Mitochondrial DNA Depletion Syndrome

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Classification according to ICD-10
G71.3 Mitochondrial myopathy, not elsewhere classified
ICD-10 online (WHO version 2019)

Mitochondrial DNA Depletion Syndrome (MDS) is the clinical picture of a disease in which the number of copies of mitochondrial DNA (mtDNA) in the mitochondria of the cells of the affected tissue is greatly reduced.

If the content of mtDNA is less than 30%, it is called mtDNA depletion. Depending on the tissue affected, this deficiency manifests itself with different signs or in clinically different forms of the syndrome . A number of congenital mitochondriopathies are known to be the primary cause of MDS , in which, however, it is not the mitochondrial DNA but rather the nuclear DNA in the cell nucleus that exhibits mutations at certain gene locations . These genes are located on different chromosomes and code for proteins which are required in the mitochondrion for its DNA replication .

In addition, a reduced content of mtDNA can also be secondary to sporadic inclusion body myositis or iatrogenic as a result of treatment with nucleoside analogs .

pathology

The primary cause of the disease are mutations in genes in the cell nucleus that code for proteins that are required in the mitochondria for replication and the provision of DNA building blocks .

distribution

The frequency is not known, the clinical picture may not be uncommon and occurs in families. An autosomal - recessive inheritance is possible.

Classification

The clinical appearance is inconsistent and dependent on the affected gene and can be tissue-specific or multisystemic. Main characteristics are onset in early childhood, weakness, hypotonia, and developmental delay .

The following forms can be distinguished:

  • hepato-cerebral form , mutations in the DGUOK , MPV17 , POLG , or C10orf2 gene, early onset of liver dysfunction and neurological involvement
  • myopathic form , also benign myopathic form with a later onset , mutations in the TK2 gene, hypotension and muscle weakness in the first two years of life
  • cardiomyopathic form
  • encephalomyopathic form , mutations in the SUCLA2 , SUCLG1 , or RRM2B genes (associated with succinyl-CoA synthetase ), hypotension and neurological abnormalities during childhood
  • neurogastrointestinal form , mitochondrial neurogastrointestinal encephalopathy (MNGIE), mutations in the TYMP gene, increasing gastrointestinal dysfunction and peripheral neuropathy occurring before the age of 20

Clinical manifestations

Clinical criteria are:

Sometimes there is a severe hepatopathy or a disorder of the kidney function renal disorder such as in De Toni Fanconi syndrome . The diagnosis is confirmed by evidence of decreased respiratory chain activity and a low mtDNA / nDNA ratio.

Typing

The following typology is used on the basis of described gene mutations:

  • MTDPS1 , Mitochondrial DNA depletion syndrome 1 ( MNGIE type ), mutations in the TYMP gene on chromosome 22 locus q13.33
  • MTDPS2 , Mitochondrial DNA depletion syndrome 2 (myopathic type), mutations in the TK2 gene on chromosome 16 at q21, which codes for the cell nucleus-encoded deoxythymidine kinase
  • MTDPS3 , Mitochondrial DNA depletion syndrome 3 (hepatocerebral type), mutations in the DGUOK gene on chromosome 2 at p13.1, which codes for the cell nucleus-encoded mitochondrial deoxyguanosine kinase
  • MTDPS4 , Mitochondrial DNA depletion syndrome 4A (Alpers type) and Mitochondrial DNA depletion syndrome 4B (MNGIE type), mutations in the POLG gene on chromosome 15 at q26.1
  • MTDPS5 , Mitochondrial DNA depletion syndrome 5 (encephalomyopathic with or without methylmalonic aciduria), mutations in the SUCLA2 gene on chromosome 13 at q14.2
  • MTDPS6 , Mitochondrial DNA depletion syndrome 6 (hepatocerebral type), mutations in the MPV17 gene on chromosome 2 at p23.3
  • MTDPS7 , Mitochondrial DNA depletion syndrome 7 (hepatocerebral type), mutations in the TWNK gene on chromosome 10 at q24.31
  • MTDPS8 , Mitochondrial DNA depletion syndrome 8A (encephalomyopathic type with renal tubulopathy) and Mitochondrial DNA depletion syndrome 8B (MNGIE type), mutations in the RRM2B gene on chromosome 8 at q22.3
  • MTDPS9 , Mitochondrial DNA depletion syndrome 9 (encephalomyopathic type with methylmalonic aciduria), mutations in the SUCLG1 gene on chromosome 2 at p11.2
  • MTDPS11 , Mitochondrial DNA depletion syndrome 11, mutations in the MGME1 gene on chromosome 20 at p11.23
  • MTDPS12 , Mitochondrial DNA depletion syndrome 12A (cardiomyopathic type), mutations in the SLC25A4 gene on chromosome 4 at q35.1, autosomal dominant and autosomal recessive
  • MTDPS13 , Mitochondrial DNA depletion syndrome 13 (encephalomyopathic type), mutations in the FBXL4 gene on chromosome 6 at q16.1-q16.2
  • MTDPS14 , Mitochondrial DNA depletion syndrome 14 (encephalocardiomyopathic type), mutations in the OPA1 gene on chromosome 3 at q29
  • MTDPS15 , Mitochondrial DNA depletion syndrome 15 (hepatocerebral type), mutations in the TFAM gene on chromosome 15 at q21.1

Prospect of healing

The prognosis is unfavorable, the children usually die in the first few years of life.

history

Mitochondrial DNA Depletion Syndrome was originally described in 1991 by CT Moraes and colleagues as congenital myopathy or hepatopathy.

literature

  • Célia Nogueira, Ligia S Almeida, Claudia Nesti, Ilaria Pezzini, Arnaldo Videira, Laura Vilarinho, Filippo M Santorelli: Syndromes associated with mitochondrial DNA depletion. In: Italian Journal of Pediatrics. Volume 40, 2014, p. 34, doi: 10.1186 / 1824-7288-40-34
  • M. Almannai, H. Dai, AW El-Hattab, LJC Wong: FBXL4-Related Encephalomyopathic Mitochondrial DNA Depletion Syndrome. In: RA Pagon, MP Adam, HH Ardinger, SE Wallace, A. Amemiya, LJH Bean, TD Bird, N. Ledbetter, HC Mefford, RJH Smith, K. Stephens (Eds.): GeneReviews® [Internet]. Seattle (WA). University of Washington, Seattle, Apr 6, 2017. PMID 28383868

Individual evidence

  1. ↑ a b c d e Mitochondrial DNA Depletion Syndrome. In: Orphanet (Rare Disease Database).
  2. ↑ a b Agnès Rötig, Joanna Poulton: Genetic causes of mitochondrial DNA depletion in humans. In: Biochimica et Biophysica Acta - Molecular Basis of Disease. 1792, 2009, p. 1103, doi: 10.1016 / j.bbadis.2009.06.009 .
  3. ↑ AW El-Hattab, F. Scaglia: Mitochondrial DNA depletion syndromes: review and updates of genetic basis, manifestations, and therapeutic options. In: Neurotherapeutics: the journal of the American Society for Experimental NeuroTherapeutics. Volume 10, No. 2, April 2013, pp. 186-198, doi: 10.1007 / s13311-013-0177-6 . PMID 23385875 , PMC 3625391 (free full text) (review).
  4. ↑ MITOCHONDRIAL DNA DEPLETION SYNDROME 1 (MNGIE TYPE); MTDPS1.  In: Online Mendelian Inheritance in Man . (English)
  5. ↑ MITOCHONDRIAL DNA DEPLETION SYNDROME 2 (MYOPATHIC TYPE); MTDPS2.  In: Online Mendelian Inheritance in Man . (English)
  6. ↑ MITOCHONDRIAL DNA DEPLETION SYNDROME 3 (HEPATOCEREBRAL TYPE); MTDPS3.  In: Online Mendelian Inheritance in Man . (English)
  7. ↑ MITOCHONDRIAL DNA DEPLETION SYNDROME 4A (ALPERS TYPE); MTDPS4A.  In: Online Mendelian Inheritance in Man . (English)
  8. ↑ MITOCHONDRIAL DNA DEPLETION SYNDROME 4B (MNGIE TYPE); MTDPS4B.  In: Online Mendelian Inheritance in Man . (English)
  9. ↑ MITOCHONDRIAL DNA DEPLETION SYNDROME 5 (ENCEPHALOMYOPATHIC With or Without methylmalonic aciduria); MTDPS5.  In: Online Mendelian Inheritance in Man . (English)
  10. ↑ MITOCHONDRIAL DNA DEPLETION SYNDROME 6 (HEPATOCEREBRAL TYPE); MTDPS6.  In: Online Mendelian Inheritance in Man . (English)
  11. ↑ MITOCHONDRIAL DNA DEPLETION SYNDROME 7 (HEPATOCEREBRAL TYPE); MTDPS7.  In: Online Mendelian Inheritance in Man . (English)
  12. ↑ Mitochondrial DNA depletion syndrome 8.  In: Online Mendelian Inheritance in Man . (English)
  13. ↑ MITOCHONDRIAL DNA DEPLETION SYNDROME 9 (ENCEPHALOMYOPATHIC TYPE WITH METHYLMALONIC ACIDURIA); MTDPS9.  In: Online Mendelian Inheritance in Man . (English)
  14. ↑ MITOCHONDRIAL DNA DEPLETION SYNDROME 11; MTDPS11.  In: Online Mendelian Inheritance in Man . (English)
  15. ↑ MITOCHONDRIAL DNA DEPLETION SYNDROME 12A (CARDIOMYOPATHIC TYPE), AUTOSOMAL DOMINANT; MTDPS12A.  In: Online Mendelian Inheritance in Man . (English)
  16. ↑ MITOCHONDRIAL DNA DEPLETION SYNDROME 12B (CARDIOMYOPATHIC TYPE), AUTOSOMAL RECESSIVE; MTDPS12B.  In: Online Mendelian Inheritance in Man . (English)
  17. ↑ MITOCHONDRIAL DNA DEPLETION SYNDROME 13 (ENCEPHALOMYOPATHIC TYPE); MTDPS13.  In: Online Mendelian Inheritance in Man . (English)
  18. ↑ MITOCHONDRIAL DNA DEPLETION SYNDROME 14 (CARDIOENCEPHALOMYOPATHIC TYPE); MTDPS14.  In: Online Mendelian Inheritance in Man . (English)
  19. ↑ MITOCHONDRIAL DNA DEPLETION SYNDROME 15 (HEPATOCEREBRAL TYPE); MTDPS15.  In: Online Mendelian Inheritance in Man . (English)
  20. ↑ CT Moraes, S. Shanske, HJ Tritschler, JR Aprille, F. Andreetta, E. Bonilla, EA Schon, S. DiMauro: mtDNA depletion with variable tissue expression: a novel genetic abnormality in mitochondrial diseases. In: American Journal of Human Genetics . Volume 48, No. 3, March 1991, pp. 492-501. PMID 1998336 , PMC 1682992 (free full text).

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