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Pelizaeus–Merzbacher disease
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{{short description|X-linked leukodystrophy}} {{Infobox medical condition (new) | name = Pelizaeus–Merzbacher disease | synonyms = | image = X-linked recessive (carrier mother).svg | caption = Pelizaeus–Merzbacher disease is inherited in an x-linked recessive manner<ref>{{cite web|title=OMIM Entry - # 312080 - Pelizaeus-Merzbacher Disease; PMD|url=https://omim.org/entry/312080|website=omim.org|access-date=5 August 2017|language=en-us}}</ref> | pronounce = | field = | symptoms = | complications = | onset = | duration = | types = | causes = | risks = | diagnosis = | differential = | prevention = | treatment = | medication = | prognosis = | frequency = | deaths = }} '''Pelizaeus–Merzbacher disease''' is an [[X-linked]] neurological disorder that damages [[oligodendrocytes]] in the [[central nervous system]]. It is caused by mutations in [[proteolipid protein 1]] (''PLP1''), a major [[myelin]] protein. It is characterized by a decrease in the amount of insulating [[myelin]] surrounding the nerves (hypomyelination) and belongs to a group of genetic diseases referred to as [[leukodystrophies]].<ref name="HobsonGarbern2012">{{cite journal|last1=Hobson|first1=Grace|last2=Garbern|first2=James|title=Pelizaeus-Merzbacher Disease, Pelizaeus-Merzbacher-Like Disease 1, and Related Hypomyelinating Disorders|journal=Seminars in Neurology|volume=32|issue=1|year=2012|pages=062–067|issn=0271-8235|doi=10.1055/s-0032-1306388|pmid=22422208|s2cid=25529422 }}</ref> ==Signs and symptoms== The hallmark signs and symptoms of Pelizaeus–Merzbacher disease include little or no movement in the arms or legs, respiratory difficulties, and characteristic horizontal movements of the eyes left to right.{{citation needed|date=September 2020}} The onset of Pelizaeus–Merzbacher disease is usually in early infancy. The most characteristic early signs are [[pathologic nystagmus|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 Pelizaeus–Merzbacher disease 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 contracture]]s 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.<ref>{{Cite web |title=Pelizaeus-Merzbacher disease: MedlinePlus Genetics |url=https://medlineplus.gov/genetics/condition/pelizaeus-merzbacher-disease/ |access-date=2022-06-25 |website=medlineplus.gov |language=en}}</ref> ==Cause== Pelizaeus–Merzbacher disease is caused by [[X-linked recessive]] mutations in the major myelin [[protein]] [[proteolipid protein 1]] (''PLP1''). This causes [[hypomyelination]] in the [[central nervous system]] and severe neurological disease. The majority of mutations result in duplications of the entire ''PLP1'' gene. Deletions of ''PLP1'' locus (which are rare) cause a milder form of Pelizaeus–Merzbacher disease than is observed with the typical duplication mutations, which demonstrates the critical importance of [[gene dosage]] at this locus for normal CNS function.<ref> {{cite journal |last1=Sima |first1=A.A.F. |last2= Pierson |first2=C.R. |last3=Woltjer |first3=R.L. |last4=et |first4=al |title=Neuronal loss in Pelizaeus–Merzbacher disease differs in various mutations of the proteolipid protein 1 |journal=Acta Neuropathol |issue=4 |pages=531–539 |date=2009 |volume=118 |doi=10.1007/s00401-009-0562-8 |pmid=19562355 |url=https://doi.org/10.1007/s00401-009-0562-8 |access-date=January 14, 2024|pmc=3876935 }} </ref> ==Diagnosis== The diagnosis of Pelizaeus–Merzbacher disease is often first suggested after identification by [[magnetic resonance imaging]] 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 a family history consistent with [[sex-linked]] inheritance exists, the condition is often misdiagnosed as cerebral palsy. Once a ''PLP1'' mutation is identified, [[prenatal diagnosis]] or preimplantation genetic diagnostic testing is possible.{{citation needed|date=September 2020}} ===Classification=== The disease is one in a group of [[genetic disorder]]s collectively known as [[leukodystrophies]] that affect the growth of the [[myelin]] sheath, the fatty covering—which acts as an insulator—on [[nerve fiber]]s in the [[central nervous system]]. The several forms of Pelizaeus–Merzbacher disease include classic, congenital, transitional, and adult variants.<ref>{{Cite web|title=Pelizaeus-Merzbacher disease (Concept Id: C0205711) - MedGen - NCBI|url=https://www.ncbi.nlm.nih.gov/medgen/61440|access-date=2021-03-03|website=www.ncbi.nlm.nih.gov|language=en}}</ref> Pelizaeus–Merzbacher disease is the common name for hypomyelinating leukodystrophies (HLD).<ref>{{cite journal |last1=Wolf |first1=Nicole |last2=Ffrench-Constant |first2=Charles |last3=van der Knaap |first3=Marjo |title=Hypomyelinating leukodystrophies — unravelling myelin biology |journal=Nat Rev Neurol |date=2021 |volume=17 |issue=2 |pages=88–103 |doi=10.1038/s41582-020-00432-1 |pmid=33324001 |s2cid=229182946 |url=https://www.nature.com/articles/s41582-020-00432-1}}</ref> There are at least 26 HLD variants cataloged by the National Institutes of Health National Library of Medicine<ref>{{cite web |title=National Library of Medicine |url=https://www.ncbi.nlm.nih.gov/medgen/?term=hld |publisher=National Institutes of Health |access-date=7 March 2024}}</ref> and the Online Mendelian Inheritance in Man (OMIM) compendium of human genes and genetic phenotypes.<ref>{{cite web |title=Online Mendelian Inheritance in Man |url=https://www.omim.org/search?index=entry&start=1&limit=10&sort=score+desc%2C+prefix_sort+desc&search=hld |publisher=Johns Hopkins University}}</ref> 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).{{citation needed|date=September 2020}} ==Treatment== No cure for Pelizaeus–Merzbacher disease has been developed.<ref name=nihinfo>{{Cite web |url=https://www.ninds.nih.gov/Disorders/All-Disorders/Pelizaeus-Merzbacher-Disease-Information-Page |title=Pelizaeus-Merzbacher Disease Information Page |publisher=National Institute of Neurological Disorders and Stroke }}</ref> Outcomes are variable: people with the most severe form of the disease do not usually survive to adolescence, although with milder forms, survival into adulthood is possible.<ref name=nihinfo/> A phase I clinical trial using an antisense oligonucleotide (known as ION356) targeted against ''PLP1'' is expected to begin in early 2024.<ref>{{Cite web |title=Ionis Innovation Day |url=https://ir.ionispharma.com/static-files/8b71dc65-dad9-4368-9014-604c5b203ca1 |access-date=October 4, 2023}}</ref> ==Research== In December 2008, [[StemCells, Inc]] received clearance in the United States to conduct a [[phase I clinical trials]] of human [[neural stem cell]] transplantation.<ref>{{Cite web | url=https://www.pmdfoundation.org/stem-cells-inc/ | title=Stem Cells, Inc}}</ref> The trial did not show meaningful efficacy and the company has since gone bankrupt.<ref>{{Cite web | url=https://ipscell.com/2016/05/end-of-line-for-stemcells-inc-pioneering-controversial-stem-cell-biotech/ |title = End of line for StemCells Inc., pioneering & controversial stem cell biotech|date = 2016-05-31}}</ref> In 2019 [[Paul J. Tesar|Paul Tesar]], a professor at Case Western Reserve University, used [[CRISPR]] and [[antisense therapy]] in a mouse model of Pelizaeus–Merzbacher with success.<ref>{{cite journal |last1=Elitt |first1=Matthew S. |last2=Barbar |first2=Lilianne |last3=Shick |first3=H. Elizabeth |last4=Powers |first4=Berit E. |last5=Maeno-Hikichi |first5=Yuka |last6=Madhavan |first6=Mayur |last7=Allan |first7=Kevin C. |last8=Nawash |first8=Baraa S. |last9=Nevin |first9=Zachary S. |last10=Olsen |first10=Hannah E. |last11=Hitomi |first11=Midori |last12=LePage |first12=David F. |last13=Jiang |first13=Weihong |last14=Conlon |first14=Ronald A. |last15=Rigo |first15=Frank |last16=Tesar |first16=Paul J. |title=Therapeutic suppression of proteolipid protein rescues Pelizaeus-Merzbacher Disease in mice |journal=bioRxiv |date=31 December 2018 |pages=508192 |doi=10.1101/508192 |doi-access=free |url=https://www.biorxiv.org/content/biorxiv/early/2018/12/31/508192.full.pdf }}</ref><ref>{{Cite journal |title=Suppression of proteolipid protein rescues Pelizaeus-Merzbacher Disease |date=2020-07-01|doi=10.1038/s41586-020-2494-3 |last1=Elitt |first1=Matthew S. |last2=Barbar |first2=Lilianne |last3=Shick |first3=H. Elizabeth |last4=Powers |first4=Berit E. |last5=Maeno-Hikichi |first5=Yuka |last6=Madhavan |first6=Mayur |last7=Allan |first7=Kevin C. |last8=Nawash |first8=Baraa S. |last9=Gevorgyan |first9=Artur S. |last10=Hung |first10=Stevephen |last11=Nevin |first11=Zachary S. |last12=Olsen |first12=Hannah E. |last13=Hitomi |first13=Midori |last14=Schlatzer |first14=Daniela M. |last15=Zhao |first15=Hien T. |last16=Swayze |first16=Adam |last17=Lepage |first17=David F. |last18=Jiang |first18=Weihong |last19=Conlon |first19=Ronald A. |last20=Rigo |first20=Frank |last21=Tesar |first21=Paul J. |journal=Nature |volume=585 |issue=7825 |pages=397–403 |pmid=32610343 |pmc=7810164 |bibcode=2020Natur.585..397E }}</ref><ref>{{Cite web|date=1 July 2020|title=Research finds new approach to treating certain neurological diseases|url=https://medicalxpress.com/news/2020-07-approach-neurological-diseases.html|access-date=1 July 2020|website=MedicalXpress|quote=Their research was published online July 1 in the journal Nature. "The pre-clinical results were profound. PMD mouse models that typically die within a few weeks of birth were able to live a full lifespan after treatment," said Paul Tesar}}</ref> In 2022 Case Western Reserve University entered an exclusive licensing agreement with Ionis Pharmaceuticals to develop a human treatment for the disorder.<ref>{{Cite web |date=2022-01-27 |title=Case Western Reserve University grants exclusive license to Ionis Pharmaceuticals to advance antisense therapy for Pelizaeus-Merzbacher disease |url=https://thedaily.case.edu/case-western-reserve-university-grants-exclusive-license-to-ionis-pharmaceuticals-to-advance-antisense-therapy-for-pelizaeus-merzbacher-disease/ |access-date=2022-03-06 |website=The Daily |language=en-US}}</ref> ==See also== * [[The Myelin Project]] * [[The Stennis Foundation]] * [[Friedrich Christoph Pelizaeus]] * [[Ludwig Merzbacher]] ==References== {{reflist}} ==Further reading== * {{cite journal |last1=Uhlenberg |first1=Birgit |last2=Schuelke |first2=Markus |last3=Rüschendorf |first3=Franz |last4=Ruf |first4=Nico |last5=Kaindl |first5=Angela M. |last6=Henneke |first6=Marco |last7=Thiele |first7=Holger |last8=Stoltenburg-Didinger |first8=Gisela |last9=Aksu |first9=Fuat |last10=Topaloğlu |first10=Haluk |last11=Nürnberg |first11=Peter |last12=Hübner |first12=Christoph |last13=Weschke |first13=Bernhard |last14=Gärtner |first14=Jutta |title=Mutations in the Gene Encoding Gap Junction Protein α12 (Connexin 46.6) Cause Pelizaeus-Merzbacher–Like Disease |journal=The American Journal of Human Genetics |date=August 2004 |volume=75 |issue=2 |pages=251–260 |doi=10.1086/422763 |pmid=15192806 |pmc=1216059 }} == External links == * [https://www.pmdfoundation.org/what-is-pmd-about?gclid=CjwKCAiAlfqOBhAeEiwAYi43F24pNN_Xyf8EMRPAvE-__xOxUI5428wQFA6fAOxmQh-pulTxDJ2jiRoCMcEQAvD_BwE Pelizaeus-Merzbacher Disease] - PMD Foundation * [http://www.ninds.nih.gov/health_and_medical/disorders/pelizaeu_doc.htm Pelizaeus-Merzbacher Disease] {{Webarchive|url=https://web.archive.org/web/20081007043820/http://www.ninds.nih.gov/health_and_medical/disorders/pelizaeu_doc.htm |date=2008-10-07 }}. NINDS/National Health Institutes. * {{GeneTests|pmd}} {{Medical resources | DiseasesDB = 29467 | ICD10 = {{ICD10|E|75|2|e|70}} | ICD9 = {{ICD9|330.0}} | ICDO = | OMIM = 312080 | MedlinePlus = | eMedicineSubj = neuro | eMedicineTopic = 520 | MeshID = D020371 | Orphanet = 702 |ICD11={{ICD11|8A44.0}}|GARDNum=4265|GARDName=pelizaeus-merzbacher-disease}} {{Lipid storage disorders}} {{Demyelinating diseases of CNS}} {{X-linked disorders}} {{DEFAULTSORT:Pelizaeus-Merzbacher Disease}} [[Category:Lipid storage disorders]] [[Category:Leukodystrophies]] [[Category:X-linked recessive disorders]] [[Category:Rare diseases]] [[Category:Demyelinating diseases of CNS]] [[Category:Diseases named after discoverers]]
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