• Disease Overview
  • Synonyms
  • Signs & Symptoms
  • Causes
  • Affected Populations
  • Disorders with Similar Symptoms
  • Diagnosis
  • Standard Therapies
  • Clinical Trials and Studies
  • References
  • Programs & Resources
  • Complete Report

Pelizaeus-Merzbacher Disease

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Last updated: August 13, 2020
Years published: 1986, 1987, 1990, 1994, 2001, 2010, 2017, 2020


Acknowledgment

NORD gratefully acknowledges Grace M. Hobson, PhD, Principal Research Scientist Emeritus, Alfred I. duPont Hospital for Children, Nemours Biomedical Research, for assistance in the preparation of this report.


Disease Overview

Summary

Pelizaeus-Merzbacher disease (PMD) is a rare X-linked genetic disorder affecting the central nervous system that is associated with abnormalities of the white matter of the brain and spinal cord. It is one of the leukodystrophies in which disease is due to abnormal development of one or more components (predominantly fats or proteins) that make up the white matter (myelin sheath) of the brain. The myelin sheath is the protective covering of the nerve and nerves cannot function normally without it. In PMD, many areas of the central nervous system may be affected, including the deep portions of the cerebrum (subcortical), cerebellum, brain stem and spinal cord. Signs may include the impaired ability to coordinate movement (ataxia), involuntary muscle spasms (spasticity) that result in slow, stiff movements of the legs, delays in reaching developmental milestones, late onset loss of motor abilities, and progressive deterioration of intellectual function. The neurologic signs of PMD are usually slowly progressive.

PMD is associated with abnormalities (mutations or variants) in the PLP1 gene. Several forms of the disorder have been identified including classic PMD; connatal (meaning “at birth”) PMD; transitional PMD; and PLP1 null syndrome (no PLP1 protein). Forms of complicated spastic paraparesis and pure spastic paraparesis (designated SPG2) and hypomyelination of early myelinating structures (HEMS) are also caused by variants of the PLP1 gene.

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Synonyms

  • PMD
  • hypomyelinating leukodystrophy 1
  • HLD1
  • sclerosis, diffuse familial brain
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Signs & Symptoms

The signs of PMD may vary widely from person to person. The signs of the classical form of PMD usually begin during early infancy, typically before 2 months of age. Initially, affected infants may fail to develop normal control of the head and eyes, specifically abnormal head bobbing and rapid, involuntary, jerky eye movements (nystagmus). Abnormally slow growth may also be an early sign. As affected infants and children age, additional signs may become apparent, including muscle tremors, weakness, facial grimacing, lack of muscle tone (hypotonia), impaired ability to coordinate voluntary movements (ataxia), and/or impairment in the acquisition of skills requiring the coordination of muscular and mental activities (psychomotor retardation) including delays in reaching developmental milestones such as sitting, standing, and walking. Affected individuals may also develop involuntary muscle spasms (spasticity) that result in slow, stiff movements of the legs and potentially partial paralysis of the arms and legs (spastic quadriparesis); abnormal, permanent fixation of certain joints (contractures); progressive degeneration of the nerves that lead to the eyes (optic atrophy); and/or difficulty speaking (dysarthria). As some affected children age, nystagmus may disappear. Some children may also develop skeletal deformities secondary to the severe spasticity that typically develops over time.

The signs of connatal PMD are present at birth or are observed during the first few weeks of life. This form of the disorder is characterized by weakness, spasticity, high-pitched sound when breathing (stridor), nystagmus, and seizures. Severe difficulty while swallowing (dysphagia) may also occur, necessitating gastrostomy feeding. Affected infants may also exhibit deterioration of mental functions and failure to reach developmental milestones such as speaking and walking. The progression of this form of PMD is more rapid and severe than the classic form and is often fatal during childhood.

Transitional PMD is a form of disease that is intermediate between the classical and connatal forms. The signs are similar to those of the classical and connatal forms of the disorder. However, the rate of progression is faster than the classical form but slower than the connatal form.

The PLP1 null syndrome is characterized by mild spastic quadriparesis, mild ataxia, absence of nystagmus during infancy and a mild demyelinating peripheral neuropathy. Patients with this form typically learn to walk, but deteriorate more rapidly beginning in late adolescence or early adulthood. Female carriers of PMD-related PLP1 variants may have mild to moderate signs of the disease. In some cases, these signs resolve with age.

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Causes

PMD is inherited as an X-linked recessive genetic disorder that affects mostly males. X-linked genetic disorders are conditions caused by an abnormal gene on the X chromosome. Females that have a disease gene present on one of their two X chromosomes are carriers for that disorder. Female carriers usually do not display symptoms because one of their two X chromosomes is inactivated so that the genes on that chromosome are nonfunctioning. It is usually the X chromosome with the abnormal gene that is inactivated. Males have one X chromosome that is inherited from their mother, and if a male inherits an X chromosome that contains a disease gene, he will develop the disease.

Female carriers of PMD have a 25% chance with each pregnancy to have a carrier daughter like themselves, a 25% chance to have a non-carrier daughter, a 25% chance to have a son affected with the disease and a 25% chance to have an unaffected son. Females from families where males have a milder phenotype, such as SPG2 or the PLP1 null syndrome, should be more cautiously counseled. In some of these families, the disorder behaves more like an X-linked dominant disorder with reduced penetrance in which females can be affected but less severely than the affected males in the family.

Male PMD patients usually do not reproduce, but males with X-linked disorders who do reproduce pass the disease gene to all of their daughters who will be carriers. A male cannot pass an X-linked gene to his sons because males always pass their Y chromosome instead of their X chromosome with the PLP1 gene on it to male offspring.

The only gene that has been found to be associated with PMD is located on the X chromosome and called the proteolipid protein gene or PLP1. Approximately 5 to 20% of males with a syndrome consistent with PMD do not have a variant in the PLP1 gene. Some of these patients have a variant of the GJC2 gene (autosomal recessive) that causes a Pelizaeus-Merzbacher-like disease (PMLD), which is clinically indistinguishable from PMD. Others have variants in a growing list of other leukodystrophy genes that are being discovered (see Related Disorders).

Spastic paraplegia 2 (SPG2), hypomyelination of early myelinating structures (HEMS) and PMD result from different variants of the same gene (allelic disorders) on the X chromosome, the PLP1 gene.

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Affected populations

The classical and connatal forms of PMD affect males far more often than females. In rare cases, heterozygous females will exhibit some of the signs associated with the disorder. However, in the milder forms of PMD and the allelic SPG2 and HEMS, carrier females may be affected.

PMD is a rare disorder. Its prevalence in the general population is unknown but estimated as approximately 1 in 100,000 in the USA.

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Diagnosis

A diagnosis of PMD may be suspected based upon a thorough clinical evaluation, a detailed patient history, and a variety of specialized tests such as magnetic resonance imaging (MRI) to detect deficiency of white matter. Recognition of early myelination defects, such as lack of myelination in the cerebellum and brainstem, may aide in early diagnosis of the severe forms of PMD. Molecular genetic testing for the PLP1 gene is available to confirm the diagnosis.

Carrier testing is possible if a disease-causing variant in the PLP1 gene has been identified in an affected family member.

Prenatal diagnosis and preimplantation genetic diagnosis is available if a PLP1 gene variant is identified in an affected family member.

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Standard Therapies

Treatment

There is no standard treatment method or regimen for individuals with PMD. Treatment is based upon specific symptoms present such as medications that prevent seizures or those used for movement disorders. Supportive care, including emotional support for family members, is recommended as needed.

Genetic Counseling is recommended for individuals affected with PMD and their families.

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Clinical Trials and Studies

Information on clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.

For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:

Toll-free: (800) 411-1222
TTY: (866) 411-1010
Email: prpl@cc.nih.gov

Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/

For information about clinical trials sponsored by private sources, contact:
www.centerwatch.com

For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/

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References

TEXTBOOKS
Ropper, A.,et al.,eds. Adams and Victor’s Principles of Neurology. 10th ed. New York, NY: McGraw-Hill, Companies; 2014:960-961.

Kliegman, R.M. and Stanton, B.M.D, eds. Nelson Textbook of Pediatrics, 19th ed. Philadelphia, PA: Elsevier Saunders; 2011:2074.

JOURNAL ARTICLES
Bahrambeigi V, et al. Distinct patterns of complex rearrangements and a mutational signature of microhomeology are frequently observed in PLP1 copy number gain structural variants. Genome Med. 2019;11:80. 

Gupta N, et al. Long-term safety, immunologic response, and imaging outcomes following neural stem cell transplantation for Pelizaeus-Merzbacher disease. Stem Cell Reports. 2019;13:254-261.

Inoue, K. Pelizaeus-Merzbacher disease: molecular and cellular pathologies and associated phenotypes. Adv Exp Med Biol. 2019;1190:201-216.

Yamamoto-Shimojima K, et al. Elucidation of the pathogenic mechanism and potential treatment strategy for a female patient with spastic paraplegia derived from a single-nucleotide deletion in PLP1. J Hum Genet. 2019;64:665-671.

Margraf RL, et al. Novel PLP1 mutations identified with next-generation sequencing expand the spectrum of PLP1-associated leukodystrophy clinical phenotypes. Child Neurol Open. 2018;5:2329048X18789282.

Morlet T, et al. Auditory function in Pelizaeus-Merzbacher disease. J Neurol. 2018;265:1580-1589.

Osório MJ, Goldman SA. Neurogenetics of Pelizaeus-Merzbacher disease. Handb Clin Neurol. 2018;148:701-722.

Sarret C, et al. Brain diffusion imaging and tractography to distinguish clinical severity of human PLP1-related disorders. Dev Neurosci. 2018;40:301-311.

Laukka JJ, et al. Novel pathologic findings in patients with Pelizaeus-Merzbacher disease. Neurosci Lett. 2016;627:222-232.

Marteyn A, Baron-Van Evercooren A. Is involvement of inflammation underestimated in Pelizaeus-Merzbacher disease? Neurosci Res. 2016;94:1572-1578.

Osório MJ, et al. Concise Review: Stem Cell-Based Treatment of Pelizaeus-Merzbacher Disease. Stem Cells 2017;35:311-315.Sarret C et al. Time-course of myelination and atrophy on cerebral imaging in 35 patients with PLP1-related disorders. Dev Med Child Neurol. 2016;58:706-713.

Sumida K, et al. The magnetic resonance imaging spectrum of Pelizaeus-Merzbacher disease: A multicenter study of 19 patients. Brain Dev. 2016;38:571-580.

Beck CR, et al. Complex genomic rearrangements at the PLP1 locus include triplication and quadruplication. PLoS Genet. 2015;11:e1005050.

Kevelam SH, et al. Altered PLP1 splicing causes hypomyelination of early myelinating structures. Ann Clin Transl Neurol. 2015; 2:648-661.

Laukka JJ, et al. Diffusion tensor imaging of patients with proteolipid protein 1 gene mutations. J Neurosci Res. 2014;92:1723-1732.

Wishnew J et al. Umbilical cord blood transplantation to treat Pelizaeus-Merzbacher Disease in 2 young boys. Pediatrics 2014;134:e1451-1457.

Laukka JJ et al. Neuroradiologic correlates of clinical disability and progression in the X-Linked leukodystrophy Pelizaeus-Merzbacher disease. J Neurol Sci. 2013;335:75–81.

Martinez-Montero P, et al. PLP1 gene analysis in 88 patients with leukodystrophy. Clin Genet. 2013;84:566-571.

Gupta N, et al. Neural stem cell engraftment and myelination in the human brain. Sci Transl Med. 2012;4:155ra137.

Hobson GM, Garbern JY. Pelizaeus-Merzbacher disease, Pelizaeus-Merzbacher-like disease 1, and related hypomyelinating disorders. Semin Neurol. 2012;32:62–67.

Grossi S, et al. Molecular genetic analysis of the PLP1 gene in 38 families with PLP1-related disorders: identification and functional characterization of 11 novel PLP1 mutations. Orphanet J Rare Dis. 2011;6:40.

Fattal-Valevski A, et al. Variable expression of a novel PLP1 mutation in members of a family with Pelizaeus-Merzbacher disease. J Child Neurol. 2009;24:618-624.

Sima AA, et al. Neuronal loss in Pelizaeus-Merzbacher disease differs in various mutations of the proteolipid protein 1. Acta Neuropathol. 2009;118:531-539.

Garbern JY. Pelizaeus-Merzbacher disease: Genetic and cellular pathogenesis. Cell Mol Life Sci. 2007;64:50-65.

Lee JA, et al. A DNA replication mechanism for generating nonrecurrent rearrangements associated with genomic disorders. Cell 2007;131:1235-1247.

McGuire LM, et al. The impact of Pelizaeus-Merzbacher disease on the family. Pediatr Neurol. 2007;36:101-105.

Combes P, et al. PLP1 and GPM6B intragenic copy number analysis by MAPH in 262 patients with hypomyelinating leukodystrophies: Identification of one partial triplication and two partial deletions of PLP1.Neurogenetics 2006;7:31-37.

Hurst S, et al. Quantifying the carrier female phenotype in Pelizaeus-Merzbacher disease. Genet Med. 2006;8:371-378.

Hanefeld FA, et al. Quantitative proton MRS of Pelizaeus-Merzbacher disease: evidence of dys- and hypomyelination. Neurology 2005;65:701-706.

Inoue K. PLP1-related inherited dysmyelinating disorders: Pelizaeus-Merzbacher disease and spastic paraplegia type 2. Neurogenetics 2005;6:1-16.

Wolf NI et al. Three or more copies of the proteolipid protein gene PLP1 cause severe Pelizaeus-Merzbacher disease. Brain 2005;28:743-751.

Golomb MR, et al. Clinical findings in Pelizaeus-Merzbacher disease.J Child Neurol. 2004;19:328-331.

Inoue K, et al. Genomic rearrangements resulting in PLP1 deletion occur by nonhomologous end joining and cause different dysmyelinating phenotypes in males and females. Am J Hum Genet. 2002;71:838-853.

INTERNET
Wolf NI, van Spaendonk ML, Hobson GM, Kamholz J. PLP1-Related Disorders. 1999 Jun 15 [Updated 2019 Dec 19]. In: Adam MP, Ardinger, HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2020. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1182/ Accessed July 31, 2020.

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