Clinical characteristics.

PLP1 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 signs are usually fairly consistent within families. Heterozygous females may manifest mild-to-moderate signs of the disease.

Diagnosis/testing.

The diagnosis of a PLP1 disorder is established in a male proband by identification of a hemizygous pathogenic variant involving PLP1. The diagnosis of a PLP1 disorder is usually established in a female with neurologic signs, a family history of a PLP1 disorder, and a heterozygous pathogenic variant in PLP1 identified by molecular 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 gastrostomy for individuals with severe dysphagia; anti-seizure medication for seizures; and routine management of spasticity including physical therapy, exercise, medications (baclofen, diazepam, tizanidine), orthotics, and surgery for joint contractures. Individuals with scoliosis benefit from proper wheelchair seating and physical therapy; surgery may be required for severe scoliosis. Specialized education and assessments are generally necessary, and assistive communication devices may be helpful.

Prevention of secondary complications: Proper wheelchair seating and physical therapy may help prevent scoliosis; speech and swallowing evaluations can identify individuals who may need a feeding tube for safer and/or adequate nutrition and hydration.

Surveillance: Semiannual to annual neurologic and physical medicine evaluations during childhood to monitor developmental progress, spasticity, and orthopedic complications.

Genetic counseling.

PLP1 disorders are inherited in an X-linked manner. De novo pathogenic variants have been reported.

• If the mother has a PLP1 pathogenic variant, the chance of transmitting the variant in each pregnancy is 50%. Males who inherit the variant will be affected; females who inherit the variant may manifest mild-to-moderate signs of the disorder. (PLP1 alleles that cause relatively mild neurologic signs in affected males are more likely to be associated with neurologic manifestations in heterozygous females.)
• Males with the PMD phenotype do not reproduce; males with SPG2 phenotype transmit the PLP1 pathogenic variant to all of their daughters and none of their sons.

Prenatal testing for a pregnancy at increased risk is possible if the PLP1 pathogenic variant in the family is known.

Suggestive Findings

A PLP1 disorder should be suspected in an individual with the following clinical and imaging features.

Establishing the Diagnosis

The diagnosis of a PLP1 disorder:

• Is established in a male proband by identification of a hemizygous pathogenic (or likely pathogenic) variant in PLP1 by molecular genetic testing (see Table 1);
• Is usually established in a female with neurologic signs, a family history of PLP1 disorder, and a heterozygous pathogenic (or likely pathogenic) variant in PLP1 identified by molecular genetic testing (see Table 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 this GeneReview is understood to include likely pathogenic variants. (2) Identification of a hemizygous or heterozygous PLP1 variant of uncertain significance does not establish or rule out the diagnosis.

Molecular genetic testing approaches can include a combination of gene-targeted testing (targeted deletion/duplication analysis, single-gene testing, multigene panel), and comprehensive genomic testing (exome sequencing, exome array, genome sequencing), depending on the phenotype.

Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of PLP1 disorders is broad, individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those with a phenotype indistinguishable from many other inherited disorders with hypotonia, cognitive impairment, and/or spastic paraparesis are more likely to be diagnosed using genomic testing (see Option 2).

Clinical Description

Genotype-Phenotype Correlations

Some genotype-phenotype correlations exist.

Most individuals with PLP1 duplications have classic PMD; however, some are classified as having connatal PMD and may have three or more copies of the PLP1 locus [Wolf et al 2005]. Variation in the extent of duplication or location(s) of the breakpoints or reinsertion sites may account for clinical variability.

The most severe clinical syndromes are typically caused by missense variants (especially nonconservative amino acid substitutions) and other PLP1 single-nucleotide variants or indels.

The milder spastic paraplegia syndrome 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 clinical phenotype. However, pathogenic variants in the PLP1-specific domain encoded by amino acid residues 117-151 and in intron 3 tend to cause less severe syndromes [Cailloux et al 2000, Taube et al 2014, Kevelam et al 2015] (see Molecular Genetics).

Although PMD has classically been regarded as a strictly CNS disorder, those with null PLP1 variants, including deletion of PLP1 [Raskind et al 1991], a frameshift variant, and a missense variant affecting the initiation codon do develop a relatively mild demyelinating peripheral neuropathy, demonstrating that myelin proteolipid protein (PLP1) and/or DM20 (an alternatively spliced transcript; see following paragraph and Molecular Genetics) does indeed function in the peripheral nervous system as well as in the CNS. Furthermore, the null phenotype has less severe CNS signs than those seen with the more typical forms of PMD. The null phenotype is associated with length-dependent degeneration of major central motor and sensory tracts and reduced levels of N-acetyl aspartate in cerebral white matter.

Peripheral neuropathy as well as a relatively mild CNS syndrome results from pathogenic variants that affect only the PLP1-specific region [Shy et al 2003] (see Molecular Genetics). The CNS syndrome can be milder than that observed in individuals with the null phenotype.

Penetrance

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

Nomenclature

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

Proteolipid protein 1 was previously called proteolipid protein. After discovery of a similar gene 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, the prevalence of PMD in the population 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 Republic PLP1 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 of PMD 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 an X-linked disorder. In a recent survey of children with inherited diseases of white matter identified by neuroimaging, 7.4% had PMD, the second most common cause of leukodystrophy [Bonkowsky et al 2010], suggesting that the disease is relatively common.

Approximately 20% of males with clinical findings consistent with a PLP1 disorder do not have identifiable pathogenic variants in PLP1. Pathogenic variants in additional genes have been identified in individuals with a PMD-like phenotype and hypomyelination on brain MRI (see Table 3).

Hypomyelination occurs in several disorders with clinical phenotypes distinct from PMD. 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 [Wolf et al 2014]. Oculodentodigital dysplasia presents sometimes in adulthood, with a SPG-like phenotype; nystagmus is usually not present [Harting et al 2019]. (For MRI characteristics and differential diagnosis of hypomyelination see also Steenweg et al [2010] and van der Knaap et al [2019]).

Spastic Paraplegia 2 (SPG2)

To date, more than 80 genetic types of hereditary spastic paraplegia have been defined. See the 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 a PLP1 disorder, the following evaluations (if not performed as part of the evaluation that led to the diagnosis) are recommended:

• Physical examination to determine extent and severity of respiratory and feeding difficulties, weakness, hypotonia, spasticity, scoliosis, ataxia, visual impairment, cognitive impairment, contractures, joint dislocations, and ambulation
• In infants and children, developmental assessment to determine capabilities and needs for cognitive, physical, and other symptomatic therapies
• Brain MRI (more helpful age ≥9 months) to determine severity of myelination abnormalities; in older children and adults, magnetic resonance spectroscopy to ascertain axonal dysfunction
• Assessment of peripheral nerve function using NCV to presumptively identify individuals with the PLP1 null syndrome (probably reliable only after age 4 years)
• Family history to identify other affected or at-risk individuals
• Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

A multidisciplinary team comprising specialists in neurology, physical medicine, orthopedics, pulmonary medicine, and gastroenterology is optimal for care [Van Haren et al 2015].

Early attention to swallowing difficulties and airway protection, especially in the most severely affected individuals, is important. Those with severe dysphagia may require feeding by gastrostomy.

Seizures are usually restricted to individuals with the most severe (connatal) syndrome and although they may not always be associated with electroencephalographic evidence for epileptiform waveforms, they generally respond to anti-seizure medication such as carbamazepine.

Spasticity management may include physical therapy and exercises, including regular stretching exercises. Anti-spasticity medications such as baclofen (including intrathecal administration), diazepam, and tizanidine may be helpful, especially in combination with physical therapy, exercise, orthotics, and other assistive devices. In advanced cases, surgery to release joint contractures may be required.

Severe scoliosis may result in pulmonary compromise as well as discomfort, especially with position changes, and necessitate corrective surgery to preserve pulmonary function. Proper seating (especially wheelchair) and physical therapy may reduce or prevent the need for surgery.

Specialized schooling arrangements are typically necessary for children with PLP1 disorders. Developmental assessments can accurately assess a child's capabilities, which may be greater than is apparent because of severe motor deficits. Electronic or other communication devices may facilitate communication especially in children with visual and auditory impairment.

Prevention of Secondary Complications

Proper wheelchair seating and physical therapy may help prevent scoliosis. Speech and swallowing evaluations can help prevent or reduce aspiration and identify individuals who may need a feeding tube for safer and/or adequate nutrition and hydration.

Surveillance

Semiannual to annual neurologic and physical medicine evaluation is indicated to monitor developmental progress during childhood and to monitor and treat spasticity and orthopedic complications as needed.

Agents/Circumstances to Avoid

Elevated body temperature, as with fever, may cause neurologic signs and symptoms to transiently worsen.

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic 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 of PLP1 should be of theoretic benefit in individuals with extra copies of PLP1, as well as those with pathogenic variants associated with protein overexpression. Gene therapy using inhibitory RNA may be efficient; care should be taken to ascertain the right amount of PLP1 expression, as abolishing PLP1 expression altogether would lead to the PLP1 null syndrome.

Several interventions had positive effects in mouse models (e.g., ketogenic diet, cholesterol supplementation) and/or cell models of PMD (e.g., deferiprone) [Saher et al 2012, Nobuta et al 2019, Stumpf et al 2019].

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

Mode of Inheritance

The PLP1 disorders are inherited in an X-linked manner.

Risk to Family Members

Parents of a male proband

• The father of an affected male will not have the disorder nor will he be hemizygous for the PLP1 pathogenic variant; therefore, he does not require further evaluation/testing.
• In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote and may manifest mild-to-moderate signs of the disease. Note: If a woman has more than one affected child and no other affected relatives and if the PLP1 pathogenic variant cannot be detected in her leukocyte DNA, she most likely has germline mosaicism.
• In most families, the mother of a proband is heterozygous for a PLP1 pathogenic variant regardless of family history.
• If a male is the only affected family member (i.e., he represents a simplex case), the mother may be a heterozygote or the affected male may have a de novo PLP1 pathogenic variant, in which case the mother is not heterozygous [Hodes et al 1998, Grossi et al 2011].

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

• If the mother of the proband has a PLP1 pathogenic variant, the chance of transmitting it in each pregnancy is 50%.
  • Males who inherit the pathogenic variant will be affected. Significant intrafamilial clinical variability is uncommon in PLP1 disorders; still, families in which males have had a milder phenotype are at risk of having affected offspring who may display a more severe phenotype.
  • Females who inherit the pathogenic variant will be heterozygotes and may manifest mild-to-moderate signs of the disorder. Female sibs are more likely to develop neurologic signs if the phenotype in affected males is relatively mild (complicated or pure spastic paraparesis) [Hurst et al 2006]. The risk to a heterozygous female of being clinically affected is highest when the brother has the PLP1 null syndrome, and lowest when he has a PLP1 duplication. Heterozygous females with PLP1 duplication have been reported to have favorably skewed X inactivation [Woodward et al 2000].
• If the proband represents a simplex case (i.e., a single occurrence in a family) and if the PLP1 pathogenic 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 maternal germline mosaicism [Woodward et al 2003].

Offspring of a male proband

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

Other family members of a male proband

• The proband's maternal aunts and their offspring may be at risk of being heterozygous, and manifesting mild-to-moderate signs of the disease, or of being hemizygous and affected (depending on their sex, family relationship, and the genetic status of the proband's mother).
• Females who are heterozygous are more likely to have neurologic signs (usually adult-onset spastic paraparesis) if affected males in their family have a less severe syndrome.

Heterozygote Detection

Molecular genetic testing of at-risk female relatives to determine their genetic status is most informative if the pathogenic variant has been identified in the proband.

Note: (1) Females who are heterozygous for this X-linked disorder are usually neurologically normal but may manifest mild-to-moderate signs of the disease. (2) Identification of female heterozygotes requires either (a) prior identification of the PLP1 pathogenic variant in the family or, (b) if an affected male is not available for testing, molecular genetic testing first by sequence analysis, and if no pathogenic variant is identified, by gene-targeted deletion/duplication analysis.

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 milder phenotype 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 of PLP1 disorders, they may raise potentially difficult genetic counseling issues because the inheritance pattern may not be X-linked [Hodes et al 2000, Inoue et al 2002].

Family planning

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

DNA banking. Because it is likely that testing methodology and our understanding of genes, pathogenic mechanisms, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been confirmed (i.e., the causative pathogenic mechanism is unknown). For more information, see Huang et al [2022].

Prenatal Testing and Preimplantation Genetic Testing

Once the PLP1 pathogenic variant has been identified in an affected family member, prenatal testing and preimplantation genetic testing (PGT) are possible. However; the prenatal or PGT finding of a familial PLP1 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 milder phenotype 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 of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

Introduction. 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 additional gene product, the isoform DM20, which lacks the PLP1-specific domain encoded by amino acids 117-151, is also encoded by PLP1. 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 PMD, both in affected individuals with indels and those with duplications.

Mechanism of disease causation. Duplication of PLP1 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 by Mar & Noetzel [2010].

Pathogenic missense 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 of PLP1, and probably other loss-of-function variants, results in mild myelin defects but subsequent more severe axonal degeneration [Garbern et al 2002].

Variants in the PLP1 specific part of the gene (described as exon 3B) and the adjacent intron 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 deep intronic variants outside of the immediate splice junction regions have been associated with PLP1 disorders [Taube et al 2014, Kevelam et al 2015]. Of note, the complete conservation of amino acid sequence between rodent and human PLP1 suggests little tolerance for sequence variation.

Acknowledgments

The authors are grateful to the PMD Foundation, the Children's Research Center of Michigan, the Nemours Foundation, the NIH, and the PMD families.

Author History

James Y Garbern, MD, PhD; University of Rochester Medical Center (1999-2011*)
Grace M Hobson, PhD (2006-present)
John Kamholz, MD, PhD (2013-present)
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

• 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
• 7 October 2004 (jg) Revision: Table 3
• 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

Literature Cited

• Aggarwal S, Yurlova L, Simons M. Central nervous system myelin: structure, synthesis and assembly. Trends Cell Biol. 2011;21:585–93. [PubMed: 21763137]
• Barkovich AJ. Magnetic resonance techniques in the assessment of myelin and myelination. J Inherit Metab Dis. 2005;28:311–43. [PubMed: 15868466]
• Boespflug-Tanguy O, Mimault C, Melki J, Cavagna A, Giraud G, Pham Dinh D, Dastugue B, Dautigny A. Genetic homogeneity of Pelizaeus-Merzbacher disease: tight linkage to the proteolipoprotein locus in 16 affected families. PMD Clinical Group. Am J Hum Genet. 1994;55:461–7. [PMC free article: PMC1918422] [PubMed: 7915877]
• Bonavita S, Schiffmann R, Moore DF, Frei K, Choi B, Patronas MD N, Virta A, Boespflug-Tanguy O, Tedeschi G. Evidence for neuroaxonal injury in patients with proteolipid protein gene mutations. Neurology. 2001;56:785–8. [PubMed: 11274318]
• Bonkowsky JL, Nelson C, Kingston JL, Filloux FM, Mundorff MB, Srivastava R. The burden of inherited leukodystrophies in children. Neurology. 2010;75:718–25. [PMC free article: PMC2931652] [PubMed: 20660364]
• Boulloche J, Aicardi J. Pelizaeus-Merzbacher disease: clinical and nosological study. J Child Neurol. 1986;1:233–9. [PubMed: 3598129]
• Cailloux F, Gauthier-Barichard F, Mimault C, Isabelle V, Courtois V, Giraud G, Dastugue B, Boespflug-Tanguy O. Genotype-phenotype correlation in inherited brain myelination defects due to proteolipid protein gene mutations. Clinical European Network on Brain Dysmyelinating Disease. Eur J Hum Genet. 2000;8:837–45. [PubMed: 11093273]
• Combes P, Bonnet-Dupeyron MN, Gauthier-Barichard F, Schiffmann R, Bertini E, Rodriguez D, Armour JA, Boespflug-Tanguy O, Vaurs-Barrière C. 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;7:31–7. [PubMed: 16416265]
• Daffu G, Sohi J, Kamholz J. Proteolipid protein dimerization at cysteine 108: Implications for protein structure. Neurosci Res. 2012;74:144–55. [PubMed: 22902553]
• Elitt MS, Shick HE, Madhavan M, Allan KC, Clayton BLL, Weng C, Miller TE, Factor DC, Barbar L, Nawash BS, Nevin ZS, Lager AM, Li Y, Jin F, Adams DJ, Tesar PJ. Chemical screening identifies enhancers of mutant oligodendrocyte survival and unmasks a distinct pathological phase in Pelizaeus-Merzbacher disease. Stem Cell Reports. 2018;11:711–26. [PMC free article: PMC6135742] [PubMed: 30146490]
• Garbern J, Hobson G. Prenatal diagnosis of Pelizaeus-Merzbacher disease. Prenat Diagn. 2002;22:1033–5. [PubMed: 12424770]
• Garbern JY, Yool DA, Moore GJ, Wilds IB, Faulk MW, Klugmann M, Nave KA, Sistermans EA, van der Knaap MS, Bird TD, Shy ME, Kamholz JA, Griffiths IR. Patients lacking the major CNS myelin protein, proteolipid protein 1, develop length-dependent axonal degeneration in the absence of demyelination and inflammation. Brain. 2002;125:551–61. [PubMed: 11872612]
• Griffiths I, Klugmann M, Anderson T, Thomson C, Vouyiouklis D, Nave KA. Current concepts of PLP and its role in the nervous system. Microsc Res Tech. 1998;41:344–58. [PubMed: 9672418]
• Grossi S, Regis S, Biancheri R, Mort M, Lualdi S, Bertini E, Uziel G, Boespflug-Tanguy O, Simonati A, Corsolini F, Demir E, Marchiani V, Percesepe A, Stanzial F, Rossi A, Vaurs-Barrière C, Cooper DN, Filocamo M. 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. [PMC free article: PMC3125326] [PubMed: 21679407]
• Gupta N, Henry RG, Kang S-M, Strober J, Lim DA, Ryan T, Perry R, Farrell J, Ulman M, Rajalingam R, Gage A, Huhn SL, Barkovich AJ, Rowitch DH. Long-term safety, immunologic response, and imaging outcomes following neural stem cell transplantation for Pelizaeus-Merzbacher disease. Stem Cell Reports. 2019;13:254–61. [PMC free article: PMC6700500] [PubMed: 31378671]
• Gupta N, Henry RG, Strober J, Kang SM, Lim DA, Bucci M, Caverzasi E, Gaetano L, Mandelli ML, Ryan T, Perry R, Farrell J, Jeremy RJ, Ulman M, Huhn SL, Barkovich AJ, Rowitch DH. Neural stem cell engraftment and myelination in the human brain. Sci Transl Med. 2012;4:155ra137. [PMC free article: PMC3893824] [PubMed: 23052294]
• Harting I, Karch S, Moog U, Seitz A, Pouwels P, Wolf N. Oculodentodigital dysplasia: a hypomyelinating leukodystrophy with a characteristic MRI pattern of brain stem involvement. Am J Neuroradiol. 2019;40:903–907. [PMC free article: PMC7053886] [PubMed: 31048294]
• Heim P, Claussen M, Hoffmann B, Conzelmann E, Gartner J, Harzer K, Hunneman DH, Kohler W, Kurlemann G, Kohlschutter A. Leukodystrophy incidence in Germany. Am J Med Genet. 1997;71:475–8. [PubMed: 9286459]
• Hobson GM, Ritterson CM, Bird TD, Raskind WH, Garbern JY, Sperle K. Deletion breakpoint analysis in a patient with Pelizaeus-Merzbacher disease (PMD) and comparison with duplications. Am J Hum Genet. 2002;71:2045A.
• Hodes ME, Aydanian A, Dlouhy SR, Whelan DT, Heshka T, Ronen G. A de novo mutation (C755T; Ser252Phe) in exon 6 of the proteolipid protein gene responsible for Pelizaeus-Merzbacher disease. Clin Genet. 1998;54:248–9. [letter] [PubMed: 9788732]
• Hodes ME, Pratt VM, Dlouhy SR. Genetics of Pelizaeus-Merzbacher disease. Dev Neurosci. 1993;15:383–94. [PubMed: 7530633]
• Hodes ME, Woodward K, Spinner NB, Emanuel BS, Enrico-Simon A, Kamholz J, Stambolian D, Zackai EH, Pratt VM, Thomas IT, Crandall K, Dlouhy SR, Malcolm S. Additional copies of the proteolipid protein gene causing Pelizaeus-Merzbacher disease arise by separate integration into the X chromosome. Am J Hum Genet. 2000;67:14–22. [PMC free article: PMC1287072] [PubMed: 10827108]
• Hodes ME, Zimmerman AW, Aydanian A, Naidu S, Miller NR, Garcia Oller JL, Barker B, Aleck KA, Hurley TD, Dlouhy SR. Different mutations in the same codon of the proteolipid protein gene, PLP, may help in correlating genotype with phenotype in Pelizaeus- Merzbacher disease/X-linked spastic paraplegia (PMD/SPG2). Am J Med Genet. 1999;82:132–9. [PubMed: 9934976]
• Huang SJ, Amendola LM, Sternen DL. Variation among DNA banking consent forms: points for clinicians to bank on. J Community Genet. 2022;13:389-97. [PMC free article: PMC9314484] [PubMed: 35834113]
• Hurst S, Garbern J, Trepanier A, Gow A. Quantifying the carrier female phenotype in Pelizaeus-Merzbacher disease. Genet Med. 2006;8:371–8. [PubMed: 16778599]
• Ida T, Miharu N, Hayashitani M, Shimokawa O, Harada N, Samura O, Kubota T, Niikawa N, Matsumoto N. Functional disomy for Xq22-q23 in a girl with complex rearrangements of chromosomes 3 and X. Am J Med Genet A. 2003;120A:557–61. [PubMed: 12884439]
• Inoue K, Osaka H, Thurston VC, Clarke JT, Yoneyama A, Rosenbarker L, Bird TD, Hodes ME, Shaffer LG, Lupski JR. 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;71:838–53. [PMC free article: PMC378540] [PubMed: 12297985]
• Inoue K, Tanaka H, Scaglia F, Araki A, Shaffer LG, Lupski JR. Compensating for central nervous system dysmyelination: females with a proteolipid protein gene duplication and sustained clinical improvement. Ann Neurol. 2001;50:747–54. [PubMed: 11761472]
• Inoue K. Cellular pathology of Pelizaeus-Merzbacher disease involving chaperones associated with endoplasmic reticulum stress. Front Mol Biosci. 2017;4:7. [PMC free article: PMC5323380] [PubMed: 28286750]
• Keogh MJ, Jaiser SR, Steele HE, Horvath R, Chinnery PF, Baker MR. PLP1 mutations and central demyelination: Evidence from electrophysiologic phenotyping in female manifesting carriers. Neurol Clin Pract. 2017;7:451–4. [PMC free article: PMC5874467] [PubMed: 29620084]
• Kevelam SH, Taube JR, van Spaendonk RM, Bertini E, Sperle K, Tarnopolsky M, Tonduti D, Valente EM, Travaglini L, Sistermans EA, Bernard G, Catsman-Berrevoets CE, van Karnebeek CD, Østergaard JR, Friederich RL, Fawzi Elsaid M, Schieving JH, Tarailo-Graovac M, Orcesi S, Steenweg ME, van Berkel CG, Waisfisz Q, Abbink TE, van der Knaap MS, Hobson GM, Wolf NI. Altered PLP1 splicing causes hypomyelination of early myelinating structures. Ann Clin Transl Neurol. 2015;2:648–61. [PMC free article: PMC4479525] [PubMed: 26125040]
• Lee JA, Carvalho CM, Lupski JR. A DNA replication mechanism for generating nonrecurrent rearrangements associated with genomic disorders. Cell. 2007;131:1235–47. [PubMed: 18160035]
• Lee JA, Madrid RE, Sperle K, Ritterson CM, Hobson GM, Garbern J, Lupski JR, Inoue K. Spastic paraplegia type 2 associated with axonal neuropathy and apparent PLP1 position effect. Ann Neurol. 2006;59:398–403. [PubMed: 16374829]
• Mar S, Noetzel M. Axonal damage in leukodystrophies. Pediatr Neurol. 2010;42:239–42. [PubMed: 20304325]
• Masliah-Planchon J, Dupont C, Vartzelis G, Trimouille A, Eymard-Pierre E, Gay-Bellile M, Renaldo F, Dorboz I, Pagan C, Quentin S, Elmaleh M, Kotsogianni C, Konstantelou E, Drunat S, Tabet AC, Boespflug-Tanguy O. Insertion of an extra copy of Xq22.2 into 1p36 results in functional duplication of the PLP1 gene in a girl with classical Pelizaeus-Merzbacher disease. BMC Med Genet. 2015;16:77. [PMC free article: PMC4557901] [PubMed: 26329556]
• Miyake N, Wolf NI, Cayami FK, Crawford J, Bley A, Bulas D, Conant A, Bent SJ, Gripp KW, Hahn A, Humphray S, Kimura-Ohba S, Kingsbury Z, Lajoie BR, Lal D, Micha D, Pizzino A, Sinke RJ, Sival D, Stolte-Dijkstra I, Superti-Furga A, Ulrick N, Taft RJ, Ogata T, Ozono K, Matsumoto N, Neubauer BA, Simons C, Vanderver A. X-linked hypomyelination with spondylometaphyseal dysplasia (H-SMD) associated with mutations in AIFM1. Neurogenetics. 2017;18:185–94. [PMC free article: PMC5705759] [PubMed: 28842795]
• Muncke N, Wogatzky BS, Breuning M, Sistermans EA, Endris V, Ross M, Vetrie D, Catsman-Berrevoets CE, Rappold G. Position effect on PLP1 may cause a subset of Pelizaeus-Merzbacher disease symptoms. J Med Genet. 2004;41:e121. [PMC free article: PMC1735635] [PubMed: 15591263]
• Nobuta H, Yang N, Ng YH, Marro SG, Sabeur K, Chavali M, Stockley JH, Killilea DW, Walter PB, Zhao C, Huie P Jr, Goldman SA, Kriegstein AR, Franklin RJM, Rowitch DH, Wernig M. Oligodendrocyte death in Pelizaeus-Merzbacher disease is rescued by iron chelation. Cell Stem Cell. 2019;25:531–41. [PMC free article: PMC8282124] [PubMed: 31585094]
• Plecko B, Stockler-Ipsiroglu S, Gruber S, Mlynarik V, Moser E, Simbrunner J, Ebner F, Bernert G, Harrer G, Gal A, Prayer D. Degree of hypomyelination and magnetic resonance spectroscopy findings in patients with Pelizaeus Merzbacher phenotype. Neuropediatrics. 2003;34:127–36. [PubMed: 12910435]
• Raskind WH, Williams CA, Hudson LD, Bird TD. Complete deletion of the proteolipid protein gene (PLP) in a family with X-linked Pelizaeus-Merzbacher disease. Am J Hum Genet. 1991;49:1355–60. [PMC free article: PMC1686465] [PubMed: 1720927]
• Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17:405-24. [PMC free article: PMC4544753] [PubMed: 25741868]
• Saher G, Rudolphi F, Corthals K, Ruhwedel T, Schmidt K-F, Löwel S, Dibaj P, Barrette B, Möbius W, Nave KA. Therapy of Pelizaeus-Merzbacher disease in mice by feeding a cholesterol-enriched diet. Nat Med. 2012;18:1130–5. [PubMed: 22706386]
• 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;58:706–13. [PubMed: 26786043]
• Scala M, Traverso M, Capra V, Vari MS, Severino M, Grossi S, Zara F, Striano P, Minetti C. Pelizaeus-Merzbacher disease due to PLP1 frameshift mutation in a female with nonrandom skewed X-chromosome inactivation. Neuropediatrics. 2019;50:268–70. [PubMed: 31137068]
• Seeman P, Krsck P, Namestkova K, Malikova M, Belsan T, Proskova M. Pelizaeus-Merzbacher's disease (PMD) - detection of the most frequent mutation of the proteolipid protein gene in Czech patients and famillies with the classical form of PMD. Ceska Slovenska Neurol Neurochir. 2003;66:95–104.
• Shy ME, Hobson G, Jain M, Boespflug-Tanguy O, Garbern J, Sperle K, Li W, Gow A, Rodriguez D, Bertini E, Mancias P, Krajewski K, Lewis R, Kamholz J. Schwann cell expression of PLP1 but not DM20 is necessary to prevent neuropathy. Ann Neurol. 2003;53:354–65. [PMC free article: PMC4744322] [PubMed: 12601703]
• Simons M, Kramer EM, Thiele C, Stoffel W, Trotter J. Assembly of myelin by association of proteolipid protein with cholesterol- and galactosylceramide-rich membrane domains. J Cell Biol. 2000;151:143–54. [PMC free article: PMC2189802] [PubMed: 11018060]
• Sistermans EA, de Coo RF, De Wijs IJ, Van Oost BA. Duplication of the proteolipid protein gene is the major cause of Pelizaeus-Merzbacher disease. Neurology. 1998;50:1749–54. [PubMed: 9633722]
• Sivakumar K, Sambuughin N, Selenge B, Nagle JW, Baasanjav D, Hudson LD, Goldfarb LG. Novel exon 3B proteolipid protein gene mutation causing late-onset spastic paraplegia type 2 with variable penetrance in female family members. Ann Neurol. 1999;45:680–3. [PubMed: 10319897]
• Southwood CM, Garbern J, Jiang W, Gow A. The unfolded protein response modulates disease severity in Pelizaeus-Merzbacher disease. Neuron. 2002;36:585–96. [PMC free article: PMC4603660] [PubMed: 12441049]
• Steenweg ME, Vanderver A, Blaser S, Bizzi A, de Koning TJ, Mancini GM, van Wieringen WN, Barkhof F, Wolf NI, van der Knaap MS. Magnetic resonance imaging pattern recognition in hypomyelinating disorders. Brain. 2010;133:2971–82. [PMC free article: PMC3589901] [PubMed: 20881161]
• Stumpf SK, Berghoff SA, Trevisiol A, Spieth L, Düking T, Schneider LV, Schlaphoff L, Dreha-Kulaczewski S, Bley A, Burfeind D, Kusch K, Mitkovski M, Ruhwedel T, Guder P, Röhse H, Denecke J, Gärtner J, Möbius W, Nave KA, Saher G. Ketogenic diet ameliorates axonal defects and promotes myelination in Pelizaeus–Merzbacher disease. Acta Neuropathol. 2019;138:147–61. [PMC free article: PMC6570703] [PubMed: 30919030]
• Taube JR, Sperle K, Banser L, Seeman P, Cavan BC, Garbern JY, Hobson GM. PMD patient mutations reveal a long-distance intronic interaction that regulates PLP1/DM20 alternative splicing. Hum Mol Genet. 2014;23:5464–78. [PMC free article: PMC4168831] [PubMed: 24890387]
• van der Knaap MS, Schiffmann R, Mochel F, Wolf NI. Diagnosis, prognosis, and treatment of leukodystrophies. Lancet Neurol. 2019;18:962–72. [PubMed: 31307818]
• Van Haren K, Bonkowsky JL, Bernard G, Murphy JL, Pizzino A, Helman G, Suhr D, Waggoner J, Hobson D, Vanderver A, Patterson MC. Consensus statement on preventive and symptomatic care of leukodystrophy patients. Mol Genet Metab. 2015;114:516–26. [PubMed: 25577286]
• Vaurs-Barrière C, Wong K, Weibel TD, Abu-Asab M, Weiss MD, Kaneski CR, Mixon TH, Bonavita S, Creveaux I, Heiss JD, Tsokos M, Goldin E, Quarles RH, Boespflug-Tanguy O, Schiffmann R. Insertion of mutant proteolipid protein results in missorting of myelin proteins. Ann Neurol. 2003;54:769–80. [PMC free article: PMC4294275] [PubMed: 14681886]
• Wolf NI, Salomons GS, Rodenburg RJ, Pouwels PJ, Schieving JH, Derks TG, Fock JM, Rump P, van Beek DM, van der Knaap MS, Waisfisz Q. Mutations in RARS cause hypomyelination. Ann Neurol. 2014;76:134–9. [PubMed: 24777941]
• Wolf NI, Sistermans EA, Cundall M, Hobson GM, Davis-Williams AP, Palmer R, Stubbs P, Davies S, Endziniene M, Wu Y, Chong WK, Malcolm S, Surtees R, Garbern JY, Woodward KJ. Three or more copies of the proteolipid protein gene PLP1 cause severe Pelizaeus-Merzbacher disease. Brain. 2005;128:743–51. [PubMed: 15689360]
• Woodward K, Cundall M, Palmer R, Surtees R, Winter RM, Malcolm S. Complex chromosomal rearrangement and associated counseling issues in a family with Pelizaeus-Merzbacher disease. Am J Med Genet. 2003;118A:15–24. [PubMed: 12605435]
• Woodward K, Kendall E, Vetrie D, et al. Variation in PLP gene duplications causing Pelizaeus-Merzbacher disease. Am J Hum Genet. 1998;63:A394.
• Woodward K, Kirtland K, Dlouhy S, Raskind W, Bird T, Malcolm S, Abeliovich D. X inactivation phenotype in carriers of Pelizaeus-Merzbacher disease: skewed in carriers of a duplication and random in carriers of point mutations. Eur J Hum Genet. 2000;8:449–54. [PubMed: 10878666]
• Woodward KJ, Cundall M, Sperle K, Sistermans EA, Ross M, Howell G, Gribble SM, Burford DC, Carter NP, Hobson DL, Garbern JY, Kamholz J, Heng H, Hodes ME, Malcolm S, Hobson GM. Heterogeneous duplications in patients with Pelizaeus-Merzbacher disease suggest a mechanism of coupled homologous and nonhomologous recombination. Am J Hum Genet. 2005;77:966–87. [PMC free article: PMC1285180] [PubMed: 16380909]
• Yan H, Helman G, Murthy SE, Ji H, Crawford J, Kubisiak T, Bent SJ, Xiao J, Taft RJ, Coombs A, Wu Y, Pop A, Li D, de Vries LS, Jiang Y, Salomons GS, van der Knaap MS, Patapoutian A, Simons C, Burmeister M, Wang J, Wolf NI. Heterozygous variants in the mechanosensitive ion channel TMEM63A result in transient hypomyelination during infancy. Am J Hum Genet. 2019;105:996–1004. [PMC free article: PMC6848986] [PubMed: 31587869]
• Yiu EM, Farrell SA, Soman T. Classic Pelizaeus-Merzbacher disease in a girl with an unbalanced chromosomal translocation and functional duplication of PLP1. Mov Disord. 2009;24:2171–2. [PubMed: 19705472]
• Yool DA, Edgar JM, Montague P, Malcolm S. The proteolipid protein gene and myelin disorders in man and animal models. Hum Mol Genet. 2000;9:987–92. [PubMed: 10767322]