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Mitochondrial DNA depletion syndrome, myopathic form(MTDPS2)

MedGen UID:
461100
Concept ID:
C3149750
Disease or Syndrome
Synonyms: MITOCHONDRIAL DNA DEPLETION MYOPATHY, TK2-RELATED; Mitochondrial DNA depletion syndrome 2; MITOCHONDRIAL DNA DEPLETION SYNDROME 2 (MYOPATHIC TYPE); MTDPS2; TK2-Related Mitochondrial DNA Depletion Syndrome, Myopathic Form
SNOMED CT: TK2-related mitochondrial DNA depletion syndrome myopathic form (703527003); TK2-related mitochondrial deoxyribonucleic acid depletion syndrome myopathic form (703527003); Mitochondrial DNA depletion syndrome 2 myopathic type (703527003); TK2-related mitochondrial DNA depletion myopathy (703527003)
Modes of inheritance:
Autosomal recessive inheritance
MedGen UID:
141025
Concept ID:
C0441748
Intellectual Product
Source: Orphanet
A mode of inheritance that is observed for traits related to a gene encoded on one of the autosomes (i.e., the human chromosomes 1-22) in which a trait manifests in individuals with two pathogenic alleles, either homozygotes (two copies of the same mutant allele) or compound heterozygotes (whereby each copy of a gene has a distinct mutant allele).
 
Gene (location): TK2 (16q21)
 
Monarch Initiative: MONDO:0012301
OMIM®: 609560
Orphanet: ORPHA254875

Disease characteristics

TK2-related mitochondrial DNA (mtDNA) maintenance defect is a phenotypic continuum that ranges from severe to mild. To date, approximately 107 individuals with a molecularly confirmed diagnosis have been reported. Three main subtypes of presentation have been described: Infantile-onset myopathy with neurologic involvement and rapid progression to early death. Affected individuals experience progressive muscle weakness leading to respiratory failure. Some individuals develop dysarthria, dysphagia, and/or hearing loss. Cognitive function is typically spared. Juvenile/childhood onset with generalized proximal weakness and survival to at least 13 years. Late-/adult-onset myopathy with facial and limb weakness and mtDNA deletions. Some affected individuals develop respiratory insufficiency, chronic progressive external ophthalmoplegia, dysphagia, and dysarthria. [from GeneReviews]
Authors:
Julia Wang  |  Ayman W El-Hattab  |  Lee-Jun C Wong   view full author information

Additional descriptions

From OMIM
Mitochondrial DNA depletion syndrome-2 is an autosomal recessive disorder characterized primarily by childhood onset of muscle weakness associated with depletion of mtDNA in skeletal muscle. There is wide clinical variability; some patients have onset in infancy and show a rapidly progressive course with early death due to respiratory failure, whereas others have later childhood onset of a slowly progressive myopathy (Oskoui et al., 2006). For a discussion of genetic heterogeneity of autosomal recessive mtDNA depletion syndromes, see MTDPS1 (603041).  http://www.omim.org/entry/609560
From MedlinePlus Genetics
TK2-related mitochondrial DNA depletion syndrome, myopathic form (TK2-MDS) is an inherited condition that causes progressive muscle weakness (myopathy).

The signs and symptoms of TK2-MDS typically begin in early childhood. Development is usually normal early in life, but as muscle weakness progresses, people with TK2-MDS lose motor skills such as standing, walking, eating, and talking. Some affected individuals have increasing weakness in the muscles that control eye movement, leading to droopy eyelids (progressive external ophthalmoplegia).

Most often in TK2-MDS, the muscles are the only affected tissues; however, the liver may be enlarged (hepatomegaly), seizures can occur, and hearing loss caused by nerve damage in the inner ear (sensorineural hearing loss) may be present. Intelligence is usually not affected.

As the disorder worsens, the muscles that control breathing become weakened and affected individuals frequently have to rely on mechanical ventilation. Respiratory failure is the most common cause of death in people with TK2-MDS, often occurring in childhood. Rarely, the disorder progresses slowly and affected individuals survive into adolescence or adulthood.  https://medlineplus.gov/genetics/condition/tk2-related-mitochondrial-dna-depletion-syndrome-myopathic-form

Clinical features

From HPO
Aminoaciduria
MedGen UID:
116067
Concept ID:
C0238621
Disease or Syndrome
An increased concentration of an amino acid in the urine.
Limb muscle weakness
MedGen UID:
107956
Concept ID:
C0587246
Finding
Reduced strength and weakness of the muscles of the arms and legs.
Hearing impairment
MedGen UID:
235586
Concept ID:
C1384666
Disease or Syndrome
A decreased magnitude of the sensory perception of sound.
Seizure
MedGen UID:
20693
Concept ID:
C0036572
Sign or Symptom
A seizure is an intermittent abnormality of nervous system physiology characterised by a transient occurrence of signs and/or symptoms due to abnormal excessive or synchronous neuronal activity in the brain.
Cerebral atrophy
MedGen UID:
116012
Concept ID:
C0235946
Disease or Syndrome
Atrophy (wasting, decrease in size of cells or tissue) affecting the cerebrum.
Inability to walk
MedGen UID:
107860
Concept ID:
C0560046
Finding
Incapability to ambulate.
Loss of ability to walk in early childhood
MedGen UID:
324406
Concept ID:
C1835993
Finding
Delayed gross motor development
MedGen UID:
332508
Concept ID:
C1837658
Finding
A type of motor delay characterized by a delay in acquiring the ability to control the large muscles of the body for walking, running, sitting, and crawling.
Intellectual disability, progressive
MedGen UID:
337397
Concept ID:
C1846149
Mental or Behavioral Dysfunction
The term progressive intellectual disability should be used if intelligence decreases/deteriorates over time.
Irritability
MedGen UID:
397841
Concept ID:
C2700617
Mental Process
A proneness to anger, i.e., a tendency to become easily bothered or annoyed.
Abnormal basal ganglia morphology
MedGen UID:
1619147
Concept ID:
C4520981
Anatomical Abnormality
Abnormality of the basal ganglia.
Hypotonia
MedGen UID:
10133
Concept ID:
C0026827
Finding
Hypotonia is an abnormally low muscle tone (the amount of tension or resistance to movement in a muscle). Even when relaxed, muscles have a continuous and passive partial contraction which provides some resistance to passive stretching. Hypotonia thus manifests as diminished resistance to passive stretching. Hypotonia is not the same as muscle weakness, although the two conditions can co-exist.
Gowers sign
MedGen UID:
65865
Concept ID:
C0234182
Finding
A phenomenon whereby patients are not able to stand up without the use of the hands owing to weakness of the proximal muscles of the lower limbs.
Generalized amyotrophy
MedGen UID:
234650
Concept ID:
C1389113
Disease or Syndrome
Generalized (diffuse, unlocalized) amyotrophy (muscle atrophy) affecting multiple muscles.
Facial diplegia
MedGen UID:
322796
Concept ID:
C1836003
Finding
Facial diplegia refers to bilateral facial palsy (bilateral facial palsy is much rarer than unilateral facial palsy).
Generalized hypotonia
MedGen UID:
346841
Concept ID:
C1858120
Finding
Generalized muscular hypotonia (abnormally low muscle tone).
Ragged-red muscle fibers
MedGen UID:
477048
Concept ID:
C3275417
Finding
An abnormal appearance of muscle fibers observed on muscle biopsy. Ragged red fibers can be visualized with Gomori trichrome staining as irregular and intensely red subsarcolemmal zones, whereas the normal myofibrils are green. The margins of affect fibers appear red and ragged. The ragged-red is due to the accumulation of abnormal mitochondria below the plasma membrane of the muscle fiber, leading to the appearance of a red rim and speckled sarcoplasm.
Depletion of mitochondrial DNA in muscle tissue
MedGen UID:
867163
Concept ID:
C4021521
Finding
EMG: myopathic abnormalities
MedGen UID:
867362
Concept ID:
C4021726
Pathologic Function
The presence of abnormal electromyographic patterns indicative of myopathy, such as small-short polyphasic motor unit potentials.
Respiratory insufficiency due to muscle weakness
MedGen UID:
812797
Concept ID:
C3806467
Finding
Lactic acidosis
MedGen UID:
1717
Concept ID:
C0001125
Disease or Syndrome
An abnormal buildup of lactic acid in the body, leading to acidification of the blood and other bodily fluids.
Elevated circulating creatine kinase concentration
MedGen UID:
69128
Concept ID:
C0241005
Finding
An elevation of the level of the enzyme creatine kinase (also known as creatine phosphokinase (CK; EC 2.7.3.2) in the blood. CK levels can be elevated in a number of clinical disorders such as myocardial infarction, rhabdomyolysis, and muscular dystrophy.
Decreased activity of mitochondrial complex I
MedGen UID:
393796
Concept ID:
C2677650
Finding
A reduction in the activity of the mitochondrial respiratory chain complex I, which is part of the electron transport chain in mitochondria.
Decreased activity of mitochondrial complex III
MedGen UID:
460434
Concept ID:
C3149083
Finding
A reduction in the activity of the mitochondrial respiratory chain complex III, which is part of the electron transport chain in mitochondria.
Decreased activity of mitochondrial complex IV
MedGen UID:
866520
Concept ID:
C4020800
Finding
A reduction in the activity of the mitochondrial respiratory chain complex IV, which is part of the electron transport chain in mitochondria.
Decreased activity of mitochondrial ATP synthase complex
MedGen UID:
892442
Concept ID:
C4023125
Finding
A reduction in the activity of the mitochondrial proton-transporting ATP synthase complex, which makes ATP via oxidative phosphorylation, and is sometimes described as Complex V of the electron transport chain.

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
  • CROGVMitochondrial DNA depletion syndrome, myopathic form
Follow this link to review classifications for Mitochondrial DNA depletion syndrome, myopathic form in Orphanet.

Recent clinical studies

Etiology

Sukhudyan B, Gevorgyan A, Sarkissian A, Boltshauser E
Eur J Paediatr Neurol 2019 May;23(3):537-540. Epub 2019 Feb 14 doi: 10.1016/j.ejpn.2019.02.002. PMID: 30799093
Chanprasert S, Wang J, Weng SW, Enns GM, Boué DR, Wong BL, Mendell JR, Perry DA, Sahenk Z, Craigen WJ, Alcala FJ, Pascual JM, Melancon S, Zhang VW, Scaglia F, Wong LJ
Mol Genet Metab 2013 Sep-Oct;110(1-2):153-61. Epub 2013 Jul 17 doi: 10.1016/j.ymgme.2013.07.009. PMID: 23932787
Montero R, Grazina M, López-Gallardo E, Montoya J, Briones P, Navarro-Sastre A, Land JM, Hargreaves IP, Artuch R; Coenzyme Q₁₀ Deficiency Study Group
Mitochondrion 2013 Jul;13(4):337-41. Epub 2013 Apr 11 doi: 10.1016/j.mito.2013.04.001. PMID: 23583954
Navarro-Sastre A, Tort F, Garcia-Villoria J, Pons MR, Nascimento A, Colomer J, Campistol J, Yoldi ME, López-Gallardo E, Montoya J, Unceta M, Martinez MJ, Briones P, Ribes A
Mol Genet Metab 2012 Nov;107(3):409-15. Epub 2012 Aug 31 doi: 10.1016/j.ymgme.2012.08.018. PMID: 22980518

Diagnosis

Sukhudyan B, Gevorgyan A, Sarkissian A, Boltshauser E
Eur J Paediatr Neurol 2019 May;23(3):537-540. Epub 2019 Feb 14 doi: 10.1016/j.ejpn.2019.02.002. PMID: 30799093
Wang J, Kim E, Dai H, Stefans V, Vogel H, Al Jasmi F, Schrier Vergano SA, Castro D, Bernes S, Bhambhani V, Long C, El-Hattab AW, Wong LJ
Mol Genet Metab 2018 Jun;124(2):124-130. Epub 2018 Apr 28 doi: 10.1016/j.ymgme.2018.04.012. PMID: 29735374
Martín-Hernández E, García-Silva MT, Quijada-Fraile P, Rodríguez-García ME, Rivera H, Hernández-Laín A, Coca-Robinot D, Fernández-Toral J, Arenas J, Martín MA, Martínez-Azorín F
Pediatr Dev Pathol 2017 Sep-Oct;20(5):416-420. Epub 2017 Jan 25 doi: 10.1177/1093526616686439. PMID: 28812460
Finsterer J, Ahting U
Can J Neurol Sci 2013 Sep;40(5):635-44. doi: 10.1017/s0317167100014852. PMID: 23968935
Navarro-Sastre A, Tort F, Garcia-Villoria J, Pons MR, Nascimento A, Colomer J, Campistol J, Yoldi ME, López-Gallardo E, Montoya J, Unceta M, Martinez MJ, Briones P, Ribes A
Mol Genet Metab 2012 Nov;107(3):409-15. Epub 2012 Aug 31 doi: 10.1016/j.ymgme.2012.08.018. PMID: 22980518

Therapy

Vita G, Vita GL, Musumeci O, Rodolico C, Messina S
Neurol Sci 2019 Apr;40(4):671-681. Epub 2019 Feb 25 doi: 10.1007/s10072-019-03764-z. PMID: 30805745
Rothstein A, Lewis A
Neurology 2018 May 1;90(18):857-859. doi: 10.1212/WNL.0000000000005416. PMID: 29712807

Prognosis

Wang J, Kim E, Dai H, Stefans V, Vogel H, Al Jasmi F, Schrier Vergano SA, Castro D, Bernes S, Bhambhani V, Long C, El-Hattab AW, Wong LJ
Mol Genet Metab 2018 Jun;124(2):124-130. Epub 2018 Apr 28 doi: 10.1016/j.ymgme.2018.04.012. PMID: 29735374
Rothstein A, Lewis A
Neurology 2018 May 1;90(18):857-859. doi: 10.1212/WNL.0000000000005416. PMID: 29712807

Clinical prediction guides

Sukhudyan B, Gevorgyan A, Sarkissian A, Boltshauser E
Eur J Paediatr Neurol 2019 May;23(3):537-540. Epub 2019 Feb 14 doi: 10.1016/j.ejpn.2019.02.002. PMID: 30799093
Chanprasert S, Wang J, Weng SW, Enns GM, Boué DR, Wong BL, Mendell JR, Perry DA, Sahenk Z, Craigen WJ, Alcala FJ, Pascual JM, Melancon S, Zhang VW, Scaglia F, Wong LJ
Mol Genet Metab 2013 Sep-Oct;110(1-2):153-61. Epub 2013 Jul 17 doi: 10.1016/j.ymgme.2013.07.009. PMID: 23932787

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