtypes reported in cases diagnosed over various time periods in 17 studies varied substantially, but late-infantile and juvenile MLD accounted for at least two-thirds of cases in most studies. Conclusions This review provides a foundation for further analysis of the regional epidemiology of MLD. Data gaps indicate the need for better global coverage, increased use of epidemiological measures (e.g. prevalence estimates) and more stratification of outcomes by clinical and genetic disease subtype.

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Section: Discussionmentioning

confidence: 99%

A systematic review on the birth prevalence of metachromatic leukodystrophy

Chang,

Bergamasco,

Bonnin

et al. 2024

Orphanet J Rare Dis

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“…Moreover, a condition called ARSA pseudo-deficiency occurs in individuals possessing pseudo-deficiency alleles (c.1055A>G and/or c.*96A>G) in the ARSA gene. In these individuals, residual ARSA activity can be in the range of MLD patients', but the carriers remain healthy throughout their life and exhibit no or negligible sulfatide accumulation in urine [19,20].…”

Section: Diagnosis Of Metachromatic Leukodystrophymentioning

confidence: 99%

Newborn screening in metachromatic leukodystrophy – European consensus-based recommendations on clinical management

Laugwitz,

Schoenmakers,

Adang

et al. 2024

European Journal of Paediatric Neurology

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“…MLD is most commonly caused by pathogenic variants in ARSA , though can also result from pathogenic variants in PSAP , which encodes the activator protein saposin B [8]. ASA activity as measured in leukocytes is broadly associated with MLD sub-types, as it is lowest in younger-onset cases and higher in later-onset cases, though there are a number of reports of individuals with low levels of ASA activity who remain clinically and pathologically unaffected by MLD [2, 9]. Arsa deficient mice do not exhibit leukodystrophy unless the sulfatide-synthesising enzyme, Gal3st1 , is also over-expressed, suggesting abundance of sulfatide deposition rather than Arsa deficiency alone leads to leukodystrophy in MLD [10].…”

Section: Introductionmentioning

confidence: 99%

Inflammation and autophagy dysfunction in metachromatic leukodystrophy: a central role for mTOR?

Catchpole,

Hartanto,

Kataura

et al. 2023

Preprint

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Metachromatic leukodystrophy (MLD) is a lysosomal storage disorder typically resulting from bi-allelic loss-of-function variants in the ARSA gene which encodes the lysosomal enzyme, arylsulphatase A, leading to the accumulation of its substrate, sulphatide, and widespread demyelination. Although gene therapy is available for MLD, it is limited by high cost and a narrow window for intervention, which means the development of therapies for MLD remains a key goal. The aim of the present study was to explore disease mechanisms in MLD with a view to identifying novel targets for therapeutic intervention for patients who cannot avail of gene therapy. Post-mortem globus pallidus and dentate nucleus tissue was obtained from MLD cases (N=5; age 2-33 years old) and compared to age-, sex- and ethnicity- matched controls (N=5) and studied using discovery proteomics which demonstrated a marked inflammatory response, activation of the mTOR pathway, oxidative stress and metabolic remodelling in MLD cases. Histological analysis of inflammatory markers, including the terminal fragment of complement pathway activation, C3d, and the secreted glycoprotein YKL-40, a commonly used biomarker for inflammation, demonstrated their enrichment in MLD cases. Given that the mTOR pathway plays a key role in supressing autophagy, we next investigated autophagy and identified the accumulation of autophagosomes in MLD cases, consistent with deficient autophagy. Taken together, these findings suggest inflammation and autophagy dysfunction are key processes involved in MLD and that the mTOR pathway could be a novel therapeutic target for MLD.

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Extremely low arylsulfatase A enzyme activity does not necessarily cause symptoms: A long‐term follow‐up and review of the literature

Cited by 8 publications

References 45 publications

A systematic review on the birth prevalence of metachromatic leukodystrophy

A systematic review on the birth prevalence of metachromatic leukodystrophy

Newborn screening in metachromatic leukodystrophy – European consensus-based recommendations on clinical management

Inflammation and autophagy dysfunction in metachromatic leukodystrophy: a central role for mTOR?

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