Pelizaeus-Merzbacher disease is an inherited condition involving the brain and spinal cord (central nervous system) that primarily affects males. This disease is one of a group of genetic disorders called leukodystrophies. Leukodystrophies are conditions that involve abnormalities of the nervous system's white matter, which consists of nerve fibers covered by a fatty substance called myelin. Myelin insulates nerve fibers and promotes the rapid transmission of nerve impulses. In particular, Pelizaeus-Merzbacher disease involves hypomyelination, which means that the nervous system has a reduced ability to form myelin. As a result, overall neurological function is reduced.

Pelizaeus-Merzbacher disease is divided into classic and connatal (present from birth) types. Although these two types differ in severity, their features can overlap.

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 sitting or grasping objects. Some individuals are able to walk with assistance. Despite these neurological problems, intellectual and motor skills develop throughout childhood, but development usually stops around adolescence, and these skills are slowly lost (developmental regression). As the condition worsens, nystagmus usually goes away but other movement disorders develop, including muscle stiffness (spasticity), problems with movement and balance (ataxia), head and neck tremors (titubation), involuntary tensing of the muscles (dystonia), and jerking (choreiform) movements.

Connatal Pelizaeus-Merzbacher disease is the more severe of the two types. Symptoms can begin in infancy and include problems with feeding, poor weight gain and slow growth, high-pitched breathing caused by an obstructed airway (stridor), nystagmus, progressive speech difficulties (dysarthria), severe ataxia, hypotonia, and seizures. As the condition worsens, affected children develop spasticity leading to joint deformities (contractures) that restrict movement. Individuals with connatal Pelizaeus-Merzbacher disease are never able to walk, and many are not able to purposefully use their arms. They also have problems producing speech (expressive language) but can generally understand speech (receptive language).

The prevalence of Pelizaeus-Merzbacher disease is estimated to be 1 in 200,000 to 500,000 males in the United States. This condition rarely affects females.

Mutations in the PLP1 gene cause Pelizaeus-Merzbacher disease. The PLP1 gene provides instructions for making proteolipid protein 1 and a modified version (isoform) of that protein called DM20. Proteolipid protein 1 is found primarily in nerves in the central nervous system and DM20 is produced mainly in nerves that connect the brain and spinal cord to muscles (peripheral nervous system). These two proteins are found within the cell membrane of nerve cells, where they make up the majority of myelin and anchor it to the cells.

Most mutations that cause Pelizaeus-Merzbacher disease copy (duplicate) the PLP1 gene, which results in increased production of proteolipid protein 1 and DM20. Other mutations lead to production of abnormal proteins that are often misfolded. Excess or abnormal proteins become trapped within cell structures and cannot travel to the cell membrane. As a result, proteolipid protein 1 and DM20 are not available to form myelin. The accumulation of excess proteins leads to swelling and breakdown of nerve fibers. Still other mutations delete the PLP1 gene, which prevents proteolipid protein 1 and DM20 protein production and results in a lack of these proteins in the cell membrane, which causes any myelin that is formed to be unstable and quickly broken down. All of these PLP1 gene mutations lead to hypomyelination, nerve fiber damage, and impairment of nervous system function, resulting in the signs and symptoms of Pelizaeus-Merzbacher disease.

It is estimated that 5 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.

Genetic Testing Information

• Genetic Testing Registry: Pelizaeus-Merzbacher disease

Genetic and Rare Diseases Information Center

• Pelizaeus-Merzbacher disease

Patient Support and Advocacy Resources

• National Organization for Rare Disorders (NORD)

Clinical Trials

• ClinicalTrials.gov

Catalog of Genes and Diseases from OMIM

• PELIZAEUS-MERZBACHER DISEASE; PMD

Scientific Articles on PubMed

• PubMed

• Garbern JY. Pelizaeus-Merzbacher disease: Genetic and cellular pathogenesis. Cell Mol Life Sci. 2007 Jan;64(1):50-65. doi: 10.1007/s00018-006-6182-8. Citation on PubMed
• Garbern JY. Pelizaeus-Merzbacher disease: pathogenic mechanisms and insights into the roles of proteolipid protein 1 in the nervous system. J Neurol Sci. 2005 Feb 15;228(2):201-3. doi: 10.1016/j.jns.2004.10.010. Epub 2004 Dec 16. No abstract available. Citation on PubMed
• Inoue K. PLP1-related inherited dysmyelinating disorders: Pelizaeus-Merzbacher disease and spastic paraplegia type 2. Neurogenetics. 2005 Feb;6(1):1-16. doi: 10.1007/s10048-004-0207-y. Epub 2004 Dec 31. Citation on PubMed
• Laukka JJ, Kamholz J, Bessert D, Skoff RP. Novel pathologic findings in patients with Pelizaeus-Merzbacher disease. Neurosci Lett. 2016 Aug 3;627:222-32. doi: 10.1016/j.neulet.2016.05.028. Epub 2016 May 17. Citation on PubMed or Free article on PubMed Central
• Mierzewska H, Jamroz E, Mazurczak T, Hoffman-Zacharska D, Szczepanik E. Pelizaeus-Merzbacher disease in patients with molecularly confirmed diagnosis. Folia Neuropathol. 2016;54(1):59-65. doi: 10.5114/fn.2016.58916. Citation on PubMed
• Sarret C, Lemaire JJ, Tonduti D, Sontheimer A, Coste J, Pereira B, Feschet F, Roche B, Boespflug-Tanguy O. Time-course of myelination and atrophy on cerebral imaging in 35 patients with PLP1-related disorders. Dev Med Child Neurol. 2016 Jul;58(7):706-13. doi: 10.1111/dmcn.13025. Epub 2016 Jan 19. Citation on PubMed
• Torii T, Miyamoto Y, Yamauchi J, Tanoue A. Pelizaeus-Merzbacher disease: cellular pathogenesis and pharmacologic therapy. Pediatr Int. 2014 Oct;56(5):659-66. doi: 10.1111/ped.12450. Citation on PubMed
• Wolf NI, van Spaendonk RML, Hobson GM. PLP1-Related Disorders. 1999 Jun 15 [updated 2025 Jun 12]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A, editors. GeneReviews(R) [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2025. Available from http://www.ncbi.nlm.nih.gov/books/NBK1182/ Citation on PubMed
• Xie H, Feng H, Ji J, Wu Y, Kou L, Li D, Ji H, Wu X, Niu Z, Wang J, Jiang Y. Identification and functional study of novel PLP1 mutations in Chinese patients with Pelizaeus-Merzbacher disease. Brain Dev. 2015 Sep;37(8):797-802. doi: 10.1016/j.braindev.2014.11.007. Epub 2014 Dec 6. Citation on PubMed