title: Mitochondrial DNA depletion syndromes: review and updates of genetic basis, manifestations, and therapeutic options.
abstract: Mitochondrial DNA (mtDNA) depletion syndromes (MDS) are a genetically and clinically heterogeneous group of autosomal recessive disorders that are characterized by a severe reduction in mtDNA content leading to impaired energy production in affected tissues and organs. MDS are due to defects in mtDNA maintenance caused by mutations in nuclear genes that function in either mitochondrial nucleotide synthesis (TK2, SUCLA2, SUCLG1, RRM2B, DGUOK, and TYMP) or mtDNA replication (POLG and C10orf2). MDS are phenotypically heterogeneous and usually classified as myopathic, encephalomyopathic, hepatocerebral or neurogastrointestinal. Myopathic MDS, caused by mutations in TK2, usually present before the age of 2 years with hypotonia and muscle weakness. Encephalomyopathic MDS, caused by mutations in SUCLA2, SUCLG1, or RRM2B, typically present during infancy with hypotonia and pronounced neurological features. Hepatocerebral MDS, caused by mutations in DGUOK, MPV17, POLG, or C10orf2, commonly have an early-onset liver dysfunction and neurological involvement. Finally, TYMP mutations have been associated with mitochondrial neurogastrointestinal encephalopathy (MNGIE) disease that typically presents before the age of 20 years with progressive gastrointestinal dysmotility and peripheral neuropathy. Overall, MDS are severe disorders with poor prognosis in the majority of affected individuals. No efficacious therapy is available for any of these disorders. Affected individuals should have a comprehensive evaluation to assess the degree of involvement of different systems. Treatment is directed mainly toward providing symptomatic management. Nutritional modulation and cofactor supplementation may be beneficial. Liver transplantation remains controversial. Finally, stem cell transplantation in MNGIE disease shows promising results.
authors: Division of Medical Genetics, Department of Pediatrics, The Children's Hospital, King Fahad Medical City and Faculty of Medicine, King Saud bin Abdulaziz University for Health Science, Riyadh, Kingdom of Saudi Arabia.
authors: Ayman W
authors: AW
authors: El-Hattab
authors: Fernando
authors: F
authors: Scaglia
mesh_terms: D004261:DNA Replication / Q000235:genetics / Q000502:physiology; D004272:DNA, Mitochondrial / Q000235:genetics* / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D016031:Liver Transplantation; D028361:Mitochondrial Diseases / Q000235:genetics* / Q000503:physiopathology* / Q000628:therapy; D017237:Mitochondrial Encephalomyopathies / Q000235:genetics / Q000473:pathology / Q000628:therapy; D017240:Mitochondrial Myopathies / Q000235:genetics / Q000473:pathology / Q000628:therapy; D009154:Mutation / Q000235:genetics / Q000502:physiology; D009422:Nervous System Diseases / Q000235:genetics* / Q000503:physiopathology* / Q000628:therapy; D009711:Nucleotides / Q000378:metabolism; D018529:Nutritional Support; D013936:Thymidine / Q000378:metabolism
chemical_list: D004272:DNA, Mitochondrial; D009711:Nucleotides; D013936:Thymidine
references: Neuromuscul Disord. 2009 Nov;19(11):784-7
references: 19736010
references: Nat Genet. 2001 Jul;28(3):211-2
references: 11431686
references: Hum Mutat. 2008 Feb;29(2):330-1
references: 18205204
references: Dev Med Child Neurol. 2012 May;54(5):397-406
references: 22283595
references: Nat Genet. 2006 May;38(5):570-5
references: 16582910
references: J Neurol Sci. 2011 May 15;304(1-2):9-16
references: 21402391
references: Brain. 2007 Nov;130(Pt 11):3032-40
references: 17921179
references: Mol Genet Metab. 2009 Nov;98(3):300-4
references: 19616983
references: Neuromuscul Disord. 2009 Feb;19(2):147-50
references: 19138848
references: Neurology. 2005 Apr 12;64(7):1204-8
references: 15824347
references: Hum Mutat. 2008 Sep;29(9):E150-72
references: 18546365
references: Am J Pathol. 2008 Oct;173(4):1120-8
references: 18787099
references: J Neurol. 2012 May;259(5):862-8
references: 21993618
references: Biochem J. 2007 Mar 1;402(2):377-85
references: 17073823
references: J Hepatol. 1999 Jan;30(1):149-55
references: 9927162
references: Arch Neurol. 2003 Sep;60(9):1279-84
references: 12975295
references: Neuromuscul Disord. 2008 Apr;18(4):306-9
references: 18396044
references: Am J Hum Genet. 2006 Sep;79(3):544-8
references: 16909392
references: Ann Neurol. 2002 Aug;52(2):237-9
references: 12210798
references: Gene. 1997 Jan 31;185(1):147-52
references: 9034326
references: Arch Neurol. 2009 Aug;66(8):1028-32
references: 19667227
references: Neuromuscul Disord. 2010 Mar;20(3):198-203
references: 20083405
references: J Pediatr Gastroenterol Nutr. 2002 Sep;35(3):377-83
references: 12352533
references: J Neurol Neurosurg Psychiatry. 2004 Aug;75(8):1125-8
references: 15258213
references: Hum Mol Genet. 2010 Mar 15;19(6):1098-107
references: 20042463
references: Brain. 2012 Nov;135(Pt 11):3404-15
references: 23043144
references: Gastroenterology. 2006 Mar;130(3):893-901
references: 16530527
references: Mol Genet Metab. 2010 Jan;99(1):53-7
references: 19815440
references: Pediatr Res. 2010 Aug;68(2):151-4
references: 20421844
references: Mol Genet Metab. 2012 Sep;107(1-2):95-103
references: 22608879
references: Pediatr Neurol. 1996 Sep;15(2):153-8
references: 8888051
references: Biosci Rep. 2007 Jun;27(1-3):151-63
references: 17549623
references: Neurology. 2007 May 22;68(21):1872; author reply 1872; discussion 1872-3
references: 17515557
references: Seizure. 2010 Apr;19(3):140-6
references: 20138553
references: Neurologist. 2004 Jan;10(1):8-17
references: 14720311
references: Am J Surg Pathol. 1998 Sep;22(9):1141-7
references: 9737248
references: Arch Neurol. 2005 May;62(5):745-7
references: 15883261
references: Neurology. 2011 Jun 7;76(23):2032-4
references: 21646632
references: Arch Neurol. 2007 Mar;64(3):435-8
references: 17353390
references: Neurology. 2011 Nov 15;77(20):1847-52
references: 22084276
references: Ann Neurol. 2001 Mar;49(3):377-83
references: 11261513
references: Neurology. 2005 Nov 8;65(9):1493-5
references: 16177225
references: J Clin Invest. 2003 Jun;111(12):1913-21
references: 12813027
references: Hum Mol Genet. 2012 Jan 1;21(1):66-75
references: 21937588
references: Ann Neurol. 2002 Aug;52(2):211-9
references: 12210792
references: Seizure. 2012 Jun;21(5):316-21
references: 22459315
references: Am J Med Genet A. 2005 Jun 15;135(3):289-91
references: 15887277
references: AJNR Am J Neuroradiol. 1995 Aug;16(7):1427-33
references: 7484627
references: Neuromuscul Disord. 2010 Jul;20(7):429-37
references: 20444604
references: Mol Genet Metab. 2010 Mar;99(3):300-8
references: 20074988
references: Nat Genet. 2001 Jul;28(3):223-31
references: 11431692
references: J Med Genet. 2004 Feb;41(2):125-9
references: 14757860
references: J Pediatr Gastroenterol Nutr. 2004 Feb;38(2):216-20
references: 14734888
references: J Pediatr. 2007 May;150(5):531-4, 534.e1-6
references: 17452231
references: Nat Genet. 2007 Jun;39(6):776-80
references: 17486094
references: Mitochondrion. 2009 Nov;9(6):438-42
references: 19666145
references: Semin Neurol. 2001 Sep;21(3):309-25
references: 11641821
references: Ann Neurol. 2007 Dec;62(6):579-87
references: 17722119
references: Hepatology. 2007 Oct;46(4):1218-27
references: 17694548
references: Nat Genet. 2001 Nov;29(3):337-41
references: 11687800
references: Proc Natl Acad Sci U S A. 1996 Jul 9;93(14):7258-62
references: 8692979
references: Case Rep Pediatr. 2012;2012:303096
references: 22928142
references: Arch Biochem Biophys. 2002 Feb 15;398(2):160-9
references: 11831846
references: Clin Neuropathol. 1998 Mar-Apr;17(2):63-8
references: 9561326
references: Science. 1999 Jan 29;283(5402):689-92
references: 9924029
references: Am J Hum Genet. 2005 Sep;77(3):430-41
references: 16080118
references: Neurology. 2012 Feb 28;78(9):644-8
references: 22345218
references: Neurology. 1998 Oct;51(4):1086-92
references: 9781534
references: Neuromuscul Disord. 2012 Jul;22(7):587-91
references: 22508010
references: Mol Genet Metab. 2005 Dec;86(4):462-5
references: 16263314
references: Pediatr Transplant. 2000 Aug;4(3):170-2
references: 10933314
references: Brain. 2006 Jul;129(Pt 7):1685-92
references: 16638794
references: Brain. 2007 Mar;130(Pt 3):853-61
references: 17287286
references: J Hepatol. 2005 Aug;43(2):333-41
references: 15964659
references: Am J Hum Genet. 2009 Aug;85(2):290-5
references: 19664747
references: Liver Transpl. 2008 Oct;14(10):1480-5
references: 18825706
references: Mol Genet Metab. 2011 Jul;103(3):262-7
references: 21478040
references: Semin Fetal Neonatal Med. 2011 Aug;16(4):190-6
references: 21652274
references: Neurology. 2006 Oct 24;67(8):1461-3
references: 16971699
references: Brain. 2006 Jul;129(Pt 7):1674-84
references: 16621917
references: J Hepatol. 2009 Jan;50(1):215-21
references: 19012992
references: J Biol Chem. 1997 Mar 28;272(13):8454-8
references: 9079672
references: Am J Hum Genet. 2007 Aug;81(2):383-7
references: 17668387
references: J Neurol. 2008 Sep;255(9):1384-91
references: 18575922
references: Brain. 2005 Apr;128(Pt 4):723-31
references: 15689359
references: Neurology. 2006 Oct 24;67(8):1458-60
references: 16971696
references: Hepatology. 2001 Oct;34(4 Pt 1):776-84
references: 11584375
references: Bone Marrow Transplant. 2011 Mar;46(3):330-337
references: 20436523
references: Neuromuscul Disord. 2008 Jun;18(6):453-9
references: 18504129
references: Acta Neuropathol. 2004 Aug;108(2):168-71
references: 15150663
references: Am J Hum Genet. 2005 Jun;76(6):1081-6
references: 15877282
references: Mol Genet Metab. 2010 Jan;99(1):58-61
references: 19766516
references: Pediatr Neurol. 2006 Mar;34(3):177-85
references: 16504786
references: Muscle Nerve. 1994 May;17(5):509-15
references: 8159181
references: Ann Neurol. 2004 May;55(5):706-12
references: 15122711
references: Arch Neurol. 2006 Aug;63(8):1122-6
references: 16908738
references: Semin Neurol. 2012 Feb;32(1):55-61
references: 22422207
references: J Inherit Metab Dis. 2009 Apr;32(2):143-58
references: 19125351
references: J Neurol Sci. 1994 Jan;121(1):50-6
references: 8133312
references: Biochim Biophys Acta. 2012 May;1820(5):632-6
references: 21855607
references: Ann Neurol. 2002 Sep;52(3):311-7
references: 12205643
references: Muscle Nerve. 2007 Feb;35(2):235-42
references: 17080429
references: Ann Neurol. 1999 Jan;45(1):54-8
references: 9894877
references: Neurology. 2002 Sep 24;59(6):926-9
references: 12297582
references: Neuromuscul Disord. 2008 Jul;18(7):557-60
references: 18508266
references: Mol Genet Metab. 2005 Jan;84(1):75-82
references: 15639197
references: Neuromuscul Disord. 2003 Feb;13(2):133-42
references: 12565911
references: Clin Chem. 2004 Jan;50(1):120-4
references: 14633909
references: Brain. 2007 Mar;130(Pt 3):862-74
references: 17301081
references: Neuropediatrics. 2001 Jun;32(3):150-2
references: 11521212
references: Arch Neurol. 2008 Aug;65(8):1108-13
references: 18695062
references: Arch Dis Child. 2009 Jan;94(1):55-8
references: 19103789
references: Eur J Pediatr. 2010 Feb;169(2):201-5
references: 19526370
references: Arch Neurol. 2006 Aug;63(8):1129-34
references: 16908739
references: Ann Neurol. 1992 Dec;32(6):767-75
references: 1471867
references: Neurology. 1994 Apr;44(4):721-7
references: 8164833
references: J Neurol Sci. 2009 Aug 15;283(1-2):143-8
references: 19268975
references: Brain. 2008 Nov;131(Pt 11):2841-50
references: 18819985
references: J Hepatol. 2006 Jul;45(1):108-16
references: 16545482
references: J Neurol. 2012 Dec;259(12):2699-706
references: 22711161
references: Mitochondrion. 2007 Feb-Apr;7(1-2):6-12
references: 17280874
references: Mol Genet Metab. 2008 Jun;94(2):234-9
references: 18329934
references: Ann Neurol. 2000 Jun;47(6):792-800
references: 10852545
references: Mol Genet Metab. 2009 Aug;97(4):292-6
references: 19520594
references: Proc Natl Acad Sci U S A. 2008 Nov 18;105(46):17801-6
references: 18997010
references: Neurology. 1997 Jul;49(1):239-45
references: 9222196
references: Neuropediatrics. 1995 Oct;26(5):263-6
references: 8552218
references: Gastroenterol Clin Biol. 2005 Aug-Sep;29(8-9):773-8
references: 16294144
references: Am J Hum Genet. 1991 Mar;48(3):492-501
references: 1998336
references: AJNR Am J Neuroradiol. 2012 Mar;33(3):E34-5
references: 21511859