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Spinocerebellar Ataxia with Axonal Neuropathy, Autosomal Recessive

Synonym: SCAN1

, BSc, , MD, Dr Med Sci, FRCPCH, , MD, PhD, and , MD, PhD.

Author Information

Initial Posting: ; Last Revision: December 20, 2012.

Estimated reading time: 13 minutes


Clinical characteristics.

Spinocerebellar ataxia with axonal neuropathy (SCAN1) is characterized by late-childhood-onset slowly progressive cerebellar ataxia, followed by areflexia and signs of peripheral neuropathy. Gaze nystagmus and cerebellar dysarthria usually develop after the onset of ataxic gait. As the disease advances, pain and touch sensation become impaired in the hands and legs; vibration sense disappears in hands and lower thigh. Individuals with advanced disease develop a steppage gait and pes cavus and eventually become wheelchair dependent.


Diagnosis is based on clinical findings, family history, MRI, and nerve conduction studies (NCS)/EMG. TDP1 is the only gene in which pathogenic variants are known to cause SCAN1.


Treatment of manifestations: Prostheses, walking aids, and wheelchairs help mobility; physical therapy may help maintain a more active lifestyle.

Surveillance: Routine visits to the neurologist.

Agents/circumstances to avoid: Because TDP1 codes for a DNA repair enzyme, genotoxic anti-cancer drugs such as camptothecins (e.g., irinotecan and topotecan) and bleomycin are likely to be extremely harmful and possibly fatal; exposure to radiation is likely to be extremely harmful and possibly fatal.

Genetic counseling.

SCAN1 is inherited in an autosomal recessive manner. The parents of an affected child are obligate heterozygotes and therefore carry one mutated allele. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3. Carrier testing for at-risk family members is possible if the pathogenic variants in the family have been identified. Prenatal testing for pregnancies at increased risk is possible through laboratories offering either testing for the gene of interest or custom testing.


Clinical Diagnosis

Spinocerebellar ataxia with axonal neuropathy (SCAN1) is suspected in individuals with the following findings [Takashima et al 2002]:

  • Cerebellar ataxia and areflexia followed by signs of peripheral neuropathy
  • Late childhood onset (age 13-15 years)
  • Slow progression
  • Absence of:
    • Oculomotor apraxia
    • Extraneurologic findings common in ataxia-telangiectasia (telangiectasias, immunodeficiency, and cancer predisposition)
  • Family history consistent with autosomal recessive inheritance

MRI. Cerebellar atrophy especially of the vermis is present in all affected individuals [Takashima et al 2002].

Nerve conduction studies (NCS)/EMG. Signs of axonal neuropathy are found on NCS/EMG in all individuals with SCAN1 [Takashima et al 2002].


Decreased serum concentration of albumin and increased serum concentration of cholesterol (hypercholesterolemia) may support the diagnosis of SCAN1 [Takashima et al 2002].

Nerve biopsy confirms axonal neuropathy [Takashima et al 2002].

Molecular Genetic Testing

Gene. TDP1 is the only gene in which pathogenic variants are known to cause SCAN1 [Takashima et al 2002].

Table 1.

Molecular Genetic Testing Used in Autosomal Recessive Spinocerebellar Ataxia with Axonal Neuropathy

Gene 1Test MethodAllelic Variants Detected 2Variant Detection Frequency by Test Method 3
TDP1Sequence analysis of all coding exons and exon-intron boundariesSequence variants 2 (including c.1478A>G 3)~99%

See Molecular Genetics for information on allelic variants.


The ability of the test method to detect a variant that is present in the indicated gene


Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.


Detected in one family from Saudi Arabia; the only variant known to be associated with SCAN1 [Takashima et al 2002]

Testing Strategy

To confirm/establish the diagnosis in a proband. The diagnosis is established in a proband on the basis of clinical findings, family history, MRI, and EMG.

Carrier testing for at-risk relatives requires prior identification of the pathogenic variants in the family.

Note: Carriers are heterozygotes for this autosomal recessive disorder and are not at risk of developing the disorder.

Predictive testing for at-risk asymptomatic adult family members requires prior identification of the pathogenic variants in the family.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the pathogenic variants in the family.

Clinical Characteristics

Clinical Description

The clinical description in this section is a summary of the findings in three persons with spinocerebellar ataxia with axonal neuropathy (SCAN1) [Takashima et al 2002].

Cerebellar ataxia. Ataxic gait appears in the second decade of life between ages 13 and 15 years. The ataxia progresses slowly, initially manifesting as mild incoordination of the upper limbs and lower limbs and then progressing to inability to walk. Gaze nystagmus and cerebellar dysarthria usually develop after the onset of ataxic gait.

Neuropathy. Weakness initially develops in the distal muscles and is not accompanied by sensory disturbance. Progression of the weakness is accompanied by atrophy of the muscles of the fingers and feet. Deep tendon reflexes are lost in the third decade of life. As the disease advances, pain and touch sensation become severely impaired in the hands and lower thigh and vibration sense disappears in hands and legs. In the advanced stages of the disease, affected persons develop a steppage gait and pes cavus.


  • Intellect is normal.
  • One affected individual developed adult-onset epilepsy (grand mal).

Genotype-Phenotype Correlations

The TDP1 homozygous pathogenic missense variant c.1478A>G is associated with SCAN1 [Takashima et al 2002]. No other disease-related variants in TDP1 have been reported.


One family from Saudi Arabia with nine affected individuals has been reported [Takashima et al 2002].

Differential Diagnosis

Ataxia with oculomotor apraxia type 1 (AOA1) is characterized by early-onset cerebellar ataxia, axonal neuropathy, oculomotor apraxia, and chorea or dystonia [Shimazaki et al 2002]. Serum concentration of albumin is decreased and total cholesterol is increased [Date et al 2001, Moreira et al 2001, Shimazaki et al 2002]. AOA1 can be distinguished from autosomal recessive spinocerebellar ataxia with axonal neuropathy (SCAN1) by the presence of oculomotor apraxia (80% of individuals with AOA1); however, this sign is not obvious in the early stages of the disease. AOA1 is caused by pathogenic variants in APTX [Date et al 2001, Moreira et al 2001]

Ataxia with oculomotor apraxia type 2 (AOA2) is characterized by early-onset cerebellar ataxia, axonal neuropathy, oculomotor apraxia, and chorea or dystonia [Moreira et al 2004, Anheim et al 2009]. Serum concentration of alpha-fetoprotein (AFP) is increased [Moreira et al 2004, Asaka et al 2006]. AOA2 is caused by pathogenic variants in SETX [Moreira et al 2004].

Friedreich ataxia (FRDA) is characterized by slowly progressive ataxia with depressed tendon reflexes, dysarthria, muscle weakness, spasticity in the lower limbs, optic nerve atrophy, scoliosis, bladder dysfunction, and loss of position and vibration senses [Schöls et al 1997, Filla et al 2000]. The onset is usually before age 25 years. FRDA can be excluded by the presence of pyramidal signs, cardiomyopathy, or usual absence of cerebellar atrophy on CT/MRI [Salih et al 1990, Ormerod et al 1994, Bhidayasiri et al 2005]. Molecular genetic testing of FXN, the gene in which pathogenic variants cause FRDA, is helpful for diagnostic confirmation [Campuzano et al 1996].

Ataxia with vitamin E deficiency (AVED) is characterized by cerebellar ataxia, loss of proprioception, areflexia [Burck et al 1981, Harding et al 1985], and markedly reduced plasma vitamin E (alpha-tocopherol) concentration. AVED can be treated by vitamin E supplementation. The diagnosis can be confirmed by identification of pathogenic variants in TTPA, the gene encoding the alpha-tocopherol transfer protein [Ouahchi et al 1995, Cavalier et al 1998].


Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with autosomal recessive spinocerebellar ataxia with axonal neuropathy (SCAN1), the following evaluations are recommended: complete neurologic examination (including assessment of muscle strength, reflexes, coordination, and sensation) is appropriate.

Treatment of Manifestations

Prostheses, walking aids, and wheelchairs are helpful for mobility depending on disabilities.

Physical therapy may be helpful in maintaining a more active lifestyle.


Routine visits to a neurologist are appropriate.

Agents/Circumstances to Avoid

Exposure to genotoxic anti-cancer drugs such as camptothecins (e.g., irinotecan and topotecan) and bleomycin is likely to be extremely harmful and possibly fatal [Hirano et al 2007].

Exposure to radiation is likely to be extremely harmful and possibly fatal [El-Khamisy et al 2007].

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search in the US and in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Spinocerebellar ataxia with axonal neuropathy (SCAN1) is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

  • The parents of an affected child are obligate heterozygotes and therefore carry one mutated allele.
  • Heterozygotes (carriers) are asymptomatic.

Sibs of a proband

  • At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
  • Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3.
  • Heterozygotes (carriers) are asymptomatic.

Offspring of a proband. The offspring of an individual with SCAN1 are obligate heterozygotes (carriers) for a pathogenic variant.

Other family members of a proband. Each sib of the proband's parents is at a 50% risk of being a carrier.

Carrier (Heterozygote) Detection

Carrier testing for at-risk family members is possible if the pathogenic variants in the family have been identified.

Related Genetic Counseling Issues

Family planning

  • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or at risk of being carriers.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Diagnosis

Once the pathogenic variants have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis are possible.


GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • euro-ATAXIA (European Federation of Hereditary Ataxias)
    Ataxia UK
    Lincoln House, Kennington Park, 1-3 Brixton Road
    London SW9 6DE
    United Kingdom
    Phone: +44 (0) 207 582 1444
  • National Ataxia Foundation
    2600 Fernbrook Lane
    Suite 119
    Minneapolis MN 55447
    Phone: 763-553-0020
  • CoRDS Registry
    Sanford Research
    2301 East 60th Street North
    Sioux Falls SD 57104
    Phone: 605-312-6423

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

Spinocerebellar Ataxia with Axonal Neuropathy, Autosomal Recessive: Genes and Databases

GeneChromosome LocusProteinLocus-Specific DatabasesHGMDClinVar
TDP114q32​.11Tyrosyl-DNA phosphodiesterase 1TDP1 databaseTDP1TDP1

Data are compiled from the following standard references: gene from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click here.

Table B.

OMIM Entries for Spinocerebellar Ataxia with Axonal Neuropathy, Autosomal Recessive (View All in OMIM)


Molecular Genetic Pathogenesis

TDP1 encodes tyrosyl-DNA phosphodiesterase 1 (TDP1), a DNA repair enzyme that is involved in correction of the DNA strand breaks in which the 3' end is blocked by stalled topoisomerase I or phosphoglycolate [Plo et al 2003, Pommier 2004, El-Khamisy et al 2005, Interthal et al 2005a]. In the mitochondria, TDP1 participates in base excision repair of the mitochondrial genome [Das et al 2010]. The histidine at amino acid residue 493 (His493) is a key residue in the active site of TDP1 and its mutation impairs enzymatic activity [Interthal et al 2001, Davies et al 2002]. In particular, the p.His493Arg pathogenic variant identified in spinocerebellar ataxia with axonal neuropathy (SCAN1) reduces enzymatic activity 25-fold and results in accumulation of topoisomerase I DNA complexes [Interthal et al 2005b, Miao et al 2006]. Also, the mutated TDP1 protein forms a prolonged covalent intermediate with the DNA and fails to resolve 3'-phosphoglycolates of double-strand breaks [Interthal et al 2005b, Hirano et al 2007, Hawkins et al 2009].

Consistent with these in vitro studies, lymphoblastoid cells from persons with SCAN1 are more sensitive to camptothecins and to radiation [El-Khamisy et al 2005, Interthal et al 2005b, El-Khamisy et al 2007]. Despite these findings, SCAN1 does not appear to arise solely from deficient functional Tdp1 because Tdp1-deficient mice have normal growth and survival under ideal growth conditions, although they are highly sensitive to camptothecins and bleomycin [Hirano et al 2007]. This suggests that (at least in mice and yeast) redundant pathways exist for Tdp1 and that this redundancy is sufficient under ideal conditions.

Studies in mice and yeast suggest that, in addition to reduced enzymatic activity, the pathology of SCAN1 can be partially attributed to the prolonged half-life of the His493Arg Tdp1-DNA complexes and the increased level of DNA damage in neuronal cells.

Murine and yeast cells expressing the normal human ortholog are more sensitive to DNA-damaging agents than are Tdp1-deficient cells [He et al 2007, Hirano et al 2007]. The latter observation would also provide an explanation for the rarity of SCAN1 because recurrence of the disease would require recurrence of the specific c.1478A>G pathogenic variant or a functional equivalent.

Therefore, the p.His493Arg pathogenic isoform of TDP1 has both loss of function and dominant gain of function activity. The autosomal recessive inheritance of a pathogenic variant is explained by the finding that the covalent intermediate formed by the mutated Tdp1 protein (p.His493Arg) is rapidly repaired by wild-type TDP1 [Interthal et al 2005b, Hirano et al 2007].

Benign variants. None confirmed to date

Pathogenic variants. Only the c.1478A>G TDP1 missense variant has been associated with SCAN1 [Takashima et al 2002]. (See Table 2.)

Table 2.

Selected TDP1 Pathogenic Variants

DNA Nucleotide ChangePredicted Protein ChangeReference Sequences

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen​ See Quick Reference for an explanation of nomenclature.

Normal gene product. TDP1 encodes the nuclear protein tyrosyl-DNA phosphodiesterase 1 (TDP1). TDP1 is a member of phospholipase D superfamily and contains a pair of HKD motifs [Interthal et al 2001].

Abnormal gene product


Literature Cited

  • Anheim M, Monga B, Fleury M, Charles P, Barbot C, Salih M, Delaunoy JP, Fritsch M, Arning L, Synofzik M, Schöls L, Sequiros J, Goizet C, Marelli C, Le Ber I, Koht J, Gazulla J, De Bleecker J, Mukhtar M, Drouot N, Ali-Pacha L, Benhassine T, Chbicheb M, M'Zahem A, Hamri A, Chabrol B, Pouget J, Murphy R, Watanabe M, Coutinho P, Tazir M, Durr A, Brice A, Tranchant C, Koenig M. Ataxia with oculomotor apraxia type 2: clinical, biological and genotype/phenotype correlation study of a cohort of 90 patients. Brain. 2009;132:2688–98. [PubMed: 19696032]
  • Asaka T, Yokoji H, Ito J, Yamaguchi K, Matsushima A. Autosomal recessive ataxia with peripheral neuropathy and elevated AFP: novel mutations in SETX. Neurology. 2006;66:1580–1. [PubMed: 16717225]
  • Bhidayasiri R, Perlman SL, Pulst SM, Geschwind DH. Late-onset Friedreich ataxia: phenotypic analysis, magnetic resonance imaging findings, and review of the literature. Arch Neurol. 2005;62:1865–9. [PubMed: 16344344]
  • Burck U, Goebel HH, Kuhlendahl HD, Meier C, Goebel KM. Neuromyopathy and vitamin E deficiency in man. Neuropediatrics. 1981;12:267–78. [PubMed: 6945489]
  • Campuzano V, Montermini L, Molto MD, Pianese L, Cossee M, Cavalcanti F, Monros E, Rodius F, Duclos F, Monticelli A, Zara F, Canizares J, Koutnikova H, Bidichandani SI, Gellera C, Brice A, Trouillas P, De Michele G, Filla A, De Frutos R, Palau F, Patel PI, Di Donato S, Mandel JL, Cocozza S, Koenig M, Pandolfo M. Friedreich's ataxia: autosomal recessive disease caused by an intronic GAA triplet repeat expansion. Science. 1996;271:1423–7. [PubMed: 8596916]
  • Cavalier L, Ouahchi K, Kayden HJ, Di Donato S, Reutenauer L, Mandel JL, Koenig M. Ataxia with isolated vitamin E deficiency: heterogeneity of mutations and phenotypic variability in a large number of families. Am J Hum Genet. 1998;62:301–10. [PMC free article: PMC1376876] [PubMed: 9463307]
  • Chiang SC, Carroll J, El-Khamisy SF. TDP1 serine 81 promotes interaction with DNA ligase IIIalpha and facilitates cell survival following DNA damage. Cell Cycle. 2010;9:588–95. [PubMed: 20009512]
  • Das BB, Antony S, Gupta S, Dexheimer TS, Redon CE, Garfield S, Shiloh Y, Pommier Y. Optimal function of the DNA repair enzyme TDP1 requires its phosphorylation by ATM and/or DNA-PK. EMBO J. 2009;28:3667–80. [PMC free article: PMC2790489] [PubMed: 19851285]
  • Das BB, Dexheimer TS, Maddali K, Pommier Y. Role of tyrosyl-DNA phosphodiesterase (TDP1) in mitochondria. Proc Natl Acad Sci. 2010;107:19790–5. [PMC free article: PMC2993338] [PubMed: 21041670]
  • Date H, Onodera O, Tanaka H, Iwabuchi K, Uekawa K, Igarashi S, Koike R, Hiroi T, Yuasa T, Awaya Y, Sakai T, Takahashi T, Nagatomo H, Sekijima Y, Kawachi I, Takiyama Y, Nishizawa M, Fukuhara N, Saito K, Sugano S, Tsuji S. Early-onset ataxia with ocular motor apraxia and hypoalbuminemia is caused by mutations in a new HIT superfamily gene. Nat Genet. 2001;29:184–8. [PubMed: 11586299]
  • Davies DR, Interthal H, Champoux JJ, Hol WG. The crystal structure of human tyrosyl-DNA phosphodiesterase, Tdp1. Structure. 2002;10:237–48. [PubMed: 11839309]
  • Dexheimer TS, Stephen AG, Fivash MJ, Fisher RJ, Pommier Y. The DNA binding and 3'-end preferential activity of human tyrosyl-DNA phosphodiesterase. Nucleic Acids Res. 2010;38:2444–52. [PMC free article: PMC2853120] [PubMed: 20097655]
  • El-Khamisy SF, Caldecott KW. DNA single-strand break repair and spinocerebellar ataxia with axonal neuropathy-1. Neuroscience. 2007;145:1260–6. [PubMed: 17045754]
  • El-Khamisy SF, Hartsuiker E, Caldecott KW. TDP1 facilitates repair of ionizing radiation-induced DNA single-strand breaks. DNA Repair (Amst). 2007;6:1485–95. [PubMed: 17600775]
  • El-Khamisy SF, Saifi GM, Weinfeld M, Johansson F, Helleday T, Lupski JR, Caldecott KW. Defective DNA single-strand break repair in spinocerebellar ataxia with axonal neuropathy-1. Nature. 2005;434:108–13. [PubMed: 15744309]
  • Filla A, De Michele G, Coppola G, Federico A, Vita G, Toscano A, Uncini A, Pisanelli P, Barone P, Scarano V, Perretti A, Santoro L, Monticelli A, Cavalcanti F, Caruso G, Cocozza S. Accuracy of clinical diagnostic criteria for Friedreich's ataxia. Mov Disord. 2000;15:1255–8. [PubMed: 11104216]
  • Harding AE, Matthews S, Jones S, Ellis CJ, Booth IW, Muller DP. Spinocerebellar degeneration associated with a selective defect of vitamin E absorption. N Engl J Med. 1985;313:32–5. [PubMed: 4000224]
  • Hawkins AJ, Subler MA, Akopiants K, Wiley JL, Taylor SM, Rice AC, Windle JJ, Valerie K, Povirk LF. In vitro complementation of Tdp1 deficiency indicates a stabilized enzyme-DNA adduct from tyrosyl but not glycolate lesions as a consequence of the SCAN1 mutation. DNA Repair (Amst). 2009;8:654–63. [PMC free article: PMC2844109] [PubMed: 19211312]
  • He X, van Waardenburg RC, Babaoglu K, Price AC, Nitiss KC, Nitiss JL, Bjornsti MA, White SW. Mutation of a conserved active site residue converts tyrosyl-DNA phosphodiesterase I into a DNA topoisomerase I-dependent poison. J Mol Biol. 2007;372:1070–81. [PubMed: 17707402]
  • Hirano R, Interthal H, Huang C, Nakamura T, Deguchi K, Choi K, Bhattacharjee MB, Arimura K, Umehara F, Izumo S, Northrop JL, Salih MA, Inoue K, Armstrong DL, Champoux JJ, Takashima H, Boerkoel CF. Spinocerebellar ataxia with axonal neuropathy: consequence of a Tdp1 recessive neomorphic mutation? EMBO J. 2007;26:4732–43. [PMC free article: PMC2080798] [PubMed: 17948061]
  • Inamdar KV, Pouliot JJ, Zhou T, Lees-Miller SP, Rasouli-Nia A, Povirk LF. Conversion of phosphoglycolate to phosphate termini on 3' overhangs of DNA double strand breaks by the human tyrosyl-DNA phosphodiesterase hTdp1. J Biol Chem. 2002;277:27162–8. [PubMed: 12023295]
  • Interthal H, Champoux JJ. Effects of DNA and protein size on substrate cleavage by human tyrosyl-DNA phosphodiesterase 1. (TDP1). Biochem J. 2011;436:559–66. [PMC free article: PMC3151729] [PubMed: 21463258]
  • Interthal H, Chen HJ, Champoux JJ. Human Tdp1 cleaves a broad spectrum of substrates, including phosphoamide linkages. J Biol Chem. 2005a;280:36518–28. [PMC free article: PMC1351008] [PubMed: 16141202]
  • Interthal H, Chen HJ, Kehl-Fie TE, Zotzmann J, Leppard JB, Champoux JJ. SCAN1 mutant Tdp1 accumulates the enzyme--DNA intermediate and causes camptothecin hypersensitivity. EMBO J. 2005b;24:2224–33. [PMC free article: PMC1150888] [PubMed: 15920477]
  • Interthal H, Pouliot JJ, Champoux JJ. The tyrosyl-DNA phosphodiesterase Tdp1 is a member of the phospholipase D superfamily. Proc Natl Acad Sci U S A. 2001;98:12009–14. [PMC free article: PMC59758] [PubMed: 11572945]
  • Lebedeva NA, Rechkunova NI, Lavrik OI. AP-site cleavage activity of tyrosyl-DNA phosphodiesterase 1. FEBS Lett. 2011;585:683–6. [PubMed: 21276450]
  • Miao ZH, Agama K, Sordet O, Povirk L, Kohn KW, Pommier Y. Hereditary ataxia SCAN1 cells are defective for the repair of transcription-dependent topoisomerase I cleavage complexes. DNA Repair (Amst). 2006;5:1489–94. [PubMed: 16935573]
  • Moreira MC, Barbot C, Tachi N, Kozuka N, Uchida E, Gibson T, Mendonca P, Costa M, Barros J, Yanagisawa T, Watanabe M, Ikeda Y, Aoki M, Nagata T, Coutinho P, Sequeiros J, Koenig M. The gene mutated in ataxia-ocular apraxia 1 encodes the new HIT/Zn-finger protein aprataxin. Nat Genet. 2001;29:189–93. [PubMed: 11586300]
  • Moreira MC, Klur S, Watanabe M, Németh AH, Le Ber I, Moniz JC, Tranchant C, Aubourg P, Tazir M, Schöls L, Pandolfo M, Schulz JB, Pouget J, Calvas P, Shizuka-Ikeda M, Shoji M, Tanaka M, Izatt L, Shaw CE, M'Zahem A, Dunne E, Bomont P, Benhassine T, Bouslam N, Stevanin G, Brice A, Guimarães J, Mendonça P, Barbot C, Coutinho P, Sequeiros J, Dürr A, Warter JM, Koenig M. Senataxin, the ortholog of a yeast RNA helicase, is mutant in ataxia-ocular apraxia 2. Nat Genet. 2004;36:225–7. [PubMed: 14770181]
  • Murai J, Huang SY, Das BB, Dexheimer TS, Takeda S, Pommier Y. Tyrosyl-DNA phosphodiesterase 1 (TDP1) repairs DNA damage induced by topoisomerases I and II and base alkylation in vertebrate cells. J Biol Chem. 2012;287:12848–57. [PMC free article: PMC3339927] [PubMed: 22375014]
  • Ormerod IE, Harding AE, Miller DH, Johnson G, MacManus D, du Boulay EP, Kendall BE, Moseley IF, McDonald WI. Magnetic resonance imaging in degenerative ataxic disorders. J Neurol Neurosurg Psychiatry. 1994;57:51–7. [PMC free article: PMC485039] [PubMed: 8301305]
  • Ouahchi K, Arita M, Kayden H, Hentati F, Ben Hamida M, Sokol R, Arai H, Inoue K, Mandel JL, Koenig M. Ataxia with isolated vitamin E deficiency is caused by mutations in the alpha-tocopherol transfer protein. Nat Genet. 1995;9:141–5. [PubMed: 7719340]
  • Plo I, Liao ZY, Barcelo JM, Kohlhagen G, Caldecott KW, Weinfeld M, Pommier Y. Association of XRCC1 and tyrosyl DNA phosphodiesterase (Tdp1) for the repair of topoisomerase I-mediated DNA lesions. DNA Repair (Amst). 2003;2:1087–100. [PubMed: 13679147]
  • Pommier Y. Camptothecins and topoisomerase I: a foot in the door. Targeting the genome beyond topoisomerase I with camptothecins and novel anticancer drugs: importance of DNA replication, repair and cell cycle checkpoints. Curr Med Chem Anticancer Agents. 2004;4:429–34. [PubMed: 15379698]
  • Salih MA, Ahlsten G, Stalberg E, Schmidt R, Sunnegardh J, Michaelsson M, Gamstorp I. Friedreich's ataxia in 13 children: presentation and evolution with neurophysiologic, electrocardiographic, and echocardiographic features. J Child Neurol. 1990;5:321–6. [PubMed: 2174072]
  • Schöls L, Amoiridis G, Przuntek H, Frank G, Epplen JT, Epplen C. Friedreich's ataxia. Revision of the phenotype according to molecular genetics. Brain. 1997;120:2131–40. [PubMed: 9448568]
  • Shimazaki H, Takiyama Y, Sakoe K, Ikeguchi K, Niijima K, Kaneko J, Namekawa M, Ogawa T, Date H, Tsuji S, Nakano I, Nishizawa M. Early-onset ataxia with ocular motor apraxia and hypoalbuminemia: the aprataxin gene mutations. Neurology. 2002;59:590–5. [PubMed: 12196655]
  • Takashima H, Boerkoel CF, John J, Saifi GM, Salih MA, Armstrong D, Mao Y, Quiocho FA, Roa BB, Nakagawa M, Stockton DW, Lupski JR. Mutation of TDP1, encoding a topoisomerase I-dependent DNA damage repair enzyme, in spinocerebellar ataxia with axonal neuropathy. Nat Genet. 2002;32:267–72. [PubMed: 12244316]
  • Zhou T, Akopiants K, Mohapatra S, Lin PS, Valerie K, Ramsden DA, Kees-Miller SP, Povirk LF. Tyrosyl-DNA phosphodiesterase and the repair of 3'-phosphoglycolate-terminated DNA double-strand breaks. DNA Repair (Amst). 2009;8:901–11. [PMC free article: PMC2763370] [PubMed: 19505854]
  • Zhou T, Lee JW, Tatavarthi H, Lupski JR, Valerie K, Povirk LF. Deficiency in 3'-phosphoglycolate processing in human cells with a hereditary mutation in tyrosyl-DNA phosphodiesterase (TDP1). Nucleic Acids Res. 2005;33:289–97. [PMC free article: PMC546157] [PubMed: 15647511]

Chapter Notes


We thank Dr Linlea Armstrong and Dr Ken Inoue for critical review.

Author History

Cornelius Boerkoel, MD, PhD (2007-present)
Hok Khim Fam, BSc (2012-present)
Ryuki Hirano, MD, PhD; Kagoshima University (2007-2012)
Mustafa AM Salih, MD, Dr Med Sci, FRCPCH (2007-present)
Hiroshi Takashima, MD, PhD (2007-present)

Revision History

  • 20 December 2012 (cd) Revision: TDP1 sequence analysis available clinically
  • 26 April 2012 (me) Comprehensive update posted live
  • 22 October 2007 (me) Review posted live
  • 26 September 2007 (cfb) Original submission
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Bookshelf ID: NBK1105PMID: 20301284


Tests in GTR by Gene

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