Pelizaeus-Merzbacher Disease (PMD)

What Causes Pelizaeus-Merzbacher Disease (PMD)?

PMD is caused by abnormal changes (mutations) in the PLP1 gene. This gene is responsible for the production of proteins vital in the creation of myelin. The two proteins are especially important in the central nervous system cells and cells that connect the central nervous system to muscles.

The mutations associated with PMD usually cause excess production of the two proteins, causing an abnormal accumulation that interferes with the creation of myelin. Without the protection of functional myelin, the nerve cells in the affected tissues gradually deteriorate and die, causing the symptoms of PMD.

Is Pelizaeus-Merzbacher Disease (PMD) Hereditary?

PMD is inherited in an X-linked pattern. The PLP1 gene is located on the X chromosome. Females have two X chromosomes, one inherited from each parent. Males have only one X chromosome inherited from their mother and a Y chromosome inherited from their father.

When females inherit an X chromosome with the PMD-causing mutation, they generally have a non-mutated copy of the gene on the other X chromosome. In these cases, the person may have only mild symptoms of the disorder or no symptoms at all. However, they carry the mutated gene and can pass it on to their children.

Males who inherit a mutated PLP1 gene will develop the disorder. Males with the condition typically don’t have children, but if they do, any of their female children will be carriers. Any male children will not inherit the mutation.

How Is Pelizaeus-Merzbacher Disease (PMD) Detected?

In most cases, the symptoms of PMD begin in the first weeks or months of a baby’s life and may be present at birth. Common early signs of the disorder include:

• Involuntary eye movements
• Weak muscle tone
• High-pitched wheezing
• Feeding difficulties
• Seizures

How Is Pelizaeus-Merzbacher Disease (PMD) Diagnosed?

When symptoms suggest the possibility of PMD, a doctor will conduct diagnostic tests and exams to look for the characteristic features of the disorder and to rule out other possible causes of the symptoms.

Diagnostic steps often include:

• Evaluation of the child’s medical history
• Physical and neurological exams
• Magnetic resonance imaging (MRI) to look for white matter abnormalities
• Genetic testing to look for PLP1 gene mutations

PLEASE CONSULT A PHYSICIAN FOR MORE INFORMATION.

How Is Pelizaeus-Merzbacher Disease (PMD) Treated?

Pelizaeus-Merzbacher disease has no cure, and no treatment will stop or reverse its symptoms. Instead, treatments and therapies aim to lessen the impact of symptoms, prevent complications, and improve the child’s quality of life.

Common treatment options include:

• Feeding tubes
• Anti-seizure medications
• Physical therapy
• Medication or surgery for joint contractures
• Assistive devices for communication and mobility

How Does Pelizaeus-Merzbacher Disease (PMD) Progress?

PMD is progressive, and many of its symptoms will get worse over time. Children with connatal PMD are vulnerable to breathing difficulties that may be fatal in infancy or childhood. However, when the disorder’s complications are effectively managed, a person with classic PMD may survive to adulthood.

How Is Pelizaeus-Merzbacher Disease (PMD) Prevented?

There is no known way to prevent PMD. However, parents with a family history of the disorder or who have had another child with PMD are advised to consult a genetic counselor to assess their risk if they plan to have another child.

Pelizaeus-Merzbacher Disease (PMD) Caregiver Tips

• Stay up to date on PMD research. Developments happen quickly, and keeping abreast of new research can help give you hope as you learn to live with PMD.
• Let others help. Parents often want to go it alone and shoulder the burden of caring for their child. However, for the sake of your own health, it’s essential to accept (and even ask for) help from your family and friends when you need it.
• Remember that other families have gone through what you’re going through. Hunter’s Hope has compiled a list of organizations and foundations dedicated to helping families living with leukodystrophies. These organizations provide education, support, equipment-sharing, and financial assistance to families who need it.

Some people with PMD also suffer from other brain and mental health-related issues, a condition called co-morbidity. Women who carry one of the PMD gene mutations are at increased risk of dementia, and female carriers may experience intellectual disabilities and muscle stiffness.

Pelizaeus-Merzbacher Disease (PMD) Brain Science

Researchers are pursuing the possibility that stem-cell therapies may lead to breakthroughs in the treatment of PMD. Studies involving stem cells have shown promise in multiple areas, including:

• Scientists have used stem-cell technology to turn skin cells from children with PMD into myelin-producing brain cells in a laboratory environment. In doing so, they’ve observed that the cells die because of a toxic build-up of iron. By reducing the iron level in the lab-created cells, they were able to protect the cells and increase their myelin production.
• Researchers have implanted stem cells directly into the white matter of children with severe PMD. Their study aimed to determine whether the implantation would have any adverse effects and if it would increase myelin production in the children’s cells. After five years, the scientists observed no significant adverse effects of the implantation, and half of the study subjects showed increases in their myelin production.

Pelizaeus-Merzbacher Disease (PMD) Research

Title:  Longitudinal Study of Neurodegenerative Disorders

Stage: Recruiting

Principal investigator: Maria L. Escolar, MD, MS

The Program for the Study of Neurodevelopment in Rare Disorders, Children’s Hospital of Pittsburgh of UPMC

Pittsburgh, PA

The purpose of this study is to understand the course of rare genetic disorders that affect the brain. This data is being analyzed to better understand the progression of the rare neurodegenerative disorders and the effects of interventions.

Patients would be evaluated by a multidisciplinary team at specific time points every three months the first year, every six months the second year, and once a year thereafter.

Title: UCB Transplant of Inherited Metabolic Diseases With Administration of Intrathecal UCB Derived Oligodendrocyte-Like Cells (DUOC-01)

Stage: Recruiting

Principal investigator: Joanne Kurtzberg, MD

Duke University

Durham, NC

The primary objective of the study is to determine the safety and feasibility of intrathecal administration of DUOC-01 as an adjunctive therapy in patients with inborn errors of metabolism who have evidence of early demyelinating disease in the central nervous system (CNS) who are undergoing standard treatment with unrelated umbilical cord blood transplantation (UCBT). The study’s secondary objective is to describe the efficacy of UCBT with intrathecal administration of DUOC-01 in these patients.

The inherited metabolic disorders (IMD) are a heterogeneous group of genetic diseases, most of which involve a single gene mutation resulting in an enzyme defect. In the majority of cases, the enzyme defect leads to the accumulation of substrates that are toxic and/or interfere with normal cellular function. Often, patients may appear normal at birth but during infancy begin to exhibit disease manifestations, frequently including progressive neurological deterioration due to absent or abnormal brain myelination. The ultimate result is death in later infancy or childhood.

Currently, the only effective therapy to halt the neurologic progression of the disease is allogeneic hematopoietic stem cell transplantation (HSCT), which serves as a source of permanent cellular ERT.3 However, one barrier to the success of this therapy is delayed engraftment of donor cells in the CNS when administered through the intravenous route, which is associated with ongoing disease progression over 2-4 months before stabilization. The engraftment of donor cells in a patient with an IMD provides a constant source of enzyme replacement, thereby slowing or halting the progression of the disease.

This study will evaluate the safety of a potential new treatment for patients with certain IMDs known to benefit from HSCT using allogeneic UCB donor cells. The new intervention, intrathecal administration of UCB-derived oligodendrocyte-like cells (DUOC-01), will serve as an adjunctive therapy to a standard UCB transplant. This therapy aims to accelerate delivery of donor cells to the CNS, thereby bridging the gap between systemic transplant and engraftment of cells in the CNS and preventing disease progression. The DUOC-01 cells and cells used for HSCT will be derived from the same UCB donor unit.

Title: The Myelin Disorders Biorepository Project (MDBP)

Stage: Recruiting

Principal investigator: Adeline Vanderver, MD

Children’s Hospital of Philadelphia

Philadelphia, PA

Genetic white matter disorders (leukodystrophies) are estimated to have an incidence of approximately 1:7000 live births. In the past, patients with white matter disease of unknown cause evaluated by the investigator achieved a diagnosis in fewer than 46% of cases after extensive conventional clinical testing. Even when a diagnosis is achieved, the diagnosis takes an average of eight years. This “odyssey” results in testing charges to patients and insurers in excess of $8,000 on average per patient, including the patients who never achieve a diagnosis at all. With next-generation approaches such as whole-exome sequencing, the diagnostic efficacy is closer to 70%, but approximately a third of individuals do not achieve a specific etiologic diagnosis. This remaining group of patients (unclassified leukodystrophy) offers the opportunity to describe novel disorders and provide improved diagnostic tools. These diagnostic challenges represent an urgent and unresolved gap in knowledge and disease characterization, as obtaining a definitive diagnosis is paramount for leukodystrophy patients.

Moreover, the mechanisms of disease in many leukodystrophies of known cause are very poorly understood: many are systemic abnormalities that manifest only testing white matter. Finally, little is known about the best symptomatic management of the many leukodystrophies without an etiologic cure. Thus, limited standards of care are available for the management of these patients.

The purpose of this study is to: (Aim 1) define novel homogeneous groups of patients with unclassified leukodystrophy and work toward finding the cause of these disorders; (Aim 2) assess the validity and utility of next-generation sequencing in the diagnosis of leukodystrophies; (Aim 3) establish disease mechanisms in selected known leukodystrophies; and (Aim 4) track current care and natural history of these patients to define the longitudinal course and determinants of outcomes in these disorders.

It is hoped that the present study will help clarify the nosology of the leukodystrophies and significantly advance our understanding of the pathogenesis of these diseases, the best diagnostic testing tools, and the best symptomatic management of these conditions. Due to the breadth of this approach and the rarity of these conditions, these approaches will be carried out at multiple clinical centers with specialized expertise in leukodystrophies.