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Metachromatic leukodystrophy (MLD) is a rare and life-threatening inherited disease of the body’s neurometabolic system1,2

Metachromatic leukodystrophy (MLD) is a rare and life-threatening inherited disease of the body’s neurometabolic system1,2

MLD is an autosomal recessive disease and a lysosomal storage disorder caused by the lack of an enzyme called arylsulfatase A (ARSA)1

MLD is both a neurometabolic disorder and a leukodsytrophy that leads to progressive loss of motor function (loss of muscle tone, weakness, frequent falls, loss of balance) and cognitive skills (decline in school performance, speech difficulties, behavioral changes), dysphagia (difficulty swallowing), seizures, severe neurological disability, and ultimately death.1,3-5
Because patients with MLD progressively lose motor and cognitive function and some may never achieve the ability to walk, caregivers tend to spend an average of 15 hours per day caring for an affected child.4,6
Because patients with MLD progressively lose motor and cognitive function and some may never achieve the ability to walk, caregivers tend to spend an average of 15 hours per day caring for an affected child.4,6
Listen to one mother share the impact MLD had on her daughter
Lysosomal storage disorders come in many forms and cause toxic materials to build up in cells7

MLD happens when mutations in the ARSA gene stop the body from making the ARSA enzyme, which is responsible for the breakdown of sulfatides. This buildup of sulfatides happens in various tissue types, such as2,8,9:

Brain
Liver
Gallbladder
Kidneys

It is thought that this missing enzyme causes the breakdown of the myelin sheath and damages nerve fibers.2,10

The role of the ARSA enzyme in the body

Physiologic
sulfatides

Sulfatides are a major component of the myelin sheath.11

ARSA enzeme

The role of the ARSA enzyme is to break down sulfatides in the lysosome.10

Pathologic
ARSA Gene

MLD occurs when there are variants in the ARSA gene, causing a deficiency of the ARSA enzyme and decreasing the breakdown of these sulfatides.1,8

Accumulation of sulfatides

This accumulation of sulfatides leads to demyelination (damage to the myelin sheath) and neurodegeneration (decline of the nervous system).1,8

MLD mainly affects children, but has different subtypes based on age of symptom onset9,12

It is critical to diagnose MLD early before the disease progresses; MLD is fatal if left untreated.2 Patients may appear healthy at birth, but age of first symptoms can range from anywhere under 30 months to 17 years old.4,9 The average survival is 4.2 years for late infantile and 17.4 years for early juvenile patients.2
Patients with pre-symptomatic late infantile, pre-symptomatic early juvenile, and early symptomatic early juvenile MLD may have a treatment option. Learn more now

Patients with pre-symptomatic late infantile, pre-symptomatic early juvenile, and early symptomatic early juvenile MLD may have a treatment option.
Learn more now

References: 1. Biffi A, Cesani M, Fumagalli F, et al. Metachromatic leukodystrophy-mutation analysis provides further evidence of genotype-phenotype correlation. Clin Genet. 2008:74;349-357. 2. Mahmood A, Berry J, Wenger DA, et al. Metachromatic leukodystrophy: a case of triplets with the late infantile variant and a systematic review of the literature. J Child Neurol. 2010;25(5):572-580. 3. Lamichhane A, Cabrero RF. Metachromatic leukodystrophy. In: StatPearls [internet]. StatPearls Publishing; January 2024. Accessed June 12, 2024. https://www.ncbi.nlm.nih.gov/books/NBK560744/ 4. Eichler F, Sevin C, Barth M. Understanding caregiver descriptions of initial signs and symptoms to improve diagnosis of metachromatic leukodystrophy. Orphanet J Rare Dis. 2022;17:370. 5. Kehrer C, Elgun S, Raabe C, et al. Association of age at onset and first symptoms with disease progression in patients with metachromatic leukodystrophy. Neurology. 2021(96):e255-e266. 6. Lin G, Suh K, Fahim SM, et al. Atidarsagene autotemcel for metachromatic leukodystrophy. Institute for Clinical and Economic Review; October 30, 2023. Accessed June 12, 2024. https://icer.org/assessment/metachromatic-leukodystrophy-2023/#timeline 7. Lysosomal storage disorders. National Organization for Rare Disorders. Accessed June 12, 2024. https://rarediseases.org/rare-diseases/lysosomal-storage-disorders/ 8. Gieselmann V, Krägeloh-Mann I. Metachromatic leukodystrophy – an update. Neuropediatrics. 2010;41:1-6. 9. Wang RY, Bodamer OA, Watson MS, et al. Lysosomal storage diseases: diagnostic confirmation and management of presymptomatic individuals. Gen Med. 2011:13;457-484. 10. Metachromatic leukodystrophy. Cleveland Clinic. Accessed June 12, 2024. https://my.clevelandclinic.org/health/diseases/6067-metachromatic-leukodystrophy 11. Jeon SB, Yoon HJ, Park SH, Kim IH, Park EJ. Sulfatide, a major lipid component of myelin sheath, activates inflammatory responses as an endogenous stimulator in brain-resident immune cells. J Immunol. 2008;181(11):8077-8087. 12. Gomez-Ospina N. Arylsulfatase A deficiency. In: Adam MP, Feldman J, Mirzaa GM, et al, eds. GeneReviews® [internet]. University of Washington; 1993-2024. Revised April 25, 2024. Accessed July 10, 2024. https://www.ncbi.nlm.nih.gov/books/NBK1130/