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 ... 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 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).
Boustany et al. (1983) reported an infant girl with a fatal mitochondrial myopathy characterized by progressive generalized hypotonia, progressive external ophthalmoplegia, and severe lactic acidosis. Electron microscopy of skeletal muscle in the proband showed marked proliferation of enlarged ... Boustany et al. (1983) reported an infant girl with a fatal mitochondrial myopathy characterized by progressive generalized hypotonia, progressive external ophthalmoplegia, and severe lactic acidosis. Electron microscopy of skeletal muscle in the proband showed marked proliferation of enlarged mitochondria, many containing concentric rings of cristae, and biochemical studies showed severely decreased cytochrome c oxidase activity (less than 1% of normal). Mitochondria from kidney, liver, heart, lung, and brain examined postmortem had normal cytochromes and preserved cytochrome c oxidase activity. A second cousin, related through the maternal grandfather, died at 9 months of hepatic failure with generalized aminoaciduria, but without lactic acidosis or muscle involvement, consistent with the hepatocerebral form of the disorder. In the second cousin, liver biopsy showed enlarged mitochondria and decreased cytochrome c oxidase activity (less than 10% of normal). Kidney mitochondria showed normal cytochromes. In an addendum, the authors noted that a sister of the proband presented at 2 months of age with hypotonia, ophthalmoplegia, and lactic acidosis. Findings of electron microscopy and biochemical analysis of muscle and liver biopsy specimens were identical to those in the proband. In tissue samples from the original proband and second cousin reported by Boustany et al. (1983), Moraes et al. (1991) found a quantitative defect of mtDNA restricted to skeletal muscle (2% of control values) in the proband, and involving liver (12% of control values) in the second cousin. A third unrelated patient had mtDNA deficiency in muscle only (3% of control values), and a fourth in muscle and kidney only (17% control values in both tissues). There was no evidence of an mtDNA mutation in the areas surrounding the origin of replication of the heavy strand (H-strand) or light strand (L-strand) of mtDNA. Moraes et al. (1991) concluded that affected individuals exhibit variable levels of mtDNA depletion (up to 98%) in affected tissues, while unaffected tissues have relatively normal levels of mtDNA. In addition, different tissues may be involved in related patients. Tritschler et al. (1992) reported 5 children with mitochondrial myopathy manifesting within or soon after the first year of life. Muscle biopsies showed ragged-red fibers and decreased respiratory chain activity associated with a decreased amount (2 to 34% of normal) of muscle mitochondrial DNA. Vila et al. (2003) described an unusual case of a 14-year-old boy with the myopathic form of the disorder who was a compound heterozygote for mutations in the TK2 gene. Symptoms were manifest since birth, and muscle examination at ages 3 and 8 years showed ragged-red fibers, deficiency of cytochrome c oxidase, and severe depletion of mtDNA. Activities of mitochondrial respiratory chain enzymes at that time were normal. Reexamination at age 14 years showed progression of the disease and muscle biopsy showed severe muscle atrophy, no mtDNA depletion, and decreased activities of all respiratory chain enzymes. Vila et al. (2003) noted that the patient had an unusually long survival time and suggested that mtDNA-depleted muscle fibers had become atrophic or died over time, while fibers with normal mtDNA had survived. Respiratory enzyme deficiency was attributed to accumulation of somatic mitochondrial mutations. In a study of skeletal muscle fibers from 2 sibs with mtDNA depletion myopathy due to TK2 mutations, who were previously reported by Mancuso et al. (2002), Durham et al. (2005) determined that muscle fiber mtDNA density of 0.01 mtDNA per cubic micrometer was the minimal amount of mtDNA required to maintain residual cytochrome c oxidase (COX) activity. Oskoui et al. (2006) reported 4 unrelated patients with the myopathic form of mtDNA depletion syndrome due to TK2 mutations. There was significant clinical variability: 1 patient had a rapidly progressive course with death at age 19 months, whereas the others showed a more protracted course. One died at age 6 years and another at age 16 years. The fourth child was alive at age 9 years and could walk independently with lumbar lordosis and toe walking. She had facial diplegia, decreased muscle mass, diffuse muscle weakness, and normal pulmonary function. Behin et al. (2012) reported 3 unrelated patients with genetically confirmed MTDPS2 who had a milder course and slower progression than usually associated with this disorder. Although all patients reported some form of hypotonia, early fatigue, or delayed walking in early childhood and 2 had proximal muscle weakness in childhood, all presented in their early thirties with more significant impairment. Features included waddling gait, distal and proximal muscle weakness, axial weakness, and respiratory insufficiency. One patient was wheelchair-bound and 1 could not walk for more than 15 minutes. More variable features included ptosis, hypophonia, and facial weakness. Cognition, hearing, and cardiac function were normal in all patients. EMG showed a myogenic pattern, and muscle biopsies showed dystrophic changes consistent with a mitochondrial myopathy, including deficiencies of complexes I, III, and IV. Muscle mtDNA depletion was apparent, with mtDNA levels at about 30% of normal controls. This report expanded the phenotypic spectrum of MTDPS2 to include patients with much slower progression, which may have been due to better preservation of residual muscle mtDNA compared to more severely affected patients. However, there were no genotype/phenotype correlations, as 2 patients were homozygous for a previously reported mutation (T108M; 188250.0003) that had been observed in children with a more severe form of the disorder.
In patients with the myopathic form of mtDNA depletion syndrome, Saada et al. (2001) identified mutations in the mitochondrial thymidine kinase gene, H90N and I181N, now H163N (188250.0001) and I254N (188250.0002), respectively.
To characterize further the ... In patients with the myopathic form of mtDNA depletion syndrome, Saada et al. (2001) identified mutations in the mitochondrial thymidine kinase gene, H90N and I181N, now H163N (188250.0001) and I254N (188250.0002), respectively. To characterize further the frequency and clinical spectrum of the causative mutations, Mancuso et al. (2002) screened 20 patients with myopathic mtDNA depletion syndrome. No patient had mutations in the deoxyguanosine kinase gene (DGUOK; 601465), but 4 patients from 2 families had TK2 mutations. Two sibs were compound heterozygotes for a previously reported H163N mutation (188250.0001) and a novel T77M mutation (now T150M; 188250.0003). Another pair of sibs harbored a homozygous I22M mutation (now I95M; 188250.0004), and 1 had evidence of lower motor neuron disease. Thus, the clinical expression of TK2 mutations is not limited to myopathy. The pathogenicity of these mutations was confirmed by reduced TK2 activity in muscle (28 to 37% of controls). In a family originally described by Tritschler et al. (1992) in which 3 sibs had myopathic mtDNA depletion syndrome, Mancuso et al. (2003) identified homozygosity for the T150M mutation. The patients had 80 to 90% mtDNA depletion in muscle biopsy specimens, and all died by age 40 months. The authors noted that exon 5 is a hotspot for TK2 mutations.
TK2-related mitochondrial DNA (mtDNA) depletion syndrome is a phenotypic continuum that ranges from severe to mild. The most typical presentation, which occurs in infants and children, is progressive muscle disease characterized by generalized hypotonia, proximal muscle weakness, loss of previously acquired motor skills, poor feeding, and respiratory difficulties leading to respiratory failure and death within a few years after diagnosis. ...
DiagnosisClinical DiagnosisTK2-related mitochondrial DNA (mtDNA) depletion syndrome is a phenotypic continuum that ranges from severe to mild. The most typical presentation, which occurs in infants and children, is progressive muscle disease characterized by generalized hypotonia, proximal muscle weakness, loss of previously acquired motor skills, poor feeding, and respiratory difficulties leading to respiratory failure and death within a few years after diagnosis. Other severe presentations include the following:Rapidly progressive proximal muscle weakness in the newborn period with encephalopathy, epilepsy, and early death [Lesko et al 2010]Spinal muscular atrophy-like presentation [Pons et al 1996]Progressive myopathy with dystrophic changes [Collins et al 2009]Sensorineural hearing loss at disease onset associated with progressive mitochondrial myopathy [Martí et al 2010]Hepatomegaly and elevated liver enzymes associated with progressive mitochondrial myopathy [Zhang et al 2010] Milder presentations include the following:Late-onset proximal muscle weakness and prolonged survival [Oskoui et al 2006]Adult-onset forms with progressive mitochondrial myopathy [Béhin et al 2012]. In addition to severe mtDNA depletion, multiple mtDNA deletions are also observed.TestingSerum creatine phosphokinase (CK) concentration is usually elevated 5-10 times the upper limit of normal; however, in affected individuals with severe muscle wasting, serum CK concentration can be normal.Note: Serum lactate as well as serum aminotransferases are usually normal. Electromyography (EMG) is useful in distinguishing between a myopathic and neurogenic disorder; however, the findings are nonspecific as they occur in all myogenic disorders.Pathology. Histopathologic findings on skeletal muscle include prominent variance in fiber size, sarcoplasmic vacuoles, and increased connective tissue. Ragged red fibers are invariably present. Succinate dehydrogenase (SDH) activity is increased; cytochrome c oxidase (COX) activity is low to absent. Electron microscopy shows abnormal mitochondria with circular cristae [Lesko et al 2010]. Mitochondrial DNA (mtDNA) content (copy number) analysis in skeletal muscle. Mitochondrial DNA content is severely reduced, usually from 5% to 30% of tissue- and age-matched controls [Dimmock et al 2010]; however, mtDNA content ranging from 60% to normal has been reported in rare cases [Vilà et al 2003, Leshinsky-Silver et al 2008]. Electron transport chain (ETC) activity in skeletal muscle. Assays of ETC activity typically show decreased activity of multiple complexes with complex I, I+III, and IV being the most affected [Pons et al 1996, Mancuso et al 2002, Wang et al 2005, Galbiati et al 2006, Martí et al 2010, Béhin et al 2012].Molecular Genetic TestingGene. TK2 is the only gene in which mutations are known to cause TK2-related mitochondrial DNA depletion syndrome, myopathic form with isolated or highly predominant myopathy. Table 1. Summary of Molecular Genetic Testing Used in TK2-Related Mitochondrial DNA Depletion Syndrome, Myopathic FormView in own windowGene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method 1Test AvailabilityTK2Sequence analysis / mutation scanning 2Sequence variants 3>99%ClinicalDeletion / duplication analysis 4Exonic or whole-gene deletions<1% 51. The ability of the test method used to detect a mutation that is present in the indicated gene2. Sequence analysis and mutation scanning of the entire gene can have similar mutation detection frequencies; however, mutation detection rates for mutation scanning may vary considerably between laboratories depending on the specific protocol used.3. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected.4. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.5. One of approximately 45 affected individuals reported to date was found to have a 5.8-kb deletion in TK2 by using custom oligonucleotide based array CGH [Zhang et al 2010]. The deletion extended from the 5’UTR to intron 2 of TK2.Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.Information on specific allelic variants may be available in Molecular Genetics (see Table A. Genes and Databases and/or Pathologic allelic variants).Testing StrategyTo confirm/establish the diagnosis in a proband Single gene testing. One strategy for molecular diagnosis of an infant or child with progressive proximal muscle weakness and elevated CK concentration is the following: 1.Perform a skeletal muscle biopsy. Because biallelic TK2 mutations essentially impair the mtDNA content in muscle resulting in isolated progressive muscle weakness without symptoms or metabolic findings that suggest mitochondrial disease, the mtDNA depletion syndrome may well be missed if a muscle biopsy is not performed. If histopathologic and biochemical findings on skeletal muscle biopsy suggest mitochondrial disease and mtDNA depletion, 2.Perform mtDNA content analysis in skeletal muscle. If mtDNA copy number is severely reduced (typically <20% of age- and tissue-matched healthy controls), 3.Perform sequence analysis of the entire coding and exon/intron junction regions of TK2. a.If compound heterozygous or homozygous deleterious mutations are identified, the diagnosis is confirmed.b.If sequence analysis does not identify two compound heterozygous or homozygous deleterious mutations, deletion/duplication analysis should be considered [Zhang et al 2010].Multi-gene panel. If the clinical presentation is highly suspicious for mtDNA depletion syndrome and it is not possible to obtain a muscle biopsy, molecular genetic testing using a panel of genes known to cause mtDNA depletion syndrome should be performed. See also Differential Diagnosis.Carrier testing for at-risk relatives requires prior identification of the disease-causing mutations in the family. Note: Carriers are heterozygotes for this autosomal recessive disorder and are not at risk of developing the disorder. Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutations in the family. Genetically Related (Allelic) DisorderTwo individuals with adult-onset chronic progressive external ophthalmoplegia and proximal muscle weakness who had biallelic TK2 mutations were found to have multiple mtDNA deletions in skeletal muscle by Southern blot analysis; no mtDNA depletion was observed [Tyynismaa et al 2012].
The clinical presentation of TK2-related mtDNA depletion syndrome is variable; as understanding of the disorder increases, the phenotype continues to broaden (Table 2). ...
Natural History The clinical presentation of TK2-related mtDNA depletion syndrome is variable; as understanding of the disorder increases, the phenotype continues to broaden (Table 2). To date, approximately 45 patients with molecularly confirmed TK2-related mtDNA depletion syndrome have been reported [Pons et al 1996, Galbiati et al 2006, Oskoui et al 2006, Blakely et al 2008, Gotz et al 2008, Collins et al 2009, Lesko et al 2010, Martí et al 2010, Zhang et al 2010, Béhin et al 2012]. The prenatal and perinatal histories are usually unremarkable; onset is typically in the first two years of life. Initial development is normal, followed by gradual onset of hypotonia. Subsequently generalized fatigue, decreased physical stamina, proximal muscle weakness (manifest as difficulty getting to standing or walking), and feeding difficulties develop. Muscle atrophy becomes evident [Martí et al 2010]. Some children develop bulbar weakness including dysarthria and dysphagia. Previously acquired motor skills are lost.Cognitive function is typically spared. Muscle weakness rapidly progresses leading to respiratory failure and death within a few years after onset. Most children succumb to complications of respiratory muscle weakness; several are ventilator dependent before age six years. The most common cause of death is pulmonary infection.Only a handful of affected individuals have survived to late childhood and adolescence.Less frequent manifestations. TK2 mutations were previously thought to cause a purely myopathic form of mtDNA depletion syndrome; however, recent reports have expanded the clinical spectrum to include sensorineural hearing loss, chronic external ophthalmoplegia, early severe muscle weakness with encephalopathy and intractable epilepsy, and late-onset proximal muscle weakness and prolonged survival. In addition, one individual whose EMG showed denervation changes had a spinal muscular atrophy type 3-like presentation [Pons et al 1996].During the first year of life a few children with molecularly confirmed TK2-related mtDNA depletion syndrome have developed muscle weakness, elevated serum concentrations of aminotransferases and CK, and mtDNA depletion in muscle and liver. The observed elevation in serum transaminases may reflect skeletal muscle involvement [Zhang et al 2010].Table 2. Clinical Manifestations of TK2-Related mtDNA Depletion SyndromeView in own windowClinical ManifestationsFrequencyAge of onsetAge 0-2 years38/45 (84%)Age >2 years7/45 (16%)Neurologic and neuromuscular findingsHypotonia, muscle weakness45/45 (100%)Progressive external ophthalmoplegia8/45 (17%)Seizures6/45 (13%)Dysarthria3/45 (6%)Facial muscle weakness3/45 (6%)Dysphagia2/45 (4%)Intellectual disability2/45 (4%)OtherLiver dysfunction4/45 (8%)
Mitochondrial DNA depletion syndromes. The clinical presentation of this group of disorders (Table 3) is protean and may have multi-organ involvement. ...
Differential Diagnosis Mitochondrial DNA depletion syndromes. The clinical presentation of this group of disorders (Table 3) is protean and may have multi-organ involvement. Biallelic mutations in one of the following genes can cause encephalopathy as well as myopathy:SUCLA2 (encoding ATP-dependent succinyl CoA synthase)SUCLG1 (encoding GTP-dependent succinyl CoA synthase)RRM2B (encoding p53-induced ribonucleotide reductase B subunit)The diagnosis is based on histopathology and mtDNA content analysis of affected tissues followed by molecular genetic testing.Biallelic mutations in TK2 account for approximately 20% of the myopathic form of mtDNA depletion syndrome [Martí et al 2010]. Table 3. Mitochondrial DNA Depletion Syndrome: OMIM Phenotypic SeriesView in own windowPhenotypePhenotype MIM NumberGene / LocusGene / Locus MIM NumberMitochondrial DNA depletion syndrome 1 (MNGIE type) 603041 TYMP131222Mitochondrial DNA depletion syndrome 2 (myopathic type) 609560 TK2188250Mitochondrial DNA depletion syndrome 3 (hepatocerebral type) 251880 DGUOK601465Mitochondrial DNA depletion syndrome 4A (Alpers type) 203700 POLG 174763Mitochondrial DNA depletion syndrome 4B (MNGIE type) 613662 POLG174763Mitochondrial DNA depletion syndrome 5 (encephalomyopathic with methylmalonic aciduria) 612073 SUCLA2603921Mitochondrial DNA depletion syndrome 6 (hepatocerebral type) 256810MPV17137960Mitochondrial DNA depletion syndrome 7 (hepatocerebral type) 271245C10orf2606075Mitochondrial DNA depletion syndrome 8A (encephalomyopathic type with renal tubulopathy) 612075RRM2B604712Mitochondrial DNA depletion syndrome 8B (MNGIE type) 612075RRM2B604712Mitochondrial DNA depletion syndrome 9 (encephalomyopathic type with methylmalonic aciduria) 245400SUCLG1611224From Online Mendelian Inheritance in ManThe differential diagnosis of TK2-related mtDNA depletion syndrome includes disorders that cause hypotonia and progressive proximal muscle weakness: Prader-Willi syndrome (PWS) is characterized by severe hypotonia and feeding difficulties in early infancy followed by improvement of muscle tone and excessive eating and obesity. PWS is caused by absence of the paternally derived PWS/Angelman syndrome (AS) region of chromosome 15 by one of several genetic mechanisms.Spinal muscular atrophy (SMA) is characterized by degeneration of the anterior horn cells of spinal cord. The age of onset ranges from early infancy to adulthood. Affected individuals typically develop severe and progressive muscle weakness involving respiratory muscles. The diagnosis of SMA is based on molecular genetic testing of the two genes associated with SMA, SMN1 and SMN2. Congenital myopathies (including X-linked myotubular myopathy, central core disease, centronuclear myopathy, and nemaline myopathy) typically have normal or near-normal serum CK concentration and histologic evidence on muscle biopsy of developmental/structural muscle changes rather than dystrophic changes. The diagnosis is suggested by muscle biopsy and often can be confirmed by the results of molecular genetic testing.Pompe disease (glycogen storage disease 2) is characterized by progressive proximal muscle weakness early in the first few months of life accompanied with hypertrophic cardiomyopathy. The diagnosis is based on complete deficiency of activity of the enzyme alpha-glucosidase (GAA) (also called acid maltase) or detection of biallelic GAA mutations.Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).
To establish the extent of disease and needs of an individual diagnosed with TK2-related mitochondrial DNA depletion syndrome, myopathic form, the following evaluations are recommended:...
ManagementEvaluations Following Initial Diagnosis To establish the extent of disease and needs of an individual diagnosed with TK2-related mitochondrial DNA depletion syndrome, myopathic form, the following evaluations are recommended:Neurology consultation with comprehensive neurologic examinationDevelopmental evaluationOccupational therapy assessment, including oromotor functions such as chewing and swallowing Physical therapy consultationConsultation with a pediatric pulmonologist to evaluate pulmonary function Brain MRI in patients with encephalopathy or seizuresMedical genetics consultationTreatment of ManifestationsCurrently there is no definitive treatment. Management should involve a multidisciplinary team. Feeding difficulties should be managed aggressively, including use of a nasogastric tube or gastrostomy tube when the risk of aspiration is high.Physical therapy can help maintain muscle function and prevent joint contractures. A physical medicine and rehabilitation (PM&R) specialist can be helpful for individuals with walking difficulty. As mobility becomes increasingly restricted, the use of a wheelchair should be considered. Early referral to a pediatric pulmonologist is recommended for assessment of pulmonary function and the need for chest physiotherapy to improve pulmonary function and reduce the risk of pulmonary infection. Pulmonary infection should be treated urgently in a standard manner to prevent deterioration in pulmonary function capacity. Once the patient becomes ventilator dependent due to respiratory compromise, chest physiotherapy can help reduce the risk of pulmonary infection. SurveillanceAlthough no clinical guidelines are available, treating physicians should consider the following:Beginning in infancy: periodic neurodevelopmental assessment and speech/language evaluation by a developmental pediatrician or pediatric neurologistSoon after diagnosis is established: Routine assessments of nutritional status, weight gain, and growth parametersRoutine pulmonary function tests, including assessment of blood gases, to monitor for respiratory insufficiency (alveolar hypoventilation and chronic hypercapnia) Evaluation of Relatives at RiskSee Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes. Therapies Under InvestigationSearch ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED....
Molecular GeneticsInformation in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.Table A. TK2-Related Mitochondrial DNA Depletion Syndrome, Myopathic Form: Genes and DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDTK216q21Thymidine kinase 2, mitochondrialTK2 homepage - Mendelian genesTK2Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for TK2-Related Mitochondrial DNA Depletion Syndrome, Myopathic Form (View All in OMIM) View in own window 188250THYMIDINE KINASE, MITOCHONDRIAL; TK2 609560MITOCHONDRIAL DNA DEPLETION SYNDROME 2 (MYOPATHIC TYPE); MTDPS2Molecular Genetic PathogenesisMitochondrial DNA (mtDNA) depletion syndrome is characterized by a significant reduction in the number of copies of mtDNA in one or more tissues. TK2, encoding thymidine kinase 2 (which mediates the first and rate-limiting step in the phosphorylation of deoxypyrimidine nucleosides in the mitochondrial matrix), was the first gene to be associated with the myopathic form of mtDNA depletion syndrome. To date, biallelic mutations in TK2 account for approximately 20% of myopathic mtDNA depletion syndrome [Martí et al 2010]. Normal allelic variants. TK2 comprises ten coding exons. Alternate splicing results in multiple transcript variants (see Table A, Gene Symbol). The longest transcript variant is NM_004614.4.Pathologic allelic variants. To date, 32 different TK2 mutations have been reported in persons with myopathic mtDNA depletion (Table 4) [Pons et al 1996, Galbiati et al 2006, Oskoui et al 2006, Blakely et al 2008, Gotz et al 2008, Collins et al 2009, Lesko et al 2010, Martí et al 2010, Zhang et al 2010, Béhin et al 2012].About 70% of reported mutations are missense; the remainder include nonsense and splice site mutations and small (1-4 nucleotide) deletions and insertions. A large deletion spanning 5.8 kb has been reported [Zhang et al 2010].All mutations are private except for the two mutations p.Arg130Trp and p.Arg183Trp observed in affected individuals from Finland (Table 4) — most likely founder mutations in the Finnish population [Gotz et al 2008].Table 4. Selected TK2 Pathologic Allelic VariantsView in own windowType of Pathologic mtDNA VariantDNA Nucleotide Change (Alias 1)Protein Amino Acid Change Reference SequencesMissense mutationc.133C>Tp.Gln45XNM_004614.4 NP_004605.4c.159C>Gp.Ile53Metc.173A>Gp.Asn58Serc.191C>Tp.Thr64Metc.198C>Gp.Cys66Trpc.268C>Tp.Arg90Cysc.278A>Gp.Asn93Serc.323C>Tp.Thr108Metc.334T>Ap.Tyr112Asnc.361C>Ap.His121Asnc.373C>Tp.Gln125Xc.389G>Ap.Arg130Glnc.388C>Tp.Arg130Trpc.416C>Tp.Ala139Val c.547C>Gp.Arg183Glyc.547C>Tp.Arg183Trpc.562A>Gp.Thr188Alac.575G>Ap.Arg192Lysc.635T>Ap.Ile212Asnc.644T>Cp.Leu215Proc.760C>Tp.Arg254XSplicing mutationc.156+2T>CSmall deletion/insertionc.129_132delAGAAp.Lys43Asnfs*9 c.604_606delAAGp.Lys202delc.8dupTp.Trp4Valfs*40 c.142dupGp.GluGly48fs*102c.150dupAp.Ser51Ilefs*99c.218_219dupCGp.Thr74Argfs*7c.335_336dupATp.Val113Metfs*20c.360_361delGCinsAAp.His121AsnGross deletionc.1-495_283-2899del (5.8kb del incl exons1-2)Complex rearrangementc.-270+2561delins;7287-7335inv 2See Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www.hgvs.org). 1. Variant designation that does not conform to current naming conventions2. Stewart et al [2011]Normal gene product. The TK2 isoform is 265 amino acids. TK2 encodes thymidine kinase 2, the first and rate-limiting step in phosphorylation of deoxypyrimidine nucleosides (salvage pathway) in the mitochondrial matrix. Deoxynucloside triphosphate (dNTPs) can be synthesized via either the de novo pathway which is cell-cycle regulated or via the salvage pathway in which dNTPs are produced by utilizing pre-existing deoxynucleosides to synthesize DNA precursors. Both pathways may be required for mtDNA maintenance in post-mitotic tissues. Since mtDNA synthesis is continuous throughout the cell cycle, thymidine kinase 2 becomes indispensable for mtDNA maintenance.Abnormal gene product. TK2 mutations result in dysfunction of the enzyme thymidine kinase 2 resulting in impaired synthesis of mtDNA precursors leading to mtDNA depletion.