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
nt06541 Cytoskeleton in neurons
H00679 Hypomyelinating leukodystrophy
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
DOPA-responsive dystonia (DRD) [DS:H02557] Episodic kinesigenic dyskinesia (EKD) Childhood-onset dystonia with optic atrophy and basal ganglia abnormalities (DYTOABG)
Description
Dystonias are a heterogeneous group of hyperkinetic movement disorders characterized by involuntary sustained muscle contractions that lead to abnormal postures and repetitive movements. Presently, 30 distinct monogenic primary dystonias have been recognized. They can be divided into Primary torsion dystonias (PTDs), dystonia-plus syndromes without brain degeneration, dystonia-parkinsonism with brain degeneration (i.e. DYT3), and paroxysmal dyskinesias.
Category
Nervous system disease
Brite
Human diseases in ICD-11 classification [BR:br08403]
08 Diseases of the nervous system
Movement disorders
8A02 Dystonic disorders
H00831 Primary dystonia
Pathway-based classification of diseases [BR:br08402]
Cellular process
nt06515 Regulation of kinetochore-microtubule interactions
H00831 Primary dystonia
nt06532 Autophagy
H00831 Primary dystonia
nt06535 Efferocytosis
H00831 Primary dystonia
nt06539 Cytoskeleton in muscle cells
H00831 Primary dystonia
nt06541 Cytoskeleton in neurons
H00831 Primary dystonia
Makino S, Kaji R, Ando S, Tomizawa M, Yasuno K, Goto S, Matsumoto S, Tabuena MD, Maranon E, Dantes M, Lee LV, Ogasawara K, Tooyama I, Akatsu H, Nishimura M, Tamiya G
Title
Reduced neuron-specific expression of the TAF1 gene is associated with X-linked dystonia-parkinsonism.
Hersheson J, Mencacci NE, Davis M, MacDonald N, Trabzuni D, Ryten M, Pittman A, Paudel R, Kara E, Fawcett K, Plagnol V, Bhatia KP, Medlar AJ, Stanescu HC, Hardy J, Kleta R, Wood NW, Houlden H
Title
Mutations in the autoregulatory domain of beta-tubulin 4a cause hereditary dystonia.
Zimprich A, Grabowski M, Asmus F, Naumann M, Berg D, Bertram M, Scheidtmann K, Kern P, Winkelmann J, Muller-Myhsok B, Riedel L, Bauer M, Muller T, Castro M, Meitinger T, Strom TM, Gasser T
Title
Mutations in the gene encoding epsilon-sarcoglycan cause myoclonus-dystonia syndrome.
de Carvalho Aguiar P, Sweadner KJ, Penniston JT, Zaremba J, Liu L, Caton M, Linazasoro G, Borg M, Tijssen MA, Bressman SB, Dobyns WB, Brashear A, Ozelius LJ
Title
Mutations in the Na+/K+ -ATPase alpha3 gene ATP1A3 are associated with rapid-onset dystonia parkinsonism.
Charlesworth G, Plagnol V, Holmstrom KM, Bras J, Sheerin UM, Preza E, Rubio-Agusti I, Ryten M, Schneider SA, Stamelou M, Trabzuni D, Abramov AY, Bhatia KP, Wood NW
Title
Mutations in ANO3 cause dominant craniocervical dystonia: ion channel implicated in pathogenesis.
Fuchs T, Saunders-Pullman R, Masuho I, Luciano MS, Raymond D, Factor S, Lang AE, Liang TW, Trosch RM, White S, Ainehsazan E, Herve D, Sharma N, Ehrlich ME, Martemyanov KA, Bressman SB, Ozelius LJ
Meyer E, Carss KJ, Rankin J, Nichols JM, Grozeva D, Joseph AP, Mencacci NE, Papandreou A, Ng J, Barral S, Ngoh A, Ben-Pazi H, Willemsen MA, Arkadir D, Barnicoat A, Bergman H, Bhate S, Boys A, Darin N, Foulds N, Gutowski N, Hills A, Houlden H, Hurst JA, Israel Z, Kaminska M, Limousin P, Lumsden D, McKee S, Misra S, Mohammed SS, Nakou V, Nicolai J, Nilsson M, Pall H, Peall KJ, Peters GB, Prabhakar P, Reuter MS, Rump P, Segel R, Sinnema M, Smith M, Turnpenny P, White SM, Wieczorek D, Wiethoff S, Wilson BT, Winter G, Wragg C, Pope S, Heales SJ, Morrogh D, Pittman A, Carr LJ, Perez-Duenas B, Lin JP, Reis A, Gahl WA, Toro C, Bhatia KP, Wood NW, Kamsteeg EJ, Chong WK, Gissen P, Topf M, Dale RC, Chubb JR, Raymond FL, Kurian MA
Title
Mutations in the histone methyltransferase gene KMT2B cause complex early-onset dystonia.
Monfrini E, Cogiamanian F, Salani S, Straniero L, Fagiolari G, Garbellini M, Carsana E, Borellini L, Biella F, Moggio M, Bresolin N, Corti S, Duga S, Comi GP, Aureli M, Di Fonzo A
Title
A Novel Homozygous VPS11 Variant May Cause Generalized Dystonia.
Sleiman S, Marshall AE, Dong X, Mhanni A, Alidou-D'Anjou I, Frosk P, Marin SE, Stark Z, Del Bigio MR, McBride A, Sadedin S, Gallacher L, Christodoulou J, Boycott KM, Dragon F, Kernohan KD
Title
Compound heterozygous variants in SHQ1 are associated with a spectrum of neurological features, including early-onset dystonia.
Harrer P, Schalk A, Shimura M, Baer S, Calmels N, Spitz MA, Warde MA, Schaefer E, Kittke VMS, Dincer Y, Wagner M, Dzinovic I, Berutti R, Sato T, Shirakawa T, Okazaki Y, Murayama K, Oexle K, Prokisch H, Mall V, Melcak I, Winkelmann J, Zech M
Title
Recessive NUP54 Variants Underlie Early-Onset Dystonia with Striatal Lesions.
