(medicine) A hereditary degenerative disease transmitted as an autosomal recessive, due to sulfatase A deficiency, with excess accumulation of sulfated lipids responsible for metachromasia in various tissues. Abbreviated MLD. Also known as sulfatide lipidosis.
Metachromatic leukodystrophy
| Sci-Tech Dictionary: metachromatic leukodystrophy |
(¦med·ə·krō′mad·ik ′lü·kə′dis·trə·fē)
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Neurological Disorder:
Metachromatic leukodystrophy |
Definition
Metachromatic leukodystrophy (MLD) is a rare degenerative neurological disease, and is the most common form of the leukodystrophies, a group of disorders affecting the fatty covering that acts as an insulator around nerve fibers known as the myelin sheath. With destruction of the myelin sheath, progressive deterioration of muscle control and intellectual ability occurs. Metachromatic leukodystrophy is inherited as an autosomal recessive trait, meaning that that the disease is inherited from parents that are both carriers, but do not have the disorder. There are three forms of MLD, distinguished by the age of onset and by the molecular defect in the gene underlying the disease.
Description
The late infantile form of metachromatic leukodystrophy, which is the most common form, usually begins in the second year of life (ranges 1–3 years). After normal early development, the infant displays irritability and an unstable walk. As the disease progresses, physical and mental deterioration occur. Developmental milestones, such as language development, are not met, and muscle wasting eventually gives way to spastic movements, then profound weakness. Seizures usually occur, followed by paralysis.
The juvenile form of MLD usually begins between the ages of 4 and 10 (ranges 3–20 years), and presents with disturbances in the ability to walk (gait disturbances), urinary incontinence, mental deterioration, and emotional difficulties. Some scientists distinguish between early and late juvenile MLD. Late juvenile MLD is similar to the adult form of the disease. Adult MLD begins after the age of 20 (ranges 16–30 years) and presents mainly with emotional disturbances and psychiatric symptoms, leading to a diagnosis of psychosis. Disorders of movement and posture appear later. Dementia (loss of mental capacity), seizures, and decreased visual function also occur.
Demographics
The frequency of MLD is estimated to be 1 in 40,000 persons in the United States. No differences have been identified on the basis of race, sex, or ethnic origin.
Causes and symptoms
MLD is caused by a deficiency of the enzyme arylsulfatase A (ARSA). Without properly functioning ARSA, a fatty substance known as sulfatide accumulates in the brain and other areas of the body such as the liver, gall bladder, kidneys, and/or spleen. The buildup of sulfatide in the central nervous system causes demyelination, the destruction of the myelin protective covering on nerve fibers. With progressive demyelination, motor skills and mental function diminish.
MLD is an autosomal recessive inherited disease and can be caused by mutations in two different genes, the ARSA and the prosaposin gene. Mutations in the ARSA gene are far more frequent. So far, about 50 mutations have been identified in ARSA gene.
Diagnosis
Diagnosis of MLD is suspected in a person displaying its symptoms. Magnetic resonance imaging may be used to identify lesions and atrophy (wasting) in the white matter of the brain that are characteristic of MLD. Urine tests usually show elevated sulfatide levels. Some psychiatric disorders coupled with difficulty walking or muscle wasting suggest the possibility of MLD. Blood testing can show a reduced activity of the ARSA enzyme.
Deficiency of the ARSA enzyme alone is not proof of MLD, because a substantial ARSA deficiency without any symptoms or clinical consequences is frequent in the general population. During diagnosis and genetic counseling, these harmless ARSA enzyme deficiencies must be distinguished from those causing MLD. The only diagnostic test that solves this problem and is definitive for MLD diagnosis is analysis of the genetic mutation.
Treatment team
The treatment team usually involves a neurologist, a pediatrician, an ophthalmologist, an orthopedist, a genetic counselor, a neurodevelopmental psychologist, a bone marrow transplant physician, a genetic and/or metabolic disease specialist, and also a physical and an occupational therapist.
Treatment
No effective treatment is available to reverse the course of MLD. Drug therapy is part of supportive care for symptoms such as behavioral disturbances, feeding difficulties, seizures, and constipation. Bone marrow transplantation has been tried and there is evidence that this treatment might slow the progression of the disease. In infants, during a symptom-free phase of the late infantile form, neurocognitive function may be stabilized, but the symptoms of motor function loss progress. Persons with the juvenile and adult forms of MLD and with mild or no symptoms are more likely to be stabilized with bone marrow transplantation. Gene therapy experimentation on animal models as a possible therapy is still under consideration, and there are not yet any gene therapy-related clinical trials for MLD.
Recovery and rehabilitation
MLD patients require follow-up evaluation and treatment. Physical therapists, occupational therapists, orthopedists, ophthalmologists, and neuropsychologists are often involved in helping maintain optimal function for as long as possible.
Clinical trials
As of early 2004, there is one open clinical trial for MLD sponsored by Fairview University and the National Institutes of Health: "Phase II Study of Allogeneic Bone Marrow or Umbilical Cord Blood Transplantation in Patients With Lysosomal or Peroxisomal Inborn Errors of Metabolism." Further information about the trial can be found at the National Institutes of Health clinical trials website
Prognosis
In young children with the late infantile form of MLD, progressive loss of motor and cognitive functions is rapid. Death usually results within five years after the onset of clinical symptoms. In the early juvenile form of MLD, although progression is less rapid, death usually occurs within 10–15 years of diagnosis, and most young people with the disease die before the age of 20. Persons with the late juvenile form often survive into early adulthood, and patients with the adult form may have an even slower progression.
Special concerns
Genetic counseling is important to inform the family about the risk of occurrence of MLD in future offspring. Prenatal testing may be available on an experimental basis in some centers.
Resources
BOOKS
Icon Health Publications. The Official Parent's Sourcebook on Metachromatic Leukodystrophy: A Revised and Updated Directory for the Internet Age. San Diego: Icon International Publishers, 2002.
von Figura, K., V. Gieselman, and J. Jaeken. "Metachromatic leukodystrophy." In The Metabolic and Molecular Bases of Inherited Disease, 8th ed., C. Scriver, A. Beadet, D. Valle, W. Sly, et al, eds. New York: McGraw-Hill Professional, 2001.
PERIODICALS
Giesselmann, V. "Metachromatic leukodystrophy: recent research developments." J Child Neurol. 18, no. 9 (September 2003): 591–594.
OTHER
"NINDS Metachromatic Leukodystrophy Information Page." National Institute of Neurological Disorders and Stroke. (March 4, 2004). http://www.ninds.nih.gov/health_and_medical/disorders/meta_leu_doc.htm.
ORGANIZATIONS
National Tay-Sachs and Allied Diseases Association. 2001 Beacon Street, Suite 204, Brighton, MA 02135. (617) 277-4463 or (800) 90-NTSAD (906-8723). info@ntsad.org. http://www.ntsad.org.
United Leukodystrophy Foundation. 2304 Highland Drive, Sycamore, IL 60178. (815) 895-3211 or (800) 728-5483; Fax: (815) 895-2432. ulf@tbcnet.com. http://www.ulf.org.
Igor Medica, MD, PhD
| Medical Dictionary: metachromatic leukodystrophy |
n.
An inherited metabolic disorder characterized by myelin loss, accumulation of metachromatic lipids in the white matter of the central and peripheral nervous systems, a marked excess of sulfatidates in white matter and in urine, progressive paralysis, and dementia.
| Wikipedia: Metachromatic leukodystrophy |
 |
This article does not cite any references or sources. Please help improve this article by adding citations to reliable sources. Unsourced material may be challenged and removed. (December 2007) |
| 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 cannot function properly.
Genetics
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.
For further information, see recessive gene and dominance relationship. Also, consult the MLD genetics page.
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, affected children begin having difficulty walking after the first year of life. 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.
- 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.
In rare cases the body can compensate for the deficiency and the person will exhibit no symptoms.
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 has organized 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 2009, but the team is optimistic that this will change later in 2009.
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. The active MLD trials are at the University of Minnesota, however, these therapies are also available at other institutions. Contact: Paul Orchard, M.D. +1 612-626-2961. (updated March 2009)
Enzyme replacement therapy (ERT)
- International Phase II/III clinical trials of HGT-1111 (a temporary name assigned by Shire) are scheduled to start by the end of 2009. 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 July 2009). As of July 2009 the IRB and FDA reviews are in process but approval for the proposed trial has not been granted. Recruiting of patients is expected to start in 2H'09.
- 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 scheduled to start by the end of 2009 from the March 2009 MLD Family Conference in Munich can be see here.(updated May 2009)
- Shire Human Genetics is expediting its acquired HGT-1111 therapy in front of its internally developed and now shelved HGT-1110 ERT.
- 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)
- The Cooper Health System (New Jersey) has a clinical trial underway to determine the safety and efficacy of a Vitamin K antagonist (Warfarin) in treating Metachromatic Leukodystrophy (MLD).(current May 2009)
Research & Clinical trial updates provided by the MLD Foundation
See also
MLD Specific Organizations:
Leukodystophy & Lysosmal Disease Organizations:
- Bethany's Hope (Canada)
- ELA, The European Leukodystrophy Association
- The Evanosky Foundation
- Hide & Seek Foundation for Lysosomal Disease Research
- The Myelin Project
- The Stennis Foundation
External links
- Some portions of this article are courtesy of the public domain text available at the National Institute of Neurological Disorders and Stroke [4]
- Further information regarding MLD, treatments, genetics, and current research projects, can be found at:
- 2008 eMedicine article about MLD by Ikeda & Moore of UCLA and Steiner of OHSU
- NIH/GeneReviews at NIH/UW GeneTests overview of MLD written by Arvan Fluharty of UCLA (updated September 2008)
References
- ^ metachromatic leukodystrophy at Dorland's Medical Dictionary
- ^ 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:. PMID 15720392. http://dx.doi.org/10.1111/j.1742-4658.2005.04553.x.
- ^ 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:. PMID 18978739. http://dx.doi.org/10.1038/bmt.2008.275.
- ^ "NINDS Metachromatic Leukodystrophy Information Page". http://www.ninds.nih.gov/disorders/metachromatic_leukodystrophy/metachromatic_leukodystrophy.htm. Retrieved 2009-06-07.
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Mentioned in
- Sphingolipid (biochemistry and molecular biology)
- MLD
- Leukodystrophy
- The Stennis Foundation
- Arylsulfatase A
- Hypotonia
- Sulfatide
- Sulfatidosis
- Sphingolipidoses
- Gangliosidosis
