20 years after the end of the Civil War, a German physician, Friedrich Pelizaeus, clinically described 5 boys of a single family with involuntary eye movements, spasticity, limited head and truck control, and delayed cognitive development. That was 130 years ago, 1885. He observed that “the disease goes through the mother but does not do anything to her.” He recognized similarities to multiple sclerosis, but confirmation of a myelin disease came a few decades later.
4 years before World War I, a German-Argentine neuropathologist and psychiatrist born in Florence, Italy, Ludwig Merzbacher, re-examined the same family as Pelizaeus, which then included 14 individuals, 12 boys and 2 girls, and described their disease both clinically and pathologically. That was 105 years ago, 1910. Merzbacher determined that the loss of myelin in the nerve fibers from the Central Nervous System (CNS) was substantial on all individuals. He also noted that myelin appeared normal in the peripheral nerves. This is important as a number of PMD children nowadays start with a hearing loss diagnosis (like Leonardo).
Right in the middle of Beatle-mania in the USA in the 1960s, RM Norman (1961) and Seitelberger (1970) classified Pelizaeus-Merzbacher Disease (PMD) as a leukodystrophy and categorized it into 6 groups: classical, congenital, transitional, adult, variants with patchy myelin, and Cockayne’s Syndrome. There are also milder forms like Spastic Paraplegia Type 2 (SPG2). During this time, the underlying gene responsible, PLP, which governs the production of the Proteolipid Protein 1 (PLP1), was identified.
So let’s describe what PMD is
PMD is a genetic disorder
It is caused by mutations in the PLP1 gene located in the X chromosome at q21-q22 regions (more on this on a later post). The extent of the disease depends on the type and location of the mutations / deletions / duplications / triplications / quadriplications of this protein. Abnormalities on this protein are toxic to the octopus-like cells called oligodendrocytes, whose job is to make myelin.
PMD is a leukodystrophy (leuko = white, dystrophy = disorder)
A leukodystrophy is a group of inherited diseases that affect the myelination and development of the white matter in the brain. Just like there are many types of cancers, there are many types of leukodystrophies. PMD is one of about 40 (ie. ALD, MLD, Krabbe, Alexander).
PMD is a dysmyelinating disorder (as opposed to demyelinating)
This means that from birth the myelin sheath that surrounds nerves does not form properly (as opposed to the myelin being destroyed after it has properly formed as in other leukodystrophies). This myelin sheath acts as an insulator to the signals traveling from the Central Nervous System to the rest of our bodies. Thus, when affected it will prevent signals from being transmitted from one neuron to the next noise free. It is just like an electrical cable that has been chewed along its path.
An interesting side note is the fact the the auditory nerve is a peripheral nerve. The myelination of the peripheral nervous system is controlled by Schwann Cells vs Oligodendrocytes. Although I found hearing loss to be an important diagnosis to jump start the search for PMD, it is not of much concern, as PMD children are known to hear at normal levels. Speech on the other hand, which is controlled from the Central Nervous System, is another story for PMD children. There is definitely a negative impact on speech.
PMD is a hereditary disorder
It is X-linked recessive. This means that females are carriers and males are affected. On every pregnancy, a carrier mother has a 1 in 4 chance of having a daughter who is also a carrier of the genetic disorder, and a 1 in 4 chance of having a boy affected with PMD. Not having family history does not mean that PMD could not occur. A de novo mutation (alteration in a gene that is present for the first time in one family member) can happen at any time. And from there it could start passing through generations of females until the first case is seen. In my case, I have an undiagnosed daughter, a son without PMD, and a son with PMD. I have met families with de novo mutations, families with several generations of PMD, and families with multiple PMD boys. PMD families come in all shapes and sizes. One such family I met, adopted a PMD boy from China, Lee, after they had raised a PMD boy of their own. They are the epitome of human kindness, selflessness, and being true instruments for the Lord.
PMD is rare
It is believed that PMD occurs in 1 of 300,000 to 1,000,000 births. That means that there should be between 300 and 1,000 PMD patients in the USA, and between 7,000 and 24,000 PMD patients in the world. Patient registries in the USA (ie. www.pmdfoundation.org), have between 100-150 registered cases. Where are the rest? Either families have not registered, they have not been diagnosed or they have been misdiagnosed. Medical research relies on patient registries to find its patients for their studies. In layman’s terms, if the medical community cannot find us, they cannot study us, they cannot cure us. Rare disease families, please register yourselves in patient registries. PMD families, please contact the pmdfoundation.org.
PMD is misdiagnosed
Cerebral Palsy is a catch all condition for a number of neurological diseases, especially for PMD. My brother in law, Saul, was misdiagnosed with CP for 40 years, until Leonardo was born. Nystagmus (uncontrollable eye movements – one of Leo’s initial symptoms) is a clinical sign found in PMD and not in CP. It is vital for the medical establishment not to leave any stone unturned when diagnosing a neurological condition. There is a saying in medical school that says “if you hear hoofbeats, think horses”, which directs doctors to think of common diagnosis to common symptoms. With neurological conditions, like PMD, the saying should go, “if you hear hoofbeats, it could be a zebra”.
A misdiagnosis costs the disease a patient for a study. A misdiagnosis costs the patient access to future newborn screening, treatments, or cures. A misdiagnosis costs families their right to family planning, and blinds them of increasing risks to their children and future generations. I am blessed for having the opportunity to raise, to love, and get to know Leonardo as well as PMD, because now my daughter will be better informed when the time comes in how she wants to grow her own family. Cerebral Palsy families, please double check your diagnosis. Look into
PMD, specially if you find your child having nystagmus.
PMD does not have a newborn screening or a cure
Several leukodystrophies can be detected at birth by a series of tests. When found early they can be treated, and the disease can be stopped from developing. Depending on the severity of PMD, it could take hours for the symptoms show up, or years before parents realize their child is not reaching his milestones. If symptoms are evident from birth (stridor, nystagmus) then it is most likely PMD will be the most severe connatal type. Life expectancy of a few years to teen years. If symptoms appear a month or later after birth (nystagmus, hypotonia), then it is most likely the classic type of PMD. Life expectancy could extend to their 40s.
In order for PMD to be accurately diagnosed, a brain MRI and a genetic blood test are done. An MRI at around 6 months old would show decreased white matter volume in the T2 region. A genetic blood test will reveal the PLP1 mutation. A FISH or PCR methods can be used to detect duplications of the PLP1 gene, while genetic sequence analysis is needed to detect specific mutations in the PLP1 DNA sequence.
PMD is a FUNDAMENTAL Disease
The nonprofit, FindACure, coins the concept of fundamental diseases. They claim that rare diseases are gateways to understanding common conditions and human physiology. By redefining this group of diseases, the medical establishment can unlock new insights and discover potential treatments for conditions which affect millions. Neuroacanthocytosis has helped in the understanding of Parkinson’s, Familial Hypercholesterolemia has helped the development of statins which are now used to treat high cholesterol. In similar fashion, PMD provides an extremely attractive human model to work with. PMD patients typically reach a developmental plateau where their condition remains relatively stable, unlike individuals affected with other leukodystrophies. PMD is not a progressive, demyelinating disease. Human PMD studies can provide researchers with a longer timeframe to study specific patients. PMD research can potentially shorten the timeline towards a cure for all diseases of myelin, including Multiple Sclerosis.
Intellectual Fallacy of PMD Children
There is often the misconception that PMD children are intellectually delayed by nature of their disease. This is not necessarily the case. Their intellectual functions work fine. It is their motor skills which are impaired. The fact that they cannot perform tasks with the fluidity of a “normal” child, gives people the illusion of cognitive delay. In this manner I have heard of a classic PMD boy attending high school, and being in the top 10% of his class, taking subjects as complex as physics. I believe that the opportunities the PMD child has to explore is essential for his cognitive evolution. If the child cannot move to explore/learn from his surroundings, it will inevitably affect him in the short and long run.
This is Leo’s disease. This has been Leo’s fight, and countless others, from the time of conception. 130 years and counting.