Metachromatic leukodystrophy

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Metachromatic leukodystrophy
Classification and external resources
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Metachromatic leukodystrophy
Classification and external resources

Metachromatic leukodystrophy (MLD, also called Arylsulfatase A deficiency) is a lysosomal storage disease which is commonly listed in the family of leukodystrophies as well as among the sphingolipidoses as it affects the metabolism of sphingolipids. Leukodystrophies affect the growth and/or development of myelin, the fatty covering which acts as an insulator around nerve fibers throughout the central and peripheral nervous systems. MLD involves cerebroside sulfate accumulation.[1][2] Metachromatic leukodystrophy, like most enzyme deficiencies, has an autosomal recessive inheritance pattern.[2]


Diagram showing the disrupted pathway

MLD is directly caused by a deficiency of the enzyme arylsulfatase A[3] (ARSA) and is characterized by enzyme activity in leukocytes that is less than 10% of normal controls.[4] However, assay of the ARSA enzyme activity alone is not sufficient for diagnosis; ARSA pseudodeficiency, which is characterized by enzyme activity that is 5~20% of normal controls does not cause MLD.[5] Without this enzyme, sulfatides build up in many tissues of the body, eventually destroying the myelin sheath of the nervous system. The myelin sheath is a fatty covering that protects nerve fibers. Without it, the nerves in the brain (central nervous system - CNS) and the peripheral nerves (peripheral nervous system - PNS) which control, among other things the muscles related to mobility, cease to function properly.

Arylsulfatase A is activated by Saposin B (Sap B), a non-enzymatic proteinaceous cofactor. When the Arylsulfatase A enzyme level is normal but the sulfatides are still high - meaning that they are not being broken down because the enzyme is not activated the resulting disease is Saposin B Deficiency. Saposin B Deficiency is very rare, much more rare than traditional MLD. The enzyme that is present is not "enabled" to a normal level of efficiency and can't break down the sulfatides which results in all of the same MLD symptoms and progression. - See more at:

A recent study contended sulfatide is not completely responsible for MLD because it is nontoxic. It has been suggested lysosulfatide, sulfatide which has had its acyl group removed, plays a role because of its cytotoxic properties in vitro.[6]



MLD has an autosomal recessive inheritance pattern. The inheritance probabilities per birth are as follows:

In addition to these frequencies there is a 'pseudo'-deficiency that affects 7%-15% of the population.[7][8] People with the pseudo deficiency do not have any MLD problems unless they also have affected status. With the current diagnostic tests, Pseudo-deficiency reports as low enzyme levels but sulfatide is processed normally so MLD symptoms do not exist. This phenomenon wreaks havoc with traditional approaches to Newborn Screening so new screening methods are being developed.

For further information, see recessive gene and dominance relationship. Also, consult the MLD genetics page at the MLD Foundation.


The incidence of metachromatic leukodystrophy is estimated to occur in 1 in 40,000 to 1 in 160,000 individuals worldwide.[9] There is a much higher incidence in certain genetically isolated populations, such as 1 in 75 in Habbanites (a small group of Jews who immigrated to Israel from southern Arabia), 1 in 2,500 in the western portion of the Navajo Nation, and 1 in 8,000 among Arab groups in Israel.[9]

Symptoms and forms[edit]

Like many other genetic disorders that affect lipid metabolism, there are several forms of MLD, which are late infantile, juvenile, and adult.

Palliative care can help with many of the symptoms and usually improves quality of life and longevity.

Carriers have low enzyme levels compared to their family population ("normal" levels vary from family to family) but even low enzyme levels are adequate to process the body's sulfatide.


There is currently no treatment or cure for MLD. Children with advanced juvenile or adult onset and late infantile patients displaying symptoms receive treatment limited to pain and symptom management. Presymptomatic late infantile MLD patients, as well as those with juvenile or adult MLD that are either presymptomatic or displaying mild to moderate symptoms, have the option of bone marrow transplantation (including stem cell transplantation), which is under investigation to see if it may slow down progression of the disease or stop its progression in the central nervous system. However, results in the peripheral nervous system have been less dramatic, and the long-term results of these therapies have been mixed.

Several future treatment options are currently being investigated. These include gene therapy, enzyme replacement therapy (ERT), substrate reduction therapy (SRT), and potentially enzyme enhancement therapy (EET).

A team of international researchers and foundations organized in 2008 to form an International MLD Registry to create and manage a shared repository of knowledge, including the natural history of MLD. This consortium consists of scientific, academic and industry resources. This registry never became operational.[10]

Clinical trials[edit]

Bone marrow and stem cell transplant therapies[edit]

Gene therapy[edit]

Main article: Gene therapy

Two different approaches to gene therapy are currently being researched for MLD.

Enzyme replacement therapy (ERT)[edit]

(current as of June 2014)

Substrate reduction therapy[edit]

Natural History Studies[edit]

Main article: Natural History Studies

more information here (current June 2014)

Research & Clinical Trial updates provided by the MLD Foundation

See also[edit]


  1. ^ "metachromatic leukodystrophy" at Dorland's Medical Dictionary
  2. ^ a b Le, Tao; Bhushan, Vikas; Hofmann, Jeffrey (2012). First Aid for the USMLE Step 1. McGraw-Hill. p. 117. 
  3. ^ Poeppel P, Habetha M, Marcão A, Büssow H, Berna L, Gieselmann V (March 2005). "Missense mutations as a cause of metachromatic leukodystrophy, Degradation of arylsulfatase A in the endoplasmic reticulum". FEBS J. 272 (5): 1179–88. doi:10.1111/j.1742-4658.2005.04553.x. PMID 15720392. 
  4. ^ Fluharty, Arvan. "Arylsulfatase A Deficiency: Metachromatic Leukodystrophy, ARSA Deficiency". GeneReviews, 2006
  5. ^ Fluharty, Arvan. "Arylsulfatase A Deficiency: Metachromatic Leukodystrophy, ARSA Deficiency". GeneReviews, 2006
  6. ^ Blomqvist, M.; Gieselmann, V.; Månsson, J. E. (2011). "Accumulation of lysosulfatide in the brain of arylsulfatase A-deficient mice". Lipids in Health and Disease 10 (1): 28. doi:10.1186/1476-511X-10-28. PMC 3041674. PMID 21299873.  edit
  7. ^ Hohenschutz, C; Eich P; Friedl W; Waheed A; Conzelmann E; Propping P. (April 1989). "Pseudodeficiency of arylsulfatase A". Human Genetics 45–8. PMID 2565866. Retrieved 2012-09-30. 
  8. ^ Herz, Barbara; Bach, G. (1984). HUMAN GENETICS 66: 147–150 |url= missing title (help). Retrieved 2012-09-30. 
  9. ^ a b Metachromatic leukodystrophy at Genetics Home Reference. Reviewed September 2007
  10. ^ MLD Registry
  11. ^ Biffi A, Lucchini G, Rovelli A, Sessa M (October 2008). "Metachromatic leukodystrophy: an overview of current and prospective treatments". Bone Marrow Transplant. 42 Suppl 2: S2–6. doi:10.1038/bmt.2008.275. PMID 18978739. 
  12. ^ Biffi, A.; Montini, E.; Lorioli, L.; Cesani, M.; Fumagalli, F.; Plati, T.; Baldoli, C.; Martino, S.; Calabria, A.; Canale, S.; Benedicenti, F.; Vallanti, G.; Biasco, L.; Leo, S.; Kabbara, N.; Zanetti, G.; Rizzo, W. B.; Mehta, N. A. L.; Cicalese, M. P.; Casiraghi, M.; Boelens, J. J.; Del Carro, U.; Dow, D. J.; Schmidt, M.; Assanelli, A.; Neduva, V.; Di Serio, C.; Stupka, E.; Gardner, J.; Von Kalle, C. (2013). "Lentiviral Hematopoietic Stem Cell Gene Therapy Benefits Metachromatic Leukodystrophy". Science 341 (6148): 1233158. doi:10.1126/science.1233158.  edit
  13. ^ Inclusion criteria, Therapy Description & Contact information
  14. ^ "GSK Product Pipeline". GSK. March 2014. Retrieved 29 June 2014. 
  15. ^
  16. ^ [1]
  17. ^ [2]
  18. ^ EU/3/10/813 European Commission orphan designation EU/3/10/813 issued 26-November-2010
  19. ^ FDA/OOPD issued 27-February-2008
  20. ^
  21. ^
  22. ^ [3]
  23. ^

External links[edit]

Some portions of this article are courtesy of the public domain text available at the National Institute of Neurological Disorders and Stroke:

MLD Specific Global Organizations:

Leukodystrophy & Lysosomal Disease Organizations:

Further information