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Mitochondrial DNA depletion syndrome 18(MTDPS18)

MedGen UID:: 1713890
•Concept ID:: C5394140
•: Disease or Syndrome

Synonyms:	MITOCHONDRIAL DNA DEPLETION SYNDROME 18; MTDPS18

Gene (location): Gene(s) directly associated with this condition or phenotype.	SLC25A21 (14q13.3)

Monarch Initiative:	MONDO:0032932
OMIM®:	618811

Definition

Mitochondrial DNA depletion syndrome-18 (MTDPS18) is an autosomal recessive neuromuscular disorder characterized by early-onset progressive weakness and atrophy of the distal limb muscles, resulting in loss of ambulation as well as atrophy of the intrinsic hand muscles with clawed hands. Affected individuals may also develop scoliosis and have hypo- or hyperreflexia and decreased pulmonary vital capacity. Examination of skeletal muscle shows neurogenic atrophy and combined mitochondrial oxidative phosphorylation deficiency associated with mtDNA depletion. The clinical phenotype is reminiscent of spinal muscular atrophy (see SMA, 253300) and the metabolic profile is reminiscent of 2-aminoadipic 2-oxoadipic aciduria (AMOXAD; 204750), which is caused by mutation in the DHTKD1 gene (614984) (summary by Boczonadi et al., 2018). For a discussion of genetic heterogeneity of autosomal recessive mtDNA depletion syndromes, see MTDPS1 (603041). [from OMIM]

Clinical features

From HPO

Lacticaciduria

MedGen UID:: 871116
•Concept ID:: C4025585
•: Finding

An increased concentration of lactic acid in the urine.

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Foot dorsiflexor weakness

MedGen UID:: 356163
•Concept ID:: C1866141
•: Finding

Weakness of the muscles responsible for dorsiflexion of the foot, that is, of the movement of the toes towards the shin. The foot dorsiflexors include the tibialis anterior, the extensor hallucis longus, the extensor digitorum longus, and the peroneus tertius muscles.

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Failure to thrive

MedGen UID:: 746019
•Concept ID:: C2315100
•: Disease or Syndrome

Failure to thrive (FTT) refers to a child whose physical growth is substantially below the norm.

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Clonus

MedGen UID:: 40341
•Concept ID:: C0009024
•: Sign or Symptom

A series of rhythmic and involuntary muscle contractions (at a frequency of about 5 to 7 Hz) that occur in response to an abruptly applied and sustained stretch.

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Falls

MedGen UID:: 39084
•Concept ID:: C0085639
•: Finding

A sudden movement downward, usually resulting in injury.

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Areflexia

MedGen UID:: 115943
•Concept ID:: C0234146
•: Finding

Absence of neurologic reflexes such as the knee-jerk reaction.

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Axonal degeneration

MedGen UID:: 332464
•Concept ID:: C1837496
•: Finding

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Microcytic anemia

MedGen UID:: 1673948
•Concept ID:: C5194182
•: Disease or Syndrome

A kind of anemia in which the volume of the red blood cells is reduced.

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Scoliosis

MedGen UID:: 11348
•Concept ID:: C0036439
•: Disease or Syndrome

The presence of an abnormal lateral curvature of the spine.

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Proximal muscle weakness

MedGen UID:: 113169
•Concept ID:: C0221629
•: Finding

A lack of strength of the proximal muscles.

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Hand muscle atrophy

MedGen UID:: 116091
•Concept ID:: C0239830
•: Finding

Muscular atrophy involving the muscles of the hand.

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Weakness of facial musculature

MedGen UID:: 98103
•Concept ID:: C0427055
•: Disease or Syndrome

Reduced strength of one or more muscles innervated by the facial nerve (the seventh cranial nerve).

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Distal muscle weakness

MedGen UID:: 140883
•Concept ID:: C0427065
•: Finding

Reduced strength of the musculature of the distal extremities.

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Distal amyotrophy

MedGen UID:: 338530
•Concept ID:: C1848736
•: Disease or Syndrome

Muscular atrophy affecting muscles in the distal portions of the extremities.

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Reduced forced vital capacity

MedGen UID:: 337630
•Concept ID:: C1846678
•: Finding

An abnormal reduction in the amount of air a person can expel following maximal inspiration.

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Tongue fasciculations

MedGen UID:: 65987
•Concept ID:: C0239548
•: Finding

Fasciculations or fibrillation affecting the tongue muscle.

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Abnormality of blood and blood-forming tissues
- Microcytic anemia
Abnormality of head or neck
- Tongue fasciculations
Abnormality of limbs
- Foot dorsiflexor weakness
Abnormality of the genitourinary system
- Lacticaciduria
Abnormality of the musculoskeletal system
Abnormality of the nervous system
Abnormality of the respiratory system
- Reduced forced vital capacity
Growth abnormality
- Failure to thrive

Professional guidelines

PubMed

232nd ENMC international workshop: Recommendations for treatment of mitochondrial DNA maintenance disorders. 16 - 18 June 2017, Heemskerk, The Netherlands.

López-Gómez C, Cámara Y, Hirano M, Martí R; 232nd ENMC Workshop Participants
Neuromuscul Disord 2022 Jul;32(7):609-620. Epub 2022 May 14 doi: 10.1016/j.nmd.2022.05.008. PMID: 35641351

See all (1)

Recent clinical studies

Etiology

Hepatic presentations of mitochondrial DNA depletion syndrome in children: A single tertiary liver centre experience.

Vara R, Pinon M, Fratter C, Hegarty R, Hadzic N
J Inherit Metab Dis 2023 Jul;46(4):634-648. Epub 2023 May 28 doi: 10.1002/jimd.12633. PMID: 37204315

Clinical and molecular basis of hepatocerebral mitochondrial DNA depletion syndrome in Japan: evaluation of outcomes after liver transplantation.

Shimura M, Kuranobu N, Ogawa-Tominaga M, Akiyama N, Sugiyama Y, Ebihara T, Fushimi T, Ichimoto K, Matsunaga A, Tsuruoka T, Kishita Y, Umetsu S, Inui A, Fujisawa T, Tanikawa K, Ito R, Fukuda A, Murakami J, Kaji S, Kasahara M, Shiraki K, Ohtake A, Okazaki Y, Murayama K
Orphanet J Rare Dis 2020 Jul 24;15(1):169. doi: 10.1186/s13023-020-01441-5. PMID: 32703289 Free PMC Article

Late-onset thymidine kinase 2 deficiency: a review of 18 cases.

Domínguez-González C, Hernández-Laín A, Rivas E, Hernández-Voth A, Sayas Catalán J, Fernández-Torrón R, Fuiza-Luces C, García García J, Morís G, Olivé M, Miralles F, Díaz-Manera J, Caballero C, Méndez-Ferrer B, Martí R, García Arumi E, Badosa MC, Esteban J, Jimenez-Mallebrera C, Encinar AB, Arenas J, Hirano M, Martin MÁ, Paradas C
Orphanet J Rare Dis 2019 May 6;14(1):100. doi: 10.1186/s13023-019-1071-z. PMID: 31060578 Free PMC Article

Reference Intervals of Mitochondrial DNA Copy Number in Peripheral Blood for Chinese Minors and Adults.

Xia CY, Liu Y, Yang HR, Yang HY, Liu JX, Ma YN, Qi Y
Chin Med J (Engl) 2017 Oct 20;130(20):2435-2440. doi: 10.4103/0366-6999.216395. PMID: 29052564 Free PMC Article

Defects in mitochondrial DNA replication and human disease.

Copeland WC
Crit Rev Biochem Mol Biol 2012 Jan-Feb;47(1):64-74. doi: 10.3109/10409238.2011.632763. PMID: 22176657 Free PMC Article

See all (15)

Diagnosis

Outcomes of liver transplantation for mitochondrial respiratory chain disorder in children.

Uchida H, Sakamoto S, Shimizu S, Yanagi Y, Fukuda A, Horikawa R, Ito R, Matsunaga A, Murayama K, Kasahara M
Pediatr Transplant 2021 Dec;25(8):e14091. Epub 2021 Jul 15 doi: 10.1111/petr.14091. PMID: 34265160

Clinical and molecular basis of hepatocerebral mitochondrial DNA depletion syndrome in Japan: evaluation of outcomes after liver transplantation.

Reference Intervals of Mitochondrial DNA Copy Number in Peripheral Blood for Chinese Minors and Adults.

Xia CY, Liu Y, Yang HR, Yang HY, Liu JX, Ma YN, Qi Y
Chin Med J (Engl) 2017 Oct 20;130(20):2435-2440. doi: 10.4103/0366-6999.216395. PMID: 29052564 Free PMC Article

Depleted leukocyte mitochondrial DNA copy number in metabolic syndrome.

Huang CH, Su SL, Hsieh MC, Cheng WL, Chang CC, Wu HL, Kuo CL, Lin TT, Liu CS
J Atheroscler Thromb 2011;18(10):867-73. Epub 2011 Aug 16 doi: 10.5551/jat.8698. PMID: 21844659

Disorders of the mitochondria.

Treem WR, Sokol RJ
Semin Liver Dis 1998;18(3):237-53. doi: 10.1055/s-2007-1007160. PMID: 9773424

See all (16)

Therapy

Efficacy and Safety of Elamipretide in Individuals With Primary Mitochondrial Myopathy: The MMPOWER-3 Randomized Clinical Trial.

Karaa A, Bertini E, Carelli V, Cohen BH, Enns GM, Falk MJ, Goldstein A, Gorman GS, Haas R, Hirano M, Klopstock T, Koenig MK, Kornblum C, Lamperti C, Lehman A, Longo N, Molnar MJ, Parikh S, Phan H, Pitceathly RDS, Saneto R, Scaglia F, Servidei S, Tarnopolsky M, Toscano A, Van Hove JLK, Vissing J, Vockley J, Finman JS, Brown DA, Shiffer JA, Mancuso M; MMPOWER-3 Trial Investigators
Neurology 2023 Jul 18;101(3):e238-e252. Epub 2023 Jun 2 doi: 10.1212/WNL.0000000000207402. PMID: 37268435 Free PMC Article

Recent advances in thymidine kinase 2 (TK2) inhibitors and new perspectives for potential applications.

Priego EM, Karlsson A, Gago F, Camarasa MJ, Balzarini J, Pérez-Pérez MJ
Curr Pharm Des 2012;18(20):2981-94. doi: 10.2174/138161212800672787. PMID: 22571666

Upregulation of nuclear-encoded mitochondrial LON protease in HAART-treated HIV-positive patients with lipodystrophy: implications for the pathogenesis of the disease.

Pinti M, Gibellini L, Guaraldi G, Orlando G, Gant TW, Morselli E, Nasi M, Salomoni P, Mussini C, Cossarizza A
AIDS 2010 Mar 27;24(6):841-50. doi: 10.1097/QAD.0b013e32833779a3. PMID: 20168207

Gene expression and immunohistochemistry in adipose tissue of HIV type 1-infected patients with nucleoside analogue reverse-transcriptase inhibitor-associated lipoatrophy.

Sievers M, Walker UA, Sevastianova K, Setzer B, Wågsäter D, Eriksson P, Yki-Järvinen H, Sutinen J
J Infect Dis 2009 Jul 15;200(2):252-62. doi: 10.1086/599986. PMID: 19519254

Assessment of adipokine expression and mitochondrial toxicity in HIV patients with lipoatrophy on stavudine- and zidovudine-containing regimens.

Jones SP, Qazi N, Morelese J, Lebrecht D, Sutinen J, Yki-Jărvinen H, Back DJ, Pirmohamed M, Gazzard BG, Walker UA, Moyle GJ
J Acquir Immune Defic Syndr 2005 Dec 15;40(5):565-72. doi: 10.1097/01.qai.0000187443.30838.3e. PMID: 16284533

See all (7)

Prognosis

Clinical and molecular basis of hepatocerebral mitochondrial DNA depletion syndrome in Japan: evaluation of outcomes after liver transplantation.

Late-onset thymidine kinase 2 deficiency: a review of 18 cases.

Hepatocerebral form of mitochondrial DNA depletion syndrome due to mutation in MPV17 gene.

AlSaman A, Tomoum H, Invernizzi F, Zeviani M
Saudi J Gastroenterol 2012 Jul-Aug;18(4):285-9. doi: 10.4103/1319-3767.98439. PMID: 22824774 Free PMC Article

Two novel POLG mutations causing hepatic mitochondrial DNA depletion with recurrent hypoketotic hypoglycaemia and fatal liver dysfunction.

Bortot B, Barbi E, Biffi S, Lunazzi G, Bussani R, Burlina A, Norbedo S, Ventura A, Carrozzi M, Severini GM
Dig Liver Dis 2009 Jul;41(7):494-9. Epub 2009 Feb 4 doi: 10.1016/j.dld.2008.11.013. PMID: 19195941

Variation in mitochondrial DNA levels in muscle from normal controls. Is depletion of mtDNA in patients with mitochondrial myopathy a distinct clinical syndrome.

Poulton J, Sewry C, Potter CG, Bougeron T, Chretien D, Wijburg FA, Morten KJ, Brown G
J Inherit Metab Dis 1995;18(1):4-20. doi: 10.1007/BF00711367. PMID: 7623440

See all (7)

Clinical prediction guides

Efficacy and Safety of Elamipretide in Individuals With Primary Mitochondrial Myopathy: The MMPOWER-3 Randomized Clinical Trial.

Outcomes of liver transplantation for mitochondrial respiratory chain disorder in children.

The Human Mitochondrial DNA Depletion Syndrome Gene MPV17 Encodes a Non-selective Channel That Modulates Membrane Potential.

Antonenkov VD, Isomursu A, Mennerich D, Vapola MH, Weiher H, Kietzmann T, Hiltunen JK
J Biol Chem 2015 May 29;290(22):13840-61. Epub 2015 Apr 10 doi: 10.1074/jbc.M114.608083. PMID: 25861990 Free PMC Article

Recent advances in thymidine kinase 2 (TK2) inhibitors and new perspectives for potential applications.

Priego EM, Karlsson A, Gago F, Camarasa MJ, Balzarini J, Pérez-Pérez MJ
Curr Pharm Des 2012;18(20):2981-94. doi: 10.2174/138161212800672787. PMID: 22571666

Early-onset liver mtDNA depletion and late-onset proteinuric nephropathy in Mpv17 knockout mice.

Viscomi C, Spinazzola A, Maggioni M, Fernandez-Vizarra E, Massa V, Pagano C, Vettor R, Mora M, Zeviani M
Hum Mol Genet 2009 Jan 1;18(1):12-26. Epub 2008 Sep 24 doi: 10.1093/hmg/ddn309. PMID: 18818194 Free PMC Article

See all (11)

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Mitochondrial DNA depletion syndrome 18(MTDPS18)

Definition

Clinical features

Professional guidelines

PubMed

Recent clinical studies

Etiology

Diagnosis

Therapy

Prognosis

Clinical prediction guides

Supplemental Content

Table of contents

Genetic Testing Registry

Clinical resources

Practice guidelines

Molecular resources

Consumer resources

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