Introduction

Pelizaeus-Merzbacher disease (PMD) is a rare and complex neurodegenerative disorder that primarily affects the central nervous system (your brain and spinal cord). This disease was first described in 1885 by physician Friedrich Pelizaeus and later in 1910 by Ludwig Merzbacher, hence called Pelizaeus-Merzbacher disease.¹

PMD is classified as a leukodystrophy - a group of disorders that affect the white matter of your nervous system. In PMD, your body doesn’t produce enough myelin, the protective covering that wraps around your nerves, resulting in neurological symptoms such as problems with movements or balancing. This disease is progressive, meaning that these symptoms usually worsen over time.²

What causes pelizaeus-merzbacher disease?

PMD is primarily a genetic disorder caused by mutations in the PLP1 gene. This gene is responsible for producing a protein called proteolipid protein-1 (PLP1), which is crucial for myelination in the central nervous system. Myelination is the process by which nerve fibres in the brain and spinal cord are wrapped in a fatty substance called myelin, which is crucial for fast nerve signalling. In PMD, this process is disrupted, thus affecting the transmission of nerve signals in the central nervous system and causing neurological symptoms.²

Image source: Sutherland C. Biorender.

PMD is inherited in an X-linked pattern as the genetic mutation is located on the X chromosome. This means that people assigned male at birth (AMAB) are more likely to be affected by PMD because they only have one X chromosome. If this PMD-causing mutation occurs on the X chromosome of people AMAB, they will definitely develop the condition. In contrast, if people assigned female at birth (AFAB) have this mutation on one of their two X chromosomes, they most likely will not develop PMD and instead will be a genetic carrier of this mutation. As a carrier, you typically do not experience symptoms of PMD yourself, but can still pass on the disease to your children. If they do develop PMD, people AFAB typically experience much milder symptoms.^1,3

Although the majority of PMD cases are caused by genetic mutations, some cases do not have a genetic link. It is currently not known what causes these cases of PMD.

Signs and symptoms of pelizaeus-merzbacher disease

The symptoms of PMD typically manifest in infancy and progressively worsen over time. Symptoms can include:¹

• Motor and cognitive developmental delays
• Impaired coordination (ataxia)
• Involuntary eye movements (nystagmus)
• Uncontrollable muscle movements and spasms (dystonia)
• Muscle weakness (hypotonia)
• Seizures

However, PMD can vary in the severity of its symptoms and the age of onset. Based on this, PMD can be classified into 3 main types:⁴

Connatal PMD

Congenital PMD is the most severe form of PMD, with almost all of the myelin in the central nervous system missing. In these cases, symptoms are present at birth. People affected by congenital PMD show profound developmental and motor delays, with severe movement problems, poor growth, feeding problems, and seizures in infancy. Typically, people also have difficulties speaking due to weakness of the muscles used for speech (dysarthria), but can generally understand others. 

Classic PMD

Classic PMD is the most common form of PMD and is typically less severe than the other types. Here, symptoms develop in your baby’s first year of life, causing muscle and movement problems. People affected by classic PMD typically develop intellectual and motor skills normally throughout childhood. However, this development usually stops around adolescence, and these skills are slowly lost after this (developmental regression).⁵

Transitional PMD

Transitional PMD falls between classic and connatal forms of PMD in terms of the severity of the symptoms and age of onset.

How is pelizaeus-merzbacher disease diagnosed?

Your healthcare provider may suspect PMD based on a symptom assessment or physical examination. Other tests may then be used to confirm this diagnosis, including:

• Genetic testing: Blood tests can be taken to check for mutations in the PLP1 gene that typically cause PMD
• Imaging scans: Imaging tests such as MRI and CT scans can help visualise any abnormalities in the white matter of the brain, a hallmark of PMD³

Treatment and management of pelizaeus-merzbacher disease

There is currently no cure for PMD. Instead, treatment focuses on managing symptoms and providing supportive care. Treatments might include a range of therapies that vary between individuals depending on your specific symptoms and challenges including:³

• Medication, such as muscle relaxants (e.g. baclofen, tizanidine, diazepam) or anti-epileptic drugs (e.g. carbamazepine, lamotrigine, levetiracetam)
• Physical therapy
• Occupational therapy
• Speech or communication therapy
• Eye treatments, such as glasses or surgery, to correct involuntary eye movements
• Physiotherapy or surgery for scoliosis

Quality of life and prognosis

The prognosis of PMD depends on the type of PMD you have and how severe your symptoms are. People affected by severe symptoms of PMD typically have a shortened lifespan due to worsening symptoms and respiratory complications. However, people with mild symptoms of PMD can live an average lifespan with little disruption to their daily activities.⁶

Your healthcare provider can help you understand how PMD might affect you or your child’s life. 

FAQs

How common is pelizaeus-merzbacher disease?

PMD is a rare disorder with approximately 1 in 200,000 individuals affected. The majority of people affected by this disease are people assigned male at birth.

What is the life expectancy of someone with pelizaeus-merzbacher disease?

The life expectancy of PMD patients varies depending on the severity and the age of onset of symptoms (the type of PMD). In most mild or moderate forms of PMD, life expectancy can be long or relatively normal as the disease progresses slowly after adolescence. However, people with severe forms of PMD usually experience a significantly shortened lifespan and typically do not survive past 20 years old.

How can I prevent pelizaeus-merzbacher disease?

There is no way to prevent PMD. If you or your partner have PMD, or you have a family history of this disease and think you might be a carrier, you should talk to your healthcare provider about genetic testing and counselling to understand the potential risks of passing PMD to your children.

What triggers pelizaeus-merzbacher disease?

PMD is most often caused by a mutation in the proteolipid protein-1 (PLP1) gene, which is important in the production of myelin. The severity and age of onset of symptoms of this disease vary depending on the type of PLP1 mutation. Some cases of PMD are not associated with any genetic mutations - the cause of these cases is unknown. 

What is the age of onset of pelizaeus-merzbacher disease?

PMD symptoms typically present in early infancy, although the exact age of onset varies between individuals based on the type of PMD they have. In connatal PMD, symptoms are apparent from birth, while in classic PMD, symptoms typically develop through the first year of life. 

Summary

Pelizaeus-Merzbacher disease is a complex and rare neurodegenerative disorder with a genetic basis that affects the production of myelin in the central nervous system. This disease manifests with a range of symptoms and developmental delays depending on the severity and age of onset of symptoms. While there is no cure for PMD, treatments and supportive care aim to manage any symptoms and improve the quality of life of those affected. Increasing awareness of this rare disease and support for PMD patients and their families is essential to ensure they receive the care and assistance they need.