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Metachromatic leukodystrophy
Classification and external resources

Sulfatide
ICD-10 E75.2
ICD-9 330.0
OMIM 250100
DiseasesDB 8080
eMedicine ped/2893
MeSH D007966

Metachromatic leukodystrophy (MLD, also called Arylsulfatase A deficiency) is a lysosomal storage disease which is commonly listed in the family of leukodystrophies. 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. It involves sulfatide accumulation.[1]

Contents

Causes

MLD is directly caused by a deficiency of the enzyme arylsulfatase A.[2] 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.

Genetics

Autorecessive.svg

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

  • If both parents are carriers:
    • 25% (1 in 4) children will have the disorder
    • 50% (2 in 4) children will be carriers (but unaffected)
    • 25% (1 in 4) children will be free of MLD - unaffected child that is not a carrier
  • If one parent is affected and one is free of MLD:
    • 0% (0) children will have the disorder - only one parent is affected, other parent always gives normal gene
    • 100% (4 in 4) children will be carriers (but unaffected)
  • If one parent is a carrier and the other is free of MLD:
    • 50% (2 in 4) children will be carriers (but unaffected)
    • 50% (2 in 4) children will be free of MLD - unaffected child that is not a carrier

In addition to these frequencies there is a 'pseudo'-deficiency that affects 7% of the population. People with the pseudo deficiency do not have any MLD problems unless they also have carrier or affected status. Psuedo-deficiency tests as low enzyme levels but sulfatide is processed normally so MLD symptoms do not exist.

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

Symptoms and forms

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

  • In the late infantile form, which is the most common form of MLD (50-60%), affected children begin having difficulty walking after the first year of life, usually at 15-24 months. Symptoms include muscle wasting and weakness, muscle rigidity, developmental delays, progressive loss of vision leading to blindness, convulsions, impaired swallowing, paralysis, and dementia. Children may become comatose. Untreated, most children with this form of MLD die by age 5, often much sooner.
  • Children with the juvenile form of MLD (onset between 3–10 years of age) usually begin with impaired school performance, mental deterioration, and dementia and then develop symptoms similar to the late infantile form but with slower progression. Age of death is variable, but normally within 10 to 15 years of symptom onset although some juveniles can live for several decades or longer after onset.
  • The adult form commonly begins after age 16 as a psychiatric disorder or progressive dementia. Adult-onset MLD progresses more slowly than the late infantile and juvenile forms, with a protracted course of a decade or more.

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

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.

Treatment

There is no cure for MLD, and no standard treatment. It is a terminal illness. Children with advanced juvenile or adult onset, and late infantile patients displaying symptoms have 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 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 treatment options for the future are currently being investigated.[3] These include gene therapy and 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. The registry is not up and operating as of January 2010.

Research Towards a Cure and Clinical Trials

Bone Marrow and Stem Cell Transplant Therapies

  • Several trials are underway to continue to improve the effectiveness and reduce the risks of bone marrow and stem cell transplants. Cord blood transplants and reduced preparative routines are being studied.

Enzyme replacement therapy (ERT)

  • International Phase II/III clinical trials of HGT-1111 (a temporary name assigned by Shire Human Genetic Therapies, a division of Shire, PLC) are scheduled to start in early 2010. HGT-1111 (formerly called Metazyme) was developed by a Danish company, Zymenex, and was acquired by Shire HGT on April 24, 2008) The product has been granted orphan drug status in the EU and US. The details, of the proposed clinical trial including proposed eligibility and time lines are summarized here (updated January 2010). IRB and FDA reviews have been in process since Q2'2009 but approval for the proposed trial has not been granted. Recruiting of patients is expected to start in Q1'10.
  • HGT-1111 completed Phase I/II trials in Europe in September 2008. All patients are now on compassionate use/named access dosages pending next steps. Results of the trial were presented at the March 2009 meeting of the ACMG. A video presentation of phase I/II trial summary and a discussion about the phase II/III international clinical trial were presented at the March 2009 Munich and updated June 2009 Valley Forge (Philadelphia, PA) MLD Family Conference™. Conference videos can be see here.(updated July 2009)
  • Shire Human Genetics is expediting its acquired HGT-1111 therapy in front of its internally developed and now shelved HGT-1110 ERT.

Gene therapy

  • Two trials are in the planning stages by groups in Europe, one in Italy and one in France. At least one of these research teams is strongly considering a simultaneous trial in the US. (current - Mar. 2009)
  • The Italian group at the San Raffaele Telethon Institute for Gene Therapy in Milan, Italy are researching the efficacy and safety of hematopoietic stem cells (HSC) to deliver the therapeutic ARSA enzyme to the nervous system by the route of the blood cells. The had success repairing the HSCs from a mouse and transplanting the repaired HSCs back into the mouse. A HSC gene therapy clinical trial for humans has been proposed to the Italian authorities and is expected to start late in 2009. Similar to the successful mouse therapy the affected patients HSCs are isolated, normal ARSA gene is transplanted into the isolated HSCs, then their own corrected HSCs are transplanted back into the patient. Using the patient's own HSC should reduce or eliminate the complications of graft vs. host disease and provide a long term solution to proper ARSA expression in MLD patients. (Current Mar. 2009)

Substrate reduction therapy

  • The Cooper Health System (New Jersey) has recently closed enrollment in a clinical trial underway to determine the safety and efficacy of a Vitamin K antagonist (Warfarin) in treating Metachromatic Leukodystrophy (MLD).(current September 2009)

Research & Clinical trial updates provided by the MLD Foundation

See also

MLD Specific Organizations:

Leukodystophy & Lysosmal Disease Organizations:

External links

References

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