Clinical manifestations

Presentation and course

Clinically, Pelizaeus-Merzbacher disease has been classified into three subtypes according to the age of presentation (43): type I, or classic Pelizaeus-Merzbacher disease; type II, or connatal form; and type III, or transitional Pelizaeus-Merzbacher disease (34). There are other disorders that can be caused by mutations of the PLP1 gene, thereby creating a spectrum of PLP1 disorders, including PLP1 null syndrome and spastic paraparesis.

Connatal Pelizaeus-Merzbacher disease. The connatal form is the most severe and presents at birth or within the first few weeks of life with hypotonia, which eventually progresses to spasticity in early childhood. Patients also demonstrate nystagmus, which may have a distinctive rotary component, but horizontal and vertical nystagmus also occur. Abnormal eye movements often dissipate with age. Laryngeal stridor and pharyngeal weakness are common and can lead to respiratory failure (08). Early-onset respiratory insufficiency can be a presenting sign in the connatal form (52). Motor deficits are severe, and it is common for infants to lack head control. Patients do not develop the ability to ambulate or speak, and cognition is significantly impaired. Affected children typically die in infancy or early childhood, usually due to aspiration.

Classic Pelizaeus-Merzbacher disease. Patients with classic Pelizaeus-Merzbacher disease typically present around 1 year of age or within the first few years of life with titubation and initial hypotonia that develops into spasticity starting by 5 years of age. Ataxia and nystagmus are common, and nystagmus can be the initial presenting symptom (07). Fundoscopy shows optic discs that range from pale to frankly atrophic by the age of 6 years due to optic nerve demyelination and atrophy (04). Some patients develop seizures and epilepsy; however, of all the leukodystrophies, Pelizaeus-Merzbacher disease has the lowest incidence of epilepsy at less than 10% (62). Many patients can achieve ambulation with assistive devices, but this is generally lost in late childhood or early adolescence as spasticity progresses. Apparent disease progression may result from contractures that develop with time. Cognition is typically impaired to some degree, but speech and language often develop. Patients can typically have a lifespan into the fifth or sixth decade (59).

PLP1 null syndrome. Patients initially present with mild spastic quadriparesis that mostly affects the lower extremities; however, symptoms do progress more rapidly than in other forms. Patients with PLP1 null syndrome, whose mutations prevent expression of PLP, typically have a complicated spastic paraplegia phenotype that leads to loss of ambulation and impaired cognitive function during late adolescence or early adulthood due to the degeneration of axons (11). These patients also have electrophysiologic evidence for mild, nonuniform demyelinating peripheral neuropathy (44). Nystagmus is not seen in PLP1 null syndrome.

Spastic paraparesis (SPG2). Patients with pure, or uncomplicated, SPG2 generally develop spastic paraparesis during childhood. Patients who do achieve useful independent ambulation, even if for just a few years, would be considered to have spastic paraplegia 2. Cognition is preserved, and many patients learn to communicate verbally; a few have attended college and held employment. Nystagmus may be present during infancy but is not as consistently seen as in patients with Pelizaeus-Merzbacher disease. Neurogenic bladder symptoms are also common. In addition to the gait and bladder signs, patients with complicated SPG2 may have one or more additional CNS signs, such as cognitive impairment, ataxia, visual impairment, or dysarthria. The gait usually deteriorates during adolescence or early adulthood, and patients typically become wheelchair-dependent during adulthood. Lifespan is normal in both complicated and uncomplicated SPG2 types.

Prognosis and complications

As with most leukodystrophies, the earlier the onset of symptoms, the more severe the disease course. Early-onset severe (connatal) Pelizaeus-Merzbacher disease carries a poor prognosis, with immobility, severe cognitive impairment, and death typically by the end of the second decade. Later-onset (classic) Pelizaeus-Merzbacher disease typically has a better prognosis, with survival into the sixth decade, but it still has similar complications related to its progression to spastic paraplegia. Feeding tubes may be needed for children with severe dysphagia and frequent aspiration episodes to minimize episodes of pneumonia as well as to provide nutrition. Constipation and neurogenic bladder are common complications and are probably caused by the underlying myelination defect, but relative immobility likely contributes. Due to spasticity, patients often progress to develop joint contractures with greater involvement in the legs. Scoliosis, sometimes severe enough to restrict breathing, may develop. Some patients with later onset of disease may be affected more mildly, and a few have been able to attend regular schools, including college, and obtain regular employment. This is especially true in spastic paraplegia 2 or in less severely affected patients with Pelizaeus-Merzbacher disease.

Clinical vignette

A male infant was born at term with unremarkable pregnancy and delivery. Neurologic examination was normal at birth. At around 2 months of age, the infant was noted to have continuous eye movements. He smiled socially but had poor head control at 4 months of age. Motor development was significantly delayed; he rolled over at 15 months and was never able to sit upright without support. He was eventually diagnosed with cerebral palsy. He acquired some speech by 4 years of age but was very dysarthric and qualified for an Individualized Education Program (IEP) at school, including therapy services. He made slow developmental progress, but he was referred to a pediatric neurologist for re-evaluation due to worsening leg spasticity. On exam, he had conjugate eye movements with subtle nystagmus. He had poor head control and truncal titubation. The child could not sit without support or walk and was noted to have significant lower extremity spasticity. Pertinent family history included his mother’s sister, who had a 1-year-old son with nystagmus, hypotonia, and developmental delay. Brain MRI showed diffuse T2 hyperintensity in the cerebral, cerebellar, and brainstem white matter, with typically normal white matter signal on T1-weighted images. Absent central conduction was demonstrated by brainstem auditory evoked response testing, and visual evoked response latencies were very prolonged, although peripheral nerve conduction velocities were normal. The diagnosis of Pelizaeus-Merzbacher disease was made.

Biological basis

Etiology and pathogenesis

Genetics. Pelizaeus-Merzbacher disease is caused by mutations affecting the PLP1 gene (10; 59). The inheritance pattern is X-linked and is most often recessive, so males are mostly affected. Female heterozygote carriers are almost always asymptomatic or only mildly affected, sometimes with spastic paraparesis. However, codominant expression has been seen in some families that have a large number of affected females (19). A case series in Poland demonstrated that in molecularly confirmed patients with Pelizaeus-Merzbacher disease, clinical phenotype can vary in severity, even amongst siblings (28). Although PLP1 point mutations were the first to be shown to cause Pelizaeus-Merzbacher disease (12), it is now clear that segmental X chromosome duplications that span the PLP1 gene are the most common cause of Pelizaeus-Merzbacher disease (47; 30), whereas only 15% to 20% have mutations within the noncoding regions of the gene (16). Triplication and even quintuplication of PLP1 has been found to cause Pelizaeus-Merzbacher disease, and it was previously suggested that severity of disease correlated with the extra gene dosage (58). However, a later study showed that PLP1 point mutations were associated with more severe disease, whereas PLP1 duplications were associated with milder forms of Pelizaeus-Merzbacher disease (07). Complete or partial deletion of the PLP1 gene is the least common cause of Pelizaeus-Merzbacher disease. These proportions of mutation types are seen in both familial and sporadic Pelizaeus-Merzbacher disease (30). The duplications of the PLP1 locus appear to occur by a mechanism involving DNA breakage and repair with non-homologous end-joining (60). Duplications most likely arise in male germ cells (ie, in the maternal grandfather of a “new mutation” patient), whereas point mutations can probably arise through either male or female germ cells (30).

Pathophysiology. A great reduction or absence of myelin in the CNS, resulting from variable degrees of oligodendrocyte death or dysfunction caused by PLP1 mutation, is the chief cause of the neurologic disturbances in Pelizaeus-Merzbacher disease (10). Historically, Pelizaeus-Merzbacher disease has also been called a sudanophilic leukodystrophy as the neutral fat breakdown products of myelin react with Sudan staining (24). Pathologically, patches of dysmyelination can be found interspaced with perivascular islands of intact myelin and are referred to as myelin islands or tigroid myelination (24; 18).

The PLP1 gene encodes the PLP protein and its alternatively spliced isoform, DM20, which are proteins expressed by oligodendrocytes and are essential for the structure of myelin in the central nervous system (38). There is prior evidence that the severity of the disease correlates with faulty trafficking of PLP and DM20 through the endoplasmic reticulum (13). Mutations that cause misfolding and prevent plasma membrane incorporation of both PLP and DM20 induce oligodendrocyte apoptosis, via elements of the unfolded protein response (48). These mutations clinically are associated with connatal Pelizaeus-Merzbacher disease. Less severe mutations seem to cause less disruption on oligodendrocyte survival and function. PLP1 duplications presumably cause overexpression of PLP and DM20. PLP overexpression also appears to cause a degree of oligodendrocyte cell death, although the mechanism probably differs from that which causes connatal disease (46). Clear-cut structure-function relationships are not identifiable; however, mutations in evolutionarily more highly conserved regions of the protein are associated with more severe clinical disease (06). There is evidence that oligodendrocytes affected by PLP1 mutations demonstrate key hallmarks of ferroptosis, including lipid peroxidation, abnormal iron metabolism, and hypersensitivity to free iron. Subsequently, iron chelation has been shown to rescue oligodendrocyte apoptosis and enable myelin formation (33).

Patients with the PLP1 gene-null syndrome, caused by mutations that prevent expression of both the PLP1 gene and DM20, develop late onset neurologic deterioration that usually begins in early adulthood. This deterioration most likely results from axonal degeneration and can be inferred by magnetic resonance spectroscopy (11).

Mutations affecting PLP1 can cause not only axonal degeneration but also neuronal loss, particularly in the cerebellum (45). The mechanisms for this neuronal loss are unclear but demonstrate that glial integrity is also important for maintaining neuronal viability.

The disease is usually limited to the CNS, where PLP is the chief protein component of myelin, but peripheral nerve involvement has been found in patients whose mutations prevent full-length PLP1 gene expression (44). Mutations that disrupt the PLP1 gene-specific domain (residues 116 to 150) as well as null mutations cause mild, demyelinating peripheral neuropathy (44).

Epidemiology

The birth incidence of rare disorders is difficult to ascertain, particularly for late-onset disorders. The most comprehensive epidemiologic survey of leukodystrophies, conducted in Germany, found the incidence of Pelizaeus-Merzbacher disease to be 1 per 770,000 live births (14). The authors acknowledged that their figures could underestimate the frequencies of leukodystrophies by up to 250%. In the Czech Republic, the incidence may be as high as 1 per 90,000 births (40). With a conservative assumption that patients with Pelizaeus-Merzbacher disease survive 10 years, the prevalence of Pelizaeus-Merzbacher disease could be at least 1 in 50,000 to 1 in 100,000.

Prevention

When a mutation or duplication in the PLP1 gene has been demonstrated, an individual prenatal and preimplantation genetic diagnosis can be offered (09; 56). When there is no demonstrable mutation or duplication, but sufficient informative family members, linkage analysis may be helpful for prenatal and preimplantation genetic diagnosis (29; 56). Genetic counseling is essential.

Differential diagnosis

Confusing conditions

The differential diagnosis is age dependent. In the newborn period through infancy, cerebral palsy, spasmus nutans, opsoclonus-myoclonus syndrome, mass lesions, congenital nystagmus, and other leukodystrophies are the chief considerations.

Pelizaeus-Merzbacher-like disease 1 (PMLD1). PMLD1 is caused by mutations in the GJC2 gene. Very similar to Pelizaeus-Merzbacher disease, PMLD1 presents in the neonatal period or in early infancy with nystagmus and hypotonia that evolves into spasticity during childhood. Patients have delayed acquisition of motor milestones and speech delay due to dysarthria; however, cognition is typically preserved. Cerebellar signs with gait ataxia, dysmetria, and titubation can manifest in childhood. Choreiform movements and dystonia are also common (32). MRI shows diffuse hyperintense T2-weighted signal in the white matter of the cerebrum and cerebellum as well as in the brainstem, with involvement of the corticospinal tracts. Evidence of brainstem involvement on MRI is typically more characteristic of PMLD1 than Pelizaeus-Merzbacher disease (17; 32).

Cerebral palsy. Cerebral palsy, the most common misdiagnosis applied to children with Pelizaeus-Merzbacher disease, must be considered in the differential (02). Titubation and truncal ataxia may be seen in both Pelizaeus-Merzbacher disease and cerebral palsy, but a severely or predominantly ataxic clinical picture argues against a diagnosis of cerebral palsy. Clinical deterioration may occur in patients with Pelizaeus-Merzbacher disease, but by definition, cerebral palsy is nonprogressive.

Spasmus nutans. Spasmus nutans consists of a triad of nystagmus, head nodding, and anomalous head positioning without other neurologic abnormalities (23). The nystagmus is either monocular or, when present in both eyes, asymmetric, whereas nystagmus in Pelizaeus-Merzbacher disease is symmetrical.

Other leukodystrophies. The other leukodystrophies differ from Pelizaeus-Merzbacher disease in several ways. Many are demyelinating rather than dysmyelinating disorders and, therefore, often show later onset and more rapid progression, whereas Pelizaeus-Merzbacher disease is usually of early onset and typically stationary or gradually progressive. Exceptions include Canavan disease and Krabbe disease, which can present in the first few months of life, and Aicardi-Goutieres syndrome, which can also be stationary or slowly progressive after an initial period of disease progression. Serum lysosomal enzymes, N-acetylaspartate levels, very long chain fatty acids, organic acids and urinary sialic acid levels should be measured to rule out Krabbe and Canavan diseases, Tay-Sachs disease, metachromatic leukodystrophy, adrenoleukodystrophy, L-2-hydroxyglutaric aciduria, and Salla disease. Adrenoleukodystrophy usually has later clinical onset, and MRI scans show occipital white matter changes. Metachromatic leukodystrophy usually presents with frontal white matter changes. Interestingly, although enlargement of the optic nerves is a feature of Krabbe disease, a patient with Pelizaeus-Merzbacher disease with enlarged optic nerves has been described (35). Magnetic resonance spectroscopy in patients with Pelizaeus-Merzbacher disease is normal in most cases, whereas Canavan disease causes greatly elevated N-acetylaspartate levels. Patients with vanishing white matter disease (also known as childhood ataxia with central hypomyelination) often have clinical worsening after febrile illness or traumatic head injury. Except for x-linked adrenoleukodystrophy and Alexander disease, these disorders are autosomal recessive.

X-linked spastic paraplegia. Some cases of X-linked spastic paraplegia are caused by mutations in the PLP1 gene. X-linked spastic paraplegia is generally of later onset than is Pelizaeus-Merzbacher disease, and its signs may be limited to the legs. When the eyes and other parts of the nervous system are involved, there may be no sure way of delineating the conditions; however, abnormal white matter on MRI scans is usually found in cases due to PLP1 gene mutations and should prompt a search for PLP1 mutation. Additionally, adrenal leukodystrophy can present with adrenomyeloneuropathy in affected males, generally in their 20s, and in carrier females over 50 years old. The spinal cord symptoms overlap with those of the genetic spastic paraplegias.

L1 syndrome. Intellectual disability, aphasia, shuffling gait, and adducted thumbs syndrome is linked to Xq28 and is caused by mutations in the L1CAM gene (57). It can present with spastic paraparesis that is similar to Pelizaeus-Merzbacher disease, but white matter MRI abnormalities are not typically found in this disease.

Cockayne syndrome. Cockayne syndrome should be readily distinguishable because of the beaked nose, large ears, skeletal changes, retinal pigmentation, cataract, and deafness. It is caused by mutations affecting one of at least two DNA repair enzymes (15). It is sometimes included with the leukodystrophies because of formal similarities of the neuropathological findings with those of Pelizaeus-Merzbacher disease.

Other. Homozygous mutations in the HSPD1 gene that encodes the mitochondrial hsp60 protein can cause early hypotonia, developmental delay, and intellectual disability that progresses to severe spastic quadriparesis. This autosomal recessive syndrome, which is fatal during childhood or adolescence, was found in an Israeli Bedouin family (25).

There are various other genetic mutations that can cause Pelizaeus-Merzbacher disease, including mutations in the gap junction C2 (GJC2, formerly GJA12) gene (53). Mutations in RARS cause a hypomyelination disorder akin to Pelizaeus-Merzbacher disease (31). X-linked early-onset hypotonia with nystagmus, developmental delay, and severe intellectual disability with white matter abnormalities on MRI can be caused by mutations in the SLC16A2 (formerly MCT8) gene (55). This syndrome is unusual in that the MRI white matter changes improve over time, even though the clinical syndrome gradually worsens.

Diagnostic workup

There are no set diagnostic criteria, but a certain constellation of symptoms can be highly suggestive of Pelizaeus-Merzbacher disease. When present, a family history of Pelizaeus-Merzbacher disease, X-linked spastic paraplegia, or "cerebral palsy" is helpful. The individual history of early-onset nystagmus (particularly rotary), respiratory stridor, and the other clinical signs are important, especially in older individuals who may no longer manifest these findings.

Diagnostic imaging and procedures. Magnetic resonance imaging (MRI) is helpful for the diagnosis of Pelizaeus-Merzbacher disease. T2-weighted images will show diffuse and symmetric hyperintense signal in the white matter of the cerebrum, cerebellum, and sometimes brainstem (22). However, this abnormality is best appreciated in children over about 1 year of age. Myelination is still actively ongoing until much later in life, and MRI is less useful in diagnosing young infants; however, in a normal newborn there should be myelination in the posterior limb of the internal capsule and brainstem (03). Therefore, with the appropriate clinical syndrome of neonatal nystagmus and hypotonia, lack of myelination in these areas should suggest the diagnosis of Pelizaeus-Merzbacher disease. Brainstem involvement may also indicate PMLD1. At later stages of Pelizaeus-Merzbacher disease, atrophy of the brain is sometimes visible in the scans. Carriers have normal or near-normal MRI scans. CT scans are not useful for diagnosis, although they may show mild signs of brain atrophy. Patients with pure spastic paraplegia 2 may have normal or only mildly abnormal white matter on MRI scans.

Magnetic resonance spectroscopy (MRS) may show slight elevation of cerebral white matter N-acetyl aspartate (NAA) levels (37; 50). Elevation of NAA levels is characteristic of Canavan disease, but in the absence of macrocephaly, rapid clinical deterioration and seizures, and with nystagmus and normal urine and serum NAA, the diagnosis of Pelizaeus-Merzbacher disease should be considered.

Nerve conduction studies are generally normal, but patients with the PLP1 null syndrome may have mild demyelinating polyneuropathy (44). Evoked potentials, particularly the brainstem auditory and visual evoked potentials, are characteristically abnormal, with delay or disappearance of the central components (26).

Laboratory and genetic testing. When the history and clinical examination indicate a strong possibility of Pelizaeus-Merzbacher disease, genetic testing should be pursued. Because duplications of the PLP1 gene are the most common cause of Pelizaeus-Merzbacher disease, genetic diagnosis usually begins with gene-targeted deletion and duplication analysis. If a duplication is not found, then quantitative polymerase chain reaction (qPCR) testing should be performed to identify patients with duplications too small to resolve by FISH analysis (58). If duplications are excluded, then a search for mutations within the PLP1 gene should be requested. The diagnosis of Pelizaeus-Merzbacher disease is confirmed when a mutation in, or duplication of, the PLP1 gene is found. If the clinical syndrome is consistent with both autosomal recessive inheritance and Pelizaeus-Merzbacher disease, testing for GJC2 (formerly GJA12) mutations should be entertained.

Management

Symptomatic treatment. Management varies with the age of the patient and is largely symptomatic. Periodic evaluations by developmental pediatricians and physiatrists are important for developmental monitoring and managing complications of disease progression, such as contractures or scoliosis. These complications may be minimized with physical therapy and anti-spasticity medications, such as baclofen or botulinum toxin injections. Swallowing and speech therapy should be arranged as needed, and severe feeding and respiratory difficulties may necessitate gastrostomy tube feeding or tracheostomy, respectively. Use of stool softeners, mild laxatives, and enemas may be needed for bowel management. Antiepileptic medications should be used for the management of seizures. General guidelines for the management of patients with leukodystrophies are available (54; 01). Genetic counseling should be provided to affected families. Prenatal and preimplantation genetic testing are available in mutation-confirmed cases (09; 56).

Drug therapies. There are no current approved medications for the direct treatment of Pelizaeus-Merzbacher disease. Further understanding of disease mechanisms is leading to the development of novel therapeutic approaches. As Pelizaeus-Merzbacher disease can result from the overexpression of the PLP1 gene, it may be a good candidate for treatment with emerging antisense oligonucleotides and microRNA therapies, which can lead to the downregulation of overexpressed genes (05). Umbilical cord blood (UCB) stem cells can be induced to differentiate into oligodendrocytes, and a current clinical study (NCT02254863) that includes Pelizaeus-Merzbacher disease is evaluating the effect of intravenous UCB transplant and intrathecal administration of UCB-derived oligodendrocytes. New Pelizaeus-Merzbacher disease research demonstrates that a high fat/low carbohydrate diet can restore oligodendrocyte integrity and increase CNS myelination, suggesting that a ketogenic diet is a potential therapy in Pelizaeus-Merzbacher disease (49).

Investigators found that PLP1 mutations lead to iron-induced cell death through lipid peroxidation, abnormal iron metabolism, and hypersensitivity to free iron (33). Iron chelation rescued oligodendrocytes from cell death, thus, suggesting a therapeutic approach to the disease in the preclinical stage. Mice that overexpress PLP1 develop cerebral inflammation that is ameliorated when the immune system is genetically ablated (20). If a similar inflammatory response occurs in humans, anti-inflammatory treatments might be of therapeutic benefit in patients with Pelizaeus-Merzbacher disease.

Special considerations

Pregnancy

Some mildly affected females have borne children, but most heterozygous asymptomatic females are healthy and do not have increased pregnancy complications.

Anesthesia

The type of anesthesia, induction, etc. are determined more by associated conditions, such as seizures and gastroesophageal reflux, than by Pelizaeus-Merzbacher disease itself (51). The difficulties and the approach to anesthesia in Pelizaeus-Merzbacher disease has been described, indicating a possible combination of general and regional anesthesia to minimize anesthetic-related respiratory depression (21). A thorough perioperative evaluation and perioperative planning is advised, and decisions should be made on a case-by-case basis.