GeneReviews^® [Internet].

Clinical characteristics.

PLP1-related disorders of central nervous system myelin formation include a range of phenotypes from Pelizaeus-Merzbacher disease (PMD) to spastic paraplegia 2 (SPG2). PMD typically manifests in infancy or early childhood with nystagmus, hypotonia, and cognitive impairment; the findings progress to severe spasticity and ataxia. Life span is shortened. SPG2 manifests as spastic paraparesis with or without CNS involvement and usually normal life span. Intrafamilial variation of phenotypes can be observed, but the clinical manifestations are usually fairly consistent within families. Heterozygous females may manifest mild-to-moderate features of the disease.

Diagnosis/testing.

The diagnosis of aPLP1-related disorder is established in a maleproband by identification of ahemizygouspathogenic variant involvingPLP1. The diagnosis of aPLP1-related disorder is usually established in a female with neurologic signs, a family history of aPLP1-related disorder, and aheterozygous pathogenic variant inPLP1 identified bymolecular genetic testing.

Management.

Treatment of manifestations: A multidisciplinary team comprising specialists in neurology, physical medicine, orthopedics, pulmonary medicine, and gastroenterology is optimal for care. Treatment may include respiratory support as needed; gastrostomy for individuals with severe dysphagia; routine management of spasticity including physical therapy, exercise, medications (baclofen, diazepam, tizanidine), orthotics, and surgery for joint contractures; anti-seizure medication for seizures; developmental, educational, and neurobehavioral support; physical and occupational therapy for ataxia with adaptive devices as needed; individuals with scoliosis benefit from proper wheelchair seating and physical therapy; surgery may be required for severe scoliosis; management of ocular manifestations as per ophthalmology; management of spastic urinary bladder as per urology; treatment of osteopenia as per endocrinologist.

Surveillance: Growth, nutrition, and feeding assessment at each visit; neurologic evaluation for weakness, hypotonia, spasticity, ataxia, and ambulation every six to 12 months; EEG as needed; developmental and educational assessment every six to 12 months in children and adolescents; cognitive assessment every six to 12 months in older individuals; orthopedic assessment of scoliosis, contractures, presence of joint dislocations, and physical medicine, occupational and physical therapy assessment of mobility and self-help skills every six to 12 months; assess for low bone density as needed; ophthalmologic evaluation to assess for nystagmus and visual impairment as recommended by ophthalmology; assess for urinary dysfunction as recommended by urology; assess family and social work needs.

Agents/circumstances to avoid: Elevated body temperature, as with fever, may cause neurologic manifestations to transiently worsen.

Genetic counseling.

PLP1-related disorders are inherited in anX-linked manner.De novo pathogenic variants have been reported. The risk to sibs of a maleproband depends on the genetic status of the mother: if the mother of the proband has aPLP1pathogenic variant, the chance of transmitting the pathogenic variant in each pregnancy is 50%. Males who inherit the pathogenic variant will be affected; females who inherit the pathogenic variant may be asymptomatic or manifest mild-to-moderate signs of the disorder. Heterozygous female sibs are more likely to develop neurologic signs if thephenotype in affected males is relatively mild. Once thePLP1 pathogenic variant has been identified in an affected family member,heterozygote detection and prenatal andpreimplantation genetic testing are possible.

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Suggestive Findings

APLP1-related disordershould be suspected in probands with the following clinical, imaging, and family history findings.

Establishing the Diagnosis

Maleproband. The diagnosis of aPLP1-related disorderis established in a male proband by identification of ahemizygous pathogenic (orlikely pathogenic) variant inPLP1 bymolecular genetic testing (seeTable 1).

Femaleproband. The diagnosis of aPLP1-related disorderis usually established in a female proband with neurologic signs, a family history ofPLP1-related disorder, and aheterozygous pathogenic (orlikely pathogenic) variant inPLP1 identified bymolecular genetic testing (seeTable 1).

Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in thisGeneReview is understood to include likely pathogenic variants. (2) Identification of ahemizygous/heterozygousPLP1 variant ofuncertain significance does not establish or rule out the diagnosis.

Molecular genetic testing approaches can include a combination ofgene-targeted testing (single gene testing,multigene panel) andcomprehensivegenomic testing (exome sequencing,genome sequencing). Gene-targeted testing requires that the clinician determine which gene(s) are likely involved (see Option 1), whereas comprehensive genomic testing does not (see Option 2).

Clinical Description

Genotype-Phenotype Correlations

Somegenotype-phenotype correlations exist.

Most individuals withPLP1 duplications have classic PMD; however, some are classified as having connatal PMD and may have three or more copies of thePLP1locus [Wolf et al 2005]. Variation in the extent ofduplication or location(s) of the breakpoints or reinsertion sites may account for clinical variability.

The most severe phenotypes are typically caused bymissense variants (especially nonconservative amino acid substitutions) and otherPLP1 single-nucleotide variants or indels.

SPG2 is most often caused by conservative amino acid substitutions in presumably less critical regions of the protein. The locations of these pathogenic variants do not provide a clear correlation between amino acid position and clinicalphenotype. However, pathogenic variants in thePLP1-specificdomain encoded by amino acid residues 117-151 and inintron 3 tend to cause less severe phenotypes [Cailloux et al 2000,Taube et al 2014,Kevelam et al 2015] (seeMolecular Genetics).

Individuals withnullPLP1 variants, includingdeletion ofPLP1 [Raskind et al 1991], aframeshift variant, and amissense variant affecting the initiation codon develop a relatively mild demyelinating peripheral neuropathy.

Peripheral neuropathy as well as a relatively mild CNS manifestations result from pathogenic variants that affect only thePLP1-specificdomain [Shy et al 2003] (seeMolecular Genetics).

Penetrance

PLP1 pathogenic variants are believed to be completely penetrant in males.

Nomenclature

Pelizaeus-Merzbacher disease is also known as sudanophilic or orthochromatic leukodystrophy.

SPG2 may also be referred to as HSP-PLP1 [Marras et al 2016].

HEMS (hypomyelination of early myelinating structures) is a subtype of SPG2 (i.e., complicated SPG2) with characteristic MRI abnormalities [Kevelam et al 2015].

Proteolipid protein 1 was previously called proteolipid protein. After discovery of a similargene that is predominantly expressed in gut, numerical designation was added.

Note also that the older literature usually begins numbering of the amino acids with the glycine encoded by codon 2, since the initiation methionine is cleaved post-translationally.

Prevalence

In the US population, the prevalence of PMD due to all causes is estimated at 1:200,000 to 1:500,000. In a survey of leukodystrophies in Germany, the incidence of PMD was approximately 0.13:100,000 live births [Heim et al 1997].

Seeman et al [2003] reported that in the Czech RepublicPLP1 pathogenic variants were detected in 1:90,000 births. While this may reflect a situation particular to the Czech Republic, it suggests that the prevalence ofPLP1-related disorders may be higher than is generally recognized.

Pelizaeus-Merzbacher Disease (PMD)

The combination of nystagmus within the first two years of life, initial hypotonia, and abnormal white matter changes on the brain MRI (e.g., abnormal signal in the posterior limbs of the internal capsule, the middle, and superior cerebellar peduncles and the medial and lateral lemnisci, all of which should be myelinated in a normal newborn) should suggest the diagnosis of PMD, especially if the family history is consistent with anX-linked disorder.

Hypomyelination occurs in several disorders with clinical phenotypes distinct from PMD.POLR3-related leukodystrophy (4H leukodystrophy) is the most frequent hypomyelinating disorder after PMD, individuals with 4H leukodystrophy usually do not have nystagmus, ataxia is prominent, and spasticity is mild or not present. Hypomyelination with atrophy of the basal ganglia and cerebellum (seeTUBB4A-Related Leukodystrophy) can present with pure hypomyelination, similar to PMD. Oculodentodigital dysplasia presents sometimes in adulthood, with a SPG-likephenotype; nystagmus is usually not present [Harting et al 2019]. (For MRI characteristics and differential diagnosis of hypomyelination see alsoSteenweg et al [2010] andvan der Knaap et al [2019]).

Approximately 20% of males with clinical findings consistent with aPLP1-related disorder do not have an identifiablePLP1pathogenic variant. Other genetic disorders associated with PMD-like phenotypes and hypomyelination on brain MRI include those listed inTable 3.

Spastic Paraplegia 2 (SPG2)

To date, more than 80 genetic types of hereditary spastic paraplegia have been defined. SeeMurala et al [2021] and theUncomplicated Hereditary Spastic Paraplegia Overview for clinical characteristics of other hereditary spastic paraplegias.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs of an individual diagnosed with aPLP1-related disorder, the evaluations summarized inTable 4 (if not performed as part of the evaluation that led to the diagnosis) are recommended:

Treatment of Manifestations

Supportive care to improve quality of life, maximize function, and reduce complications is recommended. A multidisciplinary team comprising specialists in neurology, physical medicine, orthopedics, pulmonary medicine, and gastroenterology is optimal for care (seeTable 5) [Van Haren et al 2015].

Surveillance

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the following evaluations are recommended.

Agents/Circumstances to Avoid

Elevated body temperature, as with fever, may cause neurologic manifestations to transiently worsen.

Evaluation of Relatives at Risk

SeeGenetic Counseling for issues related to testing of at-risk relatives forgenetic counseling purposes.

Therapies Under Investigation

CNS stem cells were transplanted into brains of individuals with PMD in a US FDA-approved Phase I trial [Gupta et al 2012]. The procedure was well tolerated, however minimal evidence of myelination was thought to be present in the transplanted regions. Several years later, the situation was unchanged [Gupta et al 2019].

Pharmacologic agents that lower expression ofPLP1 should be of theoretic benefit in individuals with extra copies ofPLP1, as well as those with pathogenic variants associated with protein overexpression. Gene therapy using inhibitory RNA (antisense oligonucleotides) is currently being evaluated in a clinical trial and was effective in disease models [Elitt et al 2020]. Deferiprone, an iron chelator, is currently being evaluated in a clinical trial and has shown to improve thephenotype of cell and animal models in PMD [Nobuta et al 2019]. Curcumin had promise in cell models of PMD but was not effective in a small group of individuals with PMD [Yamamoto et al 2024].

SearchClinicalTrials.gov in the US andEU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions.

Mode of Inheritance

ThePLP1-related disorders – Pelizaeus-Merzbacher disease (PMD),PLP1null syndrome, hypomyelination of early myelinating structures (HEMS), and spastic paraplegia 2 (SPG2) – are inherited in anX-linked manner.

Risk to Family Members

Parents of a maleproband

• The father of an affected male will not have the disorder nor will he behemizygous for thePLP1pathogenic variant; therefore, he does not require further evaluation/testing.
• In the majority of families (including those in which a maleproband is the only family member known to be affected), the mother of the proband isheterozygous for aPLP1pathogenic variant.
• In a family with more than one affected individual, the mother of an affected male is anobligate heterozygote and may be asymptomatic or manifest mild-to-moderate signs of the disorder. Note: If a woman has more than one affected child and no other affected relatives and if thePLP1pathogenic variant cannot be detected in her leukocyte DNA, she most likely hasgonadal mosaicism.
• If a male is the only affected family member (i.e., asimplex case), the mother may be aheterozygote, the affected male may have ade novoPLP1pathogenic variant (in which case the mother is not a heterozygote), or the mother may have somatic/gonadal mosaicism.
  • The minority of affected males have the disorder as the result of ade novopathogenic variant.
• Molecular genetic testing of the mother for thePLP1pathogenic variant identified in theproband is recommended to confirm her genetic status and to allow reliablerecurrence risk assessment.

Sibs of a maleproband. The risk to sibs depends on the genetic status of the mother:

• If the mother of theproband has aPLP1pathogenic variant, the chance of transmitting it in each pregnancy is 50%.
  • Males who inherit thepathogenic variant will be affected. Significant intrafamilial clinical variability is uncommon inPLP1-related disorders; still, families in which males have had a milderphenotype are at risk of having affected offspring who may display a more severe phenotype. PMD and SPG2 have been observed in different males within the same family [Hodes et al 1993,Sistermans et al 1998].
  • Females who inherit thepathogenic variant will be heterozygotes and may be asymptomatic or manifest mild-to-moderate signs of the disorder. Female sibs are more likely to develop neurologic signs if thephenotype in affected males is relatively mild [Hurst et al 2006]. The risk toheterozygous females of developing neurologic signs is greatest in families in which affected males have aPLP1null syndrome, followed by those in which affected males have an SPG2 syndrome or HEMS [Hurst et al 2006]. The risk of developing neurologic signs is lowest in heterozygous females with severePLP1missense variants or aPLP1duplication, who usually have favorably skewedX-chromosome inactivation [Woodward et al 2000] (see Clinical Description,Heterozygous Females andGenotype-Phenotype Correlations).
• If theproband represents asimplex case and if thePLP1pathogenic variant cannot be detected in the leukocyte DNA of the mother, the risk to sibs is greater than that of the general population because of the possibility of maternalgonadal mosaicism [Woodward et al 2003].

Offspring of a maleproband

• Males with classic PMD do not reproduce.
• Males with SPG2 may be able to father children. Affected males transmit thePLP1pathogenic variant to:
  • All of their daughters, who may be asymptomatic or manifest mild-to-moderate signs of the disease. Note:PLP1 pathogenic variants that cause relatively mild neurologic signs in affected males are more likely to be associated with neurologic manifestations inheterozygous females.
  • None of their sons.

Other family members of a maleproband. The proband's maternal aunts and their offspring may be at risk of beingheterozygous, and manifesting mild-to-moderate signs of the disease, or of beinghemizygous and affected (depending on their sex, family relationship, and the genetic status of the proband's mother).

Heterozygote Detection

Identification of female heterozygotes requires prior identification of thePLP1pathogenic variant in the family.

Note: (1) Females who areheterozygous for thisX-linked disorder are usually neurologically normal but may manifest mild-to-moderate signs of the disease. (2) Molecular genetic testing may be able to identify the family member in whom ade novopathogenic variant arose, information that could help determine genetic risk status of the extended family.

Related Genetic Counseling Issues

Phenotypic variability. It is important for couples at risk to be aware that varying phenotypes can coexist in the same kindred or sibship; thus, families in which males have had a milderphenotype are at risk of having affected offspring who may display a more severe phenotype.

Distantly inserted duplications. While distantly inserted duplications are a rare cause ofPLP1-related disorders, they may raise potentially difficultgenetic counseling issues because the inheritance pattern may not beX-linked [Hodes et al 2000,Inoue et al 2002]. In rare instances, the duplicated region can be inserted at some distance from Xq22 such as 19qtel [Inoue et al 2002] and in the Ychromosome [Woodward et al 2005].

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offergenetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected,heterozygous, or at risk of being heterozygous.

Prenatal Testing and Preimplantation Genetic Testing

Once thePLP1pathogenic variant has been identified in an affected family member, prenatal andpreimplantation genetic testing (PGT) are possible. However; the prenatal or PGT finding of afamilialPLP1 pathogenic variant cannot be used to accurately predict clinical outcome, as varying phenotypes may coexist in the same kindred or sibship; families in which males have had a milderphenotype are at risk of having affected offspring with a more severe phenotype and females may be neurologically normal or manifest mild-to-moderate signs of the disease.

Differences in perspective may exist among medical professionals and within families regarding the use ofprenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Table A.

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Table B.

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Molecular Pathogenesis

PLP1 encodes myelin proteolipid protein 1 (PLP1), which is the predominant protein constituent of central nervous system (CNS) myelin, constituting approximately 50% of the myelin protein mass. An additionalgene product, the isoform DM20, which lacks thePLP1-specificdomain encoded by amino acids 117-151, is also encoded byPLP1. PLP1 and DM20 are both transmembrane proteins that span the lipid bilayer four times and are anchored to cell membranes through covalent acyl linkages to fatty acids. There is evidence that PLP1 cements adjacent leaflets of myelin; however, additional or alternative functions are also possible [Griffiths et al 1998,Aggarwal et al 2011].

PLP1, but not DM20, has been shown to form dimers at an intracellular cysteine residue [Daffu et al 2012]. This dimerization may contribute to the molecular pathogenesis of Pelizaeus-Merzbacher disease (PMD), both in affected individuals with indels and those with duplications.

Mechanism of disease causation. Duplication ofPLP1 results in overexpression of PLP1, leading to dysfunction and death of oligodendrocytes, the myelin-forming cells in the CNS [Griffiths et al 1998,Yool et al 2000]. Increased PLP1 expression results in mislocalization of PLP1 along with cholesterol and lipids to the late endosomal/lysosomal compartment [Simons et al 2000]. The association of hypomyelination and subsequent axonal injury in PMD and other leukodystrophies is reviewed byMar & Noetzel [2010].

Pathogenicmissense variants cause misfolding of PLP1 or DM20. These misfolded proteins are retained in the endoplasmic reticulum (ER), failing to be incorporated into the cell membrane where they activate the unfolded protein response [Southwood et al 2002,Inoue 2017]. In a severe mouse model, the jimpy mouse, there is ER stress and subsequent cell death when oligodendrocyte progenitors mature [Elitt et al 2018].

Deletion ofPLP1, and probably otherloss-of-function variants, result in mild myelin defects but subsequent more severe axonal degeneration [Garbern et al 2002].

Variants in thePLP1 specific part of thegene (described asexon 3B) and the adjacentintron 3 lead to hypomyelination of early myelinating structures, through decreased PLP1 expression in relation to DM20 [Taube et al 2014,Kevelam et al 2015].

PLP1-specific laboratory considerations. Some deepintronic variants outside of the immediate splice junction regions have been associated withPLP1-related disorders (seeTable 7) [Taube et al 2014,Kevelam et al 2015]. Of note, the complete conservation of amino acid sequence between rodent and humanPLP1 suggests little tolerance for sequence variation.

Author History

James Y Garbern, MD, PhD; University of Rochester Medical Center (1999-2011*)
Grace M Hobson, PhD (2006-present)
John Kamholz, MD, PhD; University of Iowa Hospitals & Clinics (2013-2025)
Karen Krajewski, MS; Wayne State University School of Medicine/Detroit Medical Center (2006-2010)
Rosalina ML van Spaendonk, PhD (2019-present)
Nicole I Wolf, MD, PhD (2019-present)

* James Y Garbern was a specialist in leukodystrophies and hereditary neurologic disorders and an internationally recognized expert on PMD. Dr Garbern died in November 2011.

Revision History

• 12 June 2025 (sw) Comprehensive update posted live
• 19 December 2019 (sw) Comprehensive update posted live
• 28 February 2013 (me) Comprehensive update posted live
• 16 March 2010 (me) Comprehensive update posted live
• 15 September 2006 (me) Comprehensive update posted live
• 11 June 2004 (me) Comprehensive update posted live
• 20 March 2002 (me) Comprehensive update posted live
• 15 June 1999 (me) Review posted live
• 28 January 1999 (jg) Original submission

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