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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): 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.
Elevated urinary quinolinic acid level
MedGen UID:
1052908
Concept ID:
CN377144
Finding
The amount of quinolinic acid in the urine, normalized for urine concentration, is above the upper limit of normal. Quinolinic acids is a pyridinedicarboxylic acid that is pyridine substituted by carboxy groups at positions 2 and 3. It is a metabolite of tryptophan.
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.
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.
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.
Falls
MedGen UID:
39084
Concept ID:
C0085639
Finding
A sudden movement downward, usually resulting in injury.
Areflexia
MedGen UID:
115943
Concept ID:
C0234146
Finding
Absence of neurologic reflexes such as the knee-jerk reaction.
Axonal degeneration
MedGen UID:
332464
Concept ID:
C1837496
Finding
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.
Scoliosis
MedGen UID:
11348
Concept ID:
C0036439
Disease or Syndrome
The presence of an abnormal lateral curvature of the spine.
Proximal muscle weakness
MedGen UID:
113169
Concept ID:
C0221629
Finding
A lack of strength of the proximal muscles.
Hand muscle atrophy
MedGen UID:
116091
Concept ID:
C0239830
Finding
Muscular atrophy involving the muscles of the hand.
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).
Distal muscle weakness
MedGen UID:
140883
Concept ID:
C0427065
Finding
Reduced strength of the musculature of the distal extremities.
Distal amyotrophy
MedGen UID:
338530
Concept ID:
C1848736
Disease or Syndrome
Muscular atrophy affecting muscles in the distal portions of the extremities.
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.
Tongue fasciculations
MedGen UID:
65987
Concept ID:
C0239548
Finding
Fasciculations or fibrillation affecting the tongue muscle.

Professional guidelines

PubMed

Han X, Li H, Deng J, Zhuo X, Liu Z, Xu M, Feng W, Chen S, Fang F
Neurol Sci 2024 Nov;45(11):5465-5480. Epub 2024 Jun 4 doi: 10.1007/s10072-024-07586-6. PMID: 38831166
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

Recent clinical studies

Etiology

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: 37268435Free PMC Article
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
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: 32703289Free PMC Article
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: 29052564Free PMC Article
Copeland WC
Crit Rev Biochem Mol Biol 2012 Jan-Feb;47(1):64-74. doi: 10.3109/10409238.2011.632763. PMID: 22176657Free PMC Article

Diagnosis

Jha R, Patel H, Dubey R, Goswami JN, Bhagwat C, Saini L, K Manokaran R, John BM, Kovilapu UB, Mohimen A, Saxena A, Sondhi V
J Child Neurol 2022 Mar;37(4):246-255. Epub 2022 Jan 5 doi: 10.1177/08830738211067065. PMID: 34986040
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
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: 32703289Free PMC Article
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: 29052564Free PMC Article
Treem WR, Sokol RJ
Semin Liver Dis 1998;18(3):237-53. doi: 10.1055/s-2007-1007160. PMID: 9773424

Therapy

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: 37268435Free PMC Article
Rothstein A, Lewis A
Neurology 2018 May 1;90(18):857-859. doi: 10.1212/WNL.0000000000005416. PMID: 29712807
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
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
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

Prognosis

Han X, Li H, Deng J, Zhuo X, Liu Z, Xu M, Feng W, Chen S, Fang F
Neurol Sci 2024 Nov;45(11):5465-5480. Epub 2024 Jun 4 doi: 10.1007/s10072-024-07586-6. PMID: 38831166
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: 32703289Free PMC Article
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: 31060578Free PMC Article
Rothstein A, Lewis A
Neurology 2018 May 1;90(18):857-859. doi: 10.1212/WNL.0000000000005416. PMID: 29712807
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: 22824774Free PMC Article

Clinical prediction guides

Hou J, Yun Y, Jeon B, Baek J, Kim S
Int J Mol Sci 2023 Sep 19;24(18) doi: 10.3390/ijms241814241. PMID: 37762556Free PMC Article
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: 37268435Free PMC Article
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
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: 25861990Free PMC Article
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

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