Pelizaeus-Merzbacher disease

Key Points at a Glance

Key Points of This Disease

• Pelizaeus-Merzbacher disease (PMD) is an X-linked recessive hypomyelinating disorder caused by mutations in the PLP1 gene, primarily affecting males.
• The three main symptoms are nystagmus, motor developmental delay, and spasticity. Nystagmus is often noticed as the first symptom at an average age of 2–3 months.
• The disease is classified into type I (congenital), type II (intermediate), and type III (classic), with type I being the most severe.
• Duplication of the PLP1 gene accounts for 50–75% of all cases, making it the most common genetic mutation.
• Currently, there is no curative treatment; management focuses on symptomatic therapy including spasticity control, nutritional support, and rehabilitation.
• Life expectancy is up to the 30s for type I (with intervention) and up to the 70s for type III (classic).

1. What is Pelizaeus-Merzbacher Disease?

Pelizaeus-Merzbacher Disease (PMD) is an X-linked recessive hypomyelinating leukodystrophy caused by mutations in the PLP1 gene. Its three main features are nystagmus, motor developmental delay, and spasticity.

History

In 1885, Friedrich Pelizaeus identified the disease in five boys from a German family. In 1910, Ludwig Merzbacher reinvestigated the same family and described the neuropathology of 14 affected individuals. ¹⁾

Epidemiology

• Worldwide prevalence: 1 in 90,000 to 1 in 750,000 people
• United States: 1.9 per 100,000 people
• Alternative estimate of incidence in boys: 1 in 200,000 to 500,000 ²⁾

Inheritance pattern and mutation type

X-linked recessive inheritance, primarily affecting males. Females are usually asymptomatic carriers. Duplication of the PLP1 gene accounts for 50–75% of all PMD cases and is the most common causative mutation. ¹⁾ Most of the remaining cases are due to point mutations, with a small number being deletions.

Q How rare is Pelizaeus-Merzbacher disease?

A

The worldwide prevalence is estimated to be between 1 in 90,000 and 1 in 750,000, making it an extremely rare disease. Among males, the estimated prevalence is 1 in 200,000 to 1 in 500,000. ²⁾

2. Main symptoms and clinical findings

Subjective symptoms

Many symptoms appear before age 2, and caregivers often notice them first.

• Nystagmus: The earliest noticed symptom. It was the initial symptom in 68.8% (11/16) of PLP1 duplication cases, with an average onset age of 3.1 months (range: birth to 12 months). ¹⁾ In a cohort of 111 Chinese patients, 99.1% had nystagmus. ¹⁾
• Motor developmental delay: All affected children have delays in both motor and language development. ¹⁾ In the PLP1 duplication cohort, none achieved independent walking, and 94% use a wheelchair full-time. ¹⁾
• Feeding difficulties: 63% (10/16) of PLP1 duplication cases have feeding problems, and gastroesophageal reflux is seen in 40% (6/15). ¹⁾
• Initial symptoms of congenital type (type I): Respiratory distress, stridor, feeding difficulties, and failure to thrive from birth. ²⁾

Clinical Findings (Findings Confirmed by Physician Examination)

PMD disease classification (3 types)

Type I (Congenital)

Severity: Most severe type.

Onset: Symptoms appear from birth.

Main findings: Inability to walk or speak. Significant cognitive impairment. Epileptic seizures. Laryngeal stridor, pharyngeal paralysis, respiratory failure.

Type II (Intermediate)

Severity: Intermediate between type I and type III.

Onset: Often occurs in infancy.

Main findings: Neurological symptoms are milder than type I but more severe than type III.

Type III (Classic type)

Severity: Mildest form.

Onset: Usually occurs around 1 year of age.

Main findings: Limited walking ability may be maintained. Cognitive function is relatively preserved.

Neurological findings common to all types

• Hypotonia: Reported in all cases. ¹⁾
• Scoliosis, tremor, head tremor (titubation), ataxia

Ophthalmological findings

• Horizontal and rotary nystagmus: In a Colombian case series (7 cases), horizontal nystagmus 57%, rotary nystagmus 43%.
• Poor spatial vision and poor visual field
• Optic nerve hypertrophy: observed on MRI in some cases
• Reduced vestibulo-ocular reflex (VOR)

Auditory and vestibular findings

ABR shows only peak I (from cochlea/spiral ganglion), while peaks III and V from myelinated auditory pathways are absent. Tympanogram type A and DPOAE are normal (outer hair cell function preserved). Cervical vestibular evoked myogenic potentials (cVEMP) show bilateral prolongation of P1 and N1 latencies with normal amplitude, reflecting demyelination of brainstem vestibular pathways. ⁴⁾

Cognitive function (PLP1 duplication cases)¹⁾

• All patients can recognize names and follow two-step commands
• 93% can name two objects in a room
• 69% can read (level varies greatly among individuals)

Q What is the first noticed symptom?

A

In 68.8% of PLP1 duplication cases, nystagmus is the initial symptom, noticed at an average age of 3.1 months. ¹⁾ Nystagmus appears between birth and 12 months of age, and early infantile nystagmus is an important clue for this disease.

3. Causes and Risk Factors

Causative gene

The PLP1 gene (Xq22.2) consists of 7 exons and encodes proteolipid protein (PLP1), a major myelin protein, and its isoform DM20. ³⁾

Mutation types and frequency

Mutation type	Frequency	Typical phenotype
PLP1 duplication	50–75% (most common)	Mostly classic type (type III)
Point mutation (missense)	Most of the remainder	Often severe congenital type
Deletion/null mutation	Very few	Relatively mild

Duplication size ranges from 100 Kb to approximately 5 Mb. Three or more copies of PLP1 duplication are associated with more severe forms. Even with the same genotype, there is a wide range of phenotypes, making prognosis prediction based solely on genotype unreliable. ³⁾

Risk factors

• Male children of carrier mothers (50% of male children in the next pregnancy will develop PMD, and 50% of female children will become carriers) ³⁾
• Family history

About genetic counseling

Due to X-linked recessive inheritance, the risk of transmission from a carrier mother to a male child is 50%. If there is a family history, genetic counseling and consideration of prenatal diagnosis are recommended. Prenatal diagnosis using SNP array and MLPA confirmation via amniocentesis (18 weeks) is available. ³⁾

Q If the mother is a carrier, what is the genetic risk for the next child?

A

50% of male children born to carrier mothers will develop PMD, and 50% of female children will be carriers. ³⁾ Prenatal diagnosis (SNP array via amniocentesis) can confirm the presence or absence of PLP1 duplication.

4. Diagnosis and testing methods

Imaging Tests

MRI (most important imaging test)

• T2-weighted imaging: extensive high signal (posterior limb of internal capsule, optic radiation, corona radiata). White matter shows high signal relative to gray matter.
• T1-weighted imaging: white matter is isointense relative to gray matter.
• Thinning of the corpus callosum, mild cerebellar vermis atrophy, cerebellar hypoplasia
• MRS: elevated NAA, decreased choline (suggesting hypomyelination) ⁴⁾
• CT: White matter attenuation and progressive atrophy

The MRI myelination scoring system proposed by Harting et al. scores 8 items on T2-weighted images and 6 items on T1-weighted images on a scale of 0 to 2 by anatomical region (total 0–27 points). It is evaluated based on signal intensity relative to the cortex and is useful for objective and standardized assessment during follow-up.

Genetic Testing

• MLPA: Can detect all 7 exons of PLP1 with high reliability
• Chromosomal Microarray (aCGH): Detection of copy number variations (CNVs)
• SNP Array: Higher resolution than aCGH. Can detect UPD, LOH, and low-level mosaicism in addition to CNVs. Also usable for prenatal diagnosis³⁾
• FISH and droplet digital PCR (ddPCR)

Electrophysiological testing

• ABR: Only peak I appears; absence of peaks III and V is characteristic of PMD. In PMD-like diseases (PMLD), ABR is normal, which helps in differentiation. ⁴⁾ Diagnostic ABR is required, not screening ABR.
• VEP and electroretinogram (ERG): Show severe abnormalities in EIF2-related cases ⁵⁾

Functional Disability Scale (FDS): Maximum score 31 (9 domains: education/employment, speech, feeding, dressing, toileting, writing, sitting, walking, breathing). Useful for quantifying clinical course. Mean FDS1 score in PLP1 duplication cases is 11.5/31 (SD 5.1). ¹⁾

Age at diagnosis: Mean age in PLP1 duplication cohort is 5.1 years (range: birth to 18 years). ¹⁾

Differential Diagnosis

• PMD-like disease (PMLD): Differentiated from PMD by normal ABR
• Spastic paraplegia type 2 (SPG2): Slowly progressive spastic paraplegia due to PLP1 mutation
• EIF2B-related leukoencephalopathy (LEUDEN syndrome): Clinically and radiologically similar to PMD, but due to de novo mutation in EIF2B. Only 10 cases reported in literature⁵⁾
• Metachromatic leukodystrophy and Adrenoleukodystrophy

5. Standard Treatment

Currently, there is no curative treatment for PMD. Treatment is mainly symptomatic and palliative care.

Management of spasticity

• Skeletal muscle relaxants such as baclofen, diazepam, and tizanidine

Management of nutritional and swallowing disorders

• Pharyngeal paralysis and dysphagia: Tube feeding via gastrostomy
• Severe congenital (type I) cases: Tracheostomy may be performed²⁾

Management of scoliosis

• Physical therapy

Respiratory management

• In the congenital type, there is a risk of respiratory failure. Non-invasive respiratory support is used in some cases. There are no reports of ventilator dependence in the PLP1 duplication cohort. ¹⁾

Rehabilitation and assistive devices

• In a caregiver survey, “improving mobility” and “communication” were cited as the most important treatment goals.
• Use of communication devices ¹⁾
• 94% use wheelchair constantly, 38% use orthoses constantly ¹⁾

Prognosis and management considerations

There is currently no curative treatment. In congenital type with stridor and dysphagia, early airway management and nutritional support are necessary. Without intervention, life expectancy in type I (congenital) rarely exceeds childhood; with intervention, survival to the 30s is possible. In type III (classic), survival to the 70s is possible.

Q What is the current life expectancy with treatment?

A

It varies greatly by type. In type I (congenital), without intervention, survival beyond childhood is difficult, but with aggressive intervention (tracheostomy, gastrostomy, etc.), survival to the 30s is possible. In type III (classic), survival to the 70s is possible.

6. Pathophysiology and Detailed Pathogenesis

Function of the PLP1 Gene

PLP1 is mainly expressed in oligodendrocytes and is a major myelin protein, accounting for over 50% of brain proteins. DM20 is an alternatively spliced isoform of PLP1 and is a minor component of central and peripheral nervous system myelin. ¹⁾

Pathomechanisms by Mutation Type

Point Mutation (Missense)

Most severe mechanism: Misfolding of PLP occurs.

Inhibition of Golgi apparatus passage leads to accumulation in the endoplasmic reticulum (ER), causing ER dysfunction, which triggers oligodendrocyte apoptosis and axonal damage. Activation of the unfolded protein response (UPR) is involved in the pathogenesis of the congenital form.

Null mutations/deletions

Mechanism of relatively mild symptoms: A truncated protein is produced due to a premature stop codon.

No accumulation in the ER → less oligodendrocyte death → mild phenotype.

Duplication mutations

Intermediate mechanism: Overexpression of PLP1 occurs.

Disruption of membrane raft assembly → PLP1 accumulates with cholesterol and lipids in late endosomes/lysosomes → apoptosis of mature oligodendrocytes and developmental arrest of immature oligodendrocytes. ³⁾

Systemic significance of demyelination

In the central nervous system, a single oligodendrocyte nourishes multiple axons. Unlike Schwann cells in peripheral nerves, their regenerative capacity is weak, and leukodystrophies constitute a major group of demyelinating diseases.

Relationship between auditory findings and demyelination

ABR peak I (originating from spiral ganglion and unmyelinated nerve fibers) is normal, but peaks III and V (originating from myelinated auditory pathways) are absent. This finding directly reflects white matter demyelination in PMD. Prolonged cVEMP latency is also due to demyelination of brainstem vestibular pathways. ⁴⁾

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7. Latest Research and Future Prospects (Investigational Reports)

For Patients: Please Read Carefully

The following content is currently under investigation or in clinical trials and is not standard treatment available at general hospitals. It is reference information for professionals regarding future medical developments.

Gene and Molecular Targeted Therapy

• CRISPR-Cas9 system: Suppressed PLP1 expression in mouse models, showing a phenotype similar to the mild form
• PLP1 suppression (suppression of proteolipid protein): Reported to rescue PMD in mouse models²⁾
• Lonaprisan: Progesterone receptor antagonist. Reduces PLP1 expression

Nutritional and pharmacological interventions

• Curcumin: Promising results in mouse models, but an open-label trial (with a bioavailable formulation) in 9 PMD patients showed no significant therapeutic effect after 12 months
• Cholesterol-rich diet: Shown to prolong oligodendrocyte lifespan in mouse models
• Ketogenic diet (high-fat, low-carbohydrate): Shown to promote oligodendrocyte regeneration in mouse models

Novel therapies planned for future trials

• Endoplasmic reticulum stress modulator
• Iron chelator
• RNA suppression therapy
• Glial progenitor cell transplantation

EIF2AK2-related leukoencephalopathy (LEUDEN syndrome)

Macintosh et al. (2023) reported a new genetic disease, hypomyelinating leukoencephalopathy due to a de novo mutation in EIF2AK2, which is clinically and radiologically similar to PMD. ⁵⁾ The Ala109 position is a hotspot mutation, and decreased EIF2AK2 protein levels are considered to support pathogenicity. Differentiation from PMD is important.

Advances in Diagnostic and Assessment Technologies

Xue et al. (2021) demonstrated the effectiveness of SNP array-based prenatal diagnosis of PLP1 duplication. ³⁾ SNP arrays have higher resolution than aCGH and can detect not only CNVs but also UPD, LOH, and low-level mosaicism. A procedure of amniocentesis (18 weeks) → SNP array → MLPA confirmation has been proposed for subsequent pregnancies in carrier mothers.

The Functional Disability Scale (FDS) is considered essential as a quantitative assessment tool for the clinical course of PMD and for evaluating the effects of future therapeutic interventions. The mean change from FDS1 to FDS2 in PLP1 duplication cases is -0.7, suggesting slow progression, but a clear progression pattern has not been established. ¹⁾

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8. References

1. Trepanier AM, Aguilar S, Kamholz J, Laukka JJ. The natural history of Pelizaeus-Merzbacher disease caused by PLP1 duplication: A multiyear case series. Clin Case Rep. 2023.

2. Usman M, Koch A, Stolzenberg L, et al. A Patient With Pelizaeus-Merzbacher Disease Caused by a c.67G>A Mutation in the PLP1 Gene. Cureus. 2023.

3. Xue H, Yu A, Chen X, et al. Prenatal diagnosis of PLP1 duplication by single nucleotide polymorphism array in a family with Pelizaeus-Merzbacher disease. Aging. 2021.

4. Yuvaraj P, Narayana Swamy S, Chethan K, et al. Audio-vestibular Findings in a Patient with Pelizaeus-Merzbacher Disease. J Int Adv Otol. 2024.

5. Macintosh J, Thiffault I, Pastinen T, et al. A Recurrent De Novo Variant in EIF2AK2 Causes a Hypomyelinating Leukodystrophy. Child Neurol Open. 2023.