What is Pelizaeus-Merzbacher Disease?
Pelizaeus-Merzbacher disease, or PMD, is a condition that affects the central nervous system – the part of our body that includes the brain and spinal cord. It’s part of a group of conditions known as hypomyelinating leukodystrophies, which cause issues with the protective covering of nerve cells. PMD is named after two German physicians, Friederich Pelizaeus and Ludwig Merzbacher, who played a significant role in its discovery and understanding. This condition first came to light in 1885, when Pelizaeus came across a family with multiple males suffering from conditions like uncontrolled eye movement (nystagmus), stiffness and weakness in muscles (spastic paresis), loss of coordination (ataxia), and developmental delays. Merzbacher later established that PMD was genetically inherited in an X-linked recessive manner, meaning that it typically affects males more than females.
PMD is caused by various mutations in the PLP1 gene, which can result in different symptoms and degrees of severity. There are various forms of PMD based on different mutations, which can range from mild to severe. The most severe form is known as the connatal form, while the mildest is referred to as spastic paraplegia type 2 (SPG2), which is categorized into ‘complicated’ or ‘pure’ types. Falling between these extremes, the ‘classic’ form of PMDis observed.
Another type of PMD, known as the PLP-1 null syndrome, is generally milder and considered distinct as it affects the peripheral nervous system – the nerves outside the brain and spinal cord, in contrast to typical PMD.
There are several types of hypomyelinating leukodystrophies (HLD) apart from PMD, so PMD is referred to as HLD1 to distinguish it from other similar conditions. There’s also another disease, Pelizaeus-Merzbacher-Like disease (PMLD), classified as HLD2. It’s considered separate from PMD due to a mutation in a different gene, GJC2. Although this overview is primarily about PMD, it’s important to note the distinct characteristics of these similar conditions.
What Causes Pelizaeus-Merzbacher Disease?
Pelizaeus-Merzbacher disease is a disease that is passed from parents to children through genes. Specifically, it happens due to a mutation or change in the PLP1 gene found on the X chromosome, which is one of the chromosomes that determines a person’s sex. These mutations could include duplication (copying a part of the gene), missense (changing a single DNA letter), or deletion (removing part of the gene).
Normally, the PLP1 gene helps produce myelin, a substance that coats nerve cells and helps them transmit signals efficiently. Mutations in the PLP1 gene cause decreased or completely absent myelin production. Without enough myelin, the nerve cells can’t function properly, causing the symptoms of Pelizaeus-Merzbacher disease.
Risk Factors and Frequency for Pelizaeus-Merzbacher Disease
Pelizaeus-Merzbacher disease (PMD) is less common compared to other similar conditions, with incidence rates varying from 1 in 90,000 to 1 in 750,000 live births around the world. However, in the United States, this rate is slightly higher standing at approximately 1.9 in 100,000 male live births.
As PMD is genetically passed down through an X-linked recessive pattern, it predominantly affects males. Females, on the other hand, can only be carriers and typically do not show any neurological symptoms associated with the disease. Nevertheless, there are cases where females from families where males have a milder form of PMD, known as SPG2, show certain symptoms of PMD in adulthood.
Signs and Symptoms of Pelizaeus-Merzbacher Disease
Pelizaeus-Merzbacher disease (PMD) is a condition with different degrees of severity, but some common symptoms include eye tremors, developmental delays, and muscle stiffness. PMD impacts individuals in different ways depending on its type. Let’s have a closer look at the various forms of PMD and their effects.
Seitelberger categorized the more severe PMD types into three groups. Type I or the connatal form is the most severe, while type III or the classic form is the mildest. Type II is a transitional type that falls in between. The classic and connatal types both begin with trembling and significant early muscle weakness, which later transitions into increased muscle stiffness. Furthermore, both types can result in poor balance and uncontrolled eye movements.
- Patients with classic PMD usually start showing symptoms around 1 year old, become increasingly stiff, and can walk only with difficulty. Although their intelligence is affected, they can still speak to some extent.
- Connatal patients show symptoms from birth, face more severe intellectual impairment, and cannot walk or talk. These individuals may also experience difficulties with breathing and frequent throat weakness, which could be fatal if not properly managed. However, with appropriate care, some manage to live into their thirties.
At the milder end of the PMD spectrum, we have spastic paraplegia type 2 (SPG2) which begins later than the previously mentioned types. There are two forms of SPG2: complicated and pure.
- Complicated SPG2 comes with bladder stiffness, poor balance, partial paralysis, eye tremors, and some level of intellectual impairment.
- Pure SPG2 presents mainly with bladder stiffness and partial paralysis. Both types of SPG2 patients typically live a normal lifespan.
Lastly, patients with PLP1 null syndrome, another form of PMD, display unique symptoms of peripheral nerve damage which separates it from other PMD disorders. These patients generally live a normal life but suffer from mild paralysis and cognitive impairment.
Testing for Pelizaeus-Merzbacher Disease
If a doctor suspects you might have a disorder known as Pelizaeus-Merzbacher disease (PMD), imaging tests like computed tomography (CT scans) and magnetic resonance imaging (MRI scans) can be extremely helpful for making a diagnosis. PMD affects the formation of a substance called myelin in the body. This substance is important for the health and functioning of your nerves.
Both CT and MRI scans can provide images of the body that allow doctors to see the effects of PMD and confirm if you have the disorder. MRI is generally more accurate than CT, which makes it the preferred choice. On a CT scan, changes to the white matter, (the part of the brain responsible for transmitting signals), could suggest PMD.
An MRI scan can show issues with myelin, which is a key sign of PMD. Regularly, as myelin develops, MRI signals increase in T1 and decrease in T2. However, in people with PMD, this process doesn’t occur as expected, and areas usually filled with myelin instead show hyperintensities (areas that appear lighter or brighter) on T2.
Some people with this disease may also have reduced size of the cerebellum (a part of the brain). It’s also important to note that if the MRI scan shows a specific kind of damage called pontine demyelination, the doctor may consider a similar condition known as Pelizaeus-Merzbacher-like disease as well.
In addition to imaging, molecular analysis is the main way to confirm a PMD diagnosis. This involves various lab methods which focus on identifying variations in PLP1 gene that might lead to PMD. One commonly used method is called droplet-digital polymerase chain reaction, which a recent study suggests can be a good alternative to conventional ones for detecting PLP1 mutations.
Lastly, neurophysiology (a branch of medicine that studies the nervous system function) tests can help in diagnosing PMD. Abnormal brain auditory responses and nerve conduction studies can provide evidence of the disease, making them useful tools for the diagnosis of PMD.
Treatment Options for Pelizaeus-Merzbacher Disease
Pelizaeus-Merzbacher disease (PMD) is a rare condition without a known definitive cure. The disease is managed primarily through supportive treatments that manage the symptoms. Scientists are currently studying treatments that could target the underlying molecular causes of PMD.
Typically, patients with PMD have seizures, which can often be managed with general anti-seizure medicines. The stiffness and muscle spasms (spasticity) which is a common symptom in PMD, can be managed using medications like baclofen, tizanidine, or diazepam, all of which help to relax the muscles. In some cases, due to weakness in the throat area, a medical procedure called gastrostomy might be needed. This procedure involves placing a tube into the stomach for feeding purposes. For those experiencing scoliosis, a condition where the spine twists and curves to the side, they might need physical therapy or possibly surgery.
There have been some promising early findings regarding treatments targeting the root molecular reasons for PMD. These however, have mainly been tested in mice and not yet in humans. For instance, Lonaprisan, a type of drug, has shown to reduce overproduction of a protein called PLP1, which typically results from a mutation causing PMD. By doing so, it helps increase the development of a protective layer around nerve cells, called myelination. Curcumin, a compound found in turmeric, has been associated with improved motor skills and less loss of nerve cells (oligodendrocytes) in mice with overproduction of PLP1. Curcumin may have a protective effect on nerve cells and helps reduce inflammation seen in PMD.
Studies suggest dietary changes could have an effect on the disease’s progression. A diet high in cholesterol can improve the lifespan of nerve cells (oligodendrocytes) and increase the size of nerve fibers, according to one study. Another study suggested that a high-fat, low-carb diet, known as a ketogenic diet, could enhance the production of the protective coating around nerve cells (myelination) in mice with overproduction of PLP1.
What else can Pelizaeus-Merzbacher Disease be?
Pelizaeus-Merzbacher disease is a type of leukodystrophy. These are a group of conditions that often share similar symptoms, so physicians need to consider and rule out other leukodystrophies before they make a final diagnosis of PMD. Leukodystrophies generally show a gradual worsening of neurological functions, including movement and cognitive abilities. They can be organized into different categories based on the part of the cell they affect. These categories include conditions that cause problems with the lysosomes (like metachromatic leukodystrophy), the peroxisomes (like adrenoleukodystrophy), the mitochondria, and the synthesis of myelin (like PMD and PMLD). Leukodystrophies vary in their genetic causes, how they’re passed down in families, and the symptoms they cause.
PMLD is notably similar to PMD and deserves attention. At first, PMLD was mistaken for PMD. The difference between the two comes down to the mutation spot on the gene; for PMLD, it’s on the GJC2 gene. PMLD is an autosomal recessive disorder, which means it affects individuals regardless of their sex. Even though both PMD and PMLD show a lack of white matter in the brain, or hypomyelination on an MRI scan, PMLD more often affects the brainstem, particularly the pons.
The milder forms of PMD, such as SPG2, fall within a group of conditions referred to as spastic paraplegias. Physicians need to consider these as possible diagnoses when assessing a patient. Reviewing the differentiation of these diseases, there are 52 types of spastic paraplegias, each presenting with muscle stiffness and overlapping symptoms, but also unique features. For instance:
- SPG1 or MASA syndrome is characterized by intellectual disability, build-up of fluid in the brain (hydrocephalus), and difficulty speaking (aphasia) due to a mutation on the L1CAM gene.
- SPG2, a type of PMD, is differentiated from other spastic paraplegias by a mutation on the PLP1 gene.
What to expect with Pelizaeus-Merzbacher Disease
The outlook for people with Pelizaeus-Merzbacher disease varies greatly. Those who have the most severe form of the disease, known as the ‘connatal form’, typically live until childhood, but some may pass away very early due to breathing issues. With appropriate care, their lives can be extended into their thirties.
People who have the ‘classic’ form of the disease, which is less severe, often live into their seventies. On the other hand, those with the mildest forms, called ‘SPG2’ and ‘null syndrome’, tend to have a life expectancy close to that of the general population.
Possible Complications When Diagnosed with Pelizaeus-Merzbacher Disease
People with Pelizaeus-Merzbacher disease, especially severe versions, may face a large number of health complications. These can greatly affect their overall health and longevity. For instance, a study by Golomb and colleagues reported that among 11 patients with Pelizaeus-Merzbacher symptoms, birth complications were observed, such as inhaling meconium (a newborn’s first poop) and punctured lungs. These complications required long-term treatments like breathing tubes and compression machines, starting as early as 10 months of age. Other issues such as feeding problems, which needed gastrostomy, curvature of the spine and sleep disturbances were also encountered. It was found that sleep problems could be handled with melatonin.
However, early intervention has shown positive results and can help prevent complications or worsening of the neurological issues. For example, a study by Jang and his team shows that one patient received training to improve balance and developmental delay. The outcome was positive, indicating that this kind of training can help enhance motor functions and prevent long-term complications.
List of complications:
- Inhaling meconium (a newborn’s first poop)
- Punctured lungs
- Feeding problems which require gastrostomy
- Curvature of the spine (scoliosis)
- Sleep disturbances, manageable with melatonin
PMD interventions:
- Training for balance and development
Preventing Pelizaeus-Merzbacher Disease
Genetic counseling plays a key role in helping patients understand the range of PMD disorders. It’s important to educate families about what the disease is, how it spreads, and how to manage any complications. This education empowers them to make informed decisions about their health. Additionally, an evaluation of the genetic risk should also be carried out to better understand the potential for the disease to be passed on.
