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Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2014.

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PLP1-Related Disorders

, PhD and , MD, PhD.

Author Information
, PhD
Nemours Biomedical Research
AI duPont Hospital for Children
Wilmington, Delaware
, MD, PhD
Wayne State University School of Medicine
Detroit, Michigan

Initial Posting: ; Last Update: February 28, 2013.

Summary

Disease 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 signs are usually fairly consistent within families. Female carriers may manifest mild to moderate signs of the disease.

Diagnosis/testing. Clinical diagnosis of PLP1-related disorders depends on typical neurologic findings, X-linked inheritance pattern, and, usually, the finding of diffusely abnormal myelin on MRI.

Management. Treatment of manifestations: A multidisciplinary team comprising specialists in neurology, physical medicine, orthopedics, pulmonary medicine, and gastroenterology should be assembled. Treatment may include gastrostomy for individuals with severe dysphagia; antiepileptic drugs (AEDs) for seizures; and routine management of spasticity including physical therapy, exercise, medications (baclofen, diazepam, tizanidine, botulinum toxin), orthotics, and surgery for joint contractures. Individuals with scoliosis benefit from proper wheelchair seating and physical therapy; surgery may be required in severe cases. Specialized education and assessments are generally necessary, and assisted communication devices may be helpful.

Prevention of secondary complications: Proper wheelchair seating and physical therapy may help prevent scoliosis.

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

Genetic counseling. PLP1-related disorders are inherited in an X-linked manner. De novo mutations have been reported. Males with the PMD phenotype do not reproduce; males with the SPG2 phenotype may reproduce. All daughters of a male proband will be carriers; no sons will inherit the mutation. All sons of a female carrier are at a 50% risk of inheriting the mutation and having the disease; all daughters are at a 50% risk of being carriers. Carrier testing for at-risk relatives and prenatal testing for pregnancies at increased risk are possible in families in which the disease-causing PLP1 mutation has been identified.

GeneReview Scope

PLP1-Related Disorders: Included Disorders
  • Pelizaeus-Merzbacher disease (PMD)
  • Spastic paraplegia 2 (SPG 2)

For synonyms and outdated names see Nomenclature.

Diagnosis

Clinical Diagnosis

The PLP1-related disorders span a continuum of neurologic findings from Pelizaeus-Merzbacher disease (PMD) with severe CNS involvement to spastic paraparesis (SPG2). Intrafamilial variation of phenotypes can be observed, but the signs are usually fairly consistent within families.

Boulloche & Aicardi [1986], Hodes et al [1993], and Cailloux et al [2000] have summarized the clinical features of their series of individuals with PMD. The phenotypes in this spectrum cannot be neatly categorized into distinct syndromes but are summarized using designations frequently encountered in the medical literature (Table 1).

Table 1. Spectrum of PLP1-Related Disorders

PhenotypeAge of OnsetNeurologic FindingsAmbulationSpeech Age at Death
Severe ‘connatal’ PMD Neonatal period  • Nystagmus at birth
 • Pharyngeal weakness
 • Stridor
 • Hypotonia
 • Severe spasticity
 • ± Seizures
 • Cognitive impairment
Never achievedAbsent, but
nonverbal
communication
and speech comprehension
are possible
Infancy to 3rd decade
Classic PMD First 5 years  • Nystagmus in first 2 mos
 • Initial hypotonia
 • Spastic quadriparesis
 • Ataxia titubation
 • ± Dystonia, athetosis
 • Cognitive impairment
With assistance if achieved; lost in childhood / adolescence Usually present 3rd-7th decade
PLP1 null syndromeFirst 5 years • No nystagmus
 • Mild spastic quadriparesis
 • Ataxia
 • Peripheral neuropathy
 • Mild to mod cognitive impairment
PresentPresent; usually worsens after adolescence5th-7th decade
Complicated spastic paraplegia (SPG2)First 5 years  • Nystagmus
 • Ataxia
 • Autonomic dysfunction 1
 • Spastic gait
 • Little or no cognitive impairment
PresentPresent4th-7th decade
Uncomplicated spastic paraplegia (SPG2)Usually first 5 years; may be 3rd-4th decade • Autonomic dysfunction 1
 • Spastic gait
 • Normal cognition
PresentPresentNormal

1. Spastic urinary bladder

Imaging Studies

Magnetic resonance imaging (MRI) is most helpful in establishing the diagnosis in those who have CNS involvement [Nezu et al 1998]:

  • PMD. Virtually all children with the PMD phenotype have a diffuse leukoencephalopathy, best appreciated on T2-weighted or fluid-attenuated inversion recovery (FLAIR) scans. These scans show diffusely increased signal intensity in the central white matter of the cerebral hemispheres, cerebellum, and brain stem. In most children, the amount of white matter is reduced in volume and can be readily seen as thinness of the corpus callosum or general decrease in myelination [Plecko et al 2003].

    Because the bulk of myelination normally occurs during the first two years of life, the T2-weighted MRI images may not show definitive abnormalities until a child is at least age one or two years. However, a normal newborn should have myelination-related T1 and T2 signal changes in the pons and cerebellum, and a normal three-month-old infant should have evidence of myelination in the posterior limb of the internal capsule, in the splenium of the corpus callosum, and in optic radiations [Barkovich 2005]. Absence of these early changes should raise the consideration for PMD or other dysmyelinating disorders.
  • SPG2. People with the SPG2 phenotype show less severe abnormalities on MRI scanning; they may have patchy abnormalities on T2-weighted scans or more diffuse leukoencephalopathy [Hodes et al 1999].

Magnetic resonance spectroscopy (MRS) may show reduced white matter N-acetyl aspartate (NAA) levels, especially in individuals with the PLP1 null syndrome [Bonavita et al 2001, Garbern & Hobson 2002, Plecko et al 2003]. In contrast, individuals with PLP1 duplications may have increased white matter NAA levels and may be misdiagnosed with Canavan disease [Takanashi et al 2002]. The pattern of metabolite abnormalities in individuals with PLP1 duplication appears distinctive — with increased levels of glutamine, inositol, and creatine as well as of NAA — and may assist in the discrimination of PMD from other leukodystrophies and demyelinating diseases [Hanefeld et al 2005].

Testing

Cytogenetic analysis. Fewer than 1% of individuals with clinical features of PMD have interstitial duplications or more complex rearrangements of the X chromosome visible on routine cytogenetic studies [Hodes et al 2000].

Molecular Genetic Testing

Gene. PLP1-related disorders are caused by mutation of PLP1.

Clinical testing

Table 2. Summary of Molecular Genetic Testing Used in PLP1-Related Disorders

Gene 1Test MethodMutations Detected 2Mutation Detection Frequency by Test Method 3
Affected MalesCarrier Females
PLP1FISH and deletion/duplication analysis 4, 5Deletions/duplications50% 650%-75%
Sequence analysis 7Sequence variants30% 8See footnote 9

1. See Table A. Genes and Databases for chromosome locus and protein name.

2. See Molecular Genetics for information on allelic variants.

3. The ability of the test method used to detect a mutation that is present in the indicated gene. Approximately 20% of males with clinical findings consistent with PLP1-related disorders do not have an identifiable mutation in PLP1, suggesting that mutations may occur in regions of the gene not routinely analyzed, such as far upstream or downstream regions or introns.

4. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.

5. Published methods include Gao et al [2005], Hübner et al [2005], Regis et al [2005], Wolf et al [2005], Combes et al [2006], Warshawsky et al [2006].

6. Gene dosage changes of variable size are found in at least 50% of males with PLP1-related disorders [Sistermans et al 1998, Inoue et al 1999].

7. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

8. While most point mutations result in missense or frameshift changes, mutations that affect splicing also occur, along with deletions and insertions that are smaller than a whole exon [Sistermans et al 1998, Hobson et al 2000, Hobson et al 2002a, Hübner et al 2005, Hobson et al 2006, Wang et al 2006]. Sequence analysis is generally performed only when a PLP1 duplication is not detected. However, lack of amplification by PCR prior to sequence analysis can suggest a putative exonic or whole-gene deletion in affected males.

9. Sequence analysis of genomic DNA cannot detect (multi)exonic or whole-gene deletions on the X chromosome in carrier females.

Interpretation of test results. Approximately 20% of males with clinical findings consistent with the PLP1-related disorders do not have identifiable mutations in PLP1, suggesting that mutations may occur in regions of the gene not routinely analyzed (e.g., far upstream or downstream regions or introns) or that they have another disorder that clinically resembles a PLP1-related disorder. See Differential Diagnosis.

Testing Strategy

To confirm/establish the diagnosis in a proband

1.

Perform deletion/duplication analysis. Deletion/duplication analysis by CMA or other quantitative molecular method is sensitive and specific for detecting copy number variation.

2.

If deletion/duplication analysis:

a.

Identifies a copy number change in an individual of high clinical suspicion, perform interphase FISH to determine if the duplication is a direct or an insertional event. Interphase FISH testing can identify the occasional instances in which the duplicated locus is inserted into heterologous loci, and can also identify instances of somatic mosaicism for the duplication.

Note: Because the probes for FISH analysis are typically quite large (>40 kbp) and include sequences that lie outside of PLP1, which is approximately 20 kbp, it is possible that FISH testing may suggest PLP1 duplication but actually detect duplication of regions flanking PLP1 that do not involve PLP1 itself [Lee et al 2006]. Therefore, direct dosage testing of PLP1 itself, and not dosing of flanking sequences should be done if the clinical syndrome is typical of a PLP1-related disorder.

b.

Does not identify a duplication or deletion, sequence PLP1.

Identification of female carriers is made by prior identification of the disease-causing mutation in the family and testing for the specific mutation.

If an affected male is not available for testing:

1.

Perform deletion/duplication analysis.

2.

If no deletion or duplication is identified, perform sequence analysis.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family.

Clinical Description

Natural History

Pelizaeus-Merzbacher disease (PMD) and X-linked spastic paraplegia 2 (SPG2) are at opposite ends of a clinical spectrum of disease caused by mutations of PLP1, which results in defective central nervous system (CNS) myelination. PMD and SPG2 have been observed in different males within the same family [Hodes et al 1993, Sistermans et al 1998].

Severe or ‘connatal’ PMD is apparent at birth or in the first few weeks of life. Findings include pendular nystagmus, hypotonia, pharyngeal weakness, and stridor. Seizures may develop in affected infants, and motor deficits are severe.

Later, children with severe PMD may have short stature and poor weight gain. Hypotonia later evolves into spasticity of the extremities that is usually quite severe. Children do not walk or develop effective use of the upper limbs. Verbal expression is severely limited, but comprehension may be significant. Swallowing difficulties may require feeding tube placement.

Affected children may die during infancy or childhood, usually of aspiration; with attentive care, they may live into the third decade or longer.

Classic PMD was originally described by Pelizaeus [1885] and Merzbacher [1910]. Males with classic PMD usually develop nystagmus, which may not be recognized until several months of age; in rare cases, nystagmus does not develop. Affected children have hypotonia and develop titubation (tremor of the head and neck), ataxia, and spastic quadriparesis beginning in the first five years. They usually have some purposeful voluntary control of the arms. If acquired, ambulation usually requires assistive devices such as crutches or a walker; it is generally lost as spasticity increases during later childhood or adolescence.

Cognitive abilities are impaired, but exceed those of the more severely affected children; language and speech usually develop. Extrapyramidal abnormalities, such as dystonic posturing and athetosis, may occur.

Survival into the sixth or seventh decade has been observed.

A transitional form, intermediate in onset and severity to the connatal and classic forms of PMD, has also been defined.

PLP1 null syndrome is distinguished by the absence of nystagmus and the presence of relatively mild spastic quadriparesis that mostly affects the legs, with ataxia and mild multifocal demyelinating peripheral neuropathy. Those with the PLP1 null syndrome generally ambulate better than those with classic PMD but may progress more rapidly because of degeneration of axons, inferred on the basis of magnetic resonance spectroscopy, which demonstrates reduced levels of white matter NAA [Garbern et al 2002].

Complicated spastic paraparesis (SPG2) often includes autonomic dysfunction (e.g., spastic urinary bladder), ataxia, and nystagmus. A clear distinction cannot be drawn on objective criteria between complicated spastic paraplegia and relatively mild PMD (e.g., PLP1 null syndrome).

Pure spastic paraparesis (SPG2) does not, by definition, include other significant CNS signs, although autonomic dysfunction, such as spastic urinary bladder, may also occur. Life span is normal.

Males with SPG2 have reproduced; males with the PMD phenotype have not.

Neurophysiologic Studies

Visual, auditory, and somatosensory evoked potential testing show normal to near-normal latencies of the peripheral component of the respective sensory modality, but severely prolonged or absent central latencies.

Except in families with PLP1 null alleles or mutations affecting the PLP1-specific region or some splice site mutations [Shy et al 2003, Vaurs-Barrière et al 2003], peripheral nerve conduction studies are normal. When peripheral neuropathy is present, it is mild in comparison to the central nervous system disorder, and is characterized by mild slowing of conduction velocities that may be more pronounced across those regions of a limb susceptible to compression, such as the wrist and elbow.

Heterozygotes. Women with a PLP1 mutation may or may not have symptoms. Several investigators have observed that in families with severely affected males, the heterozygous women are unlikely to have clinical manifestations of the PLP1-related disorders, whereas in families with mildly affected males, the heterozygous women are more likely to have symptoms [Sivakumar et al 1999, Hurst et al 2006]. Thus, an inverse relationship exists between the severity of manifestations in males and the likelihood of heterozygous females having neurologic signs.

The risk to heterozygous females of developing neurologic signs is greatest in families in which affected males have a PLP1 null syndrome, followed by those in which affected males have an SPG2 syndrome [Hurst et al 2006]. The risk of developing neurologic signs is lowest with PLP1 duplication heterozygotes, who usually have favorably skewed X-chromosome inactivation [Woodward et al 2000].

The following explanation is offered:

  • Alleles associated with a severe phenotype cause apoptosis (cell death) of oligodendrocytes (the cells that make myelin in the CNS) during early childhood. In heterozygous females, the oligodendrocytes that express the mutant PLP1 allele on the active X chromosome undergo apoptosis early in life but are replaced over time by oligodendrocytes that express the normal PLP1 allele on the active X chromosome. Thus, females who carry a severe PLP1 mutation may develop neurologic signs because of skewed inactivation of the X chromosome with the normal PLP1 allele (as with other X-linked recessive disorders) or may have transient signs (while the oligodendrocytes expressing the mutant PLP1 are still present) that abate as the degenerating oligodendrocytes are replaced by those expressing the normal PLP1 allele [Inoue et al 2001].
  • Alleles associated with a mild phenotype in males do not cause apoptosis of oligodendrocytes. In heterozygous females, abnormal oligodendrocytes persist and can cause neurologic signs [Sivakumar et al 1999].

Hurst et al [2006] analyzed families with SPG2 or PMD and provided statistical support for the inverse correlation between the severity of phenotypes in affected males and their heterozygous relatives. These observations have important implications for genetic counseling and are discussed in Risk to Family Members, Sibs of a male proband.

Manifesting heterozygotes are usually not index cases, but rather are identified in the course of evaluating the relatives of an affected male.

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 mutations (especially non-conservative amino acid substitutions) and other PLP1 point mutations 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 mutations do not provide a clear correlation between amino acid position and clinical phenotype. However, mutations in the PLP1-specific domain encoded by amino acid residues 117-151 tend to cause less severe syndromes [Cailloux et al 2000] (see Molecular Genetics).

Although PMD has classically been regarded as a strictly central nervous system disorder, those with null PLP1 mutations, including deletion of PLP1 [Raskind et al 1991], a frameshift mutation, and a missense mutation 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 central nervous system. 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 mutations 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 mutations are believed to be completely penetrant in males. The complete conservation of amino acid sequence between rodent and human PLP1 suggests that any variation from the normal sequence may be detrimental.

Anticipation

Anticipation has not been reported for PLP1 mutations.

Nomenclature

Pelizaeus-Merzbacher disease is also known as sudanophilic 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 mutations 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.

Differential Diagnosis

See Leukodystrophy, Hypomyelinating: OMIM Phenotypic Series, a table of similar phenotypes that are genetically diverse.

Individuals with PLP1-related disorders are often initially diagnosed with cerebral palsy or static encephalopathy.

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 [Bronkowsky et al 2010], suggesting that the disease is relatively common.

Approximately 20% of males with clinical findings consistent with the PLP1-related disorders do not have identifiable mutations in PLP1. Although PLP1 mutations that lie in non-coding regions that are not analyzed during clinical testing may be a potential cause, other loci account for similar clinical syndromes. Recently another X-linked syndrome with neonatal hypotonia, nystagmus, developmental delay, and diffuse hypomyelination was shown to be caused by mutations in SLC16A2 (also known as MCT8) [Vaurs-Barrière et al 2009]. See MCT8 (SLC16A2)-Specific Thyroid Hormone Cell Transporter Deficiency.

Mutations of FAM126A (also called HYCC1, HCC, and DRCTNNB1A) cause an autosomal recessive syndrome characterized by the presence of congenital cataract, developmental delay, ataxia (which slowly progresses and is associated with diffuse leukodystrophy, often with areas with both T2-weighted hyperintensity and T1-weighted hypointensity, suggesting increased water content in those regions), and demyelinating peripheral neuropathy [Biancheri et al 2007].

An autosomal recessive syndrome characterized by early-onset nystagmus, delayed motor milestones, ataxia, progressive spasticity, partial seizures, mild peripheral neuropathy, and diffuse leukodystrophy on MRI was found to be caused by mutations in GJC2 (formerly GJA12), encoding connexin 46.6 [Uhlenberg et al 2004, Bugiani et al 2006, Orthmann-Murphy et al 2007, Salviati et al 2007, Wolf et al 2007, Henneke et al 2008, Sartori et al 2008, Ruf & Uhlenberg 2009].

Another autosomal recessive syndrome has been described in an Israeli Bedouin family. The syndrome, which resembles severe PMD, is associated with acquired microcephaly and is caused by a mutation in HSPD1 (formerly HSP60) [Magen et al 2008].

Other leukodystrophies including metachromatic leukodystrophy, X-linked adrenoleukodystrophy, Krabbe disease, and Canavan disease do not typically cause nystagmus, and the MRI usually shows a regional predilection of abnormality, e.g., occipital white matter in X-linked adrenoleukodystrophy and frontal white matter in metachromatic leukodystrophy. In these leukodystrophies, nerve conduction velocity (NCV) and evoked potentials are usually abnormal.

Childhood ataxia with central nervous system hypomyelination/vanishing white matter disease (CACH/VWM) is an autosomal recessive disorder characterized by ataxia, spasticity, and variable optic atrophy [Pronk et al 2006, Scali et al 2006, van der Knaap et al 2006]. The phenotypic range includes a subacute infantile form (onset age <1 year), an early-childhood onset form (onset age 1-5 years), a late-childhood/juvenile-onset form (onset age 5-15 years), and an adult-onset form. Chronic progressive decline can be exacerbated by rapid deterioration during febrile illnesses or following head trauma. The diagnosis of CACH/VWM is based on clinical findings, characteristic abnormalities on cranial MRI, and identifiable mutations in one of five genes (EIF2B1, EIF2B2, EIF2B3, EIF2B4, and EIF2B5) encoding the five subunits of the eukaryotic translation initiation factor eIF2B [Leegwater et al 2001].

Alexander disease is an autosomal dominant disorder caused by mutation in GFAP, the gene encoding glial fibrillary acidic protein (reviewed in Johnson [2002]). Affected individuals have developmental delay, progressive spasticity, cognitive impairment, and macrocephaly. MRI shows extensive T2-weighted hyperintensity especially in the frontal white matter, but with periventricular T1-weighted hyperintensity and T2-weighted hypointensity [van der Knaap et al 2001].

Infants with congenital muscular dystrophy with merosin deficiency have markedly increased T2 signal in the cerebral white matter. Severe weakness and hypotonia in the absence of nystagmus should direct the clinician toward consideration of myopathy [Mercuri et al 1995].

An adult-onset, autosomal dominant leukodystrophy that clinically resembles progressive multiple sclerosis has been shown to be caused by duplication of LMNB1, which encodes lamin B1 [Padiath et al 2006].

Arts syndrome, caused by mutations in PRPS1, is an X-linked disorder characterized by profound congenital sensorineural hearing impairment, early-onset hypotonia, delayed motor development, mild to moderate intellectual disability, ataxia, and increased risk for infection. Onset of all findings (except optic atrophy) is before age two years. Signs of peripheral neuropathy develop during early childhood. The MRI does not show a pattern of leukodystrophy. Twelve of 15 boys from the two families reported with Arts syndrome died before age six years of complications of infection. Carrier females can show late-onset (age >20 years) hearing impairment and other findings.

Some children with Salla disease (free sialic acid storage disorders) may present with hypotonia, nystagmus, and delay of motor and cognitive abilities. Seizures are more common than in PMD, but children with Salla disease are more likely to show improvement. A broad range of clinical severity exists, from a syndrome characterized by permanent quadriparesis and failure to acquire speech that is usually fatal during childhood to a relatively mild form with delayed speech, delayed ambulation, mild intellectual disability, and normal life expectancy. In severely affected children, MRI shows diffusely abnormal myelination with uniformly hyperintense white matter on T2-weighted images; in less severely affected children, myelination is delayed and occurs especially in the periventricular regions [Sonninen et al 1999].

PCWH, a syndrome with peripheral congenital hypomyelinating neuropathy, central dysmyelination, and Waardenburg-Hirschsprung disease, is caused by truncating mutations of SOX10 [Touraine et al 2000, Inoue et al 2002b, Inoue et al 2004].

Spastic paraplegia 2 (SPG2). Certain mutations of L1 are responsible for L1 syndrome, the phenotypic range of which includes X-linked spastic paraplegia type 1 (SPG1), MASA syndrome (intellectual disability, aphasia, shuffling gait, and adducted thumbs), and X-linked hydrocephalus. MRIs of individuals with these disorders may show enlarged ventricles or agenesis of the corpus callosum but not leukodystrophy.

Mutations of GJC2 (formerly called GJA12), encoding the connexin 47 protein, can cause a spastic paraplegia syndrome [Orthmann-Murphy et al 2009].

Several other forms of autosomal dominant and autosomal recessive spastic paraplegia need to be considered in the differential diagnosis of SPG2; see Hereditary Spastic Paraplegia Overview.

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs of an individual diagnosed with PLP1-related disorders, the following evaluations 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 four years
  • Family history to identify other affected or at-risk individuals
  • Medical genetics consultation

Treatment of Manifestations

A multidisciplinary team comprising specialists in neurology, physical medicine, orthopedics, pulmonary medicine, and gastroenterology is optimal for care.

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 antiepileptic drugs (AEDs) such as carbamazepine.

Spasticity management may include physical therapy and exercises, including regular stretching exercises. Antispasticity 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-related 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 patients 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

No specific agents or exposures are known to accelerate the long-term disease course.

Elevated body temperature, as with fever, may cause neurologic signs and symptoms to transiently worsen, as occurs in individuals with multiple sclerosis (Uthoff phenomenon).

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 recently transplanted into brains of individuals with PMD in a US FDA-approved Phase I trial [Gupta et al 2012]. The procedure was well tolerated and myelination was noted in the transplanted regions.

Pharmacologic agents that lower expression of PLP1 should be of theoretic benefit in individuals with extra copies of PLP1, and those with severe point mutations. Preclinical studies are underway to test drugs of this type.

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.

Other

No controlled studies, either successful or unsuccessful, have been reported for therapy of PMD or SPG2.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

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

Risk to Family Members

Parents of a male proband

Sibs of a male proband

  • The risk to the sibs depends on the carrier status of the mother.
  • Women with a PLP1 mutation have a 50% chance of transmitting the mutation to each child. Male sibs who inherit the mutation will be affected; female sibs who inherit the mutation will be carriers and may manifest mild to moderate signs of the disease. Of note, PLP1 alleles that cause relatively mild neurologic signs in affected males are more likely to be associated with neurologic manifestations in heterozygotes.
  • Germline mosaicism could occur in this condition. Thus, even if the disease-causing mutation has not been identified in the mother's DNA, sibs of the proband are still at increased risk of inheriting the disease-causing mutation [Woodward et al 2003].
  • 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].

Offspring of a male proband. Males with typical PMD do not reproduce, but those with spastic paraplegia may be able to father children. Affected males transmit the PLP1 mutation to all of their daughters and to 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 carriers or of being affected (depending on their gender, family relationship, and the carrier 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 have a less severe syndrome.

Carrier Detection

Heterozygotes are usually neurologically normal but may manifest mild-to-moderate signs of the disease.

Carrier testing is possible if the disease-causing PLP1 mutation has been identified in the 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 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-related 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 2002a].

Family planning

  • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal 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, are carriers, or are at risk of being carriers.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

Prenatal testing is possible for pregnancies of women who are carriers if the PLP1 mutation has been identified in the family [Woodward et al 1999, Regis et al 2001]. The usual procedure is to determine fetal sex by DNA analysis or cytogenetic analysis of fetal cells obtained by amniocentesis (usually performed at ~15-18 weeks’ gestation) or chorionic villus sampling (usually performed at ~10-12 weeks’ gestation). If the fetus is male, DNA from fetal cells can be analyzed for the known disease-causing mutation. The phenotype of an affected fetus cannot be accurately predicted as widely varying phenotypes often coexist in the same kindred or sibship; thus, families in which males have had a milder phenotype are at risk of having affected offspring with a more severe phenotype. In addition, females who inherit the mutation will be carriers and may manifest mild to moderate signs of the disease.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the disease-causing mutation has been identified.

PGD has been used successfully not only for gender selection [de Die-Smulders et al 1998] but also to select against pathogenic PLP1 point mutations [Verlinsky et al 2006]. PGD has not yet been reported in families that have PLP1 copy number changes, but it should be possible to use linked markers, unique junction fragments, and/or oligonucleotide arrays to detect PLP1 copy number changes.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • National Institute of Neurological Disorders and Stroke (NINDS)
    PO Box 5801
    Bethesda MD 20824
    Phone: 800-352-9424 (toll-free); 301-496-5751; 301-468-5981 (TTY)
  • PMD Foundation
    1307 White Horse Road
    Suite 603
    Voorhees NJ 08043
    Phone: 302-383-7748; 609-443-9623
    Email: donhobson@pmdfoundation.org; jeffleonard@pmdfoundation.org
  • Australian Leukodystrophy Support Group, Inc.
    Nerve Centre
    54 Railway Road
    Blackburn Victoria 3130
    Australia
    Phone: 1800-141-400 (toll free); +61 3 98452831
    Fax: +61 3 95834379
    Email: mail@alds.org.au
  • United Leukodystrophy Foundation (ULF)
    2304 Highland Drive
    Sycamore IL 60178
    Phone: 800-728-5483 (toll-free)
    Fax: 815-895-2432
    Email: office@ulf.org
  • Myelin Disorders Bioregistry Project
    Email: myelindisorders@cnmc.org

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A. PLP1-Related Disorders: Genes and Databases

Gene SymbolChromosomal LocusProtein NameLocus SpecificHGMD
PLP1Xq22​.2Myelin proteolipid proteinPLP1 @ LOVD
HSP mutation database (PLP1)
PLP1

Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B. OMIM Entries for PLP1-Related Disorders (View All in OMIM)

300401PROTEOLIPID PROTEIN 1; PLP1
312080PELIZAEUS-MERZBACHER DISEASE; PMD
312920SPASTIC PARAPLEGIA 2, X-LINKED; SPG2

Molecular Genetic Pathogenesis

For a review of molecular pathophysiology and genetics of Pelizaeus-Merzbacher disease (PMD), see Garbern [2007], Woodward [2008], and Hobson & Garbern [2012]

Yool et al [2000] reviewed features of PLP1 mutations both in humans and in animal models. The clinical syndromes caused by small intragenic mutations are quite broad, ranging from mild spastic paraparesis and ataxia to severe spastic quadriplegia, seizures, stridor, and childhood fatality. A compelling hypothesis to explain the variation in clinical severities of different PLP1 mutations has been put forward by Gow & Lazzarini [1996] and Southwood & Gow [2001]. Missense mutations and other small intragenic mutations presumably cause misfolding of myelin proteolipid protein (PLP1) or the PLP1 isoform DM20. These misfolded proteins fail to progress through the intracellular processing pathway and are retained in the endoplasmic reticulum (ER), failing to be incorporated into the cell membrane and to activate the unfolded protein response (UPR) [Southwood et al 2002]. As oligodendrocytes attempt to myelinate their axons, UPR-activated apoptosis ensues if both PLP1 and DM20 are retained in the ER. However, if only PLP1 but not DM20 is ER-retained, oligodendrocytes survive and myelinate, resulting in a less severe syndrome such as spastic paraplegia.

Overexpression of PLP1 is presumed to be the mechanism triggered by increased PLP1 dosage. Experimental studies suggest that increased PLP1 expression results in mislocalization of PLP1 along with cholesterol and lipids to the late endosomal/lysosomal compartment [Simons et al 2000]. In addition, increased gene dosage of PLP1 is associated with increased CSF levels of N-aspartylglutamate (NAAG) [Mochel et al 2010], suggesting that there is a diffuse axonal injury in PMD. The association of dysmyelination and axonal injury in PMD and other leukodystrophies is reviewed by Mar & Noetzel [2010].

Deletion of PLP1, and probably some splice-site mutations that preclude expression of PLP1, result in mild myelin defects but more severe axonal degeneration [Garbern et al 2002].

Some intrafamilial phenotypic variability can occur, presumably the result of genetic background or environmental effects that are not understood. An interesting animal model highlights the effect of genetic background. In the C3H mouse strain, the p.Ile187Thr missense ("rumpshaker") mutation causes a mild syndrome with normal life span (~2 years) but causes a fatal syndrome in the C57BL/6 strain background [Al-Saktawi et al 2003].

Gene structure. PLP1 comprises seven exons spanning approximately 15 kbp. PLP1 encodes two major alternatively spliced transcripts: a full-length transcript encodes myelin proteolipid protein (PLP1) and the transcript variant DM20, which lacks the PLP1-specific domain encoded by residues 117-151. For a detailed summary of gene and protein information, see Table A, Gene Symbol.

Benign allelic variants. Selected benign (non-disease-causing) allelic variants reported in PLP1 are listed here.

Normal gene product. Myelin proteolipid protein 1 (PLP1) is the predominant protein constituent of central nervous system myelin, constituting approximately 50% of the myelin protein mass. Among mammals, PLP1 is highly conserved, with the mouse, rat, and human PLP1 sequences being completely identical over the 276-amino acid sequence. Other mammalian PLP1s differ at only a handful of residues. In addition to myelin proteolipid protein, at least one additional gene product, the isoform DM20, is encoded by PLP1. PLP1 and DM20 are both predicted to be transmembrane proteins that span the lipid bilayer four times. In addition, protein is anchored further to cell membranes through covalent acyl linkages to fatty acids. It is thought that PLP1 probably cements adjacent leaflets of myelin; however, additional or alternative functions are also possible [Griffiths et al 1998].

A product of alternative splicing, the DM20 isoform is also found in the peripheral nervous system and other tissues. The splicing variation occurs at exon 3, where the 3' half of the exon is spliced out in DM20 mRNA, resulting in the in-frame deletion of amino acid residues 117-151.

Post-translational proteolytic cleavage of PLP1/DM20 appears to occur in vivo [Bizzozero et al 2002]. There is evidence that PLP1-derived peptides promote oligodendrocyte mitogenesis [Yamada et al 1999]. In addition, PLP1, but not DM20, has also recently 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 patients with indels and those with duplications.

Abnormal gene product. Duplication of PLP1 presumably results in overexpression of myelin proteolipid protein (PLP1), leading to dysfunction and death of oligodendrocytes, the myelin-forming cells in the CNS. Transgenic mice that overexpress normal myelin proteolipid protein develop both dysmelination and demyelination of the CNS [Griffiths et al 1998, Yool et al 2000].

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Suggested Reading

  1. Duncan ID. The PLP mutants from mouse to man. J Neurol Sci. 2005;228:204–5. [PubMed: 15694207]
  2. Hudson LD. Pelizaeus-Merzbacher disease and the allelic disorder X-linked spastic paraplegia type 2. In: Scriver CR, Beaudet AL, Sly WS, Valle D, Vogelstein B, eds. The Online Metabolic and Molecular Bases of Inherited Disease (OMMBID). Chap 228. New York, NY: McGraw-Hill. Available online. 2014. Accessed 7-9-14.
  3. Koeppen AH. A brief history of Pelizaeus-Merzbacher disease and proteolipid protein. J Neurol Sci. 2005;228:198–200. [PubMed: 15694205]

Chapter Notes

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)

*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

  • 28 February 2013 (me) Comprehensive update posted live
  • 16 March 2010 (me) Comprehensive update posted live
  • 15 September 2006 (me) Comprehensive update posted to live Web site
  • 7 October 2004 (jg) Revision: Table 3
  • 11 June 2004 (me) Comprehensive update posted to live Web site
  • 20 March 2002 (me) Comprehensive update posted to live Web site
  • 15 June 1999 (me) Review posted to live Web site
  • 28 January 1999 (jg) Original submission
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