Mitochondrial DNA depletion syndrome

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Mitochondrial DNA depletion syndrome
Other namesmtDNA depletion syndrome
Autosomal recessive - en.svg
Mitochondrial DNA depletion syndrome is inherited in an autosomal recessive manner

Mitochondrial DNA depletion syndrome (MDS or MDDS), or Alper's disease, is any of a group of autosomal recessive disorders that cause a significant drop in mitochondrial DNA in affected tissues. Symptoms can be any combination of myopathic, hepatopathic, or encephalomyopathic. [1] These syndromes affect tissue in the muscle, liver, or both the muscle and brain, respectively. The condition is typically fatal in infancy and early childhood, though some have survived to their teenage years with the myopathic variant and some have survived into adulthood with the SUCLA2 encephalomyopathic variant. [2] [3] There is currently no curative treatment for any form of MDDS, though some preliminary treatments have shown a reduction in symptoms. [4]

Contents

Signs and symptoms

All forms of MDDS are very rare. MDDS causes a wide range of symptoms, which can appear in newborns, infants, children, or adults, depending on the class of MDDS; within each class symptoms are also diverse. [5]

In MDDS associated with mutations in TK2, infants generally develop normally, but by around two years of age, symptoms of general muscle weakness (called "hypotonia"), tiredness, lack of stamina, and difficulty feeding begin to appear. Some toddlers start to lose control of the muscles in their face, mouth, and throat, and may have difficulty swallowing. Motor skills that had been learned may be lost, but generally the functioning of the brain and ability to think are not affected. [5]

In MDDS associated with mutations in SUCLA2 or SUCLG1 that primarily affect the brain and muscle, hypotonia generally arises in infants before they are 6 months old, their muscles begin wasting away, and there is delay in psychomotor learning (learning basic skills like walking, talking, and intentional, coordinated movement). The spine often begins to curve (scoliosis or kyphosis), and the child often has abnormal movements (dystonia, athetosis or chorea), difficulty feeding, acid reflux, hearing loss, stunted growth, and difficulty breathing that can lead to frequent lung infections. Sometime epilepsy develops. [5]

In MDDS associated with mutations in RRM2B that primarily affect the brain and muscle, there is again hypotonia in the first months, symptoms of lactic acidosis like nausea, vomiting, and rapid deep breathing, failure to thrive including the head remaining small, delay or regression in moving, and hearing loss. Many body systems are affected. [5] [6] The Charlie Gard case was associated with this sub form of the disease. [7]

In MDDS associated with mutations in DGUOK that primarily affect the brain and the liver, there are two forms. There is an early-onset form in which symptoms arise from problems in many organs in the first week of life, especially symptoms of lactic acidosis as well as low blood sugar. Within weeks of birth they can develop liver failure and the associated jaundice and abdominal swelling, and many neurological problems including developmental delays and regression, and uncontrolled eye movement. Rarely within this class of already rare diseases, symptoms only relating to liver disease emerge later in infancy or in childhood. [5]

In MDDS associated with mutations in MPV17 that primarily affect the brain and the liver, the symptoms are similar to those caused by DGUOK and also emerge shortly after birth, generally with fewer and less severe neurological problems. There is a subset of people of Navajo descent who develop Navajo neurohepatopathy, who in addition to these symptoms also have easily broken bones that do not cause pain, deformed hands or feet, and problems with their corneas. [5]

In MDDS associated with mutations in POLG that primarily affect the brain and the liver, [8] the symptoms are very diverse and can emerge anytime from shortly after birth to old age. The first signs of the disease, which include intractable seizures and failure to meet meaningful developmental milestones, usually occur in infancy, after the first year of life, but sometimes as late as the fifth year. Primary symptoms of the disease are developmental delay, progressive intellectual disability, hypotonia (low muscle tone), spasticity (stiffness of the limbs) possibly leading to quadriplegia, and progressive dementia. Seizures may include epilepsia partialis continua, a type of seizure that consists of repeated myoclonic (muscle) jerks. Optic atrophy may also occur, often leading to blindness. Hearing loss may also occur. Additionally, although physical signs of chronic liver dysfunction may not be present, many people experience liver impairment leading to liver failure. [9] [10]

In MDDS associated with mutations in PEO1/C10orf2 that primarily affect the brain and the liver, symptoms emerge shortly after birth or in early infancy, with hypotonia, symptoms of lactic acidosis, enlarged liver, feeding problems, lack of growth, and delay of psychomotor skills. Neurologically, development is slowed or stopped, and epilepsy emerges, as do sensory problems like loss of eye control and deafness, and neuromuscular problems like a lack of reflexes, muscular atrophy, and twitching, and epilepsy. [5]

In MDDS associated with mutations in the genes associated with mutations in ECGF1/TYMP that primarily affects the brain and the gastrointestinal tract, symptoms can emerge any time in the first fifty years of life; most often they emerge before the person turns 20. Weight loss is common as is a lack of the ability of the stomach and intestines to automatically expand and contract and thus move through it (called gastrointestinal motility) – this leads to feeling full after eating only small amounts of food, nausea, acid reflux, All affected individuals develop weight loss and progressive gastrointestinal dysmotility manifesting as early satiety, nausea, diarrhea, vomiting, and stomach pain and swelling. People also develop neuropathy, with weakness and tingling. There are often eye problems, and intellectual disability. [5]

Causes

MDDS is caused by mutations that may be inherited from the parents or may form spontaneously during development of the fetus. [5] It is associated with the mutations of mitochondrial genes in the nucleus and several genes including TK2, FBXL4, are known to be related to MDS. [11]

Myopathic MDS is strongly correlated to a variety of mutations in the gene TK2 , seeing a reduction of TK2 activity to less than 32% in people with MDS found with the mutation. Because TK2 plays a key role in the mitochondrial salvage pathways of several deoxyribonucleoside triphosphates (dNTPs), a lowered activity would lead to less cycling of nucleotides. This lack of nucleotide recycling is detrimental since the mitochondria cannot synthesize entirely new deoxynucleotides, and the inner membrane of the mitochondria prevents the negatively charged nucleotides of the cytosol from entering. [12]

The SUCLA2 gene codes for the beta-subunit of SCS-A. This enzyme catalyzes the synthesis of succinate and coenzyme A into succinyl-CoA, but is also associated with the complex formed by nucleoside diphosphate kinase (NDPK) in the last step of the dNTP salvage pathway. [13]

The RRM2B gene, which is expressed in the cell nucleus, codes for one of two versions of the R2 subunit of ribonucleotide reductase, which generates nucleotide precursors required for DNA replication by reducing ribonucleoside diphosphates to deoxyribonucleoside diphosphates. The version of R2 encoded by RRM2B is induced by TP53, and is required for normal DNA repair and mtDNA synthesis in non-proliferating cells. The other form of R2 is expressed only in dividing cells. [14]

The DGUOK gene encodes for mitochondrial deoxyguanosine kinase (dGK), which catalyzes the phosphorylation of deoxyribonucleosides into nucleotides. [15] POLG encodes for the catalytic subunit pol γA, which is part of mitochondrial DNA polymerase. [16]

Other causes are mutations of thymidine phosphorylase (TyMP), succinate-CoA ligase, alpha sub unit (SUCLG1) and TWNK (also known as PEO1 and C10orf2). [3] [17]

Diagnosis

MDDS is diagnosed based on systemic symptoms presenting in infants, followed by a clinical examination and laboratory tests (for example, high lactate levels are common) medical imaging, and usually is finally confirmed and formally identified by genetic testing. [5]

Classification

MDDS are a group of genetic disorders that share a common pathology — a lack of functioning DNA in mitochondria. [5] There are generally four classes of MDDS: [5]

Treatment

There are no treatments for MDDS, but some of the symptoms can be managed. For survivors living with MDDS, there are drugs to control epilepsy, and physical therapy can help with muscle control. Liver transplants may benefit people with liver involvement. [5]

Prognosis

Myopathic form

The TK2 related myopathic form results in muscle weakness, rapidly progresses, leading to respiratory failure and death within a few years of onset. The most common cause of death is pulmonary infection. Only a few people have survived to late childhood and adolescence. [5]

Encephalomyopathic form

SUCLA2 and RRM2B related forms result in deformities to the brain. [5] A 2007 study based on 12 cases from the Faroe Islands (where there is a relatively high incidence due to a founder effect) suggested that the outcome is often poor with early lethality. [18] More recent studies (2015) with 50 people with SUCLA2 mutations, with range of 16 different mutations, show a high variability in outcomes with a number of people surviving into adulthood (median survival was 20 years). There is significant evidence (p = 0.020) that people with missense mutations have longer survival rates, which might mean that some of the resulting protein has some residual enzyme activity. [2]

RRM2B mutations have been reported in 16 infants with severe encephalomyopathic MDS that is associated with early-onset (neonatal or infantile), multi-organ presentation, and mortality during infancy. [5]

Hepatopathic form

DGUOK-, POLG-, and MPV17-related forms result in defects to the liver. [5] Liver dysfunction is progressive in the majority of individuals with both forms of DGUOK-related MDS and is the most common cause of death. For children with the multi-organ form, liver transplantation provides no survival benefit. [19]

Liver disease typically progresses to liver failure in affected children with MPV17-related MDS and liver transplantation remains the only treatment option for liver failure. Approximately half of affected children reported did not undergo liver transplantation and died because of progressive liver failure – the majority during infancy or early childhood. A few children were reported to survive without liver transplantation. [20]

Research

Nucleoside bypass therapy is an experimental treatment aimed to restore the normal levels of deoxyribonucleotides (dNTPs) in mitochondria. [5] [21] [22]

See also

Related Research Articles

<span class="mw-page-title-main">Mitochondrial disease</span> Spontaneously occurring or inherited disorder that involves mitochondrial dysfunction

Mitochondrial disease is a group of disorders caused by mitochondrial dysfunction. Mitochondria are the organelles that generate energy for the cell and are found in every cell of the human body except red blood cells. They convert the energy of food molecules into the ATP that powers most cell functions.

<span class="mw-page-title-main">Leigh syndrome</span> Mitochondrial metabolism disease characterized by progressive loss of mental and movement abilities

Leigh syndrome is an inherited neurometabolic disorder that affects the central nervous system. It is named after Archibald Denis Leigh, a British neuropsychiatrist who first described the condition in 1951. Normal levels of thiamine, thiamine monophosphate, and thiamine diphosphate are commonly found, but there is a reduced or absent level of thiamine triphosphate. This is thought to be caused by a blockage in the enzyme thiamine-diphosphate kinase, and therefore treatment in some patients would be to take thiamine triphosphate daily. While the majority of patients typically exhibit symptoms between the ages of 3 and 12 months, instances of adult onset have also been documented.

<span class="mw-page-title-main">Mitochondrial myopathy</span> Medical condition

Mitochondrial myopathies are types of myopathies associated with mitochondrial disease. Adenosine triphosphate (ATP), the chemical used to provide energy for the cell, cannot be produced sufficiently by oxidative phosphorylation when the mitochondrion is either damaged or missing necessary enzymes or transport proteins. With ATP production deficient in mitochondria, there is an over-reliance on anaerobic glycolysis which leads to lactic acidosis either at rest or exercise-induced.

<span class="mw-page-title-main">MELAS syndrome</span> Medical condition

Mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) is one of the family of mitochondrial diseases, which also include MIDD, MERRF syndrome, and Leber's hereditary optic neuropathy. It was first characterized under this name in 1984. A feature of these diseases is that they are caused by defects in the mitochondrial genome which is inherited purely from the female parent. The most common MELAS mutation is mitochondrial mutation, mtDNA, referred to as m.3243A>G.

<span class="mw-page-title-main">MERRF syndrome</span> Medical condition

MERRF syndrome is a mitochondrial disease. It is extremely rare, and has varying degrees of expressivity owing to heteroplasmy. MERRF syndrome affects different parts of the body, particularly the muscles and nervous system. The signs and symptoms of this disorder appear at an early age, generally childhood or adolescence. The causes of MERRF syndrome are difficult to determine, but because it is a mitochondrial disorder, it can be caused by the mutation of nuclear DNA or mitochondrial DNA. The classification of this disease varies from patient to patient, since many individuals do not fall into one specific disease category. The primary features displayed on a person with MERRF include myoclonus, seizures, cerebellar ataxia, myopathy, and ragged red fibers (RRF) on muscle biopsy, leading to the disease's name. Secondary features include dementia, optic atrophy, bilateral deafness, peripheral neuropathy, spasticity, or multiple lipomata. Mitochondrial disorders, including MERRFS, may present at any age.

<span class="mw-page-title-main">Mitochondrial neurogastrointestinal encephalopathy syndrome</span> Medical condition

Mitochondrial neurogastrointestinal encephalopathy syndrome (MNGIE) is a rare autosomal recessive mitochondrial disease. It has been previously referred to as polyneuropathy, ophthalmoplegia, leukoencephalopathy, and intestinal pseudoobstruction. The disease presents in childhood, but often goes unnoticed for decades. Unlike typical mitochondrial diseases caused by mitochondrial DNA (mtDNA) mutations, MNGIE is caused by mutations in the TYMP gene, which encodes the enzyme thymidine phosphorylase. Mutations in this gene result in impaired mitochondrial function, leading to intestinal symptoms as well as neuro-ophthalmologic abnormalities. A secondary form of MNGIE, called MNGIE without leukoencephalopathy, can be caused by mutations in the POLG gene.

Chronic progressive external ophthalmoplegia (CPEO) is a type of eye disorder characterized by slowly progressive inability to move the eyes and eyebrows. It is often the only feature of mitochondrial disease, in which case the term CPEO may be given as the diagnosis. In other people suffering from mitochondrial disease, CPEO occurs as part of a syndrome involving more than one part of the body, such as Kearns–Sayre syndrome. Occasionally CPEO may be caused by conditions other than mitochondrial diseases.

<span class="mw-page-title-main">DGUOK</span> Protein-coding gene in the species Homo sapiens

Deoxyguanosine kinase, mitochondrial is an enzyme that in humans is encoded by the DGUOK gene.

<span class="mw-page-title-main">RRM2B</span> Protein-coding gene in the species Homo sapiens

Ribonucleotide-diphosphate reductase subunit M2 B is an enzyme that in humans is encoded by the RRM2B gene. The gene encoding the RRM2B protein is located on chromosome 8, at position 8q23.1. The gene and its products are also known by designations MTDPS8A, MTDPS8B, and p53R2.

<span class="mw-page-title-main">MPV17</span> Protein-coding gene in the species Homo sapiens

Protein MPV17 is a protein that in humans is encoded by the MPV17 gene. It is a mitochondrial inner membrane protein, which has a so far largely unknown role in mtDNA maintenance. Protein MPV17 is expressed in human pancreas, kidney, muscle, liver, lung, placenta, brain and heart. Human MPV17 is the orthologue of the mouse kidney disease gene, Mpv17. Loss of function has been shown to cause hepatocerebral mtDNA depletion syndromes (MDS) with oxidative phosphorylation failure and mtDNA depletion both in affected individuals and in Mpv17−/− mice.

<span class="mw-page-title-main">SUCLA2</span> Protein-coding gene in the species Homo sapiens

Succinyl-CoA ligase [ADP-forming] subunit beta, mitochondrial (SUCLA2), also known as ADP-forming succinyl-CoA synthetase (SCS-A), is an enzyme that in humans is encoded by the SUCLA2 gene on chromosome 13.

Mitochondrially encoded tRNA valine also known as MT-TV is a transfer RNA which in humans is encoded by the mitochondrial MT-TV gene.

Mitochondrially encoded tRNA aspartic acid also known as MT-TD is a transfer RNA which in humans is encoded by the mitochondrial MT-TD gene.

Mitochondrially encoded tRNA glutamic acid also known as MT-TE is a transfer RNA which in humans is encoded by the mitochondrial MT-TE gene. MT-TE is a small 69 nucleotide RNA that transfers the amino acid glutamic acid to a growing polypeptide chain at the ribosome site of protein synthesis during translation.

Mitochondrially encoded tRNA phenylalanine also known as MT-TF is a transfer RNA which in humans is encoded by the mitochondrial MT-TF gene.

Mitochondrially encoded tRNA lysine also known as MT-TK is a transfer RNA which in humans is encoded by the mitochondrial MT-TK gene.

Mitochondrially encoded tRNA asparagine also known as MT-TN is a transfer RNA which in humans is encoded by the mitochondrial MT-TN gene.

Mitochondrially encoded tRNA arginine also known as MT-TR is a transfer RNA which in humans is encoded by the mitochondrial MT-TR gene.

Mitochondrially encoded tRNA tryptophan also known as MT-TW is a transfer RNA which in humans is encoded by the mitochondrial MT-TW gene.

<span class="mw-page-title-main">Thymidine kinase 2, mitochondrial</span> Protein-coding gene in the species Homo sapiens

Thymidine kinase 2, mitochondrial is a protein that in humans is encoded by the TK2 gene.

References

  1. ↑ Elpeleg O (2003). "Inherited mitochondrial DNA depletion". Pediatr Res. 54 (2): 153–9. doi: 10.1203/01.PDR.0000072796.25097.A5 . PMID   12736387.
  2. 1 2 Carrozzo R, Verrigni D, Rasmussen M, de Coo R, Amartino H, Bianchi M, et al. (March 2016). "Succinate-CoA ligase deficiency due to mutations in SUCLA2 and SUCLG1: phenotype and genotype correlations in 71 patients". Journal of Inherited Metabolic Disease. 39 (2): 243–52. doi:10.1007/s10545-015-9894-9. PMID   26475597. S2CID   7881205.
  3. 1 2 Finsterer, J; Ahting, U (September 2013). "Mitochondrial depletion syndromes in children and adults". The Canadian Journal of Neurological Sciences. 40 (5): 635–44. doi: 10.1017/S0317167100014852 . PMID   23968935.
  4. ↑ Saito K, Kimura N, Oda N, Shimomura H, Kumada T, Miyajima T, Murayama K, Tanaka M, Fujii T (May 2012). "Pyruvate therapy for mitochondrial DNA depletion syndrome". Biochimica et Biophysica Acta (BBA) - General Subjects. 1820 (5): 632–6. doi:10.1016/j.bbagen.2011.08.006. PMID   21855607.
  5. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 El-Hattab AW, Scaglia F (April 2013). "Mitochondrial DNA depletion syndromes: review and updates of genetic basis, manifestations, and therapeutic options". Neurotherapeutics. 10 (2): 186–98. doi:10.1007/s13311-013-0177-6. PMC   3625391 . PMID   23385875.
  6. ↑ Gorman, Gráinne S.; Taylor, Robert W. (April 17, 2014). "RRM2B-Related Mitochondrial Disease". GeneReviews. University of Washington, Seattle. PMID   24741716.
  7. ↑ Wheaton, Oliver (2017-07-25). "What is Charlie Gard's condition mitochondrial DNA depletion syndrome (or MDDS)?". Metro . Retrieved 2021-09-24.
  8. ↑ This form of MDDS is also called "Alpers' disease", also called "Alpers' syndrome", "Alpers-Huttenlocher syndrome", "progressive sclerosing poliodystrophy", and "progressive infantile poliodystrophy". It is named after Bernard Jacob Alpers ( Alpers' disease at Who Named It?) and Peter Huttenlocher (see Easton, John (19 August 2013). "Peter Huttenlocher, pediatric neurologist, 1931–2013". The University of Chicago. Retrieved 1 November 2013.)
  9. ↑ "Alpers' Disease Information Page". National Institute of Neurological Disorders and Stroke. Retrieved 24 July 2017.
  10. ↑ Cohen, BH; Chinnery, PF; Copeland, WC (December 18, 2014). Pagon, RA; et al. (eds.). "POLG-Related Disorders". GeneReviews. PMID   20301791.
  11. ↑ Wang H, Han Y, Li S, Chen Y, Chen Y, Wang J, Zhang Y, Zhang Y, Wang J, Xia Y, Yuan J (2021). "Mitochondrial DNA Depletion Syndrome and Its Associated Cardiac Disease". Front Cardiovasc Med. 8: 808115. doi: 10.3389/fcvm.2021.808115 . PMC   8882844 . PMID   35237671.
  12. ↑ Saada A (December 2004). "Deoxyribonucleotides and disorders of mitochondrial DNA integrity". DNA and Cell Biology. 23 (12): 797–806. doi:10.1089/dna.2004.23.797. PMID   15684706. S2CID   20619194.
  13. ↑ Elpeleg O, Miller C, Hershkovitz E, Bitner-Glindzicz M, Bondi-Rubinstein G, Rahman S, Pagnamenta A, Eshhar S, Saada A (June 2005). "Deficiency of the ADP-forming succinyl-CoA synthase activity is associated with encephalomyopathy and mitochondrial DNA depletion". American Journal of Human Genetics. 76 (6): 1081–6. doi:10.1086/430843. PMC   1196446 . PMID   15877282.
  14. ↑ Copeland, WC (2012). "Defects in mitochondrial DNA replication and human disease". Critical Reviews in Biochemistry and Molecular Biology. 47 (1): 64–74. doi:10.3109/10409238.2011.632763. PMC   3244805 . PMID   22176657.
  15. ↑ Wang L, Limongelli A, Vila MR, Carrara F, Zeviani M, Eriksson S (January 2005). "Molecular insight into mitochondrial DNA depletion syndrome in two patients with novel mutations in the deoxyguanosine kinase and thymidine kinase 2 genes". Molecular Genetics and Metabolism. 84 (1): 75–82. doi:10.1016/j.ymgme.2004.09.005. PMID   15639197.
  16. ↑ Van Goethem G, Dermaut B, Löfgren A, Martin JJ, Van Broeckhoven C (July 2001). "Mutation of POLG is associated with progressive external ophthalmoplegia characterized by mtDNA deletions". Nature Genetics. 28 (3): 211–2. doi:10.1038/90034. PMID   11431686. S2CID   35417835.
  17. ↑ "Depletionssyndrom, mitochondriales (MDS)". Labor Lademannbogen (in German). Archived from the original on 2022-01-26. Retrieved 2017-04-14.
  18. ↑ Ostergaard E (18 May 2017). "SUCLA2-Related Mitochondrial DNA Depletion Syndrome, Encephalomyopathic Form with Methylmalonic Aciduria". In Pagon RA, Adam MP, Ardinger HH, Wallace SE, Amemiya A, Bean LJ, Bird TD, Fong CT, Mefford HC, Smith RJ, Stephens K (eds.). SUCLA2-Related Mitochondrial DNA Depletion Syndrome, Encephalomyopathic Form, with Mild Methylmalonic Acuduria. University of Washington, Seattle. PMID   20301762 . Retrieved 8 July 2020– via NCBI Bookshelf (National Library of Medicine).{{cite book}}: |journal= ignored (help)
  19. ↑ Dimmock DP, Dunn JK, Feigenbaum A, Rupar A, Horvath R, Freisinger P, Mousson de Camaret B, Wong LJ, Scaglia F (October 2008). "Abnormal neurological features predict poor survival and should preclude liver transplantation in patients with deoxyguanosine kinase deficiency". Liver Transplantation. 14 (10): 1480–5. doi: 10.1002/lt.21556 . PMID   18825706. S2CID   28819842.
  20. ↑ El-Hattab AW, Li FY, Schmitt E, Zhang S, Craigen WJ, Wong LJ (March 2010). "MPV17-associated hepatocerebral mitochondrial DNA depletion syndrome: new patients and novel mutations". Molecular Genetics and Metabolism. 99 (3): 300–8. doi:10.1016/j.ymgme.2009.10.003. PMID   20074988.
  21. ↑ Viscomi, Carlo; Bottani, Emanuela; Zeviani, Massimo (2015-06-01). "Emerging concepts in the therapy of mitochondrial disease". Biochimica et Biophysica Acta (BBA) - Bioenergetics. 1847 (6): 544–557. doi: 10.1016/j.bbabio.2015.03.001 . PMID   25766847.
  22. ↑ Cámara, Yolanda; González-Vioque, Emiliano; Scarpelli, Mauro; Torres-Torronteras, Javier; Martí, Ramon (2013-10-01). "Feeding the deoxyribonucleoside salvage pathway to rescue mitochondrial DNA". Drug Discovery Today. 18 (19): 950–957. doi:10.1016/j.drudis.2013.06.009. PMID   23817075.
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