Pelizaeus-Merzbacher disease

INTRODUCTION — In 1885, Friedrich Pelizaeus first identified a genetic disorder causing spasticity and developmental delay [1,2]. Twenty-five years later, Ludwig Merzbacher further described the neuropathology of 12 affected individuals related to the proband [3-6]. Together, Pelizaeus and Merzbacher identified the X-linked inheritance, the neonatal features, and the hypomyelination of the central nervous system that characterize the disease.

Pelizaeus-Merzbacher disease (PMD; MIM 312080) is classified as a dysmyelinating or hypomyelinating disorder, in which normal myelination never occurs, as opposed to a demyelinating disorder, in which normal myelin is later destroyed [7,8]. PMD is caused by pathogenic variants of the gene for proteolipid protein 1 (PLP1; MIM 300401).

This topic will review the pathogenesis, clinical features, and diagnosis of PMD and related disorders.

PATHOGENESIS — Pathogenic variants of the proteolipid protein 1 (PLP1) gene result in a range of phenotypes that form a clinical spectrum (figure 1), from the more severe PMD at one end to the relatively mild X-linked spastic paraplegia type 2 (SPG2) at the other [9].

●Connatal PMD

●Classic PMD

●PLP1 null syndrome

●Hypomyelination of early myelinating structures (HEMS)

●Complicated X-linked spastic paraplegia type 2 (SPG2)

●Pure SPG2

Role of PLP1 — The PLP1 gene encodes both proteolipid protein 1 (PLP1) and myelin DM20 proteolipid protein (DM20), major structural myelin proteins that contribute to the integrity of myelinated axons [10]. PLP1 is the predominant protein constituent of myelin in the central nervous system. Protein DM20 is a spliced isoform of PLP1, although it is not as abundant as PLP1 in the mature central nervous system [9].

Mature oligodendrocytes develop and initiate protein synthesis [11]. DM20 may be responsible for oligodendrocyte differentiation and survival [12], whereas PLP1 is involved in membrane signaling [13-15]. In addition, PLP1 is required for the production and stabilization of compact myelin, likely due to its role in forming integrin receptor adhesion complexes [4,15]. Interruption of the intracellular trafficking and secretory pathways in PMD results in cell death.

Duplications — The most common pathogenic variant is the duplication of the PLP1 gene, which accounts for approximately 60 to 70 percent of PMD [12,16,17]. Duplication is caused by unequal sister chromatid exchange in male meiosis [16,18].

Duplications of the PLP1 gene most likely cause overexpression of PLP1, which results in protein accumulation in the late endosomes and lysosomes. After synthesis in the rough endoplasmic reticulum of oligodendrocytes, PLP1 interacts with cholesterol and galactocerebroside in the Golgi to form myelin "rafts." The overexpression of PLP1 overwhelms this process, altering the composition of the rafts, and compromising the structure of the myelin sheath. Lipid rafts are unique structures within the plasma membrane composed primarily of cholesterol, sphingolipids, and scaffolding proteins that are important for vesicular trafficking, signaling mechanisms, and molecular transport. Disruption of these functions results in impaired lipid-lipid, lipid-protein, and membrane-cytoskeletal interactions which have been implicated in many neurologic diseases [19].

The size of the PLP1 duplication is variable and does not correlate with outcome. However, overexpression of PLP1, or the amount of excess protein produced, is associated with the severity of the disease [7,14]. Most patients with duplications of the PLP1 gene have classic PMD [6]. (See 'Clinical features' below.)

Missense variants — Protein misfolding caused by pathogenic PLP1 variants is another likely pathogenic mechanism of PMD [17]. In oligodendrocytes, PLP1 is synthesized in the rough endoplasmic reticulum and modified in the Golgi complex prior to transport to the myelin membrane.

Thus, the accumulation of misfolded PLP1 and DM20 in the endoplasmic reticulum leads to the expression of disease in PMD [17].

When both PLP1 and DM20 are not folded properly prior to transport, the misfolded proteins accumulate in the endoplasmic reticulum, resulting in upregulation of genes that induce apoptosis and a more severe disease phenotype [20]. However, when only PLP1 is misfolded, PLP1 is retained in the endoplasmic reticulum, but the oligodendrocyte survives, producing a less severe phenotype [21,22].

In general, the most severe phenotypes are caused by missense variants, especially amino acid substitutions in highly conserved regions of the protein [14]. Missense variants impair PLP1 protein cellular transport out of the endoplasmic reticulum in oligodendrocytes, which ultimately causes cell death as described above. In the connatal phenotype, a missense variant inhibits both PLP1 and DM20 transport, whereas only PLP1 transport is affected in missense variants that cause classic PMD [7,21]. (See 'Clinical features' below.)

Thus, the accumulation of misfolded PLP1 and DM20 in the endoplasmic reticulum leads to the expression of disease in PMD [17].

Other variants — Conservative amino acid substitutions in less-critical regions of the protein cause a similar, less severe phenotype. Nonsense variants, splice-site variants, and small deletions have also been described [7,14].

Null variants — Deletion of the PLP1 gene or disrupted translation due to a point pathogenic variant at the beginning of the coding region results in a loss of function in which no protein is produced. These null variants cause relatively mild disease, such as mild spastic paraparesis and demyelinating peripheral neuropathy [9].

Patients without PLP1 and DM20 are still able to form myelin; however, compact sheaths and axonal interactions are defective due to a loss of the structural proteins. The resulting phenotype is less severe than those associated with other pathogenic variants [5]. (See 'Clinical features' below.)

EPIDEMIOLOGY — In the United States, the estimated prevalence of PMD is between 1:200,000 and 1:500,000 [9]. A retrospective review of 122 children with an inherited leukodystrophy from a regional center in Utah reported that PMD was the etiology in 7.4 percent [23]. In a 2020 report that analyzed data from eight laboratories in the United States over a five-year period, the relative frequency of PLP1 pathogenic variants determined by whole exome sequencing, gene panel testing, and/or single-gene testing was approximately 8 percent [24]. Of note, PMD may be underrepresented in data from whole exome sequencing due to the variation in laboratory thresholds used to detect deletions and duplications. In Japan, the incidence of PMD due to a PLP1 pathogenic variant was estimated to be 1.45 per 100,000 male live births [25].

CLINICAL FEATURES — The major features of PMD are nystagmus, spasticity, athetosis, tremor, and ataxia. The symptoms vary in onset and severity, thereby producing a clinical spectrum of disease.

Various forms or phenotypes of PMD are distinguished by the severity of disease and other clinical features. These are connatal, classic, and transitional PMD; X-linked spastic paraplegia type 2 (SPG2); and proteolipid protein 1 (PLP1) null syndrome. These phenotypes of PMD do not necessarily represent distinct clinical syndromes, as overlap exists [4,26,27].

While PMD is an X-linked disease, female carriers may develop mild to moderate neurologic manifestations. (See 'Carrier females' below.)

Connatal PMD — The most severe form, connatal PMD, presents at birth or during the first weeks of life with pendular nystagmus, hypotonia, respiratory distress, pharyngeal weakness, and stridor. Affected males later develop significant spasticity and have little voluntary muscle control. They have significant head lag and cannot sit unsupported or ambulate. The motor difficulties extend to their expressive language, which usually does not develop, but they may develop receptive language. Cognitive impairment is likely. Pharyngeal weakness causes swallowing difficulties, and infants can have stridor, optic atrophy, and seizures [6,9].

Most children with connatal PMD die before the age of 10 because of aspiration, but survival until the second or third decade has been reported [6,9].

Classic PMD — Classic PMD, the most common form of the disease, also presents early, within the first five years of life [9]. Nystagmus is often detected in infancy within the first two to four months of life. Affected males later develop hypotonia with lower extremity weakness, trunk and limb ataxia, and head titubation. The motor milestones are delayed, and children develop spastic quadriparesis. Most children never walk independently. Language function can be normal, although dysarthria and cognitive impairments are common. The affected patients do not have any respiratory involvement and can survive until the third to seventh decade of life [6].

Transitional form — A transitional form between the connatal and classic forms has been proposed for patients with overlapping features involving the onset and severity of symptoms [9,18]. However, with variation in phenotypes and the age proximity between the connatal and classic forms, the utility of this subtype has been questioned [4,21].

X-linked spastic paraplegia type 2 — A milder form of PMD is known as X-linked SPG2 (figure 1). Despite a delay in gross motor skills, many children learn to walk independently, although they may become nonambulatory as they develop mild to severe spasticity. They also have a spastic urinary bladder.

Patients with SPG2 can be further subdivided into complicated spastic paraplegia and uncomplicated spastic paraplegia [5,9].

●Complicated spastic paraplegia presents in the first five years of life and is similar to the other types of PMD in which patients have limb and truncal ataxia and nystagmus. There may be mild cognitive impairment. Affected individuals survive until the fourth to seventh decade.

●Uncomplicated spastic paraplegia typically presents in the first five years of life although some have presented as late as the fourth decade. Uncomplicated spastic paraplegia has no other signs of central nervous system involvement, aside from the spastic paraparesis and urinary bladder. Cognition and lifespan are normal.

Males with SPG2 can reproduce, in contrast to all other forms of PMD [9].

PLP1 null syndrome — A subset of patients with null variants presents in the first five years of life with mild spastic quadriparesis, mostly affecting the lower extremities [28]. (See 'Null variants' above.)

Patients with the null syndrome are generally able to ambulate despite the increased tone. They have ataxia but not nystagmus. While they have mild to moderate cognitive difficulties, language skills develop initially. The PLP1 null syndrome is further distinguished from other forms of PMD by the presence of a mild multifocal demyelinating peripheral neuropathy [9,18].

Carrier females — Although PMD is an X-linked disorder, women who are heterozygous carriers may be symptomatic. Some adult females may exhibit a spastic gait or a mild peripheral neuropathy, urinary dysfunction, or (rarely) cognitive impairment or psychosis [29]. There is a paradoxical relationship between the disease severity in men and affected women, which is that women from families with mildly affected males are more likely to have neurologic symptoms than women with severely affected relatives.

This paradox is explained by the random inactivation of the X chromosome that results in an average 50 percent expression of the abnormal protein [20]. In heterozygous females, the oligodendrocytes that express the severe pathogenic variant undergo apoptosis. In time, the normal oligodendrocytes (those that express the other X chromosome) produce a sufficient amount of PLP1 protein to compensate for the loss. However, in heterozygous women who have the less severe pathogenic variants, apoptosis of the abnormal oligodendrocytes does not take place, and those women end up with abnormal myelin, resulting in neurologic dysfunction [6,9,30]. There is a single case report of a woman presenting in infancy with a "classic" male phenotype characterized by nystagmus, spasticity, and significant motor delay [31]. Genetic testing revealed a deletion of exons 1 to 7 of the PLP1 gene and nonrandom skewed X chromosome inactivation, suggesting preferential activation of the X chromosome with the deletion.

Neuroimaging — An appreciation of the normal appearance of unmyelinated and myelinated white matter structures on brain magnetic resonance imaging (MRI) is helpful for understanding imaging studies of infants and children with a hypomyelinating leukodystrophy [32-34]:

●Unmyelinated white matter has a high signal intensity on T2-weighted and low signal on T1-weighted images

●Myelinated white matter has a low signal intensity on T2-weighted and a high signal intensity on T1-weighted images

In normal development, the bulk of central nervous system myelination occurs during the first two years of life [32]. Thus, in infants younger than two years with a dysmyelination syndrome, the brain MRI may not show obvious white matter abnormalities.

In normal full-term infants, myelination is usually evident on MRI in the pons and cerebellum, and by the age of three months, normal infants show myelination in the posterior limb of the internal capsule, splenium of the corpus callosum, and optic radiations [32]. Absence of these MRI findings suggests the diagnosis of a dysmyelinating syndrome such as PMD [9].

The brain MRI of older children with the PMD phenotype often reveals diffuse leukodystrophy with increased signal intensity in the cerebral hemispheres, cerebellum, and brainstem on T2-weighted or fluid-attenuated inversion recovery (FLAIR) sequences (image 1). However, many hypomyelinating disorders have diffuse involvement, unlike the demyelinating disorders where regional involvement is easily identified on T2-weighted and FLAIR sequences. The T1-weighted images are also critical in identifying hypomyelinating disorders, such as PMD, as the white matter will also appear diffusely abnormal with mild T1 hypointensity, isointensity, or hyperintensity [34].

No clear correlation between genotype, clinical phenotype, and MRI phenotype has been established for PMD [35]. However, some experts have noted an inverse correlation between the amount of myelin present and the clinical disease severity [33,36]. As an example, no myelin is present at all in some infants with connatal PMD, the most severe form of PMD [33]. Diffuse brainstem or corticospinal tract involvement of the posterior limb of the internal capsule (hyperintensity on T2-weighted imaging) predicted patients with poorer motor outcomes in a cohort of 19 subjects [36].

In patients with the classic PMD phenotype, the white matter abnormalities on MRI have been divided into three subtypes [37]:

●Type I: diffuse abnormality in the hemispheres with lesions affecting the corticospinal tracts; this type was found in patients with a PLP1 duplication.

●Type II: similar hemispheric lesions without corticospinal involvement.

●Type III: patchy hemispheric involvement. The patchy areas of myelin forming the "tigroid" pattern are not readily apparent on neuroimaging in most patients [7].

The reported abnormalities on T2 MRI in SPG2 range from discrete or patchy hyperintensities to more diffuse leukoencephalopathy [38,39].

Studies evaluating magnetic resonance spectroscopy (MRS) in patients with PMD have found no consistent pattern of abnormalities. Some patients, particularly those with the PLP1 null syndrome, may show reduced white matter N-acetylaspartate (NAA) levels [40,41], while others, mainly those with PLP1 duplications, may have increased white matter NAA levels [42].

Pathology — Merzbacher originally described the absence of myelin sheaths specific to the central nervous system without axonal involvement and preserved myelin islets around blood vessels [2]. These patchy areas of myelin islands give the tissue a "tigroid" appearance [7,43].

Gross sections of the brain reveal atrophy, pallor, and sclerosis of white matter in the cerebrum, cerebellum, and brainstem [8]. The axons of the central nervous system lack the typical myelin sheath. In addition, there is a profound loss of oligodendrocytes, which produce myelin. Although not as remarkable, axonal damage has been demonstrated, likely due to impaired axonal transport from altered proteolipid protein-mediated oligodendrocyte-axonal interactions [6,43]. The axons do not appear to be affected by demyelination or oligodendrocyte cell death.

The peripheral nervous system is unaffected in most forms of PMD; an exception is the PLP1 null syndrome. (See 'PLP1 null syndrome' above.)

DIAGNOSIS — The diagnosis of PMD or X-linked spastic paraplegia type 2 (SPG2) is suspected in patients with the characteristic clinical and brain MRI features, particularly if there is a family history consistent with X-linked disease inheritance, although de novo single-nucleotide variants do occur [9]. (See 'Clinical features' above.)

The diagnosis should be confirmed, when possible, by genetic testing. Nerve conduction studies to assess peripheral nerve function may be helpful for identifying individuals with the proteolipid protein 1 (PLP1) null syndrome [9]. (See 'PLP1 null syndrome' above.)

Genetic testing — The diagnosis of PMD is confirmed by demonstrating a heterozygous pathogenic variant in the PLP1 gene. Approximately 80 percent of males with clinically diagnosed PMD or SPG2 have PLP1 pathogenic variants [9]. The genetic etiology for patients with clinical features of PMD but without pathogenic PLP1 variants remains unknown, with the exception of Pelizaeus-Merzbacher-like disease. (See 'Pelizaeus-Merzbacher-like disease' below.)

Duplication of the PLP1 gene is the most common defect, accounting for approximately 60 percent or more of identified pathogenic variants; deletions of the PLP1 gene account for ≤2 percent of PMD cases [9]. Therefore, the recommended initial genetic screening test in a patient with classic symptoms and MRI findings is a search for duplications or deletions [9,12]. Complex duplication-inverted triplication-duplication (DUP-TRP/INV-DUP) rearrangements of the PLP1 gene have also been reported [44,45]. If these explorations of PLP1 are nondiagnostic, next-generation methods (eg, using a gene panel or whole exome sequencing) should be pursued. Of note, for patients who do not have the classic clinical features or MRI findings for PMD, many experts advocate for the gene panel or whole exome sequencing approach as initial testing to increase diagnostic yield and reduce the time to diagnosis for families [46].

Genetic analysis of the GJC2 (formerly GJA12) gene should be considered if inheritance is autosomal recessive, the proband is female, or all the mutational mechanisms in PLP1 gene have been excluded. (See 'Pelizaeus-Merzbacher-like disease' below.)

Prenatal testing, using amniocentesis and chorionic villus sampling, has been used to detect pathogenic variants of PLP1 in at-risk fetuses [47-49]. Preimplantation genetic testing following in vitro fertilization may be an option for some couples.

DIFFERENTIAL DIAGNOSIS — The differential diagnosis for PMD and X-linked spastic paraplegia type 2 (SPG2) includes Pelizaeus-Merzbacher-like disease (PMLD), other leukodystrophies (algorithm 1), and inherited disorders with spastic paraplegia.

Pelizaeus-Merzbacher-like disease — PMLD shares similar clinical features with PMD, such as early-onset nystagmus, delayed motor milestones, spasticity, ataxia, partial seizures, and a mild peripheral neuropathy [50]. However, PMLD is not associated with pathogenic variants or duplications of the proteolipid protein 1 (PLP1) gene. The disorder appears to be genetically heterogeneous.

Some cases of PMLD are associated with dysmyelination, demyelination, autosomal recessive inheritance, and pathogenic variants of the gap junction protein gamma-2 gene (GJC2), formerly known as the GJA12 gene on chromosome 1q41-q42 [50-54]. The GJC2 gene encodes a gap junction protein that is highly expressed in oligodendrocytes [50]. Pathogenic variants have been identified in the promoter and non-coding exon in addition to the coding region of the gene [54-56]. Therefore, sequencing of the only the latter may result in delayed or missed diagnosis.

Another study screened PLP1-negative patients from a cohort of 53 families with X-linked hypomyelinated leukoencephalopathies of unknown etiology [57]. Pathogenic variants in the SLC16A2 gene (causing Allan-Herndon-Dudley syndrome) were present in 11 percent. Boys with SLC16A2 pathogenic variants presented before six months of age with severe forms of PMLD and marked hypomyelination on brain MRI. The hypomyelination improved during follow-up, suggesting that pathogenic SLC16A2 variants cause a severe delay of myelination rather than a permanent myelin defect. However, there was no neurologic improvement.

The SLC16A2 gene encodes a thyroid hormone transporter, which appears to play an important role in the movement of thyroid hormone into the brain and therefore in the effect of thyroid hormone on brain development [58]. Three patients with PMLD and pathogenic SLC16A2 variants who had thyroid function testing showed increased free T3, low free T4, and normal thyroid stimulating hormone levels [57], a profile associated with a thyroid hormone cell transporter defect. (See "Genetic defects in thyroid hormone transport and metabolism", section on 'Thyroid hormone cell membrane transport defect'.)

Pathogenic variants in RARS have been reported in four individuals who developed nystagmus at variable ages (five months to three years), along with spastic diplegia, developmental regression, and cerebellar signs [59]. MRI of the brain revealed hypomyelination of the supratentorial (and, in one patient, infratentorial) white matter. Brain atrophy also occurs.

Hypomyelinating leukodystrophies — A number of rare metabolic disorders are characterized by hypomyelination (ie, a failure to develop normal myelin). However, with the exception of PMLD, discussed above, most of these disorders are unlikely to be confused with PMD either because they lack the characteristic clinical features (ie, nystagmus, spasticity, athetosis, tremor, and ataxia), or because they have distinctive clinical features not associated with PMD (eg, the unique MRI pattern of hypomyelination with atrophy of the basal ganglia and cerebellum) [34].

●The 18q deletion syndrome (MIM 601808) is characterized by intellectual disability, hearing impairment, short stature, hypotonia, and foot deformities. Diffuse symmetric deep white matter hypomyelination is seen on brain MRI. In some cases, focal subcortical white matter abnormalities or abnormal T2 signal hypointensity in the basal ganglia and/or thalami are noted [60-63].

●Cockayne syndrome (MIM 216400 and MIM 133540) is characterized by severe physical and intellectual disability, short stature, microcephaly, retinal degeneration, kyphoscoliosis, gait defects, sun sensitivity, and white matter hypomyelination with atrophy of the cerebrum and cerebellum. (See "Neuropathies associated with hereditary disorders", section on 'Cockayne syndrome'.)

●Hypomyelination with atrophy of the basal ganglia and cerebellum (H-ABC) is characterized by normal or delayed early development followed by progressive extrapyramidal symptoms, ataxia, and spasticity. Cognition is variably affected. Brain MRI demonstrates atrophy of the cerebral white matter, basal ganglia, and cerebellum [64,65].

●Hypomyelination with congenital cataracts (MIM 610532) is characterized by bilateral congenital cataracts, developmental delay, and slowly progressive neurological impairment, with spasticity, ataxia, and intellectual disability. Hypomyelination involves both the central and peripheral nervous systems [66,67].

●A number of hypomyelinating leukodystrophies are caused by autosomal recessive pathogenic variants in the POLR3A or POLR3B genes, which encode for the two largest subunits of RNA polymerase III (Pol III) [68]. These Pol III-related leukodystrophies share clinical and neuroimaging features, and include:

•Hypomyelination with hypogonadotropic hypogonadism and hypodontia (4H syndrome) [69-72]

•Leukodystrophy with oligodontia [73]

•Ataxia, delayed dentition, and hypomyelination [74]

•Tremor-ataxia with central hypomyelination [75]

•Hypomyelination with cerebellar atrophy and hypoplasia of the corpus callosum [76]

Major clinical findings are motor dysfunction (spasticity, cerebellar ataxia, and/or tremor), abnormal dentition, and hypogonadotropic hypogonadism [77]. The predominant abnormalities detected by MRI include diffuse hypomyelination, hypointense T2-weighted signal of the bilateral globi pallidi, anterolateral thalamic nuclei, dentate nuclei, and pyramidal tracts, and cerebellar atrophy [78].

●Sialic acid storage disease (also called Salla disease or sialuria) is an autosomal recessive disorder with a variable phenotype, ranging from a severe infantile form (MIM 269920) to a milder adult form (MIM 604369) that is prevalent in Finland. Typical clinical features include hypotonia, cerebellar ataxia, and intellectual disability. In infants, visceromegaly and coarse features are additional features. Brain MRI demonstrates progressive cerebellar atrophy and dysmyelination [79-83].

●Trichothiodystrophy with photosensitivity (also known as Tay syndrome; MIM 601675) is characterized by sulfur-deficient brittle hair and nails, ichthyosis, short stature, intellectual disability, and pyramidal tract signs. Photosensitivity affects approximately half of the patients. Brain MRI reveals severe cerebral hypomyelination and patchy cerebellar hypomyelination [84,85].

Other leukodystrophies — Leukodystrophies that may present in infancy and childhood include the following:

●Alexander disease (see "Alexander disease")

●Childhood ataxia with central nervous system hypomyelination/vanishing white matter disease (see "Vanishing white matter disease")

●Krabbe disease (see "Krabbe disease")

●Metachromatic leukodystrophy (see "Metachromatic leukodystrophy")

●X-linked adrenoleukodystrophy (see "Clinical features, evaluation, and diagnosis of X-linked adrenoleukodystrophy")

Unlike PMD, these leukodystrophies do not typically present with nystagmus [9]. Furthermore, brain MRI abnormalities are typically diffuse in PMD, but usually have a regional predilection in the other leukodystrophies.

●Canavan disease is a neurodegenerative disease characterized by leukodystrophy and spongy degeneration of the brain that typically presents in early infancy with macrocephaly, hypotonia, and optic atrophy. Later, hypertonia, seizures, and progressive neurologic deterioration occur. Nystagmus is not a typical feature. On neuroimaging, there is diffuse cerebral white matter degeneration.

●Classic (merosin deficient) congenital muscular dystrophy is associated with demyelination of the cerebral hemispheres without structural central nervous system anomalies. Clinical features include hypotonia and weakness, but unlike PMD, there is no nystagmus. MRI shows extensive cerebral white matter changes [86]. (See "Oculopharyngeal, distal, and congenital muscular dystrophies", section on 'Congenital muscular dystrophies'.)

Hereditary spastic paraplegia — As discussed above, SPG2 is a milder form of PMD that can present in the first five years of life, and less often in adulthood (figure 1). (See 'X-linked spastic paraplegia type 2' above.)

In fact, SPG2 is one of the many genetic causes (table 1) of hereditary spastic paraplegia (HSP), an inherited syndrome that is characterized clinically by progressive leg weakness and spasticity. HSP is classified by mode of inheritance, chromosomal locus, or causative gene; genetic loci for HSP are designated "spastic gait" (SPG) loci 1 through 20 in order of their discovery. With the exception of SPG2, neuroimaging of the brain and spinal cord by MRI is normal in most types of HSP. (See "Hereditary spastic paraplegia".)

MANAGEMENT — No disease modifying treatment is available for PMD, X-linked spastic paraplegia type 2 (SPG2), or Pelizaeus-Merzbacher-like disease (PMLD).

Management is multidisciplinary and supportive [9,87]:

●Optimal care may require specialists in neurology, physical medicine, orthopedics, pulmonary medicine, and gastroenterology, and physical, occupational, and speech therapy. Wheelchairs are often required.

●Scoliosis may cause pulmonary compromise and pain. Prevention measures include proper seating in the wheelchair and ongoing physical therapy.

●Aspiration is a major cause of morbidity and mortality. Patients with swallowing difficulties may require a gastrostomy tube.

●Assistive devices for joint contractures are frequently needed. Antispasticity medications, such as oral diazepam or tizanidine, and intrathecal or oral baclofen, may improve tone. Surgical release of joint contractures may be required in severe cases.

●Seizures are usually restricted to the more severe syndromes, such as connatal PMD, and typically respond to antiepileptic medications. (See "Seizures and epilepsy in children: Initial treatment and monitoring" and "Overview of the management of epilepsy in adults".)

●Developmental assessment is important for infants and children with proteolipid protein 1 (PLP1)-related disorders. Specialized education is typically necessary. Communication devices may be useful in children with impaired vision and hearing.

Umbilical cord blood transplantation has been performed in selected patients with leukodystrophies, but in the absence of a control group or natural history data, it is unclear if this procedure improves neurologic outcomes. In one report, two boys with PMD (ages 9 and 29 months, respectively, at the time of transplant) demonstrated successful engraftment after the procedure [88]. The post-transplantation course was complicated by graft-versus-host disease for both, and one boy developed autoimmune hemolytic anemia and thrombocytopenia requiring long-term use of glucocorticoids with subsequent adrenal insufficiency and immunosuppression. While the authors report improvements in cognition and interval myelination on MRI, the boys continued to have cognitive impairments and both had significant motor delays.

SUMMARY AND RECOMMENDATIONS — Pelizaeus-Merzbacher disease (PMD) is a dysmyelinating disorder, in which normal myelination never occurs.

●Pathogenic variants of the proteolipid protein 1 (PLP1) gene result in a range of phenotypes that form a clinical spectrum (figure 1), from the more severe PMD at one end, to the relatively mild X-linked spastic paraplegia type 2 (SPG2) at the other. (See 'Pathogenesis' above.)

●Most cases of PMD are caused by duplication of the PLP1 gene, which most likely causes overexpression of PLP1, resulting in compromise of the myelin sheath structure. Protein misfolding caused by PLP1 missense variants is a second likely pathogenic mechanism of PMD. A third mechanism involves null variants leading to a loss of function in which no protein is produced. These cause relatively mild disease. (See 'Pathogenesis' above.)

●The major clinical features of PMD are nystagmus, spasticity, athetosis, tremor, and ataxia. The symptoms vary in onset and severity, thereby producing a clinical spectrum of disease. (See 'Clinical features' above.)

●Various forms or phenotypes of PMD are distinguished by severity of disease and other clinical features. These are:

•Connatal

•Classic

•Transitional

•X-linked SPG2

•PLP1 null syndrome

Although PMD is an X-linked disease, female carriers may develop mild to moderate neurologic manifestations. (See 'Clinical features' above.)

●Brain MRI of patients with the PMD phenotype reveals patchy or diffuse leukodystrophy with increased signal intensity in the cerebral hemispheres, cerebellum, and brainstem on T2-weighted and fluid-attenuated inversion recovery (FLAIR) sequences. (See 'Neuroimaging' above.)

●Gross sections of the brain reveal atrophy, pallor, and sclerosis of white matter in the cerebrum, cerebellum, and brainstem. The axons of the central nervous system lack the typical myelin sheath. (See 'Pathology' above.)

●The clinical diagnosis of PMD or SPG2 should be suspected in patients with the characteristic nystagmus and brain MRI findings, particularly if they have a family history consistent with X-linked disease inheritance. The diagnosis is confirmed by demonstrating a pathogenic variant in the PLP1 gene. (See 'Diagnosis' above.)

●The differential diagnosis for PMD and SPG2 includes Pelizaeus-Merzbacher-like disease (PMLD), other leukodystrophies, and hereditary spastic paraplegia. (See 'Differential diagnosis' above.)

●There is no effective treatment for PMD, SPG2, or PMLD. Management is multidisciplinary and supportive. (See 'Management' above.)