KEGG DISEASE: Hypomyelinating leukodystrophy

DISEASE: Hypomyelinating leukodystrophy

Entry

H00679                      Disease

Name

Hypomyelinating leukodystrophy;
Pelizaeus-Merzbacher disease (PMD)

Description

Hypomyelinating leukodystrophies (HMLs) are disorders involving aberrant myelin formation in the central nervous system. They are clinically characterized by early onset nystagmus, impaired motor development, ataxia, choreoathetoid movements, dysarthria and progressive limb spasticity. The prototype of primary HMLs is the X-linked Pelizaeus-Merzbacher disease (PMD) caused by mutations in PLP1 encoding proteolipid protein lipophilin. Pelizaeus-Merzbacher-like disease (PMLD) is clinically similar to classical PMD but is not associated with PLP1 mutations. PMLD appears to be inherited in an autosomal recessive manner and mutations have been identified in GJC2, AIMP1, HSPD1 and so on.

Category

Inherited metabolic disorder

Brite

Human diseases in ICD-11 classification [BR:br08403]
08 Diseases of the nervous system
  Multiple sclerosis or other white matter disorders
   8A44  Leukodystrophies
    H00679  Hypomyelinating leukodystrophy
Pathway-based classification of diseases [BR:br08402]
Cellular process
  nt06515  Regulation of kinetochore-microtubule interactions
   H00679  Hypomyelinating leukodystrophy
  nt06532  Autophagy
   H00679  Hypomyelinating leukodystrophy
  nt06535  Efferocytosis
   H00679  Hypomyelinating leukodystrophy

Pathway

hsa04140

Autophagy - animal

hsa03020

RNA polymerase

hsa04623

Cytosolic DNA-sensing pathway

hsa00970

Aminoacyl-tRNA biosynthesis

hsa04071

Sphingolipid signaling pathway

Network

nt06515 Regulation of kinetochore-microtubule interactions
nt06532 Autophagy
nt06535 Efferocytosis

Gene

(HLD1/PMD) PLP1 [HSA:5354] [KO:K17271]
(HLD2) GJC2 [HSA:57165] [KO:K07619]
(HLD3) AIMP1 [HSA:9255] [KO:K15437]
(HLD4) HSPD1 [HSA:3329] [KO:K04077]
(HLD5) FAM126A [HSA:84668] [KO:K21844]
(HLD6) TUBB4A [HSA:10382] [KO:K07375]
(HLD7) POLR3A [HSA:11128] [KO:K03018]
(HLD8) POLR3B [HSA:55703] [KO:K03021]
(HLD9) RARS1 [HSA:5917] [KO:K01887]
(HLD10) PYCR2 [HSA:29920] [KO:K00286]
(HLD11) POLR1C [HSA:9533] [KO:K03027]
(HLD12) VPS11 [HSA:55823] [KO:K20179]
(HLD13) HIKESHI [HSA:51501] [KO:K23327]
(HLD14) UFM1 [HSA:51569] [KO:K12162]
(HLD15) EPRS1 [HSA:2058] [KO:K14163]
(HLD16) TMEM106B [HSA:54664] [KO:K25048]
(HLD17) AIMP2 [HSA:7965] [KO:K15438]
(HLD18) DEGS1 [HSA:8560] [KO:K04712]
(HLD19) TMEM63A [HSA:9725] [KO:K21989]
(HLD20) CNP [HSA:1267] [KO:K01121]
(HLD21) POLR3K [HSA:51728] [KO:K03019]
(HLD22) CLDN11 [HSA:5010] [KO:K06087]
(HLD23) RNF220 [HSA:55182] [KO:K25174]
(HLD24) ATP11A [HSA:23250] [KO:K26934]
(HLD25) TMEM163 [HSA:81615] [KO:K14694]
(HLD26) SLC35B2 [HSA:347734] [KO:K15276]
(HLD27) POLR1A [HSA:25885] [KO:K02999]

Other DBs

ICD-11:

8A44.3

ICD-10:

E75.2

MeSH:

D020371

OMIM:

312080 608804 260600 612233 610532 612438 607694 614381 616140 616420 616494 616683 616881 617899 617951 617964 618006 618404 618688 619071 619310 619328 619688 619851 620243 620269 620675

Reference

PMID:17115121

Authors

Garbern JY

Title

Pelizaeus-Merzbacher disease: Genetic and cellular pathogenesis.

Journal

Cell Mol Life Sci 64:50-65 (2007)
DOI:10.1007/s00018-006-6182-8

Reference

PMID:2773936 (HLD1)

Authors

Gencic S, Abuelo D, Ambler M, Hudson LD

Title

Pelizaeus-Merzbacher disease: an X-linked neurologic disorder of myelin metabolism with a novel mutation in the gene encoding proteolipid protein.

Journal

Am J Hum Genet 45:435-42 (1989)

Reference

PMID:21959080 (HLD2)

Authors

Meyer E, Kurian MA, Morgan NV, McNeill A, Pasha S, Tee L, Younis R, Norman A, van der Knaap MS, Wassmer E, Trembath RC, Brueton L, Maher ER

Title

Promoter mutation is a common variant in GJC2-associated Pelizaeus-Merzbacher-like disease.

Journal

Mol Genet Metab 104:637-43 (2011)
DOI:10.1016/j.ymgme.2011.08.032

Reference

PMID:21092922 (HLD3)

Authors

Feinstein M, Markus B, Noyman I, Shalev H, Flusser H, Shelef I, Liani-Leibson K, Shorer Z, Cohen I, Khateeb S, Sivan S, Birk OS

Title

Pelizaeus-Merzbacher-like disease caused by AIMP1/p43 homozygous mutation.

Journal

Am J Hum Genet 87:820-8 (2010)
DOI:10.1016/j.ajhg.2010.10.016

Reference

PMID:18571143 (HLD4)

Authors

Magen D, Georgopoulos C, Bross P, Ang D, Segev Y, Goldsher D, Nemirovski A, Shahar E, Ravid S, Luder A, Heno B, Gershoni-Baruch R, Skorecki K, Mandel H

Title

Mitochondrial hsp60 chaperonopathy causes an autosomal-recessive neurodegenerative disorder linked to brain hypomyelination and leukodystrophy.

Journal

Am J Hum Genet 83:30-42 (2008)
DOI:10.1016/j.ajhg.2008.05.016

Reference

PMID:16951682 (HLD5)

Authors

Zara F, Biancheri R, Bruno C, Bordo L, Assereto S, Gazzerro E, Sotgia F, Wang XB, Gianotti S, Stringara S, Pedemonte M, Uziel G, Rossi A, Schenone A, Tortori-Donati P, van der Knaap MS, Lisanti MP, Minetti C

Title

Deficiency of hyccin, a newly identified membrane protein, causes hypomyelination and congenital cataract.

Journal

Nat Genet 38:1111-3 (2006)
DOI:10.1038/ng1870

Reference

PMID:26643067 (HLD6)

Authors

Tonduti D, Aiello C, Renaldo F, Dorboz I, Saaman S, Rodriguez D, Fettah H, Elmaleh M, Biancheri R, Barresi S, Boccone L, Orcesi S, Pichiecchio A, Zangaglia R, Maurey H, Rossi A, Boespflug-Tanguy O, Bertini E

Title

TUBB4A-related hypomyelinating leukodystrophy: New insights from a series of 12 patients.

Journal

Eur J Paediatr Neurol 20:323-30 (2016)
DOI:10.1016/j.ejpn.2015.11.006

Reference

PMID:21855841 (HLD7)

Authors

Bernard G, Chouery E, Putorti ML, Tetreault M, Takanohashi A, Carosso G, Clement I, Boespflug-Tanguy O, Rodriguez D, Delague V, Abou Ghoch J, Jalkh N, Dorboz I, Fribourg S, Teichmann M, Megarbane A, Schiffmann R, Vanderver A, Brais B

Title

Mutations of POLR3A encoding a catalytic subunit of RNA polymerase Pol III cause a recessive hypomyelinating leukodystrophy.

Journal

Am J Hum Genet 89:415-23 (2011)
DOI:10.1016/j.ajhg.2011.07.014

Reference

PMID:22036171 (HLD8)

Authors

Saitsu H, Osaka H, Sasaki M, Takanashi J, Hamada K, Yamashita A, Shibayama H, Shiina M, Kondo Y, Nishiyama K, Tsurusaki Y, Miyake N, Doi H, Ogata K, Inoue K, Matsumoto N

Title

Mutations in POLR3A and POLR3B encoding RNA Polymerase III subunits cause an autosomal-recessive hypomyelinating leukoencephalopathy.

Journal

Am J Hum Genet 89:644-51 (2011)
DOI:10.1016/j.ajhg.2011.10.003

Reference

PMID:24777941 (HLD9)

Authors

Wolf NI, Salomons GS, Rodenburg RJ, Pouwels PJ, Schieving JH, Derks TG, Fock JM, Rump P, van Beek DM, van der Knaap MS, Waisfisz Q

Title

Mutations in RARS cause hypomyelination.

Journal

Ann Neurol 76:134-9 (2014)
DOI:10.1002/ana.24167

Reference

PMID:25865492 (HLD10)

Authors

Nakayama T, Al-Maawali A, El-Quessny M, Rajab A, Khalil S, Stoler JM, Tan WH, Nasir R, Schmitz-Abe K, Hill RS, Partlow JN, Al-Saffar M, Servattalab S, LaCoursiere CM, Tambunan DE, Coulter ME, Elhosary PC, Gorski G, Barkovich AJ, Markianos K, Poduri A, Mochida GH

Title

Mutations in PYCR2, Encoding Pyrroline-5-Carboxylate Reductase 2, Cause Microcephaly and Hypomyelination.

Journal

Am J Hum Genet 96:709-19 (2015)
DOI:10.1016/j.ajhg.2015.03.003

Reference

PMID:26151409 (HLD11)

Authors

Thiffault I, Wolf NI, Forget D, Guerrero K, Tran LT, Choquet K, Lavallee-Adam M, Poitras C, Brais B, Yoon G, Sztriha L, Webster RI, Timmann D, van de Warrenburg BP, Seeger J, Zimmermann A, Mate A, Goizet C, Fung E, van der Knaap MS, Fribourg S, Vanderver A, Simons C, Taft RJ, Yates JR 3rd, Coulombe B, Bernard G

Title

Recessive mutations in POLR1C cause a leukodystrophy by impairing biogenesis of RNA polymerase III.

Journal

Nat Commun 6:7623 (2015)
DOI:10.1038/ncomms8623

Reference

PMID:27120463 (HLD12)

Authors

Zhang J, Lachance V, Schaffner A, Li X, Fedick A, Kaye LE, Liao J, Rosenfeld J, Yachelevich N, Chu ML, Mitchell WG, Boles RG, Moran E, Tokita M, Gorman E, Bagley K, Zhang W, Xia F, Leduc M, Yang Y, Eng C, Wong LJ, Schiffmann R, Diaz GA, Kornreich R, Thummel R, Wasserstein M, Yue Z, Edelmann L

Title

A Founder Mutation in VPS11 Causes an Autosomal Recessive Leukoencephalopathy Linked to Autophagic Defects.

Journal

PLoS Genet 12:e1005848 (2016)
DOI:10.1371/journal.pgen.1005848

Reference

PMID:26545878 (HLD13)

Authors

Edvardson S, Kose S, Jalas C, Fattal-Valevski A, Watanabe A, Ogawa Y, Mamada H, Fedick AM, Ben-Shachar S, Treff NR, Shaag A, Bale S, Gartner J, Imamoto N, Elpeleg O

Title

Leukoencephalopathy and early death associated with an Ashkenazi-Jewish founder mutation in the Hikeshi gene.

Journal

J Med Genet 53:132-7 (2016)
DOI:10.1136/jmedgenet-2015-103232

Reference

PMID:28931644 (HLD14)

Authors

Hamilton EMC, Bertini E, Kalaydjieva L, Morar B, Dojcakova D, Liu J, Vanderver A, Curiel J, Persoon CM, Diodato D, Pinelli L, van der Meij NL, Plecko B, Blaser S, Wolf NI, Waisfisz Q, Abbink TEM, van der Knaap MS

Title

UFM1 founder mutation in the Roma population causes recessive variant of H-ABC.

Journal

Neurology 89:1821-1828 (2017)
DOI:10.1212/WNL.0000000000004578

Reference

PMID:29576217 (HLD15)

Authors

Mendes MI, Gutierrez Salazar M, Guerrero K, Thiffault I, Salomons GS, Gauquelin L, Tran LT, Forget D, Gauthier MS, Waisfisz Q, Smith DEC, Simons C, van der Knaap MS, Marquardt I, Lemes A, Mierzewska H, Weschke B, Koehler W, Coulombe B, Wolf NI, Bernard G

Title

Bi-allelic Mutations in EPRS, Encoding the Glutamyl-Prolyl-Aminoacyl-tRNA Synthetase, Cause a Hypomyelinating Leukodystrophy.

Journal

Am J Hum Genet 102:676-684 (2018)
DOI:10.1016/j.ajhg.2018.02.011

Reference

PMID:29186371 (HLD16)

Authors

Simons C, Dyment D, Bent SJ, Crawford J, D'Hooghe M, Kohlschutter A, Venkateswaran S, Helman G, Poll-The BT, Makowski CC, Ito Y, Kernohan K, Hartley T, Waisfisz Q, Taft RJ, van der Knaap MS, Wolf NI

Title

A recurrent de novo mutation in TMEM106B causes hypomyelinating leukodystrophy.

Journal

Brain 140:3105-3111 (2017)
DOI:10.1093/brain/awx314

Reference

PMID:29215095 (HLD17)

Authors

Shukla A, Das Bhowmik A, Hebbar M, Rajagopal KV, Girisha KM, Gupta N, Dalal A

Title

Homozygosity for a nonsense variant in AIMP2 is associated with a progressive neurodevelopmental disorder with microcephaly, seizures, and spastic quadriparesis.

Journal

J Hum Genet 63:19-25 (2018)
DOI:10.1038/s10038-017-0363-1

Reference

PMID:30620338 (HLD18)

Authors

Karsai G, Kraft F, Haag N, Korenke GC, Hanisch B, Othman A, Suriyanarayanan S, Steiner R, Knopp C, Mull M, Bergmann M, Schroder JM, Weis J, Elbracht M, Begemann M, Hornemann T, Kurth I

Title

DEGS1-associated aberrant sphingolipid metabolism impairs nervous system function in humans.

Journal

J Clin Invest 129:1229-1239 (2019)
DOI:10.1172/JCI124159

Reference

PMID:31587869 (HLD19)

Authors

Yan H, Helman G, Murthy SE, Ji H, Crawford J, Kubisiak T, Bent SJ, Xiao J, Taft RJ, Coombs A, Wu Y, Pop A, Li D, de Vries LS, Jiang Y, Salomons GS, van der Knaap MS, Patapoutian A, Simons C, Burmeister M, Wang J, Wolf NI

Title

Heterozygous Variants in the Mechanosensitive Ion Channel TMEM63A Result in Transient Hypomyelination during Infancy.

Journal

Am J Hum Genet 105:996-1004 (2019)
DOI:10.1016/j.ajhg.2019.09.011

Reference

PMID:32128616 (HLD20)

Authors

Al-Abdi L, Al Murshedi F, Elmanzalawy A, Al Habsi A, Helaby R, Ganesh A, Ibrahim N, Patel N, Alkuraya FS

Title

CNP deficiency causes severe hypomyelinating leukodystrophy in humans.

Journal

Hum Genet 139:615-622 (2020)
DOI:10.1007/s00439-020-02144-4

Reference

PMID:30584594 (HLD21)

Authors

Dorboz I, Dumay-Odelot H, Boussaid K, Bouyacoub Y, Barreau P, Samaan S, Jmel H, Eymard-Pierre E, Cances C, Bar C, Poulat AL, Rousselle C, Renaldo F, Elmaleh-Berges M, Teichmann M, Boespflug-Tanguy O

Title

Mutation in POLR3K causes hypomyelinating leukodystrophy and abnormal ribosomal RNA regulation.

Journal

Neurol Genet 4:e289 (2018)
DOI:10.1212/NXG.0000000000000289

Reference

PMID:33313762 (HLD22)

Authors

Riedhammer KM, Stockler S, Ploski R, Wenzel M, Adis-Dutschmann B, Ahting U, Alhaddad B, Blaschek A, Haack TB, Kopajtich R, Lee J, Murcia Pienkowski V, Pollak A, Szymanska K, Tarailo-Graovac M, van der Lee R, van Karnebeek CD, Meitinger T, Krageloh-Mann I, Vill K

Title

De novo stop-loss variants in CLDN11 cause hypomyelinating leukodystrophy.

Journal

Brain 144:411-419 (2021)
DOI:10.1093/brain/awaa410

Reference

PMID:33964137 (HLD23)

Authors

Sferra A, Fortugno P, Motta M, Aiello C, Petrini S, Ciolfi A, Cipressa F, Moroni I, Leuzzi V, Pieroni L, Marini F, Boespflug Tanguy O, Eymard-Pierre E, Danti FR, Compagnucci C, Zambruno G, Brusco A, Santorelli FM, Chiapparini L, Francalanci P, Loizzo AL, Tartaglia M, Cestra G, Bertini E

Title

Biallelic mutations in RNF220 cause laminopathies featuring leukodystrophy, ataxia and deafness.

Journal

Brain 144:3020-3035 (2021)
DOI:10.1093/brain/awab185

Reference

PMID:34403372 (HLD24)

Authors

Segawa K, Kikuchi A, Noji T, Sugiura Y, Hiraga K, Suzuki C, Haginoya K, Kobayashi Y, Matsunaga M, Ochiai Y, Yamada K, Nishimura T, Iwasawa S, Shoji W, Sugihara F, Nishino K, Kosako H, Ikawa M, Uchiyama Y, Suematsu M, Ishikita H, Kure S, Nagata S

Title

A sublethal ATP11A mutation associated with neurological deterioration causes aberrant phosphatidylcholine flipping in plasma membranes.

Journal

J Clin Invest 131:148005 (2021)
DOI:10.1172/JCI148005

Reference

PMID:35455965 (HLD25)

Authors

Yan H, Yang S, Hou Y, Ali S, Escobar A, Gao K, Duan R, Kubisiak T, Wang J, Zhang Y, Xiao J, Jiang Y, Zhang T, Wu Y, Burmeister M, Wang Q, Cuajungco MP, Wang J

Title

Functional Study of TMEM163 Gene Variants Associated with Hypomyelination Leukodystrophy.

Journal

Cells 11:cells11081285 (2022)
DOI:10.3390/cells11081285

Reference

PMID:35325049 (HLD26)

Authors

Guasto A, Dubail J, Aguilera-Albesa S, Paganini C, Vanhulle C, Haouari W, Gorria-Redondo N, Aznal-Sainz E, Boddaert N, Planas-Serra L, Schluter A, Velez-Santamaria V, Verdura E, Bruneel A, Rossi A, Huber C, Pujol A, Cormier-Daire V

Title

Biallelic variants in SLC35B2 cause a novel chondrodysplasia with hypomyelinating leukodystrophy.

Journal

Brain 145:3711-3722 (2022)
DOI:10.1093/brain/awac110

Reference

PMID:28051070 (HLD27)

Authors

Kara B, Koroglu C, Peltonen K, Steinberg RC, Maras Genc H, Holtta-Vuori M, Guven A, Kanerva K, Kotil T, Solakoglu S, Zhou Y, Olkkonen VM, Ikonen E, Laiho M, Tolun A

Title

Severe neurodegenerative disease in brothers with homozygous mutation in POLR1A.

Journal

Eur J Hum Genet 25:315-323 (2017)
DOI:10.1038/ejhg.2016.183

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Disease (27)   
   OMIM (27)   
Gene (54)   
   KEGG ORTHOLOGY (27)   
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