Metachromatic Leukodystrophy (MLD)

Metachromatic leukodystrophy (MLD) is a rare inherited lysosomal disease in which deficiency of the enzyme arylsulfatase A (ARSA) lets sulfatides build up in the nervous system, destroying myelin in the brain and peripheral nerves. A gene therapy, atidarsagene autotemcel, is approved in the European Union (2020) and the United States (2024) for children with pre-symptomatic late infantile, pre-symptomatic early juvenile, or early symptomatic early juvenile MLD.

Table of Contents

  1. Overview and Biochemistry
  2. Clinical Forms
  3. Diagnosis
  4. Gene Therapy — Atidarsagene Autotemcel
  5. Hematopoietic Stem Cell Transplantation (HSCT)
  6. Symptomatic Management and Supportive Care
  7. Newborn Screening and Future Directions
  8. Key Research Papers
  9. Connections
  10. Featured Videos

Overview and Biochemistry

MLD is a lysosomal sphingolipid storage disorder caused by a deficiency of arylsulfatase A (ARSA), the enzyme that breaks down sulfatides, an essential lipid of myelin. When ARSA activity is insufficient, sulfatides accumulate progressively, leading to demyelination of both the central nervous system and the peripheral nerves. Demyelination is the hallmark of the disease (Gieselmann and Krägeloh-Mann, 2010; Adang et al., 2024).

MLD is inherited in an autosomal recessive pattern: it results from disease-causing variants in both copies of the ARSA gene. More rarely, it is caused by variants in the PSAP gene, which encodes the activator protein saposin B; a 2016 mutation update catalogued 200 ARSA and 10 PSAP disease-causing allele types (Cesani et al., 2016). A related disorder, multiple sulfatase deficiency, can look similar biochemically, which is one reason the US consensus guideline states that genotype is needed to tell these conditions apart (Adang et al., 2024).

Genotype and residual enzyme activity track the age of onset. ARSA variants are broadly grouped as null ("0", no or very low enzyme activity) or residual ("R", measurable activity); two null alleles are strongly associated with the late infantile form (Adang et al., 2024). Among Caucasians three disease-causing alleles are frequent; patients homozygous for null alleles have the late infantile form, while combinations with non-null alleles are associated with the juvenile and adult forms (Gieselmann and Krägeloh-Mann, 2010). P426L and I179S are the two most frequent variants in juvenile and adult MLD; in one comparison, P426L homozygotes mainly presented with progressive gait disturbance, while I179S compound heterozygotes presented with schizophrenia-like behavioural abnormalities, social dysfunction and mental decline (Rauschka et al., 2006).

An important diagnostic pitfall is ARSA pseudodeficiency: benign pseudodeficiency alleles lower measured enzyme activity without causing disease, which is why enzyme activity is interpreted together with sulfatide levels (Adang et al., 2024).

A 2024 systematic review found birth prevalence estimates from 14 studies in 13 countries ranging from 0.16 per 100,000 live births (Japan) to 1.85 per 100,000 (Portugal); in the three European studies stratified by subtype, birth prevalence was highest for late infantile cases (Chang et al., 2024, Orphanet J Rare Dis). A 2026 review in Pediatrics describes MLD as affecting approximately 1 per 100,000 newborns (Lam et al., 2026). The US Food and Drug Administration's 2024 approval announcement gives an estimate of one in every 40,000 individuals in the United States (FDA news release, March 18, 2024).

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Clinical Forms

MLD is grouped by the age at which neurological disease begins. The US consensus guideline uses late infantile (onset before 2.5 years), early juvenile (2.5 to 7 years), late juvenile (7 to 16 years) and adult (after 16 years) subtypes; late infantile and early juvenile together are called "early-onset MLD" (Adang et al., 2024). In a systematic review of birth-prevalence studies, late infantile and juvenile MLD accounted for at least two-thirds of cases in most studies (Chang et al., 2024, Orphanet J Rare Dis).

Late Infantile MLD

Late infantile MLD is the most common subtype, with rapid neurological deterioration beginning before 2.5 years of age (Adang et al., 2024). A systematic review of natural-history studies found a mean age at symptom onset of generally 16–18 months, with presentation dominated by motor symptoms and developmental delay (Chang et al., 2024, Eur J Med Res). The first symptom is often described as a plateau of gross motor skills or a failure to achieve independent walking. A subacute demyelinating peripheral neuropathy often precedes the central demyelination, and children may first be misdiagnosed with Guillain-Barré syndrome; intermittent strabismus or esotropia and an unexpected decline after a typical viral infection are also described (Adang et al., 2024). Patients with late infantile MLD had more rapid decline of motor function and lower survival than patients with juvenile MLD (Chang et al., 2024, Eur J Med Res).

Juvenile MLD

In the early juvenile form, neurological decline begins between 2.5 and 7 years, and its rate and symptoms resemble the late infantile form. In the late juvenile form (onset 7 to 16 years), the first symptoms may be cognitive or behavioural, or related to fine or gross motor difficulties (Adang et al., 2024). The systematic review found a mean age at onset of generally 6–10 years for juvenile MLD, with motor, cognitive and behavioural symptoms at presentation (Chang et al., 2024, Eur J Med Res).

Adult MLD

Adult MLD (onset after 16 years) is characterised by a predominance of early neuropsychiatric symptoms and a chronic, slower course (Adang et al., 2024); patients present with cognitive symptoms and psychiatric and mood disorders (Chang et al., 2024, Eur J Med Res). The guideline notes that, with wider use of genetic sequencing in adults with demyelination, adult MLD may prove more varied and more common than previously reported (Adang et al., 2024).

Beyond the Nervous System

Gallbladder involvement (sludging, polyps and, rarely, carcinoma) is a distinctive feature of MLD, and some patients are diagnosed through gallbladder disease before neurological symptoms (Adang et al., 2024). Ataxia, epilepsy, gallbladder abnormalities, incontinence, neuropathy and seizures were the commonly reported complications in the natural-history review (Chang et al., 2024, Eur J Med Res).

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Diagnosis

The 2024 US consensus guideline states that confirming MLD involves both genetic testing for ARSA variants and biochemical testing of residual ARSA enzyme activity and sulfatide levels; a combination of low ARSA activity, raised sulfatides and the genotype establishes the diagnosis (Adang et al., 2024).

Arylsulfatase A Enzyme Activity

All individuals with MLD have reduced ARSA activity. According to the guideline there are no standardised thresholds, but activity below 1% of normal is strongly associated with early-onset disease; one proposed scheme grades activity as severe (0 to under 2% of normal), moderate (2 to under 4%) and mild (4–13%). Because pseudodeficiency alleles also lower measured activity, enzyme results are paired with sulfatide levels (Adang et al., 2024).

Sulfatide Levels

Low ARSA activity raises sulfatide levels, and sulfatide measurement is part of the biochemical work-up described in the guideline. Sulfatide quantification in urine and neurofilament light chain are named there as biomarkers that still need validation for predicting disease subtype (Adang et al., 2024).

ARSA Gene Sequencing

Genetic testing identifies the ARSA variants, helps predict the subtype, and distinguishes MLD from saposin B (prosaposin) deficiency and multiple sulfatase deficiency, which cannot be excluded on biochemical findings alone. The guideline also describes testing the biological parents at diagnosis and testing at-risk siblings, because age at onset correlates strongly between siblings (Adang et al., 2024).

Nerve Conduction Studies

Changes in peripheral nerve myelination may be one of the first signs of MLD and typically precede demyelination visible on MRI, especially in the early-onset forms (Adang et al., 2024). The guideline lists unexplained peripheral neuropathy among the findings for which testing for MLD is to be considered at any age.

Brain MRI

In early-onset MLD the first brain MRI may look normal, show delayed myelination, or show thickening or enhancement of cranial nerves, which can lead to misdiagnosis; changes can then evolve within weeks to months. The guideline illustrates the established pattern with a child whose MRI at 29 months showed confluent, symmetric white-matter signal change with sparing of perivenular white matter (a "tigroid" pattern) and of the subcortical U-fibres, after an MRI at 22 months had shown no abnormality. A quantitative MRI severity scale exists for MLD (Adang et al., 2024).

Newborn Screening

Newborn screening pilots test dried blood spots in sequence: when sulfatide levels are raised, ARSA activity is measured, with final confirmation by molecular testing (Adang et al., 2024; Lam et al., 2026). Results are covered in the Newborn Screening section below.

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Gene Therapy — Atidarsagene Autotemcel

How It Works

Atidarsagene autotemcel (arsa-cel) is an autologous ex vivo lentiviral gene therapy. According to the European Medicines Agency (EMA) and the FDA:

  1. Blood-forming stem cells (CD34+ cells) are collected from the patient's own bone marrow or blood.
  2. A modified lentivirus, which cannot cause viral disease in humans, inserts a working copy of the ARSA gene into the cells.
  3. A few days before the infusion, the patient receives busulfan conditioning (high-dose chemotherapy) to clear existing bone marrow cells.
  4. The modified cells are given back as a single infusion into a vein; they engraft in the bone marrow and supply myeloid (immune) cells that produce ARSA, helping to break down sulfatides.

(EMA medicine overview; FDA news release.) In mouse studies, the benefit of this approach depended on, and was proportional to, ARSA overexpression in the microglia descended from the transplanted cells, whereas a peripheral source of the enzyme failed to deliver it effectively to the brain (Biffi et al., 2006).

Regulatory Approvals

The European Commission granted a marketing authorisation valid throughout the EU on 17 December 2020, after the EMA's committee adopted its opinion on 15 October 2020; the medicine had been designated an orphan medicine in 2007 (EMA). The FDA approved it on 18 March 2024 as the first FDA-approved gene therapy for children with pre-symptomatic late infantile, pre-symptomatic early juvenile, or early symptomatic early juvenile MLD; the application received Priority Review, Orphan Drug, Rare Pediatric Disease and Regenerative Medicine Advanced Therapy designations (FDA). The US consensus guideline notes approval in the United States, the European Union, the UK, Iceland, Liechtenstein and Norway (Adang et al., 2024).

Approved Indication

In the EU, the therapy is used in children with ARSA variants who have late infantile or early juvenile MLD without symptoms, and in children with early juvenile MLD who have initial symptoms but can still walk independently and have not yet developed mental deterioration (EMA). The EMA summary reports that benefit was greatest in children who had not yet developed symptoms and seemed to be lost in those who could no longer walk independently or had developed mental deterioration. This narrow window is the main argument made for newborn screening (Adang et al., 2024).

Clinical Evidence

The first clinical report, by Biffi et al. (Science, 2013; PubMed PMID: 23845948), treated three pre-symptomatic children with late infantile MLD. Gene-corrected cells engrafted extensively and stably, with high ARSA expression in blood-cell lineages and in cerebrospinal fluid, and the disease did not appear or progress 7 to 21 months beyond the predicted age of onset. An ad-hoc analysis of the phase 1/2 trial (Sessa et al., Lancet, 2016; PubMed PMID: 27289174) followed nine children for a median of 36 months: eight, seven of them treated before symptoms, had prevention of disease onset or halted progression compared with untreated historical controls, and gross motor performance in six was similar to that of normally developing children.

The long-term integrated analysis (Fumagalli et al., Lancet, 2022; PubMed PMID: 35065785) covered 29 children with pre-symptomatic or early symptomatic early-onset MLD, compared with an untreated natural-history cohort of 31. At a median follow-up of 3.16 years, 26 were alive; two died of disease progression and one of a sudden event judged unlikely to be treatment-related. Two years after treatment, the mean differences in total gross motor function scores between treated children and age- and subtype-matched untreated patients were 66% in late infantile MLD and 42% in early juvenile MLD. Most treated children gained motor skills within the range of healthy children or kept the ability to walk, and most showed normal cognitive development; benefit was particularly apparent in children treated before symptoms. All patients had at least one grade 3 or higher adverse event, mostly related to conditioning or the underlying disease; the only adverse event attributed to the therapy itself was transient anti-ARSA antibodies in four patients.

For its approval, the FDA assessed 37 children from two single-arm, open-label trials and an expanded access program. All children with pre-symptomatic late infantile MLD who were treated were alive at 6 years of age, compared with 58% in the natural-history group; at 5 years, 71% of treated children could walk without assistance; and 85% had normal language and performance IQ scores (FDA).

Safety and Limitations

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Hematopoietic Stem Cell Transplantation (HSCT)

Allogeneic hematopoietic stem cell transplantation (HSCT), a transplant of blood-forming cells from a donor, was the only treatment option clinically available for juvenile MLD for about 20 years (Groeschel et al., 2016).

Outcomes by Form

A 2023 systematic review found no benefit for survival, gross motor function or cognitive function in late infantile patients who received allogeneic HSCT; their disease progressed much like the natural history. In juvenile patients, survival did not differ from natural history, but cognitive and motor function stabilised in some, particularly those who were pre- or minimally symptomatic, while others progressed (Armstrong et al., 2023).

In a German case-control study of juvenile MLD (24 transplanted, 41 non-transplanted patients), 4 transplanted children died of transplant-related causes and 2 of rapid disease progression, giving 5-year survival of 79%; overall survival was similar between the groups during the observation period. Transplanted patients were less likely to lose gross motor or language function and had lower MRI severity scores. A stable course was more likely when transplantation took place at an early stage with no or only mild motor deficits and an IQ of at least 85, when onset was after age 4, or when MRI severity scores were low (Groeschel et al., 2016).

Risks

The systematic review associated allogeneic HSCT with severe complications, including treatment-related death, graft-versus-host disease and the need for re-transplantation (Armstrong et al., 2023). The US guideline notes that transplantation can in some cases accelerate disease progression, especially when started after gait abnormalities have begun (Adang et al., 2024).

Comparison With Gene Therapy

The same review reported that late infantile and early juvenile patients treated with gene therapy had better gross motor and cognitive function than those treated with HSCT, and a survival benefit over both natural history and HSCT in late infantile patients, while cautioning that the findings come from non-randomised studies (Armstrong et al., 2023).

Current Role

The US consensus guideline recommends considering ex vivo gene therapy for early-onset MLD and HSCT for late-onset MLD (late juvenile and adult) in patients with no or minimal disease involvement (Adang et al., 2024). European consensus recommendations for newborn-screened infants likewise pair gene therapy with early-onset and HSCT with late-onset MLD (Laugwitz et al., 2024).

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Symptomatic Management and Supportive Care

The US consensus guideline notes that, before universal newborn screening, most children are diagnosed beyond the window for treatment, and it describes multidisciplinary care to improve quality of life once symptoms have begun (Adang et al., 2024). The points below summarise that guideline.

Seizures

Reported seizure incidence in MLD ranges from 14% to 39%, with seizures more common in later stages. Focal seizures are the most common type, and various anti-seizure medicines have been used with a generally good response.

Tone, Mobility and Pain

The guideline lists physical, occupational and speech therapy for developmental delay; physiatry and equipment such as orthotics, braces, gait trainers, walkers, standers and bath chairs for mobility; and medical management of abnormal tone. Pain, irritability and disturbed sleep may come from increased tone, gut dysmotility, central irritability or peripheral neuropathy, and a sudden change in comfort is described as a reason for medical evaluation.

Feeding, Swallowing and the Gallbladder

Feeding problems, including less efficient swallowing, vomiting, intestinal dysmotility and constipation, are common in early-onset MLD and in later stages of all forms. Poor swallowing, neuropathy and low muscle tone raise the risk of aspiration pneumonia; once neurological decline has begun, a gastrostomy tube may be considered. Yearly gallbladder ultrasound appears in the guideline's monitoring table, and when a gastrostomy is placed, preventive gallbladder removal could be considered because of the potential cancer risk.

Neuropsychiatric Symptoms

For neuropsychiatric concerns, the guideline lists referral for neuropsychiatric testing, psychiatry and social work.

Bones, Skin, Bladder and Breathing

Reduced mobility and poor nutrition raise the risk of low bone mass and fractures, scoliosis and hip dislocation, skin breakdown and urinary tract infections; poor swallowing and low central tone raise the risk of pneumonia and breathing problems. MLD can also be associated with metabolic acidosis, whose incidence is unknown. Palliative care is described as a source of emotional and spiritual support and symptom management aligned with the family's goals.

Family Testing

Historically, most patients still eligible for treatment at diagnosis were found because an older sibling had the disease. The guideline describes testing the biological parents and at-risk family members, with a genetic counsellor knowledgeable in MLD involved from diagnosis.

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Newborn Screening and Future Directions

Because gene therapy and HSCT work best before symptoms, expert groups in the United States and Europe support newborn screening for MLD (Adang et al., 2024; Laugwitz et al., 2024).

Newborn Screening Programs and Pilots

A two-tier screen, raised sulfatides in dried blood spots followed by low ARSA activity, can accurately identify newborns with the early-onset forms (Lam et al., 2026). A 2025 systematic review reported that nationwide screening is carried out in Norway, with large prospective pilots in Germany, Austria, Italy and the US (Laugwitz et al., 2025). A 2026 review reported a consent-based screening study in 8 New York City hospitals, at least 4 US newborn screening programs in the process of adding MLD, and a low false-positive rate (Lam et al., 2026).

In the German and Austrian pilots, 359,282 newborns were screened between September 2021 and July 2025 with a three-tier algorithm (sulfatides, ARSA activity, ARSA sequencing). Nine screened positive and all were confirmed to have MLD, a detection rate of approximately 1 per 40,000. Seven were classified as pre-symptomatic early-onset MLD and referred for gene therapy; all treated infants had preserved neurological function up to 30 months after treatment (median 18.5 months). Two infants predicted to have late-onset MLD entered surveillance for HSCT and had remained free of nervous-system signs. No false-positive or known false-negative results were observed (Laugwitz et al., 2026).

A 2024 European Delphi consensus of 22 MLD experts, with patient advocates involved, produced 57 statements on managing infants identified by screening (Laugwitz et al., 2024).

Gene Delivery Directly to the Nervous System

Gene transfer with adeno-associated virus (AAV) vectors has been studied in animals. In MLD model mice, intrathecal AAV9 carrying ARSA reduced stored sulfatide; mice treated before symptoms also improved on a balance-beam test, while mice treated after symptoms did not, leading the authors to suggest that therapy may need to begin before neurological symptoms (Miyake et al., 2021).

Enzyme Replacement Therapy

In a phase 1/2 trial of intravenous recombinant ARSA in 13 children, motor and developmental scores declined in all dose groups, with no evidence of efficacy against motor and cognitive deterioration; the authors suggested the enzyme may not cross the blood-brain barrier in therapeutic amounts (Í Dali et al., 2021). With intrathecal delivery into the cerebrospinal fluid, a phase 1/2 trial in 24 children with onset at or before 30 months found no serious adverse events related to the enzyme, although 25% had a serious adverse event related to the intrathecal device or delivery method; cerebrospinal-fluid sulfatide levels fell to within normal ranges at the 100 mg dose, and motor decline tended to be less pronounced at that dose, though motor function generally declined (Í Dali et al., 2020). An MRI analysis of these children found that high-dose intrathecal treatment may delay neurological deterioration in some children (Groeschel et al., 2024).

Small-Molecule and Substrate Reduction Approaches

A 2013 review describes small molecules that may cross the blood-brain barrier more easily as possible enhancers of mutant ARSA, acting as pharmacological chaperones or proteostasis regulators, and small molecules that reduce sulfatide production (substrate reduction) as further possible strategies (Patil and Maegawa, 2013).

Patient Registries and Natural History Data

MLD experts started the European Metachromatic Leukodystrophy initiative (MLDi), an academia-led European registry; a modified Delphi procedure defined minimal, core and optional data sets so that treatments can be compared, monitored after marketing, and assessed for health technology appraisal (Schoenmakers et al., 2022). A 2024 systematic review found that data on regional epidemiology, quantitative cognition, the differences between early and late juvenile MLD, quality of life and economic outcomes remain limited (Chang et al., 2024, Eur J Med Res).

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Key Research Papers

  1. Biffi A, Montini E, Lorioli L, et al. Lentiviral hematopoietic stem cell gene therapy benefits metachromatic leukodystrophy. Science. 2013;341(6148):1233158. — First clinical report: three pre-symptomatic children with late infantile MLD; the disease did not manifest or progress 7 to 21 months beyond the predicted age of onset. — PubMed PMID: 23845948
  2. Gieselmann V, Krägeloh-Mann I. Metachromatic leukodystrophy — an update. Neuropediatrics. 2010;41(1):1-6 — Review of MLD clinical forms and genotype-phenotype correlation. — PubMed PMID: 20571983
  3. Sessa M, Lorioli L, Fumagalli F, et al. Lentiviral haemopoietic stem-cell gene therapy in early-onset metachromatic leukodystrophy: an ad-hoc analysis of a non-randomised, open-label, phase 1/2 trial. Lancet. 2016;388(10043):476-487. — Nine children, median follow-up 36 months; eight had prevention of disease onset or halted progression compared with untreated historical controls. — PubMed PMID: 27289174
  4. Fumagalli F, Calbi V, Natali Sora MG, et al. Lentiviral haematopoietic stem-cell gene therapy for early-onset metachromatic leukodystrophy: long-term results from a non-randomised, open-label, phase 1/2 trial and expanded access. Lancet. 2022;399(10322):372-383 — Integrated long-term analysis of 29 treated children compared with a 31-patient untreated natural-history cohort. — PubMed PMID: 35065785
  5. Groeschel S, Kühl JS, Bley AE, et al. Long-term outcome of allogeneic hematopoietic stem cell transplantation in patients with juvenile metachromatic leukodystrophy compared with nontransplanted control patients. JAMA Neurol. 2016;73(9):1133-1140 — Case-control study of 24 transplanted and 41 non-transplanted patients with juvenile MLD. — PubMed PMID: 27400410
  6. Chang SC, Eichinger CS, Field P, et al. The natural history and burden of illness of metachromatic leukodystrophy: a systematic literature review. Eur J Med Res. 2024;29(1):181 — Ages at onset, presenting symptoms and complications by subtype. — PubMed PMID: 38494502
  7. Cesani M, Lorioli L, Grossi S, et al. Mutation update of ARSA and PSAP genes causing metachromatic leukodystrophy. Hum Mutat. 2016;37(1):16-27 — Review of 200 ARSA and 10 PSAP disease-causing allele types. — PubMed PMID: 26462614
  8. Rauschka H, Colsch B, Baumann N, et al. Late-onset metachromatic leukodystrophy: genotype strongly influences phenotype. Neurology. 2006;67(5):859-863 — Clinical course of 22 P426L homozygotes compared with 20 I179S compound heterozygotes. — PubMed PMID: 16966551
  9. Í Dali C, Sevin C, Krägeloh-Mann I, et al. Safety of intrathecal delivery of recombinant human arylsulfatase A in children with metachromatic leukodystrophy: results from a phase 1/2 clinical trial. Mol Genet Metab. 2020;131(1-2):235-244 — 24 children; cerebrospinal-fluid sulfatide fell to normal ranges at 100 mg. — PubMed PMID: 32792226
  10. Biffi A, Capotondo A, Fasano S, et al. Gene therapy of metachromatic leukodystrophy reverses neurological damage and deficits in mice. J Clin Invest. 2006;116(11):3070-3082 — Mouse study: efficacy depended on ARSA overexpression in the microglia progeny of transplanted cells. — PubMed PMID: 17080200
  11. von Figura K, Gieselmann V, Jaeken J. Metachromatic leukodystrophy. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The Metabolic and Molecular Bases of Inherited Disease. 8th ed. New York: McGraw-Hill; 2001. (Textbook chapter — no PMID; foundational reference for MLD biochemistry and clinical classification.)
  12. Patil SA, Maegawa GH. Developing therapeutic approaches for metachromatic leukodystrophy. Drug Des Devel Ther. 2013;7:729-745 — Review of HSCT, intrathecal enzyme replacement, gene therapy and small-molecule strategies. — PubMed PMID: 23966770
  13. Adang LA, Bonkowsky JL, Boelens JJ, et al. Consensus guidelines for the monitoring and management of metachromatic leukodystrophy in the United States. Cytotherapy. 2024;26(7):739-748 — US expert consensus on diagnosis, subtypes, monitoring, treatment choice and supportive care. — PubMed PMID: 38613540
  14. Chang SC, Bergamasco A, Bonnin M, et al. A systematic review on the birth prevalence of metachromatic leukodystrophy. Orphanet J Rare Dis. 2024;19(1):80 — Birth prevalence 0.16 to 1.85 per 100,000 live births across 14 studies. — PubMed PMID: 38383398
  15. Armstrong N, Olaye A, Noake C, et al. A systematic review of clinical effectiveness and safety for historical and current treatment options for metachromatic leukodystrophy in children, including atidarsagene autotemcel. Orphanet J Rare Dis. 2023;18(1):248 — Allogeneic HSCT versus gene therapy versus natural history; no randomised trials. — PubMed PMID: 37644601
  16. Í Dali C, Groeschel S, Moldovan M, et al. Intravenous arylsulfatase A in metachromatic leukodystrophy: a phase 1/2 study. Ann Clin Transl Neurol. 2021;8(1):66-80 — 13 children; no evidence of efficacy against motor and cognitive decline. — PubMed PMID: 33332761
  17. Groeschel S, Beerepoot S, Amedick LB, et al. The effect of intrathecal recombinant arylsulfatase A therapy on structural brain magnetic resonance imaging in children with metachromatic leukodystrophy. J Inherit Metab Dis. 2024;47(4):778-791 — 510 MRI scans; high-dose intrathecal treatment may delay deterioration in some children. — PubMed PMID: 38321717
  18. Laugwitz L, Schoenmakers DH, Adang LA, et al. Newborn screening in metachromatic leukodystrophy — European consensus-based recommendations on clinical management. Eur J Paediatr Neurol. 2024;49:141-154 — Delphi consensus of 22 experts; 57 statements. — PubMed PMID: 38554683
  19. Laugwitz L, Shenker A, Sluys EF, et al. Newborn screening for metachromatic leukodystrophy: a systematic literature review. Int J Neonatal Screen. 2025;11(4):103 — 52 publications; nationwide screening in Norway and pilots in Germany, Austria, Italy and the US. — PubMed PMID: 41283365
  20. Lam WKK, Ream MA, Grosse SD, et al. Evidence regarding metachromatic leukodystrophy newborn screening. Pediatrics. 2026;158(Suppl 2):e2026077357E — Evidence review of the two-tier sulfatide and ARSA screen. — PubMed PMID: 42674587
  21. Laugwitz L, Martin P, Janzen N, et al. Clinical management of metachromatic leukodystrophy cases identified in the German and Austrian newborn screening pilots. Orphanet J Rare Dis. 2026;21(1):345 — 359,282 newborns screened; nine confirmed cases. — PubMed PMID: 42834411
  22. Miyake N, Miyake K, Sakai A, et al. Treatment of adult metachromatic leukodystrophy model mice using intrathecal administration of type 9 AAV vector encoding arylsulfatase A. Sci Rep. 2021;11(1):20513 — Mouse study of intrathecal AAV9 gene transfer. — PubMed PMID: 34654893
  23. Schoenmakers DH, Beerepoot S, van den Berg S, et al. Modified Delphi procedure-based expert consensus on endpoints for an international disease registry for metachromatic leukodystrophy: the European Metachromatic Leukodystrophy initiative (MLDi). Orphanet J Rare Dis. 2022;17(1):48 — Data sets for the academia-led European MLD registry. — PubMed PMID: 35164810

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