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Pelizaeus–Merzbacher disease (PMD) is an X-linked genetic disorder affecting the white matter of the brain and spinal cord. Many areas of the central nervous system (CNS) are affected by PMD due to a lack of myelin on nerve cell fibers. It causes a broad spectrum of symptoms, ranging from mild to severe intellectual disabilities to muscular malformations.

Symptoms[edit]

Patients with PMD have a wide range of phenotypes which differ on a case to case basis. The onset of symptoms usually occurs early within the first few weeks of birth. Affected patients show signs of neurological impairment and lack of motor control[1]. Involuntary motor control ranged from bobbing movements of the head, irregular contractions in the limbs, and an uncoordinated gait. Associated neurological impairments include: mental retardation, lack of verbal communication skills and struggle with comprehension[2]. PMD is classified into three overlapping types—classical, transitional, and connatal-- based on the severity of the symptoms. The most severe of the two types is connatal. Patients with the connatal type see slow development and usually never gain control of motor movement.They also struggle cognitively; having deteriorating intellectual abilities which leads to mental retardation. The progression of symptoms is usually faster and becomes fatal. Most patients of this type do not live past early infancy. Patients of all three types experience involuntary eye movement, weak muscle tone, muscle stiffness, seizures and problems ambulating. The classical type is the most common. Classical type patients usually are able to gain some control of their muscles and learn to walk. Other symptoms—involuntary eye movement-- usually fade or are recovered over time. Transitional PMD has moderate symptoms and is not as severe as connatal however its rate of progression makes it a logical intermediate form. There are cases of female patients however they experience milder symptoms at a later onset. Female patients may show symptoms of spastic movement and difficulty with balance. Any neurological symptoms are recovered in late adolescence.Ambxzd (talk)

Mode of Inheritance[edit]

Pelizaeus-Merzbacher disease has an X-linked recessive inheritance pattern. [3] X-linked recessive inheritance is correlated to the location of the affected gene on the X-chromosome. Affected phenotypes are disproportionately experienced by men, because they have one X-chromosome. Women can also display the phenotype if they are homozygous for the affected gene. Women may also be carriers if they only carry one allele with the mutation. Carriers will not display the phenotype but may pass it on to their offspring. Drsybf (talk) 23:14, 30 November 2016 (UTC)

Frequency of Occurrence[edit]

Due to its rarity, Pelizaeus-Merzbacher has minimal research on the frequency of occurrence. A survey conducted in Japan found about 1.45 in 100,000 births were diagnosed with Pelizaeus-Merzbacher disease. [4] Germany displayed a frequency of the disease at 0.13 in 100,000 births affected.[4] The United States has the least recorded prevalence of the disease at the rate of 1 in 200,000 to 500,000 births affected. [5] Drsybf (talk) 23:14, 30 November 2016 (UTC)

Gene Name & Protein Name[edit]

The gene responsible for Pelizaeus-Merzbacher disease was formerly called PLP or proteolipid protein but is now called PLP1. [6] PLP1 is located on the long arm of the X-chromosome at position Xq22.2. [6] PLP1 spans roughly 17 kilobases and contains seven coding exons. [6] PLP1 gives instructions to encode two myelin proteins, PLP1 and DM20 through alternative splicing of exon 3.[6],[7] Both PLP1 and DM20 are tetra-span membrane proteins located in the cytoplasm. [6] Drsybf (talk) 23:14, 30 November 2016 (UTC)

Molecular Pathogenesis[edit]

The PLP1 gene is a crucial factor in facilitating the creation of the myelin sheath. [4] The myelin sheath is a fatty substance that insulates the axon of neurons. The central nervous system (CNS) is comprised of these neurons and allow for processes to be fulfilled through the action of electrical pulses. Normally, the PLP1 gene will be translated into two proteins, PLP1 and an alternatively spliced version known as DM20.[8] These proteins are made in the endoplasmic reticulum and transported to the plasma membrane of the oligodendrocytes by the golgi.[4] Oligodendrocytes aid in the formation of myelin in the CNS.[8]Cme262 (talk) 22:19, 19 November 2016 (UTC)

In cases where PLP1 protein is defective through mutation, there are thought to be two different pathways that cause affected individual’s phenotypes. [8] Mutations in the PLP1 gene can result from point mutations or duplication which lead to myelin deficiency in the CNS. [4] When there is a point mutation of the PLP1 gene, the proteins are unable to transfer to the plasma membrane causing an accumulation of the protein in the ER/Golgi. [4] This accumulation causes stress on the endoplasmic reticulum due to the misfolding of the proteins, and this leads to apoptosis of the oligodendrocytes. [4] Whereas, when there is a duplication mutation, the PLP1 gene generates an abundance of PLP1 protein that remains in the lysosome and endosome which results in apoptosis of the oligodendrocytes as well.[4] Therefore, both of these mutations create a decrease in the amount of oligodendrocytes in the central nervous system, which hinders the formation of the myelin sheath in neurons creating the phenotype of PMD.Vetvy4 (talk) 17:02, 30 November 2016 (UTC)

Diagnosing (Therapy/Treatment/Testing)[edit]

Differential Diagnosis

Patients who present with indicative clinical symptoms will be considered for MRI and genetic testing. If PMD is suspected, a genetic history is taken to determine the patient's potential risk for PMD. If there is a family history of the symptoms following an X-linked inheritance pattern, especially the presence of affected male relatives, females can receive pre-natal and carrier testing[9].AKR539 (talk) 04:17, 1 December 2016 (UTC)

MRI

Monitoring of postnatal brain development during the first 3-24 months of development are key in early diagnosis of this disease. Abnormal or absent myelin levels in the corpus callosum can usually be seen by a reduction in size of the white matter when compared to a normal infant[9].AKR539 (talk) 04:17, 1 December 2016 (UTC)

Genetic Testing

Genetic and molecular testing can be used as a definitive diagnosis for affected males and carrier females who present with some symptoms. Techniques such as real time PCR,quantitative multiplex PCR, aCGH, and FISH analysis are common lab techniques used to test for duplications and deletions in the PLP1 gene,. Sequence analysis for other mutations will be used for diagnosis in males if duplications are not present in the gene. Affected males are usually infertile but their presence in a tree can help indicate carriers. Females who present with clinical symptoms of PMD without a family history of the disease may be tested for de novo mutations in the GJC2 or the PLP1 genes[9].AKR539 (talk) 04:17, 1 December 2016 (UTC)

Treatment

A team medical professionals from multiple disciplines will be necessary for monitoring and managing the symptoms. Careful attention must be paid to affected infants with swallowing and breathing difficulties; some infants require assisted feedings. Antiepileptic drugs and physical therapy can be utilized to manage seizures and spasticity in affected patients, as well as using wheelchairs along with physical therapy to manage any severe scoliosis[9].AKR539 (talk) 04:17, 1 December 2016 (UTC)

Developing Therapies[edit]

PMD does not have an effective therapy.[4] However, there are a multitude of potential therapies that are being tested. There has been some research using stem cells that have been transplanted into mice and humans with hypomyelination or PMD.[4] In both mice and humans, the stem cells led to the generation of oligodendrocytes that developed myelin that functioned properly and allowed for an increase in lifespan for those individuals.[4] Additionally, induced pluripotent stem cells have shown that they can be differentiated into oligodendrocytes that produce functional myelin.[4] In overexpression of PLP1, siRNA reduced expression levels of PLP1 and increased the formation of myelin.[4] An enriched cholesterol diet increased the levels of myelin and reduced the severity of motor defect symptoms by increasing the number of oligodendrocytes.[4] Inhibitors of MEK1/2 and ERK signaling pathways increased the levels of myelination by oligodendrocytes, counteracting the reduction in myelin formation from PLP1 overexpression.[4] The inhibitors may not cure the disease, but they could act as a way of slowing the progression of the disease. Kabg2

Notes[edit]

  1. ^ Ford, F. R. 1960. Diseases of the Nervous System in Infancy, Childhood and Adolescence. (4th ed.) Springfield, Ill.: Charles C Thomas (pub.) Pp. 831-833.
  2. ^ Arena, J. F., Schwartz, C., Stevenson, R., Lawrence, L., Carpenter, A., Duara, R., Ledbetter, D., Huang, T., Lehner, T., Ott, J., Lubs, H. A. Spastic paraplegia with iron deposits in the basal ganglia: a new X-linked mental retardation syndrome. Am. J. Med. Genet. 43: 479-490, 1992. 
  3. ^ Yamamoto, Torii, Shimojima, Keiko (2013). "Pelizaeus-Merzbacher disease as a chromosomal disorder". Congenital Anomalies. 53: 3–8.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  4. ^ a b c d e f g h i j k l m n o Tomohiro, Torii; Miyamoto, Yuki; Yamauchi, Junji; Tanoue, Akito (2014). "Pelizaeus-Merzbacher disease: Cellular pathogenesis and Pharmacologic Therapy". Pediatrics International. 56: 659-666.
  5. ^ Reference, Genetics Home. "Pelizaeus-Merzbacher disease". Genetics Home Reference. Retrieved 2016-11-30.
  6. ^ a b c d e Inoue, Ken (2005). "PLP1-related inherited dysmyelinating disorders: Pelizaeus-Merzbacher disease and spastic paraplegia type 2". Neurogenetics. 6: 1–16.
  7. ^ Gruenenfelder, Fredrik I.; Thomson, Gemma; Penderis, Jacques; Edgar, Julia M. (2011-07-01). "Axon–glial interaction in the CNS: what we have learned from mouse models of Pelizaeus–Merzbacher disease". Journal of Anatomy. 219 (1): 33–43. doi:10.1111/j.1469-7580.2011.01363.x. ISSN 1469-7580. PMC 3130158. PMID 21401588.
  8. ^ a b c Charzewska, A.; Wierzba, J.; Iźycka-Świeszewska, E.; Bekiesińka-Figatowska, M.; Jurek, M.; Gintowt, A.; Kłoswoska, A.; Bal, J.; Hoffman-Zacharska, D. (2016). "Hypomyelinating leukodystrophies-a molecular insight into the white matter pathology". Clin. Genet. 90: 293-304.
  9. ^ a b c d Hobson, Grace M., Ph.D.; Garbern, James Y., M.D., Ph.D. (2012). "Pelizaeus-Merzbacher DIsease, Pelizaeus-Merzbacher-Like Disease 1, and Related Hypomyelinating DIsorders". Seminars in Neurology. 32: 62–67.
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