Pelizaeus-Merzbacher disease

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4265

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Disease Profile

1-9 / 1 000 000

US Estimated

Europe Estimated

Age of onset

All ages

ICD-10

E75.2

Inheritance

This condition is inherited in an X-linked recessive pattern. A condition is considered X-linked if the mutated gene that causes the disorder is located on the X chromosome, one of the two sex chromosomes. In males (who have only one X chromosome), one altered copy of the gene in each cell is sufficient to cause the condition. Because females have two copies of the X chromosome, one altered copy of the gene in each cell usually leads to less severe symptoms in females than in males, or may cause no symptoms at all. A striking characteristic of X-linked inheritance is that fathers cannot pass X-linked traits to their sons.^[1]

In X-linked recessive inheritance, a female with one altered copy of the gene in each cell is called a carrier. She can pass on the gene, but generally does not experience signs and symptoms of the disorder. Some females who carry a PLP1 mutation, however, may experience muscle stiffness and a decrease in intellectual function. Females with one PLP1 mutation have an increased risk of experiencing progressive deterioration of cognitive functions (dementia) later in life.^[1]

Individuals with a family history of Pelizaeus-Merzbacher disease may benefit from consulting with a genetics professional. This type of healthcare professional can provide information regarding genetic diagnosis, natural history, treatment, mode of inheritance, and genetic risks to other family members. Information about locating a genetics professional can be found under Healthcare Resources in the Find a Specialist section of this page.

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)

PMD; Pelizaeus Merzbacher disease; Pelizaeus Merzbacher brain sclerosis

Summary

Pelizaeus-Merzbacher disease is a disorder that affects the brain and spinal cord. It is a type of leukodystrophy and is characterized by problems with coordination, motor skills, and learning. The age of onset and the severity of the symptoms varies greatly depending on the type of disease. It is caused by an inability to form myelin due to mutations in the PLP1 gene. It is passed through families in an X-linked recessive pattern.^[1] The condition primarily affects males.^[1]^[2]^[3] Treatment requires a multidisciplinary team approach, with members dictated by the presenting symptoms.^[3]

Symptoms

Pelizaeus-Merzbacher disease is divided into classic and severe (connatal) types. Although these two types differ in severity, their symptoms can overlap.^[1]

Classic Pelizaeus-Merzbacher disease is the more common type. Within the first year of life, those affected with classic Pelizaeus-Merzbacher disease typically experience weak muscle tone (hypotonia), involuntary movements of the eyes (nystagmus), and delayed development of motor skills such as crawling or walking. As the child gets older, nystagmus may improve, but other movement disorders develop, including muscle stiffness (spasticity), problems with movement and balance (ataxia), and involuntary jerking (choreiform movements).^[1] Cognitive abilities may be impaired, but speech and language are usually present.^[3]

Severe or connatal Pelizaeus-Merzbacher disease is the more severe of the two types. Symptoms are usually present at birth or develop in the first few weeks of life. Features include nystagmus, problems feeding, a whistling sound when breathing, progressive spasticity leading to joint deformities (contractures) that restrict movement, speech difficulties (dysarthria), ataxia, and seizures.^[1] Children often have short stature and poor weight gain. Those affected with connatal Pelizaeus-Merzbacher disease don't walk or develop effective use of their upper limbs. Verbal expression is usually severely affected, but comprehension may be significant.^[3]

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.

Cause

Pelizaeus-Merzbacher disease is caused by mutations in the PLP1 gene.^[1]^[2]^[3] This gene provides instructions for producing proteolipid protein 1 and a modified version (isoform) of proteolipid protein 1, called DM20. Proteolipid protein 1 and DM20 are primarily located in the central nervous system and are the main proteins found in myelin, the fatty covering that insulates nerve fibers. A lack of proteolipid protein 1 and DM20 can cause dysmyelination, which can impair nervous system function, resulting in the signs and symptoms of Pelizaeus-Merzbacher disease.^[1]

It is estimated that 5 percent to 20 percent of people with Pelizaeus-Merzbacher disease do not have identified mutations in the PLP1 gene. In these cases, the cause of the condition is unknown.^[1]

Diagnosis

Making a diagnosis for a genetic or rare disease can often be challenging. Healthcare professionals typically look at a person’s medical history, symptoms, physical exam, and laboratory test results in order to make a diagnosis. The following resources provide information relating to diagnosis and testing for this condition. If you have questions about getting a diagnosis, you should contact a healthcare 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.
Orphanet lists international laboratories offering diagnostic testing for this condition.

Treatment

There is no cure for Pelizaeus-Merzbacher disease, nor is there a standard course of treatment.^[2]^[4] Management typically involves a multidisciplinary team made of specialists in neurology, physical medicine, orthopedics, pulmonary medicine, and gastroenterology. Management tactics may include gastrostomy for individuals with severe dysphagia; antiepileptic drugs (AEDs) for seizures; and routine management of spasticity including physical therapy, exercise, medications (baclofen, diazepam, tizanidine, botulinum toxin), orthotics, and surgery for joint contractures. Individuals with scoliosis may benefit from proper wheelchair seating and physical therapy, with surgery reserved for the most severe cases. Specialized education and assessments are generally necessary, and assisted communication devices may be helpful.^[3]

Medical Terms	Other Names	Learn More: HPO ID
100% of people have these symptoms
Nystagmus	Involuntary, rapid, rhythmic eye movements	0000639
Psychomotor deterioration		0002361
80%-99% of people have these symptoms
Abnormal pyramidal sign		0007256
Ataxia		0001251
Behavioral abnormality	Behavioral changes Behavioral disorders Behavioral disturbances Behavioral problems Behavioral/psychiatric abnormalities Behavioural/Psychiatric abnormality Psychiatric disorders Psychiatric disturbances [ more ]	0000708
Cachexia	Wasting syndrome	0004326
Cerebral cortical atrophy	Decrease in size of the outer layer of the brain due to loss of brain cells	0002120
Developmental regression	Loss of developmental milestones Mental deterioration in childhood [ more ]	0002376
Dystonia		0001332
Failure to thrive in infancy	Faltering weight in infancy Weight faltering in infancy [ more ]	0001531
Gait disturbance	Abnormal gait Abnormal walk Impaired gait [ more ]	0001288
Global developmental delay		0001263
Joint stiffness	Stiff joint Stiff joints [ more ]	0001387
Kyphosis	Hunched back Round back [ more ]	0002808
Muscular hypotonia	Low or weak muscle tone	0001252
Optic atrophy		0000648
Premature birth	Premature delivery of affected infants Preterm delivery [ more ]	0001622
Progressive spastic quadriplegia		0002478
Scoliosis		0002650
Slow progression	Signs and symptoms worsen slowly with time	0003677
Spasticity	Involuntary muscle stiffness, contraction, or spasm	0001257
Visual impairment	Impaired vision Loss of eyesight Poor vision [ more ]	0000505
30%-79% of people have these symptoms
Abnormality of the urinary system	Urinary tract abnormalities Urinary tract abnormality Urinary tract anomalies [ more ]	0000079
Abnormality of visual evoked potentials		0000649
Arteriovenous malformation		0100026
Bowel incontinence	Loss of bowel control	0002607
Choreoathetosis		0001266
Delayed speech and language development	Deficiency of speech development Delayed language development Delayed speech Delayed speech acquisition Delayed speech development Impaired speech and language development Impaired speech development Language delay Language delayed Language development deficit Late-onset speech development Poor language development Speech and language delay Speech and language difficulties Speech delay [ more ]	0000750
Dysarthria	Difficulty articulating speech	0001260
Dysphagia	Poor swallowing Swallowing difficulties Swallowing difficulty [ more ]	0002015
Failure to thrive	Faltering weight Weight faltering [ more ]	0001508
Head titubation		0002599
Hearing impairment	Deafness Hearing defect [ more ]	0000365
Intellectual disability	Mental deficiency Mental retardation Mental retardation, nonspecific Mental-retardation [ more ]	0001249
Microcephaly	Abnormally small skull Decreased circumference of cranium Decreased size of skull Reduced head circumference Small head circumference [ more ]	0000252
Neurological speech impairment	Speech disorder Speech impairment Speech impediment [ more ]	0002167
Recurrent respiratory infections	Frequent respiratory infections Multiple respiratory infections respiratory infections, recurrent Susceptibility to respiratory infections [ more ]	0002205
Reduction of oligodendroglia		0100709
Respiratory insufficiency	Respiratory impairment	0002093
Seizure		0001250
Short stature	Decreased body height Small stature [ more ]	0004322
Sudanophilic leukodystrophy		0003269
5%-29% of people have these symptoms
Congenital laryngeal stridor		0004886
Peripheral neuropathy		0009830
1%-4% of people have these symptoms
Hyporeflexia	Decreased reflex response Decreased reflexes [ more ]	0001265
Percent of people who have these symptoms is not available through HPO
Cerebral dysmyelination		0007266
Generalized hypotonia	Decreased muscle tone Low muscle tone [ more ]	0001290

Conditions with similar signs and symptoms from Orphanet
Differential diagnosis includes Krabbe disease, Canavan disease, metachromatic leukodystrophy, Alexander disease, familial SPG, PMLD (see these terms), and cerebral palsy. Visit the Orphanet disease page for more information.

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

Association Européenne contre les Leucodystrophies (ELA)
European Leukodystrophy Association
2, rue Mi-les-Vignes
BP 61024
54521 Laxou Cedex, France
Telephone: 333 83 30 93 34
Fax: 333 83 30 00 68
E-mail: ela@ela-asso.com
Website: https://www.ela-asso.com
Pelizaeus-Merzbacher Disease Foundation
1 Green Tree Center
1000 Lincoln Drive East, Ste 201
Marlton, NJ 08053
Telephone: 609-443-9623
E-mail: contact@pmdfoundation.org
Website: https://www.pmdfoundation.org
The Myelin Project
P.O. Box 39
Pacific Palisades, CA 90272
Telephone: 800-869-3546; 806 356 4693
Fax: 806 356 4694
E-mail: info@myelin.org
Website: https://www.myelin.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

Medline provides a list of resources on leukodystrophies. MedlinePlus is a Web site designed by the National Library of Medicine to help you research your health questions.
Genetics Home Reference (GHR) contains information on Pelizaeus-Merzbacher disease. 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.
MeSH® (Medical Subject Headings) is a terminology tool used by the National Library of Medicine. Click on the link to view information on this topic.
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 Pelizaeus-Merzbacher disease. Click on the link to view a sample search on this topic.

References

Pelizaeus-Merzbacher disease. Genetics Home Reference. March 2008; https://ghr.nlm.nih.gov/condition/pelizaeus-merzbacher-disease.
NINDS Pelizaeus-Merzbacher Disease Information Page. National Institute of Neurological Disorders and Stroke (NINDS). October 22, 2012; https://www.ninds.nih.gov/disorders/pelizaeus_merzbacher/pelizaeus_merzbacher.htm.
Hobson G, Kamholtz J. PLP1-Related Disorders. GeneReviews. February 28, 2013; https://www.ncbi.nlm.nih.gov/books/NBK1182/.
What is Pelizaeus-Merzbacher Disease (PMD)?. Pelizaeus-Merzbacher Disease (PMD) Foundation. 2014; https://pmdfoundation.org/what-is-pmd/.
Grace M Hobson, John Kamholz. PLP1-Related disorders. GeneReviews. February 28, 2013; https://www.ncbi.nlm.nih.gov/books/NBK1182/. Accessed 9/8/2016.

Rare Neurology News

Rare Neurology News

Rare Neurology News

All ages

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

Cause

Diagnosis

Testing Resources

Treatment

Related diseases

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.