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Pelizaeus-Merzbacher Disease

What is Pelizaeus-Merzbacher Disease?

Pelizaeus-Merzbacker Disease (PMD) is an inherited condition, passed on in an X-linked fashion, associated with impaired intellectual functions, limb spasticity and ataxia [1]. It affects the formation of the myelin sheath: a fatty white substance that electrically insulates nerve cells. The disease is heterogeneous in presentation depending on the mutation type. There is an early neonatal onset of symptoms associated with difficulty breathing and decreased muscle tone, sometimes called the Connatal form of PMD. There is also a later onset of disease, called the Classic form of PMD, usually occurring during the first year of life that is associated with delayed motor milestones, nystagmus, dysarthria and lower limb spasticity. Variation of disease symptoms and age of onset within each of these types is also possible [2]. 

 

Synonyms

  • Pelizaeus-Merzbacher brain sclerosis
  • Sclerosis, diffuse familial brain
  • Sudanophilic leukodystrophy, Pelizaeus-Merzbacher type

Pelizaeus-Merzbacker Disease (PMD) is an inherited condition, passed on in an X-linked fashion, associated with impaired intellectual functions, limb spasticity and ataxia [1]. It affects the formation of the myelin sheath: a fatty white substance that electrically insulates nerve cells. The disease is heterogeneous in presentation depending on the mutation type. There is an early neonatal onset of symptoms associated with difficulty breathing and decreased muscle tone, sometimes called the Connatal form of PMD. There is also a later onset of disease, called the Classic form of PMD, usually occurring during the first year of life that is associated with delayed motor milestones, nystagmus, dysarthria and lower limb spasticity. Variation of disease symptoms and age of onset within each of these types is also possible [2]. 

Acknowledgement of Pelizaeus-Merzbacher Disease has not been added yet.

PMD affects approximately 1 in 400,000 people, with the majority affected being male (3). Females are generally carriers for the condition because the mutation causing the disease, PLP1, is located on the X-chromosome (2). Females have two X chromosomes, one from each parent, whilst males inherit one X chromosome from the mother and one Y chromosome from the father. Since only one of the two X-chromosomes is active in female cells, at least half of their cells express a normal PLP1 thus preventing the symptoms of PMD. Males, however, have only one X chromosome, so that all cells express the mutant PLP1 protein and therefore causing PMD.  

Name Abbreviation
Pelizaeus-Merzbacher brain sclerosis PMBS
Sclerosis, diffuse familial brain Sc
Sudanophilic leukodystrophy, Pelizaeus-Merzbacher type SLPM

The majority of PMD cases are caused by a mutation in the PLP1 gene that encodes proteolipid protein 1 and DM20 that form part of the myelin sheath. Mutations in PLP1 alter the assembly of the myelin sheath and the function of the nerve cells that the myelin sheath insulates. There have also been reported studies of other, unidentified genetic mutations that cause a PMD-like illness; about 5% of individuals exhibit symptoms of PMD but have a normal PLP1 gene [2]. 

The major differences between the two major forms of PMD is the age of symptom onset. Connatal PMD is noted at or around birth with very decreased muscle tone, difficulty feeding, nystagmus, and weak cry. As the infant grows and matures however, spasticity and ataxia of the limbs prevails. Individuals with the Classic form of the disease, however, usually have disease onset within the first year or two of life with delayed motor milestones, increased muscle tone, and limb ataxia and dysarthria, similar to but not as severe as individuals with the Connatal form of disease 

The major distinguishing factors of the disease are involuntary eye movement, called nystagmus, abrasive sounds while breathing, and improper motor control of the head in addition to a family history of the condition. The most common way to make the diagnosis of PMD is by genetic testing to identify a PLP1 gene mutation.(1).

In cases where individuals have been diagnosed with the condition without the mutation present, an MRI can confirm the diagnosis since it can show the depletion of the myelin sheath.(1) Note: I would not make a PMD diagnosis without a positive gene test. If the MRI is abnormal but the gene test is negative, the patient would be considered to have a leukodystrophy of unknown etiology. 

Treatments for PMD are in the works but no silver bullet cure currently exists. There are several treatment methods for the symptoms, however. A gastrostomy tube can be used to help infants with difficulty sucking consume food (4). Antiepileptic drugs and physical therapy can be used to treat seizures (1).

Due to difficulty breathing, many of those diagnosed with Connatal PMD struggle to survive past childhood. With attentive care, however, there have been studies showing that individuals with Connatal PMD can live up to 30. Those with Classic PMD have been show to live up to 50 and 60 years of age. (4)

Since this is an X-linked inherited condition, it is highly recommended to seek genetic counselling if you suspect someone in your family may have had a case of PMD. There is also an extremely large support network for individuals with PMD and their families. 

What is Pelizaeus-Merzbacher disease (PMD) The PMD Foundation website. 

http://pmdfoundation.org/what-is-pmd/

Pelizaeus-Merzbacher disease. The Genetics and Home Reference website. 

http://ghr.nlm.nih.gov/condition/pelizaeus-merzbacher-disease

Pelizaeus-Merzbacher disease. Orphanet website.

 http://www.orpha.net/consor/cgi-bin/OC_Exp.php?Expert=702

Pelizaeus-Merzbacher disease.  Emedicine website. 

http://emedicine.medscape.com/article/1153103-overview#a7

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Visit sanfordresearch.org/CoRDS to enroll.

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