Pelizaeus-Merzbacher Disease 

Updated: Jul 11, 2016
Author: Jasvinder Chawla, MD, MBA; Chief Editor: Selim R Benbadis, MD 

Overview

Background

Pelizaeus-Merzbacher disease (PMD) is a congenital hypomyelination disorder caused by changes affecting the proteolipid protein 1 gene (PLP1) located on Xq22.2. Generally, patients with PLP1 missense mutations show the most severe form of PMD (connatal form); however, two-thirds of patients with PMD carry PLP1 duplications and present typical manifestations of the disorder, recognized as the classical form. Although Pelizaeus-Merzbacher disease and X-linked spastic paraplegia type 2 are nosologically distinguished, they are at opposite ends of a clinical spectrum of X-linked diseases caused by mutations of the same gene, the proteolipid protein 1 (PLP1) gene, and result in defective central nervous system (CNS) myelination (see the image below). (See Etiology.) This disease has a progressive and almost unvarying course, which is the clinical key to differentiating it from other entities such as infantile cerebral palsy, peripheral neuropathies or multiple sclerosis, etc. It is necessary to suspect this diagnosis and confirm alterations in the PLP1 gene with the aim of obtaining a real incidence of this entity, which is probably underestimated, like other leukodystrophies.

T2-weighted magnetic resonance imaging (MRI) scan T2-weighted magnetic resonance imaging (MRI) scan of a child aged 10 months with duplication of the proteolipid protein (PLP) gene; note the high-intensity signal throughout the cerebral white matter.

Clinical signs usually include some combination of nystagmus, stridor, spastic quadriparesis, hypotonia, cognitive impairment, ataxia, tremor, and diffuse leukoencephalopathy on magnetic resonance imaging (MRI). Seizures and perinatal stridor are rare signs and are typically seen only in the most severe cases. (See Presentation and Workup.)

Severe clinical syndromes (sometimes referred to as the connatal forms of Pelizaeus-Merzbacher disease) are typically caused by missense and other small mutations that affect critical positions in PLP1, whereas the milder spastic paraplegia syndrome is caused by mutations that presumably affect less critical regions of the protein. The most common mutations that cause Pelizaeus-Merzbacher disease are duplications of a region of the X chromosome that includes the entire PLP1 gene. (See Etiology.)

Severe Pelizaeus-Merzbacher disease is often fatal during the first decade of life, typically due to respiratory complications. (See Prognosis and Treatment.)

Patient education

Families with confirmed Pelizaeus-Merzbacher disease must be referred to a geneticist or neurogeneticist for education about the disease and, especially, for genetic counseling. Pelizaeus-Merzbacher disease support online is available at http://www.pmdfoundation.org and http://groups.yahoo.com/group/PMDfamilysupport/join.

Information about Pelizaeus-Merzbacher disease is also available from the National Institutes of Health (NIH) at http://www.ninds.nih.gov/disorders/pelizaeus_merzbacher/pelizaeus_merzbacher.htm.

Etiology

In most cases, Pelizaeus-Merzbacher disease is caused by mutations of PLP1 on the long arm of the X chromosome (Xq22). Of note, the gene was previously termed PLP but is now designated as PLP1. PLP1 encodes 2 major products, PLP1 and a smaller protein, DM20, that results from alternative splicing. These proteins constitute about 50% of the mass of CNS white matter and are believed to serve an important structural function in compact myelin.[1, 2, 3, 4, 5]

Gene duplications

Approximately 60-70% of cases of Pelizaeus-Merzbacher disease result from duplications of the region of the X chromosome that contains PLP1 (caused, it has been proposed, by defective deoxyribonucleic acid [DNA] replication). The extent and breakpoints of duplications vary among different families. Inclusion of other genes in the duplicated region, or inclusion of aberrations of genes at the duplication endpoints, may potentially affect the phenotype.

Most individuals with PLP1 duplications present with classic Pelizaeus-Merzbacher disease, typified by nystagmus that begins in the first year of life, delayed motor and cognitive milestones, and ataxia. Most of these patients acquire some language function, which can be quite good (although slow).

Some patients with Pelizaeus-Merzbacher disease have been found to have 3 or more copies of the PLP1 gene.[6] These individuals have a more severe phenotype than most individuals with duplications.

Transgenic mice with extra copies of PLP1 develop a syndrome that effectively models the PLP1 duplication form of Pelizaeus-Merzbacher disease; this provides strong experimental support for the hypothesis that overexpression of PLP1 is deleterious to oligodendrocytes.[7, 8]

Point mutations

Approximately 15-20% of mutations in Pelizaeus-Merzbacher disease are point mutations or other small mutations that result in base substitutions, insertions, or deletions. Base substitutions usually result in missense mutations, but nonsense mutations (ie, substitution of an amino acid codon with a stop codon) and splicing mutations also occur. Splicing mutations are now recognized as quite common and may account for almost 20% of point mutations in the PLP1 gene.

The most severe form of Pelizaeus-Merzbacher disease, the so-called connatal form, usually results from missense substitutions. These severe mutations are believed to result in misfolding of the newly synthesized protein, which then accumulates in the endoplasmic reticulum and triggers apoptosis, or programmed cell death. Thus, oligodendrocyte numbers are severely reduced, and little (if any) myelin is made.

Mutations that prevent any PLP1 from being made result in a syndrome (PLP1 null syndrome) that is usually milder than classic Pelizaeus-Merzbacher disease. However, these mutations appear to cause a demyelinating peripheral neuropathy, although they do not result in oligodendrocyte cell death. Interestingly, mice that have been genetically engineered to prevent PLP1 expression develop a similar pathologic syndrome, characterized by severe, late-onset axonal degeneration.

Mutations that result in spastic paraplegia type 2 are generally missense mutations that do not prevent the processing of DM20, although they may interfere with the processing of PLP itself. These mutations do not appear to cause oligodendrocyte cell death.

Heterozygosity

Because females are mosaic with respect to X chromosome gene expression due to X inactivation, heterozygous females begin life with roughly equal proportions of oligodendrocytes that use the normal or mutated X chromosome. Females who are heterozygous for severe mutations are neurologically normal as adults, probably because the defective oligodendrocytes die, as described above, and are replaced by healthy ones. These females may have transient neurologic abnormalities during childhood.[9]

Females who are heterozygous for mutations that do not result in oligodendrocyte apoptosis (programmed cell death) continue to have oligodendrocytes that use the defective PLP1 and, therefore, are more likely to have detectable neurologic signs of Pelizaeus-Merzbacher disease.

Epidemiology

The frequency of Pelizaeus-Merzbacher disease in the United States is not known with certainty, but the estimated prevalence is at least 1 case per 500,000 population. However, this is a conservative estimate. Internationally, the frequency of the condition is estimated to be 1 case per 100,000-1,000,000 population.

Race-related demographics

Pelizaeus-Merzbacher disease and spastic paraplegia type 2 are global syndromes and affect all major ethnic groups.

So far, no case reports of patients of African descent have been published; however, the author is aware of African Americans with Pelizaeus-Merzbacher disease. The disease has been reported in people of Asian, Middle Eastern, and European descent.

Sex-related demographics

Pelizaeus-Merzbacher disease typically affects males, but female heterozygotes can be clinically affected, especially those who carry alleles that are relatively mild in males.

Age-related demographics

Pelizaeus-Merzbacher disease typically begins during infancy, but milder syndromes may not be recognized until early childhood. Although most heterozygous (ie, carrier) females are asymptomatic, young girls in families with severe to classic Pelizaeus-Merzbacher disease have reportedly developed classic Pelizaeus-Merzbacher disease that regresses as the child matures, followed by completely normal neurologic health.

Females who are heterozygous for the less severe alleles of PLP1 that are not believed to cause oligodendrocyte cell death or apoptosis may develop a more progressive and nonremitting syndrome, which usually begins during adulthood.

Prognosis

Individuals with connatal Pelizaeus-Merzbacher disease typically die of respiratory complications during childhood, but with attentive care, they can live into the third decade of life. Patients with classic Pelizaeus-Merzbacher disease (such as that caused by PLP1 gene duplications) can live into the fifth or sixth decade of life.

Patients with a predominantly spastic paraplegia phenotype have a normal life span and may even reproduce.

Morbidity

Each form of Pelizaeus-Merzbacher disease may have real or apparent intervals of stability, but the overall the trend is gradual progression. As discussed below, heterozygous females who carry a severe mutation are usually healthy, but those who carry a relatively mild mutation may develop neurologic signs, including spastic paraparesis and dementia, that typically manifest during adulthood.

Respiratory difficulty and stridor can be severe enough in infants with connatal disease to require the use of a tracheostomy or other airway protection. As the child grows older, the need for such measures may lessen.

Orthopedic complications are common in Pelizaeus-Merzbacher disease (PMD). Joint contractures are common in the legs and, to a lesser extent, the arms. Scoliosis can be severe enough to cause restrictive lung disease. Regular physical medicine evaluations, bracing, and physical therapy, as well as other treatments for spasticity, may reduce or delay the need for surgical therapy.

Dysphagia in Pelizaeus-Merzbacher disease can be severe enough to necessitate consideration of feeding tube placement.

Clinical course in heterozygous females

In heterozygous females with alleles that are severe in males, the defective oligodendrocytes die and are replaced by healthy oligodendrocytes, and neurologic function is maintained or improves with maturation. Females who are heterozygous for less severe alleles of PLP1 that are not believed to cause oligodendrocyte cell death or apoptosis may develop a more progressive and nonremitting syndrome, which usually begins during adulthood.[9]

Some females with Pelizaeus-Merzbacher disease (such as the original Pelizaeus-Merzbacher disease family) probably have a clinical course much like that of affected males, in which the symptoms do not remit and may be the result of skewed X inactivation (ie, most oligodendrocytes have inactivated the normal X chromosome, and insufficient healthy oligodendrocytes are available to effectively myelinate the CNS).

 

Presentation

History

The clinical severity of Pelizaeus-Merzbacher disease (PMD) widely varies, primarily depending on the precise nature of the causative mutation and, probably to a certain extent, on other genetic and environmental influences.

The presentation of classic Pelizaeus-Merzbacher disease involves infantile-onset (typically within the first 2 months of life) nystagmus, titubation, and weakness, followed by the development of ataxia, cognitive delay, and spasticity. Most patients never ambulate. Most do acquire some degree of language skills, which may approach normal levels, but the speed of language output is usually slow and may suggest a more severe degree of mental retardation than is present. These patients may survive to the sixth decade of life or beyond.

Patients who are more severely affected (ie, those with connatal Pelizaeus-Merzbacher disease) have nystagmus present beginning within the first week or 2 of life, often have stridor and respiratory difficulty and hypotonia, and may even have seizures. These patients typically have limited language skills, never ambulate, and develop severe spasticity with little voluntary movement. These individuals usually die before the third decade of life.

Individuals with the least severe form of Pelizaeus-Merzbacher disease, which overlaps with spastic paraplegia type 2, present with childhood-onset spastic paraplegia, mild cognitive impairment, ataxia, and athetosis. Survival to the sixth decade of life or later is characteristic. Typically, neurologic signs progress, but at a gradual rate, with reported periods of relative stability. Generally, persons with this form of Pelizaeus-Merzbacher disease who learn to walk begin to lose ambulatory abilities during adolescence; in some cases, however, loss of ambulation can be delayed until adulthood.

Physical Examination

The physical signs of Pelizaeus-Merzbacher disease depend on the age of the patient, the severity of the mutation, and, probably, on modifier genes, as well as, perhaps, on environmental factors.

Infants with connatal Pelizaeus-Merzbacher disease invariably have nystagmus within the first week or 2 of life and typically have stridor and hypotonia. The latter may be severe enough to suggest spinal muscular atrophy. As these children age, limb spasticity usually replaces the hypotonia, but the child has poor head control and does not learn to sit unsupported, much less walk. Seizures can occur in this severe form. Growth is poor; developmental milestones are significantly delayed or never achieved. Patients may comprehend spoken words, but verbal output is typically limited or absent. Motor function is severely limited.

Children with the classic form of Pelizaeus-Merzbacher disease generally have nystagmus present in the first few weeks of life or at least in the first year of life. Early hypotonia is succeeded by limb spasticity, which is worse in the legs than in the arms. Ataxia of truncal and limb movements is prominent; dystonic posturing and movements can occur as well. Occasionally, a child can walk, although movement is impaired by weakness and spasticity. Walking ability is usually lost by adolescence or earlier. Language ability can be mildly to moderately impaired, and some cognitive delay is usual. Diffuse hyperreflexia and Babinski signs are seen.

Patients with milder mutations may not ever have nystagmus; they have delayed sitting and walking but usually learn to walk. They have limb spasticity, which is worse in the legs, and ataxia that affects speech and impacts limb movements. Patients are hyperreflexic and have Babinski signs.

Patients with PLP1 null mutations can have mild distal sensory loss and relative hyporeflexia in addition to spastic paraparesis, but they have Babinski signs. These individuals have mild to moderate cognitive impairment. Numata et al conducted a nationwide epidemiological survey in Japan. PLP1 gene abnormalities were observed in 62%. Patients with PLP1 mutations showed a higher proportion of nystagmus and hypotonia, both of which tend to disappear over time.[10]

Clinical signs and symptoms are as follows:

  • Usually, nystagmus is of a pendular nature; it can often have horizontal and rotatory components

  • Over 95% patients have nystagmus; this sign may disappear later during childhood

  • The patient's age at onset of nystagmus alone does not predict clinical severity

  • Ataxia is evident once voluntary movements are acquired and occurs in virtually all patients

  • Spasticity develops in most patients (>90%) but may not be apparent until the second year of life or even later; hyperreflexia and Babinski signs are present

  • Most patients who are severely affected have neonatal hypotonia that may mimic spinal muscular atrophy

  • Titubation is an early characteristic sign; frequency of head bobbing is typically synchronous with or follows eye movements

  • Seizures and stridor are reported only in patients who are most severely affected, who tend to have missense or frameshift mutations of the PLP1 gene

 

DDx

Diagnostic Considerations

Gene defects other than those found in Pelizaeus-Merzbacher disease can cause a Pelizaeus-Merzbacher disease–like syndrome. In particular, these include mutations that affect the GJA12 gene on chromosome 1.[11] SOX10 mutations cause severe peripheral and central dysmyelination and dysmorphic facial abnormalities.

Salla disease, caused by defects in a lysosomal transporter protein for sialic acid (N -acetyl neuraminic acid), may manifest with nystagmus in the first months of life, as well as hypotonia and cognitive impairment. Children with severe impairment do not ambulate or acquire language but do typically learn to walk and speak and can have a normal life expectancy. MRI reveals arrested or delayed myelination.

Lazzarini described a Pelizaeus-Merzbacher disease–like disorder, observed in a single family, in which the condition was linked to Xq28.[12] However, MRI data have not been obtained on members of this family.

Other leukodystrophies, such as metachromatic leukodystrophy, adrenoleukodystrophy, Krabbe disease, Cockayne disease, and Canavan disease, do not typically cause nystagmus. MRI scans in these diseases usually reveal a disease-based regional predilection for associated abnormalities (eg, occipital white matter in adrenoleukodystrophy, frontal white matter in metachromatic leukodystrophy). Peripheral nerve conduction and evoked potential test results are usually abnormal.

Infants with merosin deficiency have a dramatically increased T2 signal in the cerebral white matter, but the presence of severe weakness and hypotonia and the absence of nystagmus should direct the clinician toward consideration of myopathy. A fatal X-linked syndrome of ataxia, blindness, deafness, and mental retardation has been described and is linked to Xq21-24, but MRI does not reveal a pattern of leukodystrophy. Mutations in the PLP1 coding regions have been excluded in this disorder.

Mutations in the cell adhesion molecule gene L1CAM at Xq28 cause X-linked spastic paraplegia type 1 (SPG1). This disorder is associated with mental retardation and adducted thumbs and is allelic to mental retardation, aphasia, shuffling gait, and adducted thumbs (MASA) syndrome and X-linked hydrocephalus. MRI scans of these disorders may reveal enlarged ventricles or agenesis of the corpus callosum but do not reveal leukodystrophy.

Conditions to consider in the differential diagnosis of Pelizaeus-Merzbacher disease include the following:

  • Alexander disease – Reportedly caused by mutations in glial fibrillary acid protein

  • Adrenoleukodystrophy

  • Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL)

  • Canavan disease

  • Cockayne disease

  • Congenital muscular dystrophy due to merosin deficiency

  • Congenital nystagmus

  • Familial spastic paraplegia

  • Krabbe disease (globoid cell leukodystrophy)

  • Metachromatic leukodystrophy

  • Pelizaeus-Merzbacher–like disease

  • Salla disease (sialic aciduria)

  • Sjögren-Larsson syndrome

  • SOX10 mutation syndrome

  • Spastic paraplegia type 1

  • X-linked ataxia, deafness, blindness, and mental retardation

  • Multiple sclerosis

  • Parkinson disease

  • Parkinson-plus syndromes

  • Peroxisomal disorders

  • Progressive supranuclear palsy

  • Striatonigral degeneration

  • Temporal lobe epilepsy

  • Tonic-clonic seizures

  • Wilson disease

Differential Diagnoses

 

Workup

Approach Considerations

Molecular diagnostic tests

Molecular diagnostic tests for mutations of the PLP1 gene are the definitive studies for the diagnosis of Pelizaeus-Merzbacher disease. Duplications of the gene can usually be identified by fluorescent in situ hybridization (FISH) testing on interphase leukocytes.

Evoked potentials

Auditory evoked-potential testing shows normal latency of wave 1, and possibly of wave 2 as well, but with prolongation or abolition of central waves 3-5. Caution should be used when interpreting this test because functional hearing is often present, even in the absence of undetectable evoked responses.[13]

Visual evoked-potential testing demonstrates increased latency of P100. Somatosensory evoked-potential testing reveals normal peripheral latencies with prolonged or absent central latencies.

Evoked potentials of other leukodystrophies typically have delayed peripheral, as well as central, components.

Nerve conduction studies

Nerve conduction test results are usually normal in Pelizaeus-Merzbacher disease, but patients with null mutations (ie, those that prevent any PLP1 expression) have a mild, multifocal, demyelinating peripheral neuropathy. In contrast, other leukodystrophies, such as Krabbe disease, Cockayne disease, metachromatic leukodystrophy, and adrenoleukodystrophy, have diffusely slow nerve conduction velocities.

Imaging

In studies of the cerebrum, brainstem, and cerebellum, MRI reveals widespread, symmetrical abnormality of the white matter.

Additional tests

Testing for lysosomal storage diseases (particularly for arylsulfatase A, galactosylceramide beta-galactosidase, and hexosaminidase), Salla disease (urine sialic acid), and adrenoleukodystrophy (very ̶ long-chain fatty acids) should be done to exclude these disorders.

If prominent peripheral, as well as central, dysmyelination is present, along with facial features of Waardenburg-Hirschsprung syndrome, then screening for mutations of the SOX10 gene should be considered.

Individuals with a clinical history and signs that are typical for Pelizaeus-Merzbacher disease, but for whom results of routine testing for PLP1 mutations is negative, should be referred to a research laboratory for possible research testing and additional mutation screening.

MRI

MRI is the most useful imaging study in Pelizaeus-Merzbacher disease, demonstrating symmetrical and widespread abnormality of the white matter of the cerebrum, brainstem, and cerebellum. Given the heterogeneous nature of the disease process, with multiple genetic and molecular mechanisms causing Pelizaeus-Merzbacher disease, white matter atrophy is a major pathological determinant of the clinical disability in most patients.[14]

White matter has increased signal intensity on T2-weighted and inversion-recovery images (see the images below) and is hypointense on T1 images. These changes may not be readily evident or as confidently detected until after age 1 year, because the newborn brain is not well myelinated at birth.

T2-weighted magnetic resonance imaging (MRI) scan T2-weighted magnetic resonance imaging (MRI) scan of a child aged 10 months with duplication of the proteolipid protein (PLP) gene; note the high-intensity signal throughout the cerebral white matter.
T2-weighted magnetic resonance imaging (MRI) scan T2-weighted magnetic resonance imaging (MRI) scan of a man aged 41 years with duplication of the proteolipid protein (PLP) gene; note the increased white matter signal, as well as diffuse atrophy.

The normal differentiation of white from gray matter is most easily observed after age 1 year, by which time, normally, myelination is actively proceeding. However, the brainstem and cerebellum are partially myelinated at birth, and the posterior limbs of the internal capsule, splenium, and genu are normally myelinated at age 3 months; therefore, absence of the normal myelin MRI signals in these areas should raise suspicion of Pelizaeus-Merzbacher disease in an appropriate clinical setting.

In addition to a diffuse, increased T2-signal intensity, another MRI characteristic often seen in Pelizaeus-Merzbacher disease is a reduction in the absolute volume of white matter; this reduction is most severe in patients with the connatal form of the disorder (see the first image below). Patients with spastic paraplegia type 2 may have only patchy areas of increased T2 signal. Patients with the null mutation may have a more subtle increase in signal intensity, relative to that seen in other patients with Pelizaeus-Merzbacher disease, and the volume of white matter may be normal (see the second image below).

T2-weighted magnetic resonance imaging (MRI) scan T2-weighted magnetic resonance imaging (MRI) scan of a man aged 20 years with connatal Pelizaeus-Merzbacher disease due to a Pro14Leu mutation; note the severe reduction in white matter volume, as well as the increased white matter signal.
T2-weighted magnetic resonance imaging (MRI) scan T2-weighted magnetic resonance imaging (MRI) scan of a boy aged 17 years with null mutation of the proteolipid protein (PLP) gene; note the more subtle increase in signal intensity relative to that seen in the previous images, and observe that the volume of white matter is normal.

MR spectroscopy

In a recent study by Mori et al, they revealed that the changes in metabolite concentrations during growth can reflect the pathological condition of Pelizaeus-Merzbacher disease. Furthermore, the lack of change in the concentration of choline-containing compounds can be useful for differentiating Pelizaeus-Merzbacher disease from other white matter disorders.[15]

Molecular Diagnostic Studies

Using molecular diagnostic testing to detect mutations of the PLP1 gene is the definitive way to diagnose Pelizaeus-Merzbacher disease. Most patients (about 70%) have duplications (or, rarely, triplication or quintuplication) of the gene, which can usually be identified by FISH testing on interphase leukocytes. Other cells, such as buccal epithelia, chorionic villus cells, and amniocytes, can be tested as well. Duplications can also be identified using the Southern blot test or quantitative polymerase chain reaction (Q-PCR) assay.

Chromosomal microarray analysis (CMA) or comparative genomic hybridization (CGH) testing can also identify duplications or other changes in dosage of the PLP1 gene. FISH testing of metaphase chromosomes can be helpful in identifying rare cases in which the duplicated PLP1 gene is inserted in anomalous sites, such as distant loci of the X or Y chromosome or autosomes.

About 15-20% of patients have small and, typically, single nucleotide mutations that result in missense substitutions. Since FISH testing, CMA, and CGH testing do not identify these mutations, patients suspected of having Pelizaeus-Merzbacher disease who do not have PLP1 duplications should have PLP1 sequence analysis performed.

Mutations have been described that cause nonsense, frameshift, and splicing changes, in addition to complete gene duplications and deletions.

The remaining 5-10% of patients, without duplication or other mutations, may have mutations in PLP1 remote from those regions that are routinely examined in testing laboratories.

Locus heterogeneity (ie, the presence of additional genes that can cause a Pelizaeus-Merzbacher disease–like syndrome) is also observed. Mutations that affect a gap junction protein, GJA12 (also known as connexin 46.6), cause a syndrome virtually identical to Pelizaeus-Merzbacher disease. Patients with this autosomal recessive syndrome have nystagmus, motor and cognitive impairment, and diffuse leukodystrophy on MRI scans. Peripheral neuropathy and seizures are more prevalent in this Pelizaeus-Merzbacher disease–like syndrome.[11]

Histologic Findings

White matter areas in Pelizaeus-Merzbacher disease classically show a tigroid or patchy pattern of staining with myelin stains, but individuals who are more severely affected may have uniform and total loss of myelin staining.

Oligodendrocyte numbers are reduced in most patients. However, patients with null or other relatively mild mutations have normal to near-normal oligodendrocyte numbers and are able to make normal amounts of myelin, although it stains poorly with conventional histochemical myelin stains, such as Luxol fast blue. Some patients have loss of axons, especially of the longer tracts.

Patients with null mutations of PLP1 develop patchy demyelination of the peripheral nerves, typically at sites prone to compression, such as the elbow and wrist.

 

Treatment

Approach Considerations

No specific treatment for Pelizaeus-Merzbacher disease is known. Medical therapy is limited to supportive care, such as the use of physical therapy, orthotics, and antispasticity agents, including intrathecal baclofen. Regular physical medicine or orthopedic evaluations, physical therapy, and careful attention to posture and seating can help to minimize the development of joint contractures, dislocations, and kyphoscoliosis.

Patients who are severely affected (ie, those who have connatal Pelizaeus-Merzbacher disease) need special attention directed to airway protection and may need anticonvulsant therapy. Developmental assessment is important to maximize cognitive achievement and to assist in proper educational program assignment.

Pharmacologic therapy

When indicated, antiepileptic medications should be used. Antispasticity medications, such as baclofen, tizanidine, or benzodiazepines, may be beneficial.

Constipation is a common complication and may require the use of mild laxatives, such as senna, fiber supplements, or osmotic agents, such as polyethylene glycol 3350 (MiraLAX, Enemeez).

Surgical care

Tracheostomy may be needed during infancy if stridor impairs respiratory function. Feeding tube placement may be needed if oral feeding is inadequate to maintain weight or sustain normal growth in a child with Pelizaeus-Merzbacher disease, or if oral feeding poses a significant risk of aspiration.

Some patients with severe spasticity, especially children, may benefit from intrathecal baclofen, as well as from surgical release of contractures and other orthopedic procedures, including the use of spinal rods to correct severe scoliosis.

Activity

Within their capabilities, patients should be encouraged to be active for their physical and emotional well-being. A physiatrist or physical therapist can be helpful in providing guidelines for a specific child. Aquatic therapy can be a helpful exercise to maintain leg strength, as well as an enjoyable form of recreation.

Genetic counseling and prenatal testing

Competent genetic counseling must be provided to the family of an affected individual to provide the most accurate prognosis for the patient and to educate the family about the implications for future pregnancies.

Confirmation of the disease is likely to have implications for more distant relatives and for the immediate family. Prenatal testing and preimplantation genetic testing are possible and should be offered when appropriate. Identification of a causative mutation would be essential before prenatal testing could be performed. Preimplantation genetic diagnosis is possible when a mutation is known.

Consultations

Consultation with a geneticist and a genetic counselor is essential for parents of an affected child to educate them about Pelizaeus-Merzbacher disease and the risks to future offspring; consultation may also be critical for establishing and confirming the diagnosis.

Neonates with the connatal form of Pelizaeus-Merzbacher disease should be evaluated by a pulmonologist and perhaps by a neonatal swallowing specialist to evaluate airway safety and swallowing safety, respectively. Feeding tube placement may be necessary.

Regular consultation with a physiatrist or orthopedist and therapy team should be arranged. As the child grows, the physiatrist can help to optimize the patient’s mobility and strengthening and maximize the patient’s capabilities. The use orthotics, custom seating and cushions, and other aids is important for minimizing the development of joint dislocations and kyphoscoliosis. For severe contractures or scoliosis, orthopedic consultation may be beneficial.

Communication therapy, including training in use of communication devices, is often valuable. In addition, a pediatric developmental specialist should be consulted to optimize the child's educational program and to maximize the patient’s functional and learning capabilities.

 

Medication

Medication Summary

No specific medications are available for treatment of Pelizaeus-Merzbacher disease. However, some patients may benefit from antispasticity medications, such as baclofen (including intrathecally administered baclofen), tizanidine, and benzodiazepines. Botulinum toxin injections in spastic muscles or salivary glands can be very helpful in managing spasticity or sialorrhea/drooling, respectively. Children with seizures need to be appropriately treated.

Anxiolytics, Benzodiazepines

Class Summary

These agents may potentiate the effects of gamma-aminobutyric acid (GABA) and facilitate inhibitory GABA neurotransmission.

Diazepam (Valium, Diastat)

Diazepam is useful in suppressing muscle contractions by facilitating inhibitory GABA neurotransmission and other inhibitory transmitters.

Lorazepam (Ativan)

Lorazepam is a sedative-hypnotic of the benzodiazepine class that has a rapid onset of effect and a relatively long half-life. By increasing the action of gamma-aminobutyric acid (GABA), a major inhibitory neurotransmitter, it may depress all levels of the central nervous system (CNS), including the limbic system and reticular formations. Lorazepam is excellent for patients who need to be sedated for longer than 24 hours.

Skeletal Muscle Relaxants

Class Summary

These agents may inhibit the transmission of monosynaptic and polysynaptic reflexes at the spinal cord level.

Baclofen (Lioresal, Gablofen)

Baclofen may induce hyperpolarization of afferent terminals and inhibit monosynaptic and polysynaptic reflexes at the spinal level.

Cyclobenzaprine (Flexeril, Fexmid, Amrix)

Cyclobenzaprine acts centrally and reduces motor activity of tonic somatic origins, influencing alpha and gamma motor neurons. It is structurally related to the tricyclic antidepressants.

Skeletal muscle relaxants have modest, short-term benefit as adjunctive therapy for nociceptive pain associated with muscle strains and, used intermittently, for diffuse and certain regional chronic pain syndromes. Long-term improvement over placebo has not been established.

Cyclobenzaprine often produces a "hangover" effect, which can be minimized by taking the nighttime dose 2-3 hours before going to sleep.

Carisoprodol (Soma)

Carisoprodol is a short-acting medication that may have depressant effects at the spinal cord level.

Skeletal muscle relaxants have modest short-term benefit as adjunctive therapy for nociceptive pain associated with muscle strains and, used intermittently, for diffuse and certain regional chronic pain syndromes. Long-term improvement over placebo has not been established.

Alpha2-adrenergic Agonist Agents

Class Summary

These agents have beneficial antispasticity effects.

Tizanidine (Zanaflex)

Tizanidine is a centrally acting muscle relaxant that is metabolized in the liver and excreted in the urine and feces.

Neuromuscular Blockers, Botulinum Toxins

Class Summary

Agents in this class cause presynaptic paralysis of the myoneural junction and reduce abnormal contractions.

Botulinum toxin (BOTOX)

Botulinum toxin may provide relief of spasticity without the systemic adverse effects of other antispasticity agents. This agent binds to receptor sites on the motor nerve terminals and, after uptake, inhibits the release of acetylcholine, blocking the transmission of impulses in neuromuscular tissue.