PMD & PMLD FAQs

Leukodystrophies are a family of dozens of inherited disorders in children and adults. In many cases the genetic cause of these disorders is known, but in some cases individuals present with all the features of a leukodystrophy but genetic testing is negative. These are called “unspecified leukodystrophy.”

Leukodystrophies all result in changes in the brain’s white matter (also known as myelin). Myelin is an insulating layer that surrounds the projections of nerve cells, called axons. Axons send information from nerve cell to nerve cell, and from nerve cell to muscles, using electrical impulses. Myelin is much like the insulating layer on electrical wires in your house or appliances, and allows the efficient trafficking of information throughout the nervous system. When myelin is absent, or doesn’t work well, the nervous system cannot send messages to help us move, talk, swallow and perform many other important functions.

Source: Living with Leukodystrophy - A Guide for Caring for Leukodystrophy Patients.

Pelizaeus-Merzbacher disease (PMD) and spastic paraplegia 2 (SPG2) are genetic diseases of the central nervous system (brain and spinal cord) caused by mutations of a gene called the proteolipid protein 1 gene (PLP1). They belong to a group of diseases of the white matter called leukodystrophies. The white matter, which is in the central part of the brain, is mostly made of a fatty substance called myelin. Myelin is produced by cells in the brain called oligodendrocytes (see Figure 1). The cell membrane on the outside of the oligodendrocyte wraps around axons forming a myelin sheath surrounding fibers that project from a different cell type, the neuron (nerve cell). The myelin sheath provides insulation for axons so that nerve impulses can be transmitted rapidly from neuron to neuron without leaking out. This is similar to how we use insulation on electric cords. In PMD, the myelin doesn’t form properly and some nerve impulses are slowed so they reach their target more slowly than normal, while some leak out and do not reach their target at all.

There is no cure for PMD.

Treatments involve management of symptoms and supportive therapies, including:

Medications for seizures and spasticity
Physical therapy and exercise
Occupational therapy
Speech therapy
Orthotics for spasticity and scoliosis management
Surgery for contractures and scoliosis
Gastrostomy (feeding tube placement) for severe dysphagia (swallowing difficulty)
Proper wheelchair seating
Special education
Assistive communication devices

Source: PMD Foundation

There is a wide spectrum of disease severities in PMD/SPG2. Patients within a family are usually similarly affected, but there can be some variability. The types of PMD from most severe to least are:

Connatal PMD

Connatal means congenital or at birth, so the connatal type of PMD is observed very early in life. Patients never develop the ability to walk, use their upper extremities, or talk, but they may comprehend what is said. Although it can be found in the literature that connatal patients die in their first decade, care has improved and they often live longer, but lifespan is shortened.

Classic PMD

This is the type of PMD that was originally described by Drs. Pelizaeus and Merzbacher (see History of PMD), and it is the most common type. Some patients develop the ability to walk with an assistive device (like a walker), and lose the ability as disease progresses. Often they can talk, but speech is dysarthric (slow and difficult to understand). Lifespan may be shortened, but patients with classic PMD have lived to their sixth or seventh decade.

Complicated spastic paraplegia 2 (SPG2)

This is a milder form of PMD called by a different clinical name, SPG2, in which patients are able to walk with a spastic gait because of muscle tightness, but they lose that ability and use a walker and then a wheelchair as disease progresses. It is called “complicated” because these patients also have dysfunction of their autonomic nervous system (the part of the nervous system that supplies the internal body parts), like issues with their urinary bladder. These patients can talk, but speech may be slow. Lifespan may be normal.

Pure spastic paraplegia 2 (SPG2)

This form is the same as complicated SPG2 but without the autonomic nervous system issues.

Source: PMD Foundation

The symptoms of PMLD are: weak muscle tone (hypotonia), involuntary movements of the eyes (nystagmus), and delayed development of speech and motor skills, such as sitting or grasping objects, and muscle stiffness (spasticity), which replaces hypotonia as children get older.

The signs and symptoms of PMLD are very similar to PMD, but the two disorders have different genetic causes.

Source: PMD Foundation

Pelizaeus-Merzbacher disease (PMD) and spastic paraplegia 2 (SPG2) are genetic diseases of the central nervous system (brain and spinal cord) caused by mutations of a gene called the proteolipid protein 1 gene (PLP1). They belong to a group of diseases of the white matter called leukodystrophies.

Source: PMD Foundation https://www.pmdfoundation.org/what-is-pmd-about

Pelizaeus-Merzbacher-like disease type 1 is caused by mutations in the GJC2 gene. This gene provides instructions for making a protein called connexin-47. This protein plays a role in forming channels called gap junctions between cells. Gap junctions made with connexin-47 facilitate communication between nervous system cells called oligodendrocytes or between oligodendrocytes and another type of nervous system cell called astrocytes. Communication between these cells is necessary for the formation of myelin.

Source: MedlinePlus [Internet]. Bethesda (MD): National Library of Medicine (US); [updated Jun 24; cited 2020 Jul 1]. Available from: Medline Plus. PMLD Type 1 available from https://medlineplus.gov/genetics/condition/pelizaeus-merzbacher-like-disease-type-1/#causes

Pelizaeus-Merzbacher-Like Disease, or PMLD, is a slowly progressive disease of myelin, which is the white matter of the central nervous system (brain and spinal cord). In patients with PMLD, the myelin does not form properly. Myelin insulates the nerves for proper conduction of nerve impulses. When the myelin does not form properly, nerve impulses do not travel properly in the central nervous system.

Source: PMD Foundation

The clinical signs of PMD include:

Nystagmus (involuntary eye movements
Hypotonia (decreased muscle tone)
Spasticity (stiffness or increased muscle tone; hypotonia progresses to spasticity)
Titubations (head-bobbing)
Stridor (high-pitched wheezing sound)
Sometimes vocal paralysis in severe cases
Feeding difficulties
Delayed developmental milestones
Ataxia of the limbs
Cognitive impairment
Sometimes seizures
Sometimes dystonic posturing (abnormal fixed posture)
Sometimes athetotic movements (involuntary writhing)

Source: PMD Foundation

Currently, there are treatments for some of the symptoms of PMLD, such as drugs that reduce spasticity, but there is no known cure.

Source: PubMed.gov - Pelizaeus-Merzbacher-Like Disease 1.

Nahhas N, Conant A, Orthmann-Murphy J, Vanderver A, Hobson G. Pelizaeus-Merzbacher-Like Disease 1. 2017 Dec 21 [updated 2019 Jan 17]. In: Adam MP, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2023. PMID: 29276893.

The primary purpose of The PMD Foundation is to support research focused on finding a cure for PMD and PMLD. This work is both time consuming and expensive.Some times it may feel like nothing is happening and that you are wasting your time being involved, however it is important that researchers have access to patient groups in order to move forward on later stages of their research such as clinical trials. In addition, having strong patient membership helps researchers obtain grants for their work and to gain support of pharmaceutical companies necessary to make useful treatments available to medical professionals. Finally the PMD Foundation relies on the support of its members to allow us to provide grants for early stages of research that might otherwise be unable to begin.

Source: Lee Robinson

Nystagmus is a condition where the eyes move rapidly and uncontrollably. They can move:

• side to side (horizontal nystagmus)
• up and down (vertical nystagmus)
• in a circle (rotary nystagmus)

The movement can vary between slow and fast and usually happens in both eyes. The eyes may shake more when looking in certain directions. People with nystagmus may tilt or turn their head to see more clearly. This helps to slow down the eye movements.

Source American Academy of Oftalmology

Rarely, hearing loss, optic atrophy, and recurrent seizures (epilepsy) can occur.

Source: MedlinePlus [Internet]. Bethesda (MD): National Library of Medicine (US); [updated 2020 Jun 24] PMLD Type 1

Gastrostomy tubes (G-tubes) are widely considered a safe and effective way to maintain the nutritional needs of individuals at risk for choking or who may struggle to eat or drink fluids. Caregivers and medical teams might want to consider using a G-tube placement to manage insufficient weight gain, to improve nutrition or hydration, and to ensure that the individual can ingest fluids and medications.

Source: Living with Leukodystrophy - A Guide for Caring for Leukodystrophy Patients.

Some children may develop skeletal deformities secondary to the severe spasticity that typically develops over time in PMD & PMLD. As these disorders progress, walking may become increasingly difficult, and patients progress to walker and then wheelchair. Many PMD affected children will not be able to walk but instead can use a manual or powered wheelchair with success.

Source: NORD

Most individuals who experience Classic PMD will usually live into mid-adulthood. Those affected with Connatal PMD show less development of motor skills and life expectancy is typically shorter than those with Classic PMD.

Source: Hunter’s Hope

In some cases, braces and external frames may be helpful. In some cases, braces improve seating position, but have not been shown to change scoliosis progression in the long term. In some cases, scoliosis can be repaired with surgery. Not all scoliosis will require surgical intervention. Surgery should be considered if the scoliosis poses other risks to the individual’s well-being, including their breathing health.

Source: Living with Leukodystrophy - A Guide for Caring for Leukodystrophy Patients.

Oral medications such as baclofen or diazepam (or other medications in the category of benzodiazepines, or other classes of medications such as clonidine), in combination with physical therapy and daily stretching routines, can help manage spasticity.

Botulin toxin or phenol injections (also called chemodenervation) can be useful to target focal areas of spasticity. As with any treatment, these interventions should be done in consultation by experienced orthopedic, neurologic, or rehabilitation specialists.

In some cases, a baclofen pump (intrathecal baclofen, via direct administration into the fluid surrounding the spinal cord) allows for better delivery of medication. A baclofen pump can lead to fewer side effects compared to oral baclofen, because it is delivered directly to the location it is needed. Because the pump must be surgically implanted, however, it poses the risk of infection or a mechanical failure that can lead to abrupt cessation of available baclofen and worsening of symptoms related to withdrawal. Also, individuals need to be big enough in size and weight to have the pump implanted. Thus, in some cases, children are too small to permit implantation.

Source: Living with Leukodystrophy - A Guide for Caring for Leukodystrophy Patients.

Caregivers can implement appropriate prevention strategies like introducing simple dietary changes, increasing hydration, and supplementing meals with dietary fiber, or adding enteral formula with fiber if the child is fed with a G-tube.

Many parents find success in using miralax (for stool consistency) and magnesium supplements such as Natural Vitality Calm (to aid in frequency of bowel movements). If symptoms persist, the first choice is typically polyethylene glycol followed by lactulose which can be used as stool softeners.

Enemas can be effective at managing constipation in individuals with limited mobility, but should not be used as a preventative approach. Stool stimulants such as senna or bisacodyl can be helpful as well. While these may lead to dependency, priority should be given to optimizing the individual’s quality of life. Finally, if disimpaction (in which stool is manually broken up) is necessary, the medical team should consider consulting a gastroenterologist or general surgeon.

Source: Living with Leukodystrophy - A Guide for Caring for Leukodystrophy Patients.

Sometimes providers may recommend a procedure called selective dorsal rhizotomy (SDR), a surgical procedure that disconnects nerve roots to reduce spasticity. While SDR has been quite effective for treating some individuals with cerebral 13 palsy, the procedure should be undertaken with extreme care in individuals affected by leukodystrophy, as many leukodystrophies also have dystonia (see below), which can become more evident with SDR, worsening function. Additionally, since many leukodystrophies are progressive, SDR done at one phase of the disease may no longer address important areas of spasticity later in the disease. In most cases, it is contraindicated in individuals with leukodystrophy.

Source: Living with Leukodystrophy - A Guide for Caring for Leukodystrophy Patients.