Pelizaeus-Merzbacher Disease

Pelizaeus-Merzbacher disease is a rare inherited condition that affects the brain and spinal cord, primarily occurring in males. The disease disrupts the body’s ability to produce enough myelin, the protective coating around nerves, leading to problems with movement, balance, and development that worsen over time.

Table of contents

• What is Pelizaeus-Merzbacher Disease?
• Types of the Disease
• Who is Affected?
• What Causes This Disease?
• Signs and Symptoms
• How is it Diagnosed?
• Treatment and Management
• Outlook and Life Expectancy

What is Pelizaeus-Merzbacher Disease?

Pelizaeus-Merzbacher disease is an inherited condition that involves the brain and spinal cord, together called the central nervous system^[1]. This disease is one of a group of genetic disorders called leukodystrophies, which are conditions that involve abnormalities of the nervous system’s white matter^[1].

White matter consists of nerve fibers covered by a fatty substance called myelin. Myelin acts like insulation around electrical wires, helping nerve signals travel quickly through the body^[1]. In Pelizaeus-Merzbacher disease, the nervous system has a reduced ability to form myelin, a condition called hypomyelination. Without enough myelin, messages from the brain travel slowly or stop altogether, which leads to reduced overall brain and body function^[1].

PMD, hypomyelinating leukodystrophy type 1, HLD1

• Brain
• Spinal cord
• Central nervous system
• White matter

Types of the Disease

Pelizaeus-Merzbacher disease exists on a spectrum ranging from very severe to milder forms. The disease is divided into several types based on how severe the symptoms are and when they appear^[1].

Classic Pelizaeus-Merzbacher disease is the most common type. Within the first year of life, affected children typically experience weak muscle tone, involuntary movements of the eyes called nystagmus, and delayed development of motor skills such as sitting or grasping objects^[1]. Some individuals are able to walk with assistance. Despite these problems, intellectual and motor skills continue to develop throughout childhood, but development usually stops around adolescence, and these skills are slowly lost over time^[1]. As the condition worsens, nystagmus usually goes away but other movement disorders develop, including muscle stiffness, problems with movement and balance, head and neck tremors, and involuntary muscle tensing and jerking movements^[1].

Connatal Pelizaeus-Merzbacher disease is the more severe type and symptoms are present from birth. This form begins in infancy and includes problems with feeding, poor weight gain and slow growth, high-pitched breathing caused by a blocked airway, nystagmus, progressive speech difficulties, severe problems with coordination and balance, weak muscle tone, and seizures^[1]. As the condition worsens, affected children develop muscle stiffness leading to joint deformities that restrict movement. Individuals with connatal Pelizaeus-Merzbacher disease are never able to walk, and many are not able to purposefully use their arms^[1]. They also have problems producing speech but can generally understand what others say^[1].

Milder forms include Spastic Paraplegia Type 2, which mainly causes leg weakness and stiffness with little or no involvement of other brain functions^[4]. There are also transitional and adult variants that fall between these forms in terms of severity^[5].

Who is Affected?

Pelizaeus-Merzbacher disease is rare. The prevalence is estimated to be 1 in 200,000 to 500,000 males in the United States^[1]. Worldwide, the incidence ranges between 1 per 90,000 to 1 per 750,000 live births^[3].

This condition primarily affects males. It is an X-linked genetic disorder, meaning it occurs because of a mutation on the X chromosome^[2]. Since females have two X chromosomes, they often have less severe symptoms or might not develop the condition at all because their second X chromosome can compensate for the defective one. Males have only one X chromosome, so if it carries the defective gene, they do not have another copy to compensate, making them much more likely to develop the disease^[2].

Mothers are typically carriers of the mutation, meaning they can pass the defective gene to their children but usually do not show symptoms themselves^[5].

What Causes This Disease?

Pelizaeus-Merzbacher disease is caused by mutations in the PLP1 gene. This gene provides instructions for making a protein called proteolipid protein 1 and a modified version called DM20^[1]. These proteins are found in the cell membrane of nerve cells, where they make up the majority of myelin and help anchor it to the cells^[1].

The PLP1 gene is located on the long arm of the X chromosome^[3]. Mutations can be of various types. Most mutations that cause Pelizaeus-Merzbacher disease duplicate the PLP1 gene, which results in too much production of these proteins^[1]. Other mutations lead to production of abnormal proteins that are often misfolded. When proteins are produced in excess or are abnormal, they become trapped within cell structures and cannot travel to the cell membrane where they are needed to form myelin^[1].

The buildup of excess proteins leads to swelling and breakdown of nerve fibers. Still other mutations delete the PLP1 gene entirely, which prevents protein production and results in a lack of these proteins in the cell membrane^[1]. Without the correct amount of these proteins, myelin that is formed becomes unstable and quickly breaks down. All of these different types of PLP1 gene mutations lead to hypomyelination and the symptoms of the disease^[1].

Up to 20% of males with Pelizaeus-Merzbacher disease do not have the PLP1 gene mutation. Some of them have a mutation in a different gene called GJC2, or they may have the disease for no known reason^[2].

Signs and Symptoms

The hallmark signs and symptoms of Pelizaeus-Merzbacher disease include little or no movement in the arms or legs, breathing difficulties, and characteristic horizontal movements of the eyes from left to right^[4]. The onset of symptoms is usually in early infancy, and the most characteristic early signs are nystagmus and low muscle tone^[4].

Symptoms usually start in babies or young children and may include^[2]:

• Balance problems
• Developmental delays
• Feeding problems
• High-pitched breathing, called stridor
• Involuntary eye movements
• Involuntary tensing or jerking movements
• Poor weight gain
• Weak muscles

Motor abilities are delayed or never acquired, depending on the severity of the mutation^[4]. Most children with Pelizaeus-Merzbacher disease learn to understand language and usually have some speech. Other signs may include tremor, lack of coordination, involuntary movements, weakness, unsteady walking, and over time, muscle stiffness in legs and arms^[4]. Muscle tightening called contractures often occurs over time. Mental functions may deteriorate. Some patients may have seizures and skeletal problems such as curved spine, resulting from abnormal muscle stress on bones^[4].

How is it Diagnosed?

A child’s healthcare provider may suspect Pelizaeus-Merzbacher disease based on symptoms. Several tests are used to confirm the diagnosis^[2].

Imaging tests, particularly magnetic resonance imaging (MRI) scans, are used to see if the child has low amounts of myelin. The diagnosis is often first suggested after identification by MRI of abnormal white matter throughout the brain^[4]. These changes are typically evident by about 1 year of age, though more subtle abnormalities should be evident during infancy^[4]. An MRI can show patterns in brain tissue that are typical of Pelizaeus-Merzbacher disease^[6].

Genetic tests, such as blood tests, are done to check for the gene mutation that causes Pelizaeus-Merzbacher disease. This test can be done from a blood or saliva sample or a cheek swab^[6]. Once a PLP1 mutation is identified, prenatal diagnosis or preimplantation genetic diagnostic testing is possible^[4].

Unless a family history consistent with X-linked inheritance exists, the condition is often misdiagnosed as cerebral palsy^[4].

Treatment and Management

There is no cure for Pelizaeus-Merzbacher disease^[2]. Treatment is symptomatic and supportive, focusing on improving quality of life and managing symptoms^[5].

Treatment may include^[2]:

• Medications to reduce muscle spasms or seizures. Drugs such as baclofen, tizanidine, or benzodiazepines may be beneficial for managing muscle stiffness^[11]
• Physical or occupational therapy to increase balance, strength and motor control. Regular physical medicine evaluations, physical therapy, and careful attention to posture and seating can help minimize the development of joint contractures, dislocations, and spine curvature^[11]
• Eye treatments such as glasses or surgery to correct involuntary eye movements
• Counseling with a licensed mental health provider to increase healthy coping skills and deal with the emotional effects of having a genetic condition

Patients who are severely affected may need special attention directed to airway protection. Tracheostomy may be needed during infancy if stridor impairs breathing function^[11]. Feeding tube placement may be needed if oral feeding is inadequate to maintain weight or sustain normal growth, or if oral feeding creates a risk of choking or aspiration^[11].

Communication therapy, including training in use of communication devices, is often valuable^[11]. A developmental specialist should be consulted to optimize the child’s educational program and to maximize functional and learning capabilities^[11].

Consultation with a geneticist and genetic counselor is essential for parents of an affected child to educate them about the disease and the risks to future offspring^[11].

Outlook and Life Expectancy

The outlook for those with Pelizaeus-Merzbacher disease varies widely depending on the type and severity. Pelizaeus-Merzbacher disease is progressive, meaning the symptoms worsen over time^[2].

The prognosis for those with the severe forms of Pelizaeus-Merzbacher disease is poor, with progressive deterioration until death^[5]. Severe Pelizaeus-Merzbacher disease, particularly the connatal form, is often fatal during the first decade of life, typically due to respiratory complications^[8].

On the other end of the disease spectrum, individuals with the mild form, in which leg stiffness and weakness is the chief symptom, may have nearly normal activity and life span^[5].