Pelizaeus-Merzbacher Disease

Disease Overview

Summary

Pelizaeus-Merzbacher disease (PMD) is a rare genetic disorder that affects the central nervous system and is linked to problems with the white matter of the brain and spinal cord. It is classified as a leukodystrophy, meaning it involves abnormal development of the myelin sheath, the protective covering of nerves. The myelin sheath is essential for normal nerve function, and without it, nerves cannot work properly.

In PMD, different areas of the central nervous system are impacted, including deep parts of the brain (subcortical), cerebellum (which helps with movement coordination, brain stem (which controls vital functions) and spinal cord.

The main symptoms of PMD include difficulty coordinating movement (ataxia), involuntary muscle spasms (spasticity), leading to stiff and slow leg movements, delays in reaching developmental milestones (e.g., sitting, walking), loss of motor abilities later in life and progressive intellectual decline.

PMD is caused by changes (variants) in the PLP1 gene. Several forms of PMD have been identified, including:

• Classic PMD
• Connatal PMD (present at birth)
• Transitional PMD
• PLP1 null syndrome (no PLP1 protein produced)

Other related conditions caused by PLP1 gene variants include complicated spastic paraparesis, pure spastic paraparesis (SPG2) and hypomyelination of early myelinating structures (HEMS).

The disease usually progresses slowly, with worsening neurological symptoms over time.

Treatment is based upon the specific symptoms that the affected person may have.

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Synonyms

• PMD
• hypomyelinating leukodystrophy 1
• HLD1
• sclerosis, diffuse familial brain

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Signs & Symptoms

PMD is a genetic disorder that affects the nervous system, causing problems with movement, coordination and development. The symptoms can vary widely from person to person, depending on the form of PMD.

Classical PMD (usually starts before 2 months of age):

• Early signs may include:
  • Difficulty controlling head and eyes
  • Abnormal head bobbing
  • Rapid, involuntary eye movements (nystagmus)
  • Slow growth
• As the child ages the following signs and symptoms may develop:
  • Muscle tremors
  • Muscle weakness
  • Facial grimacing
  • Low muscle tone (hypotonia)
  • Difficulty coordinating voluntary movements (ataxia)
  • Delays in reaching developmental milestones (such as sitting, standing, and walking)
  • Delayed coordination of mental and muscular activities (psychomotor delay)
  • Involuntary muscle spasms (spasticity), leading to:
    • Slow, stiff leg movements
    • Partial paralysis of arms and legs (spastic quadriparesis)
    • Joint contractures (permanent joint fixation)
  • Nystagmus may disappear as the child grows
  • Skeletal deformities can develop over time due to spasticity
  • Degeneration of the optic nerves (optic atrophy)
  • Speech difficulties (dysarthria)

Connatal PMD (signs are present at birth or appear within the first few weeks of life) main symptoms may include:

• • Muscle weakness
  • Severe spasticity (stiff muscles)
  • High-pitched sound when breathing (stridor)
  • Rapid, involuntary eye movements (nystagmus)
  • Seizures
  • Difficulty swallowing (dysphagia), sometimes requiring feeding through a tube (gastrostomy)
  • Cognitive decline and failure to meet developmental milestones (e.g., speaking and walking)

Progression is faster and more severe than classical PMD and it is often fatal during childhood.

Transitional PMD (an intermediate form between classical and connatal PMD)

• • Symptoms are similar to both classical and connatal PMD

Progression of the disease is faster than classical but slower than connatal PMD.

PLP1 null syndrome main symptoms may include:

• • Mild spastic quadriparesis (weakness and stiffness in arms and legs)
  • Mild ataxia (difficulty coordinating movements)
  • No nystagmus during infancy
  • Mild peripheral neuropathy (nerve damage)

People affected with this form of PMD may learn to walk but experience faster deterioration in late adolescence or early adulthood.

Female carriers of PMD-related PLP1 gene variants usually do not present any symptoms but in some people, there are mild to moderate signs of the disease and in some cases, symptoms improve with age.

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Causes

PMD is caused by changes (variants) in the proteolipid protein gene or PLP1, which is located on the X chromosome. About 5% to 20% of males with a syndrome consistent with PMD do not have a variant in the PLP1 gene. The PLP1 gene provides instructions for making two key proteins: proteolipid protein 1 and its variant DM20. Proteolipid protein 1 is mainly found in the central nervous system, while DM20 is produced in the peripheral nervous system. These proteins help form and anchor myelin, the protective covering of nerve cells.

Most gene changes causing PMD involve duplication of the PLP1 gene, leading to excess protein production. Other variants result in abnormal, misfolded proteins that can’t reach the cell membrane, causing a lack of myelin. Some variants in the PLP1 gene prevent protein production entirely, which causes myelin to be unstable and quickly break down. These variants result in hypomyelination, nerve damage and impaired nervous system function, leading to the symptoms of PMD.

Some of these patients have a variant of the GJC2 gene that causes a Pelizaeus-Merzbacher-like disease (PMLD), which may be indistinguishable from PMD.

A different disorder, spastic paraplegia 2 (SPG2), hypomyelination of early myelinating structures (HEMS) and PMD result from different variants of the same gene (allelic disorders) on the X chromosome.

PMD is inherited as an X-linked recessive genetic disorder that affects mostly males. X-linked genetic disorders are conditions caused by a disease-causing gene variant on the X chromosome. Females who have a disease-causing gene variant present on one of their two X chromosomes are carriers for that disorder. Female carriers usually do not display symptoms because one of their two X chromosomes is inactivated so that the genes on that chromosome are nonfunctioning. It is usually the X chromosome with the abnormal gene that is inactivated. Males have one X chromosome that is inherited from their mother, and if a male inherits an X chromosome that contains a disease gene, he will develop the disease.

Female carriers of PMD have a 25% chance with each pregnancy to have a carrier daughter like themselves, a 25% chance to have a non-carrier daughter, a 25% chance to have a son affected with the disease and a 25% chance to have an unaffected son. Females from families where males have a milder phenotype, such as SPG2 or the PLP1 null syndrome, should be more cautiously counseled. In some of these families, the disorder behaves more like an X-linked dominant disorder with reduced penetrance in which females can be affected but less severely than the affected males in the family.

X-linked dominant disorders are caused by a disease-causing gene variant on the X chromosome and mostly affect females. Females are affected when they have an X chromosome with the gene variant. Males with a disease-causing gene variant for an X-linked dominant disorder are more severely affected than females and often do not survive.

Male PMD patients usually do not reproduce, but males with X-linked disorders who do reproduce pass the disease gene to all of their daughters who will be carriers. A male cannot pass an X-linked gene to his sons because males always pass their Y chromosome instead of their X chromosome with the PLP1 gene on it to male offspring.

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Affected populations

The classical and connatal forms of PMD affect males far more often than females. In rare cases, carrier females will exhibit some of the signs associated with the disorder. However, in the milder forms of PMD and the allelic SPG2 and HEMS, carrier females may be affected.

PMD is a rare disorder. Its prevalence in the general population is unknown but estimated as approximately 1 in 100,000 in the USA.

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Disorders with Similar Symptoms

Symptoms of the following disorders can be similar to those of Pelizaeus-Merzbacher (PMD). Comparisons may be useful for a differential diagnosis:

SPG2, HEMS, and PMD result from different variants of the same gene (allelic disorders) on the X chromosome. SPG2 is characterized by progressive weakness (paraplegia) and increased muscle tone and stiffness (spasticity) of leg muscles. Initial findings typically include stiffness and relatively mild weakness of leg muscles, balance difficulties, involuntary eye movements (nystagmus), gradual deterioration of the nerves of the eyes (optic atrophy, and an unusually “clumsy” manner of walking). As the disorder progresses, walking may become increasingly difficult, and patients progress to walker and then wheelchair. HEMS is similar to SPG2, but a characteristic lack of myelination of the structures of the brain that should myelinate early in development is seen on magnetic resonance imaging (MRI).

PMLD (mentioned above) and the following diseases are caused by variants of different genes from the one that causes PMD. Comparisons may be useful for a differential diagnosis:

Allan-Herndon-Dudley syndrome (AHDS) is caused by variants of the SLC16A2/MCT8 gene (X-linked recessive).

Hypomyelinating leukodystrophy 7 with or without oligodontia and/or hypogonotropic hypogonadism (HLD7) is caused by variants of the POLR3A gene (autosomal recessive).

Hypomyelinating leukodystrophy 8 with or without oligodontia and/or hypogonotropic hypogonadism (HLD8), is caused by variants of the POLR3B gene (autosomal recessive).

Hypomyelination with congenital cataract (HCC) is caused by variants of the FAM126A gene (autosomal recessive).

Hypomyelination with atrophy of the basal ganglia and cerebellum (HABC) is caused by variants of the TUBB4A gene (autosomal dominant).

Autosomal dominant adult-onset leukodystrophy (ADLD) is caused by genomic duplication of the LMN1B gene (autosomal dominant).

Other leukodystrophy genes are: AIMP1, HSPD1, RARS, PYCR2, POLR1C, AARS, DARS.

PMD can be misdiagnosed as cerebral palsy, multiple sclerosis and spinal muscular atrophy. For more information on these disorders use them as search terms in the NORD Rare Disease Database.

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Diagnosis

A diagnosis of PMD may be suspected based upon a thorough clinical evaluation, a detailed patient history, and a variety of specialized tests such as magnetic resonance imaging (MRI) to detect deficiency of white matter. Recognition of early myelination defects, such as lack of myelination in the cerebellum and brainstem, may aid in early diagnosis of the severe forms of PMD. Molecular genetic testing for variants in the PLP1 gene is available to confirm the diagnosis.

Carrier testing is possible if a disease-causing variant in the PLP1 gene has been identified in an affected family member.

Prenatal diagnosis and preimplantation genetic diagnosis are available if a PLP1 gene variant is identified in an affected family member.

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Standard Therapies

Treatment

There is currently no cure for PMD. Treatments focus on managing symptoms and providing supportive care.

People with the connatal form of PMD often experience seizures, which can usually be managed with antiepileptic medications (AEDs). No specific AED is designated for PMD-related seizures, but common AEDs are effective.

Medications such as baclofen, tizanidine, or diazepam are used to reduce muscle stiffness and spasms.

Due to pharyngeal weakness (difficulty swallowing), some patients may require a gastrostomy for enteral feeding.

Many individuals with PMD develop scoliosis (curved spine), which is treated with physiotherapy and, in some cases, surgery.

Researchers are investigating new treatments targeting the molecular causes of PMD. So far, most studies have been conducted on genetically modified mice with PLP1 gene variants, and human trials have not yet been conducted. Some promising findings include:

• Lonaprisan: This drug, a progesterone receptor antagonist, reduces PLP1 overexpression in mice, which leads to increased myelination (the process of forming the protective myelin sheath).
• Curcumin: An extract from turmeric, curcumin has shown potential for motor improvement and reduced oligodendrocyte loss (the cells that produce myelin). It works by promoting axonal survival and reducing inflammation.
• Dietary changes:
  • A high-cholesterol diet has been shown to increase the lifespan of oligodendrocytes (cells in the central nervous system that produce myelin, which forms protective sheaths around nerve fibers cell in the nervous system) and improve the function of axons (the thin fiber that connects neurons (nerve cells) to that they can communicate) in mice.
  • The ketogenic diet, which is high in fat and low in carbohydrates, can help restore oligodendrocytes and increase myelination in the central nervous system (CNS). The ketone bodies produced from this diet can cross the blood-brain barrier, providing building blocks for the synthesis of CNS lipids.

Emotional and psychological support for both the patient and family is essential. Genetic counseling is also recommended for affected individuals and their families to understand the inheritance patterns and potential risks for future children.

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Clinical Trials and Studies

Information on clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.

For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:

Toll-free: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]

Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/

For information about clinical trials sponsored by private sources, contact:
www.centerwatch.com

For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/

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References

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Osório MJ, et al. Concise Review: Stem Cell-Based Treatment of Pelizaeus-Merzbacher Disease. Stem Cells 2017;35:311-315.Sarret C et al. Time-course of myelination and atrophy on cerebral imaging in 35 patients with PLP1-related disorders. Dev Med Child Neurol. 2016;58:706-713.

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Beck CR, et al. Complex genomic rearrangements at the PLP1 locus include triplication and quadruplication. PLoS Genet. 2015;11:e1005050.

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Fattal-Valevski A, et al. Variable expression of a novel PLP1 mutation in members of a family with Pelizaeus-Merzbacher disease. J Child Neurol. 2009;24:618-624.

Sima AA, et al. Neuronal loss in Pelizaeus-Merzbacher disease differs in various mutations of the proteolipid protein 1. Acta Neuropathol. 2009;118:531-539.

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Combes P, et al. PLP1 and GPM6B intragenic copy number analysis by MAPH in 262 patients with hypomyelinating leukodystrophies: Identification of one partial triplication and two partial deletions of PLP1.Neurogenetics 2006;7:31-37.

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Inoue K. PLP1-related inherited dysmyelinating disorders: Pelizaeus-Merzbacher disease and spastic paraplegia type 2. Neurogenetics 2005;6:1-16.

Wolf NI et al. Three or more copies of the proteolipid protein gene PLP1 cause severe Pelizaeus-Merzbacher disease. Brain 2005;28:743-751.

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INTERNET
Wolf NI, van Spaendonk RML, Hobson GM, et al. PLP1 Disorders. 1999 Jun 15 [Updated 2019 Dec 19]. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1182/ Accessed Sept 17, 2024.

Pelizaeus-Merzbacher disease. MedlinePlus. February 1, 2018. https://medlineplus.gov/genetics/condition/pelizaeus-merzbacher-disease/#causes Accessed Sept 17, 2024.

Singh R, Samanta D. Pelizaeus-Merzbacher Disease. [Updated 2023 Jul 4]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK560522/ Accessed Sept 17, 2024.

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