Metachromatic leukodystrophy

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3230

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Disease Profile

1-9 / 1 000 000

US Estimated

Europe Estimated

Age of onset

Childhood

ICD-10

E75.2

Inheritance

Metachromatic leukodystrophy is inherited in an autosomal recessive manner. This means that both copies of the disease-causing gene in each cell must have a mutation for an individual to be affected. Individuals inherit two copies of each gene one copy from each parent. Typically, an individual is affected because they inherited a mutated copy of the gene from each parent. Individuals with one mutated copy of the gene (such as an unaffected parent of an affected individual) are referred to as carriers; carriers typically do not have any signs or symptoms of the condition.

When two carriers of an autosomal recessive condition have children, each child has a 25% (1 in 4) chance to have the condition, a 50% (1 in 2) chance to be a carrier like each of the parents, and a 25% chance to not have the condition and not be a carrier.

Autosomal dominant A pathogenic variant in only one gene copy in each cell is sufficient to cause an autosomal dominant disease.

Autosomal recessive Pathogenic variants in both copies of each gene of the chromosome are needed to cause an autosomal recessive disease and observe the mutant phenotype.

X-linked
dominant X-linked dominant inheritance, sometimes referred to as X-linked dominance, is a mode of genetic inheritance by which a dominant gene is carried on the X chromosome.

X-linked
recessive Pathogenic variants in both copies of a gene on the X chromosome cause an X-linked recessive disorder.

Mitochondrial or multigenic Mitochondrial genetic disorders can be caused by changes (mutations) in either the mitochondrial DNA or nuclear DNA that lead to dysfunction of the mitochondria and inadequate production of energy.

Multigenic or multifactor Inheritance involving many factors, of which at least one is genetic but none is of overwhelming importance, as in the causation of a disease by multiple genetic and environmental factors.

Not applicable

Other names (AKA)

Leukodystrophy metachromatic; Metachromatic leukoencephalopathy; MLD;

Summary

Metachromatic leukodystrophy is an inherited condition characterized by the accumulation of fats called sulfatides in cells, especially cells of the nervous system. This accumulation results in progressive destruction of white matter of the brain, which consists of nerve fibers covered by myelin. Affected individuals experience progressive deterioration of intellectual functions and motor skills, such as the ability to walk. They also develop loss of sensation in the extremities, incontinence, seizures, paralysis, inability to speak, blindness, and hearing loss. Eventually they lose awareness of their surroundings and become unresponsive. This condition is inherited in an autosomal recessive pattern and is caused by mutations in the ARSA and PSAP genes.^[1]

Symptoms

This table lists symptoms that people with this disease may have. For most diseases, symptoms will vary from person to person. People with the same disease may not have all the symptoms listed. This information comes from a database called the Human Phenotype Ontology (HPO) . The HPO collects information on symptoms that have been described in medical resources. The HPO is updated regularly. Use the HPO ID to access more in-depth information about a symptom.

Medical Terms	Other Names	Learn More: HPO ID
80%-99% of people have these symptoms
Abnormal enzyme/coenzyme activity		0012379
Periventricular leukomalacia		0006970
30%-79% of people have these symptoms
Abnormality of visual evoked potentials		0000649
Ataxia		0001251
Decreased nerve conduction velocity		0000762
Developmental regression	Loss of developmental milestones Mental deterioration in childhood [ more ]	0002376
Frequent falls		0002359
Hearing impairment	Deafness Hearing defect [ more ]	0000365
Hyperintensity of cerebral white matter on MRI		0030890
Hyporeflexia	Decreased reflex response Decreased reflexes [ more ]	0001265
Increased CSF protein		0002922
Infantile muscular hypotonia	Decreased muscle tone in infant	0008947
Muscle spasm		0003394
Muscle weakness	Muscular weakness	0001324
Peripheral neuropathy		0009830
Progressive spasticity		0002191
Seizure		0001250
Visual impairment	Impaired vision Loss of eyesight Poor vision [ more ]	0000505
5%-29% of people have these symptoms
Addictive behavior		0030858
Bowel incontinence	Loss of bowel control	0002607
Dementia	Dementia, progressive Progressive dementia [ more ]	0000726
Dysarthria	Difficulty articulating speech	0001260
Dystonia		0001332
Emotional lability	Emotional instability	0000712
Gastrostomy tube feeding in infancy		0011471
Limb pain		0009763
Personality changes	Personality change	0000751
Psychosis		0000709
Schizophrenia		0100753
Toe walking	Toe-walking	0040083
Tremor		0001337
Urinary incontinence	Loss of bladder control	0000020
1%-4% of people have these symptoms
Abnormal duodenum morphology		0002246
Abnormal stomach morphology		0002577
Decerebrate rigidity		0025013
Hemobilia		0100762
Intussusception		0002576
Neoplasm of the gallbladder		0100575
Percent of people who have these symptoms is not available through HPO
Abnormality of the cerebral white matter		0002500
Autosomal recessive inheritance		0000007
Babinski sign		0003487
Bulbar palsy		0001283
Cholecystitis	Gallbladder inflammation	0001082
Chorea		0002072
Delusions		0000746
EMG: neuropathic changes		0003445
Gait disturbance	Abnormal gait Abnormal walk Impaired gait [ more ]	0001288
Gallbladder dysfunction		0005609
Generalized hypotonia	Decreased muscle tone Low muscle tone [ more ]	0001290
Hallucinations	Hallucination Sensory hallucination [ more ]	0000738
Hyperreflexia	Increased reflexes	0001347
Intellectual disability	Mental deficiency Mental retardation Mental retardation, nonspecific Mental-retardation [ more ]	0001249
Loss of speech		0002371
Mental deterioration	Cognitive decline Cognitive decline, progressive Intellectual deterioration Progressive cognitive decline [ more ]	0001268
Muscular hypotonia	Low or weak muscle tone	0001252
Optic atrophy		0000648
Peripheral demyelination		0011096
Progressive peripheral neuropathy		0007133
Spastic tetraplegia		0002510
Tetraplegia	Paralysis of all four limbs	0002445

Do you have updated information on this disease? We want to hear from you.

Diagnosis

If someone has a family history of metachromatic leukodystrophy (MLD) or someone is known to be a carrier for MLD, individuals who are biologically related to the affected individual or carrier are at risk to be a carrier. Generally speaking, the more closely related an individual is to the affected individual or carrier, the greater the chance for that person to be a carrier. Prior to genetic testing, the chance to be a carrier for some biological relatives of an affected individual are as follows:

Parent of affected individual: assumed to be 100% (called an obligate carrier)
Unaffected sibling of affected individual: 2 in 3 (~66.6%)
Aunt or uncle of affected individual: 1 in 2 (50%)
First cousin of affected individual: 1 in 4 (25%)

If someone has carrier testing and is found to be negative (not a carrier), that person's children are typically assumed to be negative also.

More information about the use of genetic carrier testing is available on GeneTests' Web site and can be viewed by clicking here.

Individuals who are interested in learning about genetic testing and about their specific risk to be a carrier should speak with a genetics professional.

Testing Resources

The Genetic Testing Registry (GTR) provides information about the genetic tests for this condition. The intended audience for the GTR is health care providers and researchers. Patients and consumers with specific questions about a genetic test should contact a health care provider or a genetics professional.

Organizations

Support and advocacy groups can help you connect with other patients and families, and they can provide valuable services. Many develop patient-centered information and are the driving force behind research for better treatments and possible cures. They can direct you to research, resources, and services. Many organizations also have experts who serve as medical advisors or provide lists of doctors/clinics. Visit the group’s website or contact them to learn about the services they offer. Inclusion on this list is not an endorsement by GARD.

Organizations Supporting this Disease

MLD Foundation
21345 Miles Drive
West Linn, OR 97068-2878
Toll-free: 800-617-8387
Telephone: 503-656-4808
Fax: 503-212-0159
E-mail: info@mldfoundation.org
Website: https://mldfoundation.org/
The Calliope Joy Foundation
PO Box 2866
Bala Cynwyd, PA 19004
Telephone: 610-664-1588
E-mail: info@thecalliopejoyfoundation.org
Website: https://www.thecalliopejoyfoundation.org

Organizations Providing General Support

Alex The Leukodystrophy Charity (Alex TLC)
45 Peckham High Street
London, SE15 5EB United Kingdom
Telephone: 020 7701 4388
E-mail: info@alextlc.org
Website: https://www.alextlc.org
United Leukodystrophy Foundation (ULF)
224 North Second Street
Suite 2
DeKalb, IL 60115
Toll-free: 1-800-728-5483
Telephone: +1-815-748-3211
Fax: +1-815-748-0844
E-mail: office@ulf.org
Website: https://ulf.org/

Learn more

These resources provide more information about this condition or associated symptoms. The in-depth resources contain medical and scientific language that may be hard to understand. You may want to review these resources with a medical professional.

Where to Start

The American Society of Gene & Cell Therapy provides information on the treatment of genetic diseases.
MedlinePlus was designed by the National Library of Medicine to help you research your health questions, and it provides more information about this topic.
Genetics Home Reference (GHR) contains information on Metachromatic leukodystrophy. This website is maintained by the National Library of Medicine.
The National Institute of Neurological Disorders and Stroke (NINDS) collects and disseminates research information related to neurological disorders. Click on the link to view information on this topic.
The National Organization for Rare Disorders (NORD) has a report for patients and families about this condition. NORD is a patient advocacy organization for individuals with rare diseases and the organizations that serve them.

In-Depth Information

GeneReviews provides current, expert-authored, peer-reviewed, full-text articles describing the application of genetic testing to the diagnosis, management, and genetic counseling of patients with specific inherited conditions.
Medscape Reference provides information on this topic. You may need to register to view the medical textbook, but registration is free.
The Monarch Initiative brings together data about this condition from humans and other species to help physicians and biomedical researchers. Monarch’s tools are designed to make it easier to compare the signs and symptoms (phenotypes) of different diseases and discover common features. This initiative is a collaboration between several academic institutions across the world and is funded by the National Institutes of Health. Visit the website to explore the biology of this condition.
Online Mendelian Inheritance in Man (OMIM) is a catalog of human genes and genetic disorders. Each entry has a summary of related medical articles. It is meant for health care professionals and researchers. OMIM is maintained by Johns Hopkins University School of Medicine.
Orphanet is a European reference portal for information on rare diseases and orphan drugs. Access to this database is free of charge.
PubMed is a searchable database of medical literature and lists journal articles that discuss Metachromatic leukodystrophy. Click on the link to view a sample search on this topic.

References

Metachromatic leukodystrophy. Genetics Home Reference. February 2013; https://ghr.nlm.nih.gov/condition/metachromatic-leukodystrophy. Accessed 9/19/2014.
Metachromatic Leukodystrophy Information Page. National Institute of Neurological Disorders and Stroke (NINDS). June 22, 2018; https://www.ninds.nih.gov/Disorders/All-Disorders/Metachromatic-Leukodystrophy-Information-Page.
Metachromatic leukodystrophy. Genetics Home Reference. September 2007; https://ghr.nlm.nih.gov/condition/metachromatic-leukodystrophy. Accessed 5/9/2012.

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Childhood

E75.2

Autosomal dominant A pathogenic variant in only one gene copy in each cell is sufficient to cause an autosomal dominant disease.

Autosomal recessive Pathogenic variants in both copies of each gene of the chromosome are needed to cause an autosomal recessive disease and observe the mutant phenotype.

X-linked dominant X-linked dominant inheritance, sometimes referred to as X-linked dominance, is a mode of genetic inheritance by which a dominant gene is carried on the X chromosome.

X-linked recessive Pathogenic variants in both copies of a gene on the X chromosome cause an X-linked recessive disorder.

Mitochondrial or multigenic Mitochondrial genetic disorders can be caused by changes (mutations) in either the mitochondrial DNA or nuclear DNA that lead to dysfunction of the mitochondria and inadequate production of energy.

Multigenic or multifactor Inheritance involving many factors, of which at least one is genetic but none is of overwhelming importance, as in the causation of a disease by multiple genetic and environmental factors.

Not applicable

Other names (AKA)

Categories

Summary

Symptoms

Diagnosis

Testing Resources

Organizations

Organizations Supporting this Disease

Organizations Providing General Support

Learn more

Where to Start

In-Depth Information

References

X-linked
dominant X-linked dominant inheritance, sometimes referred to as X-linked dominance, is a mode of genetic inheritance by which a dominant gene is carried on the X chromosome.

X-linked
recessive Pathogenic variants in both copies of a gene on the X chromosome cause an X-linked recessive disorder.