Details of Disease

General Information of Disease (ID: DISIGZSM)

• Disease Name: Mitochondrial DNA depletion syndrome
• Synonyms: mtDNA depletion syndrome
• Definition: The mitochondrial DNA (mtDNA) depletion syndrome (MDS) is a clinically heterogeneous group of mitochondrial disorders characterized by a reduction of the mtDNA copy number in affected tissues without mutations or rearrangements in the mtDNA. MDS is phenotypically heterogeneous, and can affect a specific organ or a combination of organs, with the main presentations described being either hepatocerebral (i.e. hepatic dysfunction, psychomotor delay), myopathic (i.e. hypotonia, muscle weakness, bulbar weakness), encephalomyopathic (i.e. hypotonia, muscle weakness, psychomotor delay) or neurogastrointestinal (i.e gastrointestinal dysmotility, peripheral neuropathy). Additional phenotypes include fatal infantile lactic acidosis with methylmalonic aciduria, spastic ataxia (early-onset spastic ataxia-neuropathy syndrome), and Alpers syndrome.
• Disease Hierarchy:
  DISK7IP8: Mitochondrial oxidative phosphorylation disorder
  DISIGZSM: Mitochondrial DNA depletion syndrome
• Disease Identifiers:
  MONDO ID: MONDO_0018158
  UMLS CUI: C0342782
  MedGen ID: 452449
  Orphanet ID: 35698
  SNOMED CT ID: 237995002

Molecular Interaction Atlas (MIA) of This Disease

This Disease Is Related to 2 DTT Molecule(s)

Gene Name	DTT ID	Evidence Level	Mode of Inheritance	REF
ACO2	TTMTF2P	Strong	Biomarker	[1]
CS	TTZA6B3	Strong	Biomarker	[2]

This Disease Is Related to 1 DTP Molecule(s)

Gene Name	DTP ID	Evidence Level	Mode of Inheritance	REF
SLC25A21	DT2UQYR	Strong	Biomarker	[3]

This Disease Is Related to 2 DME Molecule(s)

Gene Name	DME ID	Evidence Level	Mode of Inheritance	REF
DTYMK	DEOTVYU	Limited	Autosomal recessive	[4]
DTYMK	DEOTVYU	Strong	Biomarker	[5]

This Disease Is Related to 17 DOT Molecule(s)

Gene Name	DOT ID	Evidence Level	Mode of Inheritance	REF
DTYMK	OTJXYQYK	Limited	Autosomal recessive	[4]
FBXL4	OTZECCIQ	Disputed	Genetic Variation	[6]
DGUOK	OT78HUZB	moderate	Genetic Variation	[7]
MPV17	OT579DMU	moderate	Genetic Variation	[8]
POLG2	OTDBMZJB	Moderate	Semidominant	[9]
CHMP1B	OTP715L8	Strong	Genetic Variation	[10]
DGKB	OTTT9SZJ	Strong	Genetic Variation	[11]
DGKE	OTWS86AS	Strong	Genetic Variation	[11]
POLG	OTDUCT04	Strong	Genetic Variation	[12]
PPA2	OTRKV8WW	Strong	Genetic Variation	[13]
RRM2B	OTE8GBUR	Strong	Genetic Variation	[14]
SUCLA2	OTMZD4PW	Strong	Altered Expression	[15]
TFAM	OTXXV5V7	Strong	Genetic Variation	[16]
TK2	OTS1V4XB	Strong	Genetic Variation	[17]
TOMM20	OT76TPR2	Strong	Biomarker	[18]
TRMU	OTJ1KXM7	Strong	Biomarker	[19]
SUCLG1	OTDCSPXH	Definitive	Genetic Variation	[20]

References

• [1] Functional cellular analyses reveal energy metabolism defect and mitochondrial DNA depletion in a case of mitochondrial aconitase deficiency.Mol Genet Metab. 2016 May;118(1):28-34. doi: 10.1016/j.ymgme.2016.03.004. Epub 2016 Mar 8.
• [2] Mitochondrial DNA depletion syndrome: new descriptions and the use of citrate synthase as a helpful tool to better characterise the patients.Mol Genet Metab. 2012 Nov;107(3):409-15. doi: 10.1016/j.ymgme.2012.08.018. Epub 2012 Aug 31.
• [3] Correction: Mitochondrial oxodicarboxylate carrier deficiency is associated with mitochondrial DNA depletion and spinal muscular atrophy-like disease.Genet Med. 2019 Sep;21(9):2163-2164. doi: 10.1038/s41436-019-0506-1.
• [4] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [5] Deoxythymidylate kinase, DTYMK, is a novel gene for mitochondrial DNA depletion syndrome. Clin Chim Acta. 2019 Sep;496:93-99. doi: 10.1016/j.cca.2019.06.028. Epub 2019 Jul 2.
• [6] Characterization of the C584R variant in the mtDNA depletion syndrome gene FBXL4, reveals a novel role for FBXL4 as a regulator of mitochondrial fusion.Biochim Biophys Acta Mol Basis Dis. 2019 Nov 1;1865(11):165536. doi: 10.1016/j.bbadis.2019.165536. Epub 2019 Aug 20.
• [7] A fatal case of mitochondrial DNA depletion syndrome with novel compound heterozygous variants in the deoxyguanosine kinase gene.Oncotarget. 2017 Sep 15;8(48):84309-84319. doi: 10.18632/oncotarget.20905. eCollection 2017 Oct 13.
• [8] A defect in the mitochondrial protein Mpv17 underlies the transparent casper zebrafish.Dev Biol. 2017 Oct 1;430(1):11-17. doi: 10.1016/j.ydbio.2017.07.017. Epub 2017 Jul 28.
• [9] Whole exome sequencing identifies a homozygous POLG2 missense variant in an infant with fulminant hepatic failure and mitochondrial DNA depletion. Eur J Med Genet. 2016 Oct;59(10):540-5. doi: 10.1016/j.ejmg.2016.08.012. Epub 2016 Aug 31.
• [10] Twinkle-Associated Mitochondrial DNA Depletion.Pediatr Neurol. 2019 Jan;90:61-65. doi: 10.1016/j.pediatrneurol.2018.08.007. Epub 2018 Aug 9.
• [11] New DGK gene mutations in the hepatocerebral form of mitochondrial DNA depletion syndrome.Arch Neurol. 2005 May;62(5):745-7. doi: 10.1001/archneur.62.5.745.
• [12] Common genetic etiology between "multiple sclerosis-like" single-gene disorders and familial multiple sclerosis.Hum Genet. 2017 Jun;136(6):705-714. doi: 10.1007/s00439-017-1784-9. Epub 2017 Mar 23.
• [13] Human mitochondrial pyrophosphatase: cDNA cloning and analysis of the gene in patients with mtDNA depletion syndromes.Genomics. 2006 Mar;87(3):410-6. doi: 10.1016/j.ygeno.2005.09.017. Epub 2005 Nov 21.
• [14] The natural history of infantile mitochondrial DNA depletion syndrome due to RRM2B deficiency.Genet Med. 2020 Jan;22(1):199-209. doi: 10.1038/s41436-019-0613-z. Epub 2019 Aug 29.
• [15] Succinyl-CoA synthetase (SUCLA2) deficiency in two siblings with impaired activity of other mitochondrial oxidative enzymes in skeletal muscle without mitochondrial DNA depletion.Mol Genet Metab. 2017 Mar;120(3):213-222. doi: 10.1016/j.ymgme.2016.11.005. Epub 2016 Nov 12.
• [16] Frequent truncating mutation of TFAM induces mitochondrial DNA depletion and apoptotic resistance in microsatellite-unstable colorectal cancer.Cancer Res. 2011 Apr 15;71(8):2978-87. doi: 10.1158/0008-5472.CAN-10-3482. Epub 2011 Apr 5.
• [17] Clinical application of whole exome sequencing reveals a novel compound heterozygous TK2-mutation in two brothers with rapidly progressive combined muscle-brain atrophy, axonal neuropathy, and status epilepticus.Mitochondrion. 2015 Jan;20:1-6. doi: 10.1016/j.mito.2014.10.007. Epub 2014 Nov 4.
• [18] Acute mental stress induces mitochondrial bioenergetic crisis and hyper-fission along with aberrant mitophagy in the gut mucosa in rodent model of stress-related mucosal disease.Free Radic Biol Med. 2017 Dec;113:424-438. doi: 10.1016/j.freeradbiomed.2017.10.009. Epub 2017 Oct 7.
• [19] L-Cysteine supplementation prevents liver transplantation in a patient with TRMU deficiency.Mol Genet Metab Rep. 2019 Jan 25;19:100453. doi: 10.1016/j.ymgmr.2019.100453. eCollection 2019 Jun.
• [20] Fatal infantile lactic acidosis and a novel homozygous mutation in the SUCLG1 gene: a mitochondrial DNA depletion disorder.Mol Genet Metab. 2011 Feb;102(2):149-52. doi: 10.1016/j.ymgme.2010.10.014. Epub 2010 Oct 30.