Alternative titles; symbols
SNOMEDCT: 64855000; ICD10CM: E75.27; ORPHA: 280210, 280219, 280224, 280229, 280234, 702; DO: 3210;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| Xq22.2 | Pelizaeus-Merzbacher disease | 312080 | X-linked recessive | 3 | PLP1 | 300401 |
A number sign (#) is used with this entry because Pelizaeus-Merzbacher disease (PMD) is caused by mutation in the PLP1 gene (300401), which encodes proteolipid protein-1, on chromosome Xq22.
Spastic paraplegia-2 (SPG2; 312920) is an allelic disorder.
Pelizaeus-Merzbacher disease (PMD) is an X-linked recessive hypomyelinating leukodystrophy (HLD1) in which myelin is not formed properly in the central nervous system. PMD is characterized clinically by nystagmus, spastic quadriplegia, ataxia, and developmental delay (summary by Inoue, 2005).
Genetic Heterogeneity of Hypomyelinating Leukodystrophy
Other forms of hypomyelinating leukodystrophy include HLD2 (608804), caused by mutation in the GJC2/GJA12 gene (608803) on chromosome 1q41; HLD3 (260600), caused by mutation in the AIMP1 gene (603605) on chromosome 4q24; HLD4 (612233), caused by mutation in the HSPD1 gene (118190) on chromosome 2q33.1; HLD5 (610532), caused by mutation in the FAM126A gene (610531) on chromosome 7p15; HLD6 (612438), caused by mutation in the TUBB4A gene (602662) on chromosome 19p13; HLD7 (607694), caused by mutation in the POLR3A gene (614258) on chromosome 10q22; HLD8 (614381), caused by mutation in the POLR3B gene (614366) on chromosome 12q23; HLD9 (616140), caused by mutation in the RARS gene (107820) on chromosome 5; HLD10 (616420), caused by mutation in the PYCR2 gene (616406) on chromosome 1q42; HLD11 (616494), caused by mutation in the POLR1C gene (610060) on chromosome 6p21; HLD12 (616683), caused by mutation in the VPS11 gene (608549) on chromosome 11q23; HLD13 (616881) caused by mutation in the HIKESHI gene (614908) on chromosome 11q14; HLD14 (617899), caused by mutation in the UFM1 gene (610553) on chromosome 13q13; HLD15 (617951), caused by mutation in the EPRS gene (138295) on chromosome 1q41; HLD16 (617964), caused by mutation in the TMEM106B gene (613413) on chromosome 7p21; HLD17 (618006), caused by mutation in the AIMP2 gene (600859) on chromosome 7p22; HLD18 (618404), caused by mutation in the DEGS1 gene (615843) on chromosome 1q42; HLD19 (618688), caused by mutation in the TMEM63A gene (618685) on chromosome 1q42; HLD20 (619071), caused by mutation in the CNP gene (123830) on chromosome 17q21; HLD21 (619310), caused by mutation in the POLR3K gene (606007) on chromosome 16p13; HLD22 (619328), caused by mutation in the CLDN11 gene (601326) on chromosome 3q26; HLD23 (619688), caused by mutation in the RNF220 gene (616136) on chromosome 1p34; HLD24 (619851), caused by mutation in the ATP11A gene (605868) on chromosome 13q34; HLD25 (620243), caused by mutation in the TMEM163 gene (618978) on chromosome 2q21; HLD26 (620269), caused by mutation in the SLC35B2 gene (610788) on chromosome 6p21; and HLD27 (620675), caused by mutation in the POLR1A gene (616404) on chromosome 2p11.
Tyler (1958) noted that at first, rotary movements of the head and eyes develop but curiously may later disappear. Affected children in these families were sometimes described as 'head nodders' and 'eye waggers.' Spasticity of the legs and later the arms, cerebellar ataxia, dementia, and parkinsonian symptoms are other features developing over the first decade or two of life.
Ford (1960) referred to Pelizaeus-Merzbacher disease as the chronic infantile type of diffuse cerebral sclerosis. PMD begins in infancy as early as the eighth day and usually no later than the third month and is very slowly progressive so that the victim may survive to middle age. Initial symptoms are pendular eye movements, head shaking, hypotonia, choreoathetosis, and pyramidal signs. The myelin of the peripheral nervous system is not involved in nerve conduction and velocities are normal.
Renier et al. (1981) recognized 3 types of Pelizaeus-Merzbacher disease. (1) The classic type, with onset in infancy and death in late adolescence or young adulthood, is characterized by initial signs of nystagmoid eye movement and jerking and rolling head movements or head tremor. Nystagmus disappears and, as the patient matures, ataxia, spasticity, and involuntary movements become manifest, as well as optic atrophy, microcephaly, and subnormal somatic development. (2) The connatal type shows rapid progression and is fatal in infancy or childhood. (3) The transitional form is intermediate. Stridor in early life is a manifestation in some cases of PMD. A possible relation of the X-linked laryngeal abductor paralysis with mental deficiency (308850) to the connatal form was proposed.
Kaye et al. (1994) reported 2 brothers who demonstrated neonatal hypotonia and hyporeflexia and were found to have mutations in the PLP1 gene. The authors suggested that peripheral nervous system myelin may be affected in PMD, yielding a clinical picture suggestive of spinal muscular atrophy.
One of the patients of Pelizaeus (1885) lived to 52 years of age, and in the family reported by Tyler (1958) an affected male was still living at age 51. Johnson et al. (1991) studied a 5-generation family in which 6 persons had PMD type I. One patient was 45 years old at the time of report. 'Wavering eyes' and 'floppy head' were noted at the age of a few weeks as the first sign.
Hanefeld et al. (2005) performed quantitative proton magnetic resonance spectroscopy (MRS) on 5 children with genetically confirmed PMD. Compared to age-matched controls, affected white matter in PMD patients resembled the metabolite pattern of cortical gray matter, as indicated by increased concentrations of N-acetylaspartate and N-acetylaspartylglutamate, glutamine, myoinositol, and creatine and phosphocreatine. The concentration of choline-containing compounds was reduced. The findings were consistent with enhanced neuroaxonal density, astrogliosis, and reduction of oligodendroglia, suggestive of dys- and hypomyelination.
Stevenson et al. (2009) reported follow-up of a 2-generation African American family with X-linked spastic paraplegia, originally reported by Arena et al. (1992). Arena et al. (1992) described 5 affected males who had severe mental retardation, lower limb spasticity and atrophy, absent or dysarthric speech, and impaired ambulation requiring wheelchairs from childhood. Other features included nystagmus, dystonic posturing, and ataxia. Brain imaging studies showed macrogyria, lack of myelination, and increased paramagnetic signal suggestive of iron deposition. Stevenson et al. (2009) identified a hemizygous mutation in the PLP1 gene (D58Y; 300401.0027) in all affected individuals, confirming that the disorder was in fact PMD. Stevenson et al. (2009) noted that, although altered signals in the basal ganglia and thalamus are not specific for iron deposition, MRI findings suggestive of iron deposition in the basal ganglia have been reported in other patients with PMD.
Carrier Females
Some heterozygous females have manifestations of the disorder. The brain of such a female in the family reported by Merzbacher (1909) was studied by Spielmeyer (cited by Tyler, 1958) with demonstration of changes. In a large family in which PMD was segregating (reported by Zeman et al., 1964) and linked to a mutation in PLP by Trofatter et al. (1989), Hodes et al. (1995) observed a heterozygous female infant with typical neurologic signs and with magnetic resonance imaging (MRI) of the brain and brain auditory evoked response consistent with the diagnosis of PMD. The mother and grandmother, who were likewise heterozygous for the leu14-to-pro mutation (300401.0003), were neurologically normal and showed normal MRIs of the brain.
Warshawsky et al. (2005) reported a 49-year-old woman with a history of progressive gait disturbance, white matter disease, and CSF immunoglobulin abnormalities who met criteria for primary progressive multiple sclerosis (MS; 126200). She and her son, who died at age 10 years of an unknown congenital neurodevelopmental disorder, were found to have a mutation in the PLP1 gene, confirming a diagnosis of Pelizaeus-Merzbacher disease. Warshawsky et al. (2005) noted that the finding of an affected mother of a severely affected boy with PMD was contrary to the current belief that mothers of severely affected sons are asymptomatic as adults.
Carrier females with the submicroscopic duplication in the PLP gene that causes PMD are usually asymptomatic. Inoue et al. (2001) described 2 unrelated female patients who presented with mild PMD or spastic paraplegia. In 1 patient, clinical features as well as cranial magnetic resonance imaging and brainstem auditory evoked potential results improved dramatically over a 10-year period. The other patient, who presented with spastic diplegia and was initially diagnosed with cerebral palsy, also showed clinical improvement. Interphase fluorescence in situ hybridization analyses identified a PLP gene duplication in both patients. The same analyses in family members indicated that the duplication in both patients occurred as a de novo event. Neither skewing of X inactivation in the peripheral lymphocytes nor PLP gene coding alterations were identified in either patient. These findings indicated that females with a PLP gene duplication can occasionally manifest an early-onset neurologic phenotype. Inoue et al. (2001) hypothesized that the remarkable clinical improvement was a result of myelin compensation by oligodendrocytes expressing 1 copy of the PLP gene secondary to selection for a favorable X-inactivation pattern. These findings indicated plasticity of oligodendrocytes in the formation of central nervous system myelin and suggested a potential role for stem cell transplantation therapies.
Using clinical data compiled from a chart review at Wayne State University comprising 40 pedigrees with PMD including 55 males and 56 carrier females, Hurst et al. (2006) investigated neurologic symptoms in carrier females. They categorized patients according to disease severity and type of genetic lesion within the PLP1 gene and then analyzed the clinical data using nonparametric t tests and analyses of variance. Hurst et al. (2006) concluded that their analyses formally demonstrated the link between mild disease in males and symptoms in carrier female relatives. Conversely, mutations causing severe disease in males rarely caused clinical signs in carrier females. The greatest risk of disease in females was found for nonsense/indel or null mutations. Missense mutations carried moderate risk. The lowest risk, which represents the bulk of families with PMD, was associated with PLP1 gene duplications. Hurst et al. (2006) concluded that effective genetic counseling of PMD and spastic paraplegia carrier females must include an assessment of disease severity in affected male relatives.
Marble et al. (2007) reported 2 brothers with classic PMD resulting from a truncating mutation in the PLP1 gene. Three carrier females in the family developed clumsiness, excessive falling, and gait disturbances in the fourth decade of life. Other clinical findings included hyperreflexia, wide-based gait, tremor, and extensor plantar responses. There was also mild cognitive deterioration. X-inactivation studies showed mild skewing (85:15) only in 1 of the carriers.
Schinzel et al. (1988) and Boltshauser et al. (1988) suggested that MRI may be a suitable means for carrier detection. In obligate carriers they demonstrated bilateral multiple areas with signal hyperintensity in the periventricular and subcortical white matter.
Feldman et al. (1990) described stridor and respiratory difficulties at birth as well as polyhydramnios during pregnancy. Tracheomalacia was suspected. Typical abnormalities of the auditory brainstem responses were suggested as a means of early diagnosis.
Woodward et al. (1998) confirmed that PLP overdosage is an important genetic abnormality in PMD and showed that interphase fluorescence in situ hybridization is a reliable technique that will facilitate diagnosis and carrier detection. They characterized the duplication breakpoints in 4 families and suggested origin and mechanisms for the rearrangements. The importance of gene dosage in myelin disorders was highlighted.
Prenatal Diagnosis
Bridge et al. (1991) performed carrier detection and prenatal diagnosis by means of an intragenic MspI polymorphism of the PLP gene and closely linked DNA markers.
Boespflug-Tanguy et al. (1994) suggested that RFLP analysis could be used to improve genetic counseling for the 75 to 90% of affected families in which a PLP exon mutation cannot be demonstrated.
Woodward et al. (1999) used interphase FISH in lymphocyte preparations for prenatal diagnosis of PMD in a family with the disorder. The fetus was determined to be unaffected.
Differential Diagnosis
In a retrospective study of neurophysiologic results from 10 patients with PMD-like disease (PMLD1; 608804) caused by mutation in the GJC2 gene (608803) and 8 with classic PMD, Henneke et al. (2010) found that brainstem auditory evoked potentials (BAEP) were significantly worse among those with classic PMD. Waves III, IV, and V, which are generated in the pons and midbrain, were absent in all patients with PMD, but were clearly recordable in 11 of 13 investigations in patients with PMLD1. Investigations of auditory acuity were not available. Visual and somatosensory evoked potentials showed conductive delay in both groups of patients, without significant differences. Nerve conduction studies were normal in all patients with PMD and indicated mild peripheral neuropathy in only 2 of 10 patients with PMLD1. Henneke et al. (2010) concluded that BAEP is a helpful tool to differentiate between these 2 disorders.
On the basis of comparative mapping of the human and mouse X chromosomes, Buckle et al. (1985) predicted that PMD would map to Xq between PGK1 (311800) and GLA (300644), i.e., somewhere in the segment q13-q22--precisely the region to which Willard and Riordan (1985) assigned the PLP gene.
Boespflug-Tanguy et al. (1994) carried out a linkage analysis with polymorphic markers of the PLP genomic region in 16 families segregating Pelizaeus-Merzbacher disease. Multipoint analysis gave a maximum location score for the PMD locus and the PLP gene in the same interval between DXS94 and DXS287, suggesting that in all families PMD is linked to the PLP locus.
Koeppen et al. (1987) demonstrated absence of proteolipid apoprotein (lipophilin) by immunocytochemistry and enzyme-linked immunosorbent assay in the brain from an 18-year-old patient with PMD. On the other hand, despite the lack of myelin-specific lipids, they found residual immunoreactivity for myelin basic protein, myelin-associated glycoprotein, and 2-prime,3-prime-cyclic nucleotide-3-prime-phosphodiesterase.
Gow and Lazzarini (1996) suggested a cellular basis for the difference in disease severity between the classic and connatal forms of PMD, based on protein trafficking of the 2 products of the PLP gene, PLP and DM20. Classic PMD mutations correlated with accumulation of PLP in the endoplasmic reticulum (ER) of transfected COS-7 cells, while the cognate DM20 traversed the secretory pathway to the cell surface. On the other hand, Gow and Lazzarini (1996) found that connatal PMD mutations led to the accumulation of both mutant PLP and DM20 proteins in the ER of COS-7 cells with little of either isoform transported to the cell surface. Moreover, they showed that transport-competent mutant DM20s facilitated trafficking of cognate PLPs and hence may influence disease severity.
Inoue et al. (1996) identified PLP gene duplications (300401.0021) in 4 families with PMD. Thus, PMD may be caused by duplication or deletion of the PLP gene (Raskind et al., 1991) as well as by point mutations. This situation is similar to that in Charcot-Marie-Tooth disease type 1a (CMT1A; 118220), which may be caused by duplication, deletion, or point mutation in the PMP22 gene (601097). Inoue et al. (1996) suggested that since the homologous myelin protein gene PMP22 is duplicated in the majority of patients with CMT1A, PLP gene overdosage may be an important genetic abnormality in PMD and affect myelin formation. Animal models support PLP duplications as a molecular basis for the disease, since transgenic mice with extra copies of the wildtype PLP gene and overexpression of the mRNA exhibit a similar phenotype of abnormal CNS myelination and premature death. Neurologic symptoms and severity of the disease in transgenic mice correlates with PLP-gene copy number and with the level of overexpression.
Southwood et al. (2002) noted that different mutations in the PLP1 gene cause different disease phenotypes ranging from severe connatal PMD to milder forms characterized by pure spastic paraplegia (SPG2). They presented evidence implicating the unfolded protein response (UPR), a stress-induced signaling cascade that regulates the secretory pathway through the endoplasmic reticulum, as a modulator of disease phenotype. The authors found that oligodendrocytes and microglia from 2 mouse models of PMD with coding mutations in the Plp1 gene, msd (see 300401.0019) and rsh (see 300401.0013), in which mutant proteins accumulate in the endoplasmic reticulum, expressed the UPR-associated proteins Chop (126337) and Atf3 (603148), indicating induction of the UPR. Similarly, postmortem brain tissue from a patient with PMD and mutation in the PLP1 gene (300401.0022) showed a 5-fold increase in CHOP expression in the white matter. By contrast, brain and spinal cord tissue from mice with overexpression of Plp1 (see, e.g., 300401.0021), in which mutant protein does not accumulate in the endoplasmic reticulum, did not show evidence of UPR induction. Transgenic rsh mice who were Chop-deficient showed a more severe phenotype, suggesting that Chop modulated toxic effects of the Plp1 coding mutation. Southwood et al. (2002) concluded that variable disease severity associated with different PLP1 mutations results from graded responses to metabolic stress as modulated by the UPR: the greater the accumulation of mutated PLP1 protein in the endoplasmic reticulum, the more intense the UPR and the higher the likelihood of apoptosis and increased disease severity.
Numata et al. (2013) found that expression of the PLP1-A243V mutant (300401.0019), which causes severe disease, depleted some ER chaperones with a KDEL (lys-asp-glu-leu) motif in HeLa cells and human oligodendrocytes, and was associated with transfer of the chaperone proteins to the cytoplasm. The same PLP1 mutant also induced fragmentation of the Golgi apparatus. The organelle changes were less prominent in cells with milder disease-associated PLP1 mutants, suggesting a correlation between degree of depletion and phenotypic variability. Similar changes are also observed in cells expressing another disease-causing gene that triggers ER stress, as well as in cells treated with brefeldin A, which induces ER stress and Golgi fragmentation by inhibiting transfer of proteins from the Golgi back to the ER. Mutant PLP1 disturbed localization of the KDEL receptor in the Golgi. The data suggested that PLP1 mutants inhibit Golgi-to-ER retrograde trafficking, which reduces the supply of ER chaperones and induces Golgi fragmentation. Numata et al. (2013) proposed that depletion of ER chaperones and Golgi fragmentation induced by mutant misfolded proteins contribute to trafficking defects that underlie the pathogenesis of inherited ER stress-related diseases.
Cremers et al. (1987) found an insertional translocation into the proximal long arm of the X chromosome in a boy who showed findings typical of PMD at autopsy. Duplication of Xq21-q22 was identified using a large number of X-specific and several X-Y-specific probes. There appeared to be 2 intact copies of the PLP gene (300401) present. The duplication was apparently due to a de novo mutation, because the mother had a normal female karyotype.
In a patient with the classic form of PMD, Gencic et al. (1989) described a missense mutation in exon 5 of the PLP gene (300401.0001).
Hodes et al. (1993) found that about 30% of patients with the diagnosis of Pelizaeus-Merzbacher disease had a mutation in the coding portion of the proteolipid protein gene. Although the mutations were generally recessive, some mutations were frequently expressed in females.
Mimault et al. (1999) investigated 82 strictly selected sporadic cases of PMD and found PLP mutations in 77%. Complete PLP gene duplication was the most frequent abnormality (62%), whereas point mutations in coding or splice site regions of the gene were involved less frequently (38%).
In the same report in which they described mutations in the PLP gene in Pelizaeus-Merzbacher disease, Hudson et al. (1989) studied a 6-generation family originally described by Watanabe et al. (1973) and further characterized by Wilkus and Farrell (1976). More than 23 males were affected with a disorder fitting the textbook description of Pelizaeus-Merzbacher disease, both clinically and genetically; however, curious pathologic changes had been noted in a 3-month-old affected infant: apparently normal myelin was present but to a considerable extent the myelin sheaths were organized into ball-like structures in the oligodendrocyte perikarya and terminal processes (Watanabe et al., 1973). Hudson et al. (1989) reported that the PLP gene from this pedigree was unaltered for over 4 kb of coding and noncoding sequence, that Southern blot hybridization failed to reveal any differences from the normal gene, and that a detailed restriction map of a phage lambda genomic clone from 1 patient, containing exons 1-7, also failed to uncover any differences from the normal gene. On the basis of these findings, Hudson et al. (1989) proposed that in addition to the PLP locus another locus on the X chromosome affects myelination. However, Garbern (2004) provided information that affected members of the family described by Watanabe et al. (1973) and by Wilkus and Farrell (1976) were found to have a duplication of the PLP1 (300401.0021) gene and therefore represent bona fide cases of Pelizaeus-Merzbacher disease.
Cailloux et al. (2000) investigated 52 PMD and 28 SPG families without large PLP duplications or deletions by PCR amplification and sequencing of the 7 coding regions and splice sites of the PLP1 gene. Abnormalities were identified in 29 (56%) of the PMD and 4 (14%) of the SPG cases. Of the 33 mutations detected, 23 were missense mutations, 3 were deletion/insertions with frameshifts, and 7 were splice site mutations. Clinical severity was found to be correlated with the nature of the mutation. The severe forms of PMD were most frequently associated with missense mutations in exons 2 and 4, leading to amino acid changes at positions highly conserved in other DM proteins. The mild forms of PMD were frequently caused by mutations, resulting in the production of truncated proteins or by missense mutations. The mutations mostly affected exon 5, leading to the substitution of amino acids only partly conserved in the extracytoplasmic C-D loop. SPG was associated with splice site mutations or changes in the PLP-specific B-C loop.
Regis et al. (2008) found no association between clinical disease severity and size of PLP1 duplications among 5 unrelated PMD patients with PLP1 duplications ranging in size from 167-195 kb to 580-700 kb.
Carvalho et al. (2012) reported a family in which a complex duplication of Xq22 was associated with variable expression of PMD in a boy, 2 of his sisters, and his mother. Array CGH and breakpoint junction sequencing in all patients identified a 56-kb duplication on Xq22 that was inserted in an inverted orientation amid an 11-Mb duplication of Xq22 that included the PLP1 gene. This rearrangement resulted in a copy number gain of PLP1; the 11-Mb duplication also included about 65 protein-coding genes, 18 of which are known to be expressed in the brain. The 3-year-old male proband had classic features of the disorder, including global developmental delay, rotary nystagmus, hypotonia with peripheral hyperreflexia, abnormal white matter signals in the cerebral hemispheres on brain MRI, and small corpus callosum, perhaps suggesting delayed myelination. Two sisters, aged around 5 and 6 years, had mild developmental delay and were in special education classes. One had mild hypotonia and periventricular white matter abnormalities. All 3 children also had a forehead nevus flammeus and deep-set eyes. The mother, who was not formally evaluated, had a history of substance abuse and had lost custody of her 5 children, perhaps consistent with some degree of developmental delay. The 2 girls had a random X-inactivation pattern in blood, but a skewed to moderate pattern favoring the normal allele in buccal cells, whereas the mother had moderate skewing in both blood and buccal cells. These findings suggested tissue-specific expression of the genomic rearrangement in the female carriers. Carvalho et al. (2012) hypothesized that the large size of the rearrangement was responsible for increased penetrance in these females.
Bahrambeigi et al. (2019) analyzed genomic rearrangements in 50 unrelated male patients with Pelizaeus-Merzbacher disease and PLP1 copy number gains. Analysis with a high-density customized array showed that 33 patients had single duplications, ranging from 122 kb to approximately 4.5 Mb, and 17 patients had complex genomic rearrangements (CGR). Of the CGR patients, 9 had a pattern of interspersed duplications separated by a copy neutral region, 3 had a triplication flanked by duplications, and rearrangements with other complexities were identified in the other 5 individuals. In 40 of the 50 patients, the authors ascertained at least one breakpoint junction via PCR amplification. Microhomology was found in 26% of sequenced join-points, ranging from 2 to 9 bp, and evidence for microhomeology was observed in approximately 33% of join-points. Bahrambeigi et al. (2019) also performed a metaanalysis of published PLP1 rearrangements, including 159 join-points from 124 unrelated individuals. They found single duplications in 55% of individuals and a triplication flanked by duplications as the most common CGR in 20% of individuals. In approximately 32% of join-points, there was evidence for microhomeology, and in 22% of cases of join-points, there was evidence for microhomology.
In a retrospective hospital- and clinic-based study involving 122 children with an inherited leukodystrophy, Bonkowsky et al. (2010) found that the most common diagnoses were metachromatic leukodystrophy (250100) (8.2%), Pelizaeus-Merzbacher disease (7.4%), mitochondrial diseases (4.9%), and adrenoleukodystrophy (300100) (4.1%). No final diagnosis was reported in 51% of patients. The disorder was severe: epilepsy was found in 49%, mortality was 34%, and the average age at death was 8.2 years. The population incidence of leukodystrophy in general was found to be 1 in 7,663 live births.
Sidman et al. (1964) described 'jimpy,' an X-linked demyelination disorder in mice, which is similar to Pelizaeus-Merzbacher disease in man. The jimpy mutation was shown by Nave et al. (1986) to reside in the gene for PLP and to be of such a nature that it leads to an incorrectly spliced RNA transcript. They observed a 74-base deletion in the mRNA for PLP. Also see Dautigny et al. (1986). Hudson et al. (1987) found that PLP in jimpy mice lacks amino acids 208-232; however, the region is present in the jimpy PLP-encoding gene. The authors proposed that the jimpy mutant has a point mutation or a deletion of a few bases that alters the normal splicing pattern and generates partially deleted PLP transcripts. Hudson et al. (1989) pointed out that absence of PLP produces more devastating effects than those of dysmyelination; a block in oligodendrocyte maturation is evident in jimpy mutant mice, and mature oligodendrocytes are absent from both jimpy and Pelizaeus-Merzbacher brains.
Feutz et al. (1995) demonstrated that jimpy oligodendrocytes in tissue culture were unresponsive to basic fibroblast growth factor.
Gencic and Hudson (1990) demonstrated that the jimpy-msd (myelin synthesis deficient) mouse has an ala242-to-val (A242V; 300401.0019) mutation in the Plp1 gene.
To investigate the pathogenetic mechanism of the PLP mutation in the jimpy mouse, Schneider et al. (1995) took advantage of the X-linkage of the gene and complemented jimpy with a wildtype PLP transgene. In this artificial heterozygous situation, the jimpy mutation emerged as genetically dominant. At the cellular level, oligodendrocytes showed little increase in survival although PLP gene and the autosomal transgene were coexpressed. In surviving oligodendrocytes, wildtype PLP was functional and immunodetectable in myelin. Moreover, compacted myelin sheaths regained their normal periodicity. This suggested that, despite the presence of functional wildtype PLP, misfolded jimpy PLP is by itself the primary cause of abnormal oligodendrocyte death.
Koeppen et al. (1988) and Boison and Stoffel (1989) showed that the X-linked 'myelin deficiency' mutation (md) in the rat is homologous to PMD. Duncan et al. (1987) presented evidence that a defect in the PLP gene is responsible for the hypomyelination. The myelinated fibers were found to be positive for myelin basic protein (159430) but negative for PLP.
Schneider et al. (1992) demonstrated that the mouse mutant 'rumpshaker' (rsh) has an ile186-to-thr (I186T; 300401.0013) mutation in a membrane-embedded domain of PLP. Surprisingly, 'rumpshaker' mice, although myelin-deficient, have normal longevity and a full complement of morphologically normal oligodendrocytes. Hypomyelination can thus be genetically separated from PLP-dependent oligodendrocyte degeneration. Schneider et al. (1992) suggested that PLP has a vital function in glial cell development, distinct from its later role in myelin assembly, and that this dichotomy of action may explain the clinical spectrum of Pelizaeus-Merzbacher disease.
Paralytic tremor (pt) is a sex-linked disorder in chinchilla rabbits that causes body tremor and limb paralysis in association with hypomyelination in the central nervous system but normal myelin in the peripheral nervous system. The number of oligodendrocytes is not reduced nor is there premature death of oligodendrocytes, although the myelin is 30% of normal. In pt rabbits, Tosic et al. (1994) demonstrated a T-to-A transversion in exon 2 of the proteolipid protein gene which would cause a substitution of histidine by glutamine at the end of the first potential transmembrane domain.
Klugmann et al. (1997) generated mice deficient in PLP and DM20 by targeted disruption. Mutant mice that lacked expression of the Plp gene failed to exhibit the known dysmyelinated phenotype. Unable to encode PLP/DM20 or PLP-related polypeptides, oligodendrocytes were still competent to myelinate CNS axons of all calibers and to assemble compact myelin sheaths. Ultrastructurally, however, the electron-dense intraperiod lines in myelin remained condensed, correlating with its reduced physical stability. Klugmann et al. (1997) concluded that after myelin compaction, PLP forms a stabilizing membrane junction, similar to a zipper. They stated that dysmyelination and oligodendrocyte death emerge as an epiphenomenon of other PLP mutations and have been uncoupled in the PLP null allele from the risk of premature myelin breakdown. Griffiths et al. (1998) showed that Plp-Dm20 -/- mice assembled compact myelin sheaths but subsequently developed widespread axonal swellings and degeneration, associated predominantly with small-caliber nerve fibers. Similar swellings were absent in dysmyelinated shiverer mice, which lack myelin basic protein (MBP), but recurred in MBP/Plp double mutants. Griffiths et al. (1998) concluded that fiber degeneration, which was probably secondary to impaired axonal transport, could indicate that myelinated axons require local oligodendroglial support.
The 'shaking pup' (Nadon et al., 1990) is a PLP mutation in the dog.
Readhead et al. (1994) generated normal mouse lines expressing autosomal copies of the wildtype Plp gene and found that a 2-fold increase in Plp gene dosage resulted in hypomyelination, astrocytosis, seizures, and premature death. They concluded that the myelination process is exquisitely sensitive to the accurate level of PLP gene expression.
Prukop et al. (2014) studied the transgenic mouse strain developed by Readhead et al. (1994) with a 2-fold increase in Plp1 gene dosage. Treatment with the nuclear progesterone receptor (PGR; 607311) antagonist Lonaprisan reduced Plp1 mRNA in the central nervous system of treated transgenic mice compared to controls. After 10 weeks of therapy, treated mice showed less progression of neurologic signs compared to controls, suggesting a dosage effect of Plp1 on the motor phenotype. Lonaprisan also increased the number of myelinated axons in the corticospinal tract of mutant mice compared to untreated mice. However, Lonaprisan did not influence the extent of hypomyelination and did not alter the number of unmyelinated axons. The findings suggested that overexpression of Plp1 in oligodendrocytes leads to the loss of myelinated axons via a gain of function. Microarray and RT-PCR analysis of mouse brain indicated that Lonaprisan downregulated genes involved in apoptosis, including Bax (600040) and Casp7 (601761). Lonaprisan also prevented oligodendrocyte loss and reduced astrogliosis in mutant mouse brains. The study offered a proof of principle that pharmacologic targeting of the nuclear progesterone receptor, which is a transcription factor, can inhibit Plp1 expression in animals with increased Plp1 dosage, resulting in an amelioration of axonal loss and slowing of disease progression.
A family reported by Wolfslast (1943), with what he termed spastic diplegia, is an example of X-linked spastic paraplegia. One affected male was living at age 50 years and a second at age 20 years. Nystagmus was described in a female carrier. However, Becker (1961) expressed the opinion that Wolfslast's family suffered from the Pelizaeus-Merzbacher syndrome, and Verschuer (1958) stated the same opinion.
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