World Library  
Flag as Inappropriate
Email this Article

Pelizaeus–Merzbacher disease

Article Id: WHEBN0000056469
Reproduction Date:

Title: Pelizaeus–Merzbacher disease  
Author: World Heritage Encyclopedia
Language: English
Subject: X-linked intellectual disability, Leukodystrophies, Chronic granulomatous disease, Danon disease, Barth syndrome
Collection:
Publisher: World Heritage Encyclopedia
Publication
Date:
 

Pelizaeus–Merzbacher disease

Pelizaeus–Merzbacher disease
Classification and external resources
ICD-10 E75.2
ICD-9 330.0
OMIM 312080
DiseasesDB 29467
eMedicine neuro/520
MeSH D020371

Pelizaeus–Merzbacher disease (PMD) is a rare central nervous system disorder in which coordination, motor abilities, and intellectual function are delayed to variable extents.

Contents

  • Classification 1
  • Diagnosis 2
  • Treatment 3
  • See also 4
  • References 5
  • External links 6

Classification

The disease is one in a group of genetic disorders collectively known as leukodystrophies that affect growth of the myelin sheath, the fatty covering—which acts as an insulator—on nerve fibers in the CNS. PMD is generally caused by a recessive mutation of the gene on the long arm of the X-chromosome (Xq21-22) that codes for a myelin protein called proteolipid protein 1 or PLP1. The majority of disease-causing mutations result in duplications of the entire PLP1 gene. There are several forms of Pelizaeus-Merzbacher disease including, classic, connatal, transitional, and adult variants. Interestingly, deletions at the PLP1 locus (which are rarer) cause a milder form of PMD than is observed with the typical duplication mutations, which demonstrates the critical importance of gene dosage at this locus for normal CNS function. Some of the remaining cases of PMD are accounted for by mutations in the gap junction A12 (GJA12) gene, and are now called Pelizaeus-Merzbacher-like disease (PMLD). Other cases of apparent PMD do not have mutations in either the PLP1 or GJA12 genes, and are presumed to be caused either by mutations in other genes, or by mutations not detected by sequencing the PLP1 gene exons and neighboring intronic regions of the gene. Among these is a new genetic disorder (discovered in 2003,[1] 2004[2]) which is caused by mutation in the transporter of thyroid hormone, MCT8, also known as SLC16A2, is believed to be account for a significant fraction of the undiagnosed neurological disorders (usually resulting in hypotonic/floppy infants with delayed milestones). This genetic defect was known as Allan-Herndon-Dudley syndrome (since 1944) without knowing its actual cause. Some of the signs for this disorder are as follows: normal to slightly elevated TSH, elevated T3 and reduced T4 (ratio of T3/T4 is about double its normal value). Normal looking at birth and for the first few years, hypotonic (floppy), in particular difficulty to hold the head, possibly difficulty to thrive, possibly with delayed myelination (if so, some cases are reported with an MRI pattern similar to Pelizaeus–Merzbacher disease, known as PMD,[3]) possibly with decreased mitochondrial enzyme activities, possibly with fluctuating lactate level. Patients have an alert face, a limited IQ, patients may never talk/walk, 50% need feeding tube, patients have a normal life span. MCT8 can be ruled out with a simple TSH/T4/T3 thyroid test.

Milder mutations of the PLP1 gene that mainly cause leg weakness and spasticity, with little or no cerebral involvement, are classified as spastic paraplegia 2 (SPG2). The onset of Pelizaeus–Merzbacher disease is usually in early infancy. The most characteristic early signs are nystagmus (rapid, involuntary, rhythmic motion of the eyes) and hypotonia (low muscle tone). Motor abilities are delayed or never acquired, mostly depending upon the severity of the mutation. Most children with PMD learn to understand language, and usually have some speech. Other signs may include tremor, lack of coordination, involuntary movements, weakness, unsteady gait, and over time, spasticity in legs and arms. Muscle contractures (shrinkage or shortening of a muscle) often occur over time. Mental functions may deteriorate. Some patients may have convulsions and skeletal deformation, such as scoliosis, resulting from abnormal muscular stress on bones.

Diagnosis

The diagnosis of PMD is often first suggested after identification by magnetic resonance imaging (MRI) of abnormal white matter (high T2 signal intensity, i.e. T2 lengthening) throughout the brain, which is typically evident by about 1 year of age, but more subtle abnormalities should be evident during infancy. Unless there is a family history consistent with sex-linked inheritance, the condition is often misdiagnosed as cerebral palsy. Once a PLP1 or GJA12 mutation is identified, prenatal diagnosis or preimplantation genetic diagnostic testing is possible. .

Treatment

There is no cure for PMD, nor is there a standard course of treatment. Treatment, which is symptomatic and supportive, may include medication for seizures and spasticity. Regular evaluations by physical medicine and rehabilitation, orthopedic, developmental and neurologic specialists should be made to ensure optimal therapy and educational resources. The prognosis for those with Pelizaeus–Merzbacher disease is highly variable, with children with the most severe form (so-called connatal) usually not surviving to adolescence, but survival into the sixth or even seventh decades is possible, especially with attentive care. Genetic counseling should be provided to the family of a child with PMD.

In December 2008, StemCells Inc., a biotech company in Palo Alto, received clearance from the U.S. Food and Drug Administration (FDA) to conduct Phase I clinical trials in PMD to assess the safety of transplanting human neural stem cells as a potential treatment for PMD. The trial was initiated in November 2009 at the University of California, San Francisco (UCSF) Children's Hospital.[4]

See also

References

  1. ^ Dumitrescu Edith C. H. Friesema, Sumita Ganguly, Amal Abdalla, Jocelyn E. Manning Fox, Andrew P. Halestrap, and Theo J. Visser (October 2003-received January 2003). "Identification of Monocarboxylate Transporter 8 as a Specific Thyroid Hormone Transporter". The Journal of Biological Chemistry 278 (41): 40128–40135.  
  2. ^ Dumitrescu AM, Liao XH, Best TB, Brockmann K, Refetoff S (January 2004). "A novel syndrome combining thyroid and neurological abnormalities is associated with mutations in a monocarboxylate transporter gene". Am. J. Hum. Genet. 74 (1): 168–75.  
  3. ^ Vaurs-Barrière C, Deville M, Sarret C, Giraud G, Des Portes V, Prats-Viñas JM, De Michele G, Dan B, Brady AF, Boespflug-Tanguy O, Touraine R (January 2009). "Pelizaeus-Merzbacher-Like disease presentation of MCT8 mutated male subjects". Ann. Neurol. 65 (1): 114–8.  
  4. ^ http://www.stemcellsinc.com/clinicaltrials/clinicaltrials.html. 

External links

  • Pelizaeus-Merzbacher.org - Videos and information about the disorder's symptom, diagnosis, prognosis, research & potential treatment
  • The Stennis Foundation - Registered charity committed to raising awareness and funds for Leukodystrophies research
  • The Stennis Foundation's MySpace site
  • Pelizaeus-Merzbacher Disease. NINDS/National Health Institutes.
  • pmd at NIH/UW GeneTests
  • Uhlenberg B, Schuelke M, Rüschendorf F, Ruf N, Kaindl A, Henneke M, Thiele H, Stoltenburg-Didinger G, Aksu F, Topaloğlu H, Nürnberg P, Hübner C, Weschke B, Gärtner J (2004). "Mutations in the gene encoding gap junction protein alpha 12 (connexin 46.6) cause Pelizaeus-Merzbacher-like disease". Am J Hum Genet 75 (2): 251–60.  
  • PMD foundation web site. PMD Foundation (US)
  • PMD Clinical Trial - UCSF Neonatology Clinical Trial for PMD
This article was sourced from Creative Commons Attribution-ShareAlike License; additional terms may apply. World Heritage Encyclopedia content is assembled from numerous content providers, Open Access Publishing, and in compliance with The Fair Access to Science and Technology Research Act (FASTR), Wikimedia Foundation, Inc., Public Library of Science, The Encyclopedia of Life, Open Book Publishers (OBP), PubMed, U.S. National Library of Medicine, National Center for Biotechnology Information, U.S. National Library of Medicine, National Institutes of Health (NIH), U.S. Department of Health & Human Services, and USA.gov, which sources content from all federal, state, local, tribal, and territorial government publication portals (.gov, .mil, .edu). Funding for USA.gov and content contributors is made possible from the U.S. Congress, E-Government Act of 2002.
 
Crowd sourced content that is contributed to World Heritage Encyclopedia is peer reviewed and edited by our editorial staff to ensure quality scholarly research articles.
 
By using this site, you agree to the Terms of Use and Privacy Policy. World Heritage Encyclopedia™ is a registered trademark of the World Public Library Association, a non-profit organization.
 


Copyright © World Library Foundation. All rights reserved. eBooks from Project Gutenberg are sponsored by the World Library Foundation,
a 501c(4) Member's Support Non-Profit Organization, and is NOT affiliated with any governmental agency or department.