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/testing.

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

Management.

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 mutant 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].

Testing

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].

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 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.

Other

• 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.

Prevalence

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

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.

Surveillance

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 ClinicalTrials.gov 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.

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 mutant 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 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

If the pathogenic variants have been identified in a family member, prenatal testing may be available from a clinical laboratory that offers either testing for this disease/gene or custom prenatal testing.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the pathogenic variants have been identified.

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 mutant 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 mutant Tdp1 protein (p.His493Arg) is rapidly repaired by wild-type TDP1 [Interthal et al 2005b, Hirano et al 2007].

Benign allelic variants. None confirmed to date

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

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].

• Phosphorylation of serine 81 in the N-terminal domain of Tdp1 promotes interaction with DNA ligase III alpha, a component of single-strand break repair machinery as well as XRCC1, a scaffold protein enriched at DNA damage sites [El-Khamisy et al 2005, Das et al 2009, Chiang et al 2010].
• The two HKD motifs compose the active site of the enzyme and catalyze phosphoryl transfer reactions [Interthal et al 2001].
• TDP1 shows preferential 3'-phosphotyrosyl binding to cleave the phosphodiester bond between a covalently stalled, proteolyzed topoisomerase I and the 3' end of DNA [Interthal et al 2001, Interthal et al 2005a, Dexheimer et al 2010, Interthal & Champoux 2011].
• TDP1 also removes phosphoglycolate from the 3' termini of strand breaks, cleaves apurinic/apyrimidinic (AP) sites in the DNA backbone and processes 5'-phosphotyrosyl overhangs at a limited capacity [Inamdar et al 2002, Lebedeva et al 2011, Murai et al 2012].

Abnormal gene product

• Protein modeling shows that the p.His493Arg pathogenic variant disrupts the symmetric structure of the active center of the enzyme [Takashima et al 2002].
• The mutant TDP1 protein (p.His493Arg) has decreased enzyme activity [El-Khamisy et al 2005, Interthal et al 2005b, Zhou et al 2005, El-Khamisy & Caldecott 2007].
• The covalent intermediate with DNA is prolonged for mutant TDP1 (p.His493Arg) [Interthal et al 2005b, Hawkins et al 2009].
• The mutant TDP1 protein (p.His493Arg) is less efficient at repairing topo1-DNA complexes [Interthal et al 2005b, Miao et al 2006].
• The mutant TDP1 protein (p.His493Arg) is unable to process 3'-phosphoglycolate double-strand breaks, although this deficiency is thought not causative of SCAN1 [Zhou et al 2005, Hawkins et al 2009, Zhou et al 2009].

Literature Cited

• 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]
• Anheim M, Monga B, Fleury M, Charles P, Barbot C, Salih M, Delaunoy JP, Fritsch M, Arning L, Synofzik M, Schols 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 M2009Ataxia with oculomotor apraxia type 2: clinical, biological and genotype/phenotype correlation study of a cohort of 90 patients. Brain 1322688–98. [PubMed: 19696032]
• 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, 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]
• 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]
• 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, Nemeth AH, Le Ber I, Moniz JC, Tranchant C, Aubourg P, Tazir M, Schols 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, Guimaraes J, Mendonca P, Barbot C, Coutinho P, Sequeiros J, Durr 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]
• Schols 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]

Acknowledgments

We thank Drs. Linlea Armstrong and 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 to live Web site
• 26 September 2007 (cfb) Original submission