Metachromatic leukodystrophy
Encyclopedia
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 system
s. It involves sulfatide
accumulation.
and is usually characterized by enzyme activity which is less than 10% of human controls. Without this enzyme, sulfatide
s 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.
A recent study contended sulfatide is not completely responsible for MLD because it is non toxic. It has been suggested lysosulfatide, sulfatide which has had its acyl group removed, plays a role because of its cytotoxic properties in vitro.
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% of the population. People with the pseudo deficiency do not have any MLD problems unless they also have carrier or affected status. Pseudo-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.
, and adult.
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.
. 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. 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.
and Stem Cell Transplant Therapies
Gene therapy
Enzyme replacement therapy
(ERT)
Substrate reduction therapy
Research & Clinical trial updates provided by the MLD Foundation
Leukodystrophy & Lysosomal Disease Organizations:
Lysosomal storage disease
Lysosomal storage diseases are a group of approximately 50 rare inherited metabolic disorders that result from defects in lysosomal function...
which is commonly listed in the family of leukodystrophies. Leukodystrophies affect the growth and/or development of myelin
Myelin
Myelin is a dielectric material that forms a layer, the myelin sheath, usually around only the axon of a neuron. It is essential for the proper functioning of the nervous system. Myelin is an outgrowth of a type of glial cell. The production of the myelin sheath is called myelination...
, the fatty covering which acts as an insulator around nerve
Nerve
A peripheral nerve, or simply nerve, is an enclosed, cable-like bundle of peripheral axons . A nerve provides a common pathway for the electrochemical nerve impulses that are transmitted along each of the axons. Nerves are found only in the peripheral nervous system...
fibers throughout the central
Central nervous system
The central nervous system is the part of the nervous system that integrates the information that it receives from, and coordinates the activity of, all parts of the bodies of bilaterian animals—that is, all multicellular animals except sponges and radially symmetric animals such as jellyfish...
and peripheral
Peripheral nervous system
The peripheral nervous system consists of the nerves and ganglia outside of the brain and spinal cord. The main function of the PNS is to connect the central nervous system to the limbs and organs. Unlike the CNS, the PNS is not protected by the bone of spine and skull, or by the blood–brain...
nervous system
Nervous system
The nervous system is an organ system containing a network of specialized cells called neurons that coordinate the actions of an animal and transmit signals between different parts of its body. In most animals the nervous system consists of two parts, central and peripheral. The central nervous...
s. It involves sulfatide
Sulfatide
Sulfatides are a class of sulfated galactosylceramides synthesized primarily in the oligodendrocytes in the central nervous system. Sulfatides are a type of sulfolipid.-Clinical significance:...
accumulation.
Causes
MLD is directly caused by a deficiency of the enzyme arylsulfatase AArylsulfatase A
Arylsulfatase A is an enzyme that breaks down cerebroside 3-sulfate into cerebroside and sulfate. In humans, arylsulfatase A is encoded by the ARSA gene.-External links:* *...
and is usually characterized by enzyme activity which is less than 10% of human controls. Without this enzyme, sulfatide
Sulfatide
Sulfatides are a class of sulfated galactosylceramides synthesized primarily in the oligodendrocytes in the central nervous system. Sulfatides are a type of sulfolipid.-Clinical significance:...
s 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.
A recent study contended sulfatide is not completely responsible for MLD because it is non toxic. It has been suggested lysosulfatide, sulfatide which has had its acyl group removed, plays a role because of its cytotoxic properties in vitro.
Genetics
- 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. Pseudo-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
Dominance relationship
Dominance in genetics is a relationship between two variant forms of a single gene, in which one allele masks the effect of the other in influencing some trait. In the simplest case, if a gene exists in two allelic forms , three combinations of alleles are possible: AA, AB, and BB...
. 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, juvenileChild
Biologically, a child is generally a human between the stages of birth and puberty. Some vernacular definitions of a child include the fetus, as being an unborn child. The legal definition of "child" generally refers to a minor, otherwise known as a person younger than the age of majority...
, 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, paralysisParalysisParalysis is loss of muscle function for one or more muscles. Paralysis can be accompanied by a loss of feeling in the affected area if there is sensory damage as well as motor. A study conducted by the Christopher & Dana Reeve Foundation, suggests that about 1 in 50 people have been diagnosed...
, and dementiaDementiaDementia is a serious loss of cognitive ability in a previously unimpaired person, beyond what might be expected from normal aging...
. Children may become comaComaIn medicine, a coma is a state of unconsciousness, lasting more than 6 hours in which a person cannot be awakened, fails to respond normally to painful stimuli, light or sound, lacks a normal sleep-wake cycle and does not initiate voluntary actions. A person in a state of coma is described as...
tose. 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 illnessTerminal illness
Terminal illness is a medical term popularized in the 20th century to describe a disease that cannot be cured or adequately treated and that is reasonably expected to result in the death of the patient within a short period of time. This term is more commonly used for progressive diseases such as...
. 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. These include gene therapy
Gene therapy
Gene therapy is the insertion, alteration, or removal of genes within an individual's cells and biological tissues to treat disease. It is a technique for correcting defective genes that are responsible for disease development...
and enzyme replacement therapy
Enzyme replacement therapy
Enzyme replacement therapy is a medical treatment replacing an enzyme in patients in whom that particular enzyme is deficient or absent. Usually this is done by giving the patient an intravenous infusion containing the enzyme...
(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
Natural history
Natural history is the scientific research of plants or animals, leaning more towards observational rather than experimental methods of study, and encompasses more research published in magazines than in academic journals. Grouped among the natural sciences, natural history is the systematic study...
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 MarrowBone marrow
Bone marrow is the flexible tissue found in the interior of bones. In humans, bone marrow in large bones produces new blood cells. On average, bone marrow constitutes 4% of the total body mass of humans; in adults weighing 65 kg , bone marrow accounts for approximately 2.6 kg...
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.
Gene therapy
Gene therapy
Gene therapy is the insertion, alteration, or removal of genes within an individual's cells and biological tissues to treat disease. It is a technique for correcting defective genes that are responsible for disease development...
- Two different approaches to Gene Therapy are being researched for MLD.
- The French group is exploring a direct injection into the brain. They anticipate starting clinical trials in 2012 (current - June 2011)
- Recruiting for the Italian Phase I/II Clinical Trial formally started on March 24, 2010 after approval from the Italian Authorities.The researchers at the San Raffaele Telethon Institute for Gene Therapy in Milan, Italy are testing the efficacy and safety of using an autologous (using the patient's own cells) hematopoietic stem cell transplant (HSCT) to deliver a super-therapeutic ARSA enzyme to the nervous system by the route of the blood cells. Using the patient's own stem cells with genetic correction should reduce or eliminate the complications of graft vs. host disease and provide a long term solution to proper ARSA expression in MLD patients. Bench and animal tests showed positive results.
- Inclusion criteria are pre-symptomatic late infantiles and both pre- and early-symptomatic juveniles. See details on inclusion criteria and the trial protocol here.
- The trial is single center in Milano, Italy. All costs to be paid by the researchers. This is a 3 year study. Four patients have been enrolled and recruiting is still underway.(Current June 2011)
Enzyme replacement therapy
Enzyme replacement therapy
Enzyme replacement therapy is a medical treatment replacing an enzyme in patients in whom that particular enzyme is deficient or absent. Usually this is done by giving the patient an intravenous infusion containing the enzyme...
(ERT)
- Shire has suspended development of their HGT-1111 intravenous ERT therapy after it was shown to not have sufficient effect. They are resuming work on their internally developed HGT-1110 intrathecal ERT product at the preclinical animal testing stage.
- Work on HGT-1110 was originally stopped when Shire acquired the HGT-1111 product in April 2008. (updated February 2010)
- Shire has orphan status on its HGT-1110 product in both the US and in Europe (9/2010).
- The now canceled HGT-1111 had completed Phase I/II trials in Europe as of September 2008. Initial data looked promising, but data gathered during the post-trial compassionate use/named access period where all patients were put on a uniform higher dose showed no practical benefit.
- 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 at the June 2009 Valley Forge (Philadelphia, PA) MLD Family Conference meetings. Conference videos can be see here.(updated July 2009)
- No published data is available yet on the post-trial study.
- 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.
- With the acquisition of HGT-1111 in April 2008, Shire Human Genetic Therapies is expediting this new intravenous ERT therapy in front of its internally developed and now shelved HGT-1110 intrathecal ERT. (updated April 2008)
Substrate reduction therapy
Substrate reduction therapy
Substrate reduction therapy offers an approach to treatment of certain metabolic disorders, especially glycogen storage diseases and lysosomal storage disorders. In a storage disorder, a critical failure in a metabolic pathway prevents cellular breakdown and disposal of some large molecule...
- Zacharon Pharmaceuticals from San Diego is initiating a drug discovery program for MLD. This program is based on using assays which measure sulfatide accumulation in cultured fibroblasts as a means to discover and develop small molecule drugs for MLD. (This approach differs from other approaches which have measured enzyme activity to discover effective drugs.) As of July 2011, Zacharon has begun adapting the assays it developed for other lysosomal storage diseases so that they can be employed to discover and develop drugs for MLD.
- 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:Leukodystrophy & Lysosomal Disease Organizations:
- Bethany's Hope (Canada)
- The Stennis FoundationThe Stennis FoundationThe Stennis Foundation is a registered nonprofit organization based in the U.S. The Foundation is primarily a fundraising organization, raising money, and then sending it to various research projects...
- ELA, The European Leukodystrophy Association
- The Evanosky Foundation
- Hide & Seek Foundation for Lysosomal Disease Research
- The Myelin ProjectThe Myelin ProjectThe Myelin Project is an international scientific research organization aimed at accelerating clinical and translational research focused on myelin repair and to regenerate the nerve's myelin sheath, — a process called remyelination — destroyed in a host of diseases such as multiple...
External links
- Some portions of this article are courtesy of the public domain text available at the National Institute of Neurological Disorders and StrokeNational Institute of Neurological Disorders and StrokeThe National Institute of Neurological Disorders and Stroke is a part of the U.S. National Institutes of Health . It conducts and funds research on brain and nervous system disorders and has a budget of just over US$1.5 billion...
- Further information regarding MLD, treatments, genetics, and current research projects, can be found at:
- Zacharon Pharmaceuticals
- Shire's drug development pipeline
- 2008 eMedicine article about MLD by Ikeda & Moore of UCLA and Steiner of OHSU overview of MLD written by Arvan Fluharty of UCLA (updated August 2011)
- OMIM entries on ARSA Deficiency