Details of Disease

General Information of Disease (ID: DISVY1TT)

• Disease Name: Leukodystrophy
• Synonyms: leukodystrophy, hypomyelinating; hypomyelinating leukoencephalopathy; HLD; hypomyelinating leukodystrophy
• Disease Class: 8A44: Leukodystrophy
• Definition: Leukodystrophies are a group of rare, progressive, metabolic, genetic diseases that affect the brain, spinal cord and often the peripheral nerves. Each type of leukodystrophy is caused by a specific gene abnormality that leads to abnormal development or destruction of the white matter (myelin sheath) of the brain. The myelin sheath is the protective covering of the nerve and nerves can't function normally without it. Each type of leukodystrophy affects a different part of the myelin sheath, leading to a range of neurological problems.|Editor note: At this time DO has two classes 'hypomyelinating leukodystrophy' and one 'leukodystrophy'
• Disease Hierarchy:
  DISPN7D2: Inherited neurodegenerative disorder
  DISVY1TT: Leukodystrophy
• ICD Code:
  ICD-11: ICD-11: 8A44
  Expand ICD-11: '8A44
• Disease Identifiers:
  MONDO ID: MONDO_0019046
  UMLS CUI: C0023520
  MedGen ID: 6070
  HPO ID: HP:0002415
  Orphanet ID: 68356
  SNOMED CT ID: 192781003

Drug-Interaction Atlas (DIA) of This Disease

This Disease is Treated as An Indication in 1 Investigative Drug(s)

Drug Name	Drug ID	Highest Status	Drug Type	REF
HGT-2610	DMZZG8W	Investigative	NA	[1]

Molecular Interaction Atlas (MIA) of This Disease

This Disease Is Related to 55 DOT Molecule(s)

Gene Name	DOT ID	Evidence Level	Mode of Inheritance	REF
VPS18	OTP16WIW	No Known	Unknown	[2]
AIMP1	OTTA5C3U	Limited	Genetic Variation	[22]
ARHGEF2	OTBQTFRT	Limited	Genetic Variation	[23]
BOLA3	OTDEDY0S	Limited	Biomarker	[24]
CSH1	OT33HTRR	Limited	Genetic Variation	[25]
CSH2	OTW8JVAN	Limited	Genetic Variation	[25]
DARS1	OT0WGC2T	Limited	Genetic Variation	[26]
ERCC8	OT0T4WKI	Limited	Genetic Variation	[25]
HEPACAM	OT1MJ51D	Limited	Biomarker	[27]
ISCA2	OTKQKNTC	Limited	Biomarker	[28]
NDUFV1	OTEVK4WW	Limited	Biomarker	[29]
PLP1	OT8CM9CX	Limited	Genetic Variation	[30]
RNASET2	OTWY64L7	Limited	Biomarker	[31]
SCO2	OTJQQDRS	Limited	Genetic Variation	[32]
SDHA	OTOJ8QFF	Limited	Genetic Variation	[33]
SLC2A4RG	OTW3LX8D	Limited	Genetic Variation	[23]
SOX10	OTF25ULQ	Limited	Genetic Variation	[34]
SURF1	OTAINRSS	Limited	Genetic Variation	[35]
ACER3	OTIVQBG5	moderate	Genetic Variation	[36]
ACOX1	OTM0A0DY	moderate	Biomarker	[37]
COL4A1	OTL6D1YE	moderate	Genetic Variation	[38]
COX10	OTCYIS0L	moderate	Genetic Variation	[39]
EIF2B5	OTV3R4RB	moderate	Biomarker	[40]
LMNB2	OTXRDUOS	moderate	Genetic Variation	[41]
POLR1A	OTDWI0TG	moderate	Biomarker	[42]
PYCR2	OTS2HLGD	moderate	Genetic Variation	[43]
TMEM106B	OTUWA6NW	moderate	Genetic Variation	[44]
AARS2	OTOB0KSG	Strong	Biomarker	[45]
ACOT12	OTN4RQK8	Strong	Biomarker	[40]
ATP5F1E	OTMPLAIS	Strong	Genetic Variation	[46]
ATRN	OTTCLOPV	Strong	Biomarker	[47]
CDSN	OTQW4HV6	Strong	Genetic Variation	[48]
COA8	OTOM9C4A	Strong	Genetic Variation	[49]
DARS2	OTVPFTBG	Strong	Biomarker	[50]
DEGS1	OT4WXPKW	Strong	Biomarker	[51]
FA2H	OT8HA13U	Strong	Biomarker	[52]
GBE1	OTK2N05B	Strong	Biomarker	[53]
GPM6B	OT8Q1582	Strong	Genetic Variation	[54]
IBA57	OT9SPG2X	Strong	Genetic Variation	[55]
ISCA1	OTU230MC	Strong	Genetic Variation	[56]
KARS1	OT0EU4SV	Strong	Genetic Variation	[12]
LGALS14	OTOR23GX	Strong	Biomarker	[27]
LMNB1	OT100T3P	Strong	Genetic Variation	[57]
MLC1	OTCNZLSP	Strong	Genetic Variation	[16]
MPV17	OT579DMU	Strong	Genetic Variation	[58]
NFU1	OTL58QZS	Strong	Genetic Variation	[59]
NKX6-2	OT7FI94W	Strong	Genetic Variation	[60]
POLR1C	OT7DVQB0	Strong	Genetic Variation	[61]
RARS1	OTHPZ6JN	Strong	Biomarker	[62]
RMND1	OT7I6RBT	Strong	Genetic Variation	[63]
SDHB	OTRE1M1T	Strong	Genetic Variation	[64]
SLURP1	OT89YD2E	Strong	Genetic Variation	[12]
TMEM63A	OTIUZ0C7	Strong	Biomarker	[65]
TREX1	OTQG7K12	Strong	Genetic Variation	[66]
TSEN54	OT7MR9LY	Strong	Genetic Variation	[67]

This Disease Is Related to 18 DTT Molecule(s)

Gene Name	DTT ID	Evidence Level	Mode of Inheritance	REF
ASPA	TT6TLZP	Limited	Genetic Variation	[3]
DAG1	TT4X7PG	Limited	Genetic Variation	[4]
GJC2	TTPOCAL	Limited	Genetic Variation	[5]
HSPD1	TT9HL5R	Limited	Genetic Variation	[6]
CLCN2	TT30NW6	moderate	Altered Expression	[7]
HSD17B4	TTL1WGS	moderate	Biomarker	[8]
ARSA	TTYQANR	Strong	Biomarker	[9]
CPS1	TT42M75	Strong	Genetic Variation	[10]
CSF1R	TT7MRDV	Strong	Genetic Variation	[11]
DCPS	TTLSW9V	Strong	Genetic Variation	[12]
EIF2AK4	TT9U4EP	Strong	Biomarker	[13]
GALC	TT5IZRB	Strong	Genetic Variation	[14]
GFAP	TTI6FFX	Strong	Genetic Variation	[15]
KIF5A	TTCJPAH	Strong	Genetic Variation	[16]
MAG	TT9XFON	Strong	Biomarker	[17]
MOG	TTQAFX5	Strong	Biomarker	[18]
PDXP	TT9UYG4	Strong	Genetic Variation	[19]
PRDX5	TTLPJWH	Strong	Genetic Variation	[19]

This Disease Is Related to 2 DTP Molecule(s)

Gene Name	DTP ID	Evidence Level	Mode of Inheritance	REF
SLC16A2	DTQ8MP1	Limited	Genetic Variation	[20]
SLC27A6	DTG4CWJ	moderate	Genetic Variation	[21]

References

• [1] The ChEMBL database in 2017. Nucleic Acids Res. 2017 Jan 4;45(D1):D945-D954.
• [2] Ablation of vacuole protein sorting 18 (Vps18) gene leads to neurodegeneration and impaired neuronal migration by disrupting multiple vesicle transport pathways to lysosomes. J Biol Chem. 2012 Sep 21;287(39):32861-73. doi: 10.1074/jbc.M112.384305. Epub 2012 Aug 1.
• [3] N-acetylaspartate supports the energetic demands of developmental myelination via oligodendroglial aspartoacylase.Neurobiol Dis. 2016 Dec;96:323-334. doi: 10.1016/j.nbd.2016.10.001. Epub 2016 Oct 4.
• [4] A dystroglycan mutation (p.Cys667Phe) associated to muscle-eye-brain disease with multicystic leucodystrophy results in ER-retention of the mutant protein.Hum Mutat. 2018 Feb;39(2):266-280. doi: 10.1002/humu.23370. Epub 2017 Dec 7.
• [5] Diseases of connexins expressed in myelinating glia.Neurosci Lett. 2019 Mar 16;695:91-99. doi: 10.1016/j.neulet.2017.05.037. Epub 2017 May 23.
• [6] Hypomyelinating Leukodystrophy due to HSPD1 Mutations: A New Patient.Neuropediatrics. 2016 Oct;47(5):332-5. doi: 10.1055/s-0036-1584564. Epub 2016 Jul 12.
• [7] Drosophila ClC-a is required in glia of the stem cell niche for proper neurogenesis and wiring of neural circuits.Glia. 2019 Dec;67(12):2374-2398. doi: 10.1002/glia.23691. Epub 2019 Sep 3.
• [8] Clinical consequences of defects in peroxisomal beta-oxidation.Biochem Soc Trans. 2001 May;29(Pt 2):298-305. doi: 10.1042/0300-5127:0290298.
• [9] Gene therapy for metachromatic leukodystrophy.J Neurosci Res. 2016 Nov;94(11):1169-79. doi: 10.1002/jnr.23792.
• [10] Two novel CPS1 mutations in a case of carbamoyl phosphate synthetase 1 deficiency causing hyperammonemia and leukodystrophy.J Clin Lab Anal. 2018 Jun;32(5):e22375. doi: 10.1002/jcla.22375. Epub 2018 Jan 4.
• [11] Phenotypic impacts of CSF1R deficiencies in humans and model organisms.J Leukoc Biol. 2020 Feb;107(2):205-219. doi: 10.1002/JLB.MR0519-143R. Epub 2019 Jul 22.
• [12] Biallelic KARS pathogenic variants cause an early-onset progressive leukodystrophy.Brain. 2019 Mar 1;142(3):560-573. doi: 10.1093/brain/awz001.
• [13] General control nonderepressible 2 (GCN2) kinase protects oligodendrocytes and white matter during branched-chain amino acid deficiency in mice.J Biol Chem. 2013 Oct 25;288(43):31250-60. doi: 10.1074/jbc.M113.498469. Epub 2013 Sep 9.
• [14] Developmental defects and aberrant accumulation of endogenous psychosine in oligodendrocytes in a murine model of Krabbe disease.Neurobiol Dis. 2018 Dec;120:51-62. doi: 10.1016/j.nbd.2018.08.023. Epub 2018 Aug 31.
• [15] An unusual presentation of late-onset Alexander's disease with slow orthostatic tremor and a novel GFAP variant.Neurocase. 2018 Oct-Dec;24(5-6):266-268. doi: 10.1080/13554794.2019.1580749. Epub 2019 Feb 12.
• [16] Genome sequencing uncovers phenocopies in primary progressive multiple sclerosis.Ann Neurol. 2018 Jul;84(1):51-63. doi: 10.1002/ana.25263. Epub 2018 Jul 3.
• [17] Myelin-associated glycoprotein is altered in a familial late-onset orthochromatic leukodystrophy.Brain Pathol. 2005 Apr;15(2):116-23. doi: 10.1111/j.1750-3639.2005.tb00506.x.
• [18] Myelin oligodendrocyte glycoprotein and aquaporin-4 antibodies are highly specific in children with acquired demyelinating syndromes.Dev Med Child Neurol. 2018 Sep;60(9):958-962. doi: 10.1111/dmcn.13703. Epub 2018 Feb 22.
• [19] Pelizaeus-Merzbacher disease.J Neuropathol Exp Neurol. 2002 Sep;61(9):747-59. doi: 10.1093/jnen/61.9.747.
• [20] Clinical and endocrine features of two Allan-Herndon-Dudley syndrome patients with monocarboxylate transporter 8 mutations.Horm Res Paediatr. 2015;83(4):288-92. doi: 10.1159/000371466. Epub 2015 Apr 15.
• [21] Neurodegeneration in a Drosophila model of adrenoleukodystrophy: the roles of the Bubblegum and Double bubble acyl-CoA synthetases.Dis Model Mech. 2016 Apr;9(4):377-87. doi: 10.1242/dmm.022244. Epub 2016 Feb 18.
• [22] Pathogenic variants in AIMP1 cause pontocerebellar hypoplasia.Neurogenetics. 2019 May;20(2):103-108. doi: 10.1007/s10048-019-00572-7. Epub 2019 Mar 28.
• [23] Evaluation of the endoplasmic reticulum-stress response in eIF2B-mutated lymphocytes and lymphoblasts from CACH/VWM patients.BMC Neurol. 2010 Oct 19;10:94. doi: 10.1186/1471-2377-10-94.
• [24] Imaging phenotype of multiple mitochondrial dysfunction syndrome 2, a rare BOLA3-associated leukodystrophy.Am J Med Genet A. 2018 Dec;176(12):2787-2790. doi: 10.1002/ajmg.a.40490. Epub 2018 Oct 10.
• [25] A possible cranio-oro-facial phenotype in Cockayne syndrome.Orphanet J Rare Dis. 2013 Jan 14;8:9. doi: 10.1186/1750-1172-8-9.
• [26] Expression Pattern of the Aspartyl-tRNA Synthetase DARS in the Human Brain.Front Mol Neurosci. 2018 Mar 20;11:81. doi: 10.3389/fnmol.2018.00081. eCollection 2018.
• [27] Leukoencephalopathy-causing CLCN2 mutations are associated with impaired Cl(-) channel function and trafficking.J Physiol. 2017 Nov 15;595(22):6993-7008. doi: 10.1113/JP275087. Epub 2017 Oct 9.
• [28] Further delineation of the phenotypic spectrum ofISCA2 defect: A report of ten new cases.Eur J Paediatr Neurol. 2018 Jan;22(1):46-55. doi: 10.1016/j.ejpn.2017.10.003. Epub 2017 Oct 16.
• [29] Cystic Leucoencephalopathy in NDUFV1 Mutation.Indian J Pediatr. 2018 Dec;85(12):1128-1131. doi: 10.1007/s12098-018-2721-1. Epub 2018 Jun 9.
• [30] The wmN1 Enhancer Region of the Mouse Myelin Proteolipid Protein Gene (mPlp1) is Indispensable for Expression of an mPlp1-lacZ Transgene in Both the CNS and PNS.Neurochem Res. 2020 Mar;45(3):663-671. doi: 10.1007/s11064-019-02919-w. Epub 2019 Nov 28.
• [31] RNASET2-deficient leukoencephalopathy mimicking congenital CMV infection and Aicardi-Goutieres syndrome: a case report with a novel pathogenic variant.Orphanet J Rare Dis. 2019 Jul 26;14(1):184. doi: 10.1186/s13023-019-1155-9.
• [32] Disorders of nuclear-mitochondrial intergenomic signaling.Gene. 2005 Jul 18;354:162-8. doi: 10.1016/j.gene.2005.03.025.
• [33] SDHA mutations causing a multisystem mitochondrial disease: novel mutations and genetic overlap with hereditary tumors.Eur J Hum Genet. 2015 Feb;23(2):202-9. doi: 10.1038/ejhg.2014.80. Epub 2014 Apr 30.
• [34] Waardenburg syndrome type 4: report of two new cases caused by SOX10 mutations in Spain.Am J Med Genet A. 2014 Feb;164A(2):542-7. doi: 10.1002/ajmg.a.36302. Epub 2013 Dec 5.
• [35] SURF-1 gene mutation associated with leukoencephalopathy in a 2-year-old.J Child Neurol. 2009 Oct;24(10):1296-301. doi: 10.1177/0883073809333543.
• [36] Deficiency of the alkaline ceramidase ACER3 manifests in early childhood by progressive leukodystrophy. J Med Genet. 2016 Jun;53(6):389-96. doi: 10.1136/jmedgenet-2015-103457. Epub 2016 Jan 20.
• [37] A microglial cell model for acyl-CoA oxidase 1 deficiency.Biochim Biophys Acta Mol Cell Biol Lipids. 2019 Apr;1864(4):567-576. doi: 10.1016/j.bbalip.2018.10.005. Epub 2018 Oct 10.
• [38] Hereditary cerebral small vessel disease and stroke.Clin Neurol Neurosurg. 2017 Apr;155:45-57. doi: 10.1016/j.clineuro.2017.02.015. Epub 2017 Feb 22.
• [39] Mutations in COX10 result in a defect in mitochondrial heme A biosynthesis and account for multiple, early-onset clinical phenotypes associated with isolated COX deficiency.Hum Mol Genet. 2003 Oct 15;12(20):2693-702. doi: 10.1093/hmg/ddg284. Epub 2003 Aug 19.
• [40] Eukaryotic initiation factor 2B (eIF2B) GEF activity as a diagnostic tool for EIF2B-related disorders.PLoS One. 2009 Dec 15;4(12):e8318. doi: 10.1371/journal.pone.0008318.
• [41] "Laminopathies": a wide spectrum of human diseases.Exp Cell Res. 2007 Jun 10;313(10):2121-33. doi: 10.1016/j.yexcr.2007.03.028. Epub 2007 Mar 30.
• [42] Severe neurodegenerative disease in brothers with homozygous mutation in POLR1A.Eur J Hum Genet. 2017 Feb;25(3):315-323. doi: 10.1038/ejhg.2016.183. Epub 2017 Jan 4.
• [43] Homozygous variants in pyrroline-5-carboxylate reductase 2 (PYCR2) in patients with progressive microcephaly and hypomyelinating leukodystrophy. Am J Med Genet A. 2017 Feb;173(2):460-470. doi: 10.1002/ajmg.a.38049. Epub 2016 Nov 11.
• [44] A recurrent de novo mutation in TMEM106B causes hypomyelinating leukodystrophy.Brain. 2017 Dec 1;140(12):3105-3111. doi: 10.1093/brain/awx314.
• [45] Mitochondrial aminoacyl-tRNA synthetase disorders: an emerging group of developmental disorders of myelination.J Neurodev Disord. 2019 Dec 16;11(1):29. doi: 10.1186/s11689-019-9292-y.
• [46] A previously undescribed leukodystrophy in Leigh syndrome associated with T9176C mutation of the mitochondrial ATPase 6 gene.Dev Med Child Neurol. 2007 Jan;49(1):65-7. doi: 10.1017/s0012162207000163.x.
• [47] Hypomyelinating leukodystrophy associated with a deleterious mutation in the ATRN gene.Neurogenetics. 2017 Jul;18(3):135-139. doi: 10.1007/s10048-017-0515-7. Epub 2017 May 10.
• [48] Mutation of the iron-sulfur cluster assembly gene IBA57 causes fatal infantile leukodystrophy.J Inherit Metab Dis. 2015 Nov;38(6):1147-53. doi: 10.1007/s10545-015-9857-1. Epub 2015 May 14.
• [49] Cavitating Leukoencephalopathy With Posterior Predominance Caused by a Deletion in the APOPT1 Gene in an Indian Boy.J Child Neurol. 2018 May;33(6):428-431. doi: 10.1177/0883073818760875. Epub 2018 Mar 26.
• [50] In vivocharacterization of the aspartyl-tRNA synthetase DARS: Homing in on the leukodystrophy HBSL.Neurobiol Dis. 2017 Jan;97(Pt A):24-35. doi: 10.1016/j.nbd.2016.10.008. Epub 2016 Nov 2.
• [51] Loss of the sphingolipid desaturase DEGS1 causes hypomyelinating leukodystrophy. J Clin Invest. 2019 Mar 1;129(3):1240-1256. doi: 10.1172/JCI123959. Epub 2019 Feb 11.
• [52] FAHN/SPG35: a narrow phenotypic spectrum across disease classifications.Brain. 2019 Jun 1;142(6):1561-1572. doi: 10.1093/brain/awz102.
• [53] Acute but transient neurological deterioration revealing adult polyglucosan body disease.J Neurol Sci. 2013 Jan 15;324(1-2):179-82. doi: 10.1016/j.jns.2012.10.015. Epub 2012 Nov 10.
• [54] PLP1 and GPM6B intragenic copy number analysis by MAPH in 262 patients with hypomyelinating leukodystrophies: Identification of one partial triplication and two partial deletions of PLP1.Neurogenetics. 2006 Mar;7(1):31-7. doi: 10.1007/s10048-005-0021-1. Epub 2006 Jan 17.
• [55] Expanding the phenotype of IBA57 mutations: related leukodystrophy can remain asymptomatic.J Hum Genet. 2018 Dec;63(12):1223-1229. doi: 10.1038/s10038-018-0516-x. Epub 2018 Sep 27.
• [56] ISCA1 mutation in a patient with infantile-onset leukodystrophy causes defects in mitochondrial [4Fe-4S] proteins.Hum Mol Genet. 2018 Aug 1;27(15):2739-2754. doi: 10.1093/hmg/ddy183.
• [57] Glucose metabolism in the brain in LMNB1-related autosomal dominant leukodystrophy.Acta Neurol Scand. 2019 Feb;139(2):135-142. doi: 10.1111/ane.13024. Epub 2018 Sep 25.
• [58] Lethal hepatopathy and leukodystrophy caused by a novel mutation in MPV17 gene: description of an alternative MPV17 spliced form.Mol Genet Metab. 2008 Jun;94(2):234-9. doi: 10.1016/j.ymgme.2008.01.012. Epub 2008 Mar 10.
• [59] Novel NFU1 Variants Induced MMDS Behaved as Special Leukodystrophy in Chinese Sufferers.J Mol Neurosci. 2017 Jun;62(2):255-261. doi: 10.1007/s12031-017-0927-8. Epub 2017 May 3.
• [60] Genetic and phenotypic characterization of NKX6-2-related spastic ataxia and hypomyelination.Eur J Neurol. 2020 Feb;27(2):334-342. doi: 10.1111/ene.14082. Epub 2019 Oct 17.
• [61] Novel POLR1C mutation in RNA polymerase III-related leukodystrophy with severe myoclonus and dystonia.Mol Genet Genomic Med. 2019 Sep;7(9):e914. doi: 10.1002/mgg3.914. Epub 2019 Jul 31.
• [62] RARS1-related hypomyelinating leukodystrophy: Expanding the spectrum.Ann Clin Transl Neurol. 2020 Jan;7(1):83-93. doi: 10.1002/acn3.50960. Epub 2019 Dec 8.
• [63] RMND1-Related Leukoencephalopathy With Temporal Lobe Cysts and Hearing Loss-Another Mendelian Mimicker of Congenital Cytomegalovirus Infection.Pediatr Neurol. 2017 Jan;66:59-62. doi: 10.1016/j.pediatrneurol.2016.09.003. Epub 2016 Sep 13.
• [64] Mutations in SDHD lead to autosomal recessive encephalomyopathy and isolated mitochondrial complex II deficiency. J Med Genet. 2014 Mar;51(3):170-5. doi: 10.1136/jmedgenet-2013-101932. Epub 2013 Dec 23.
• [65] Heterozygous Variants in the Mechanosensitive Ion Channel TMEM63A Result in Transient Hypomyelination during Infancy.Am J Hum Genet. 2019 Nov 7;105(5):996-1004. doi: 10.1016/j.ajhg.2019.09.011. Epub 2019 Oct 3.
• [66] A homozygote TREX1 mutation in two siblings with different phenotypes: Chilblains and cerebral vasculitis.Eur J Med Genet. 2017 Dec;60(12):690-694. doi: 10.1016/j.ejmg.2017.09.004. Epub 2017 Sep 13.
• [67] TSEN54 missense variant in Standard Schnauzers with leukodystrophy.PLoS Genet. 2019 Oct 4;15(10):e1008411. doi: 10.1371/journal.pgen.1008411. eCollection 2019 Oct.