DiagnosisClinical DiagnosisSpinocerebellar 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]. TestingDecreased 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 TestingGene. TDP1 is the only gene in which mutations are known to cause SCAN1 [Takashima et al 2002]. Table 1. Summary of Molecular Genetic Testing Used in Autosomal Recessive Spinocerebellar Ataxia with Axonal NeuropathyView in own windowGene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method ^{1Test AvailabilityTDP1Sequence analysis of all coding exons and exon-intron boundariesSequence variants 2 (including c.1478A>G 3)~99%Clinical1. The ability of the test method to detect a mutation that is present in the indicated gene2. 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.3. Detected in one family from Saudi Arabia; the only mutation known to be associated with SCAN1 [Takashima et al 2002]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. 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 disease-causing mutations 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 disease-causing mutations in the family.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) DisordersNo other phenotypes are known to be associated with mutations in TDP1.}

Natural HistoryThe natural history described 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 CorrelationsHomozygous c.1478A>G missense mutation of TDP1 is associated with SCAN1 [Takashima et al 2002]. No other disease-related mutations in TDP1 have been reported.

Differential DiagnosisAtaxia 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 mutations 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 mutations 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 [Schols 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 mutations 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 mutations in TTPA, the gene encoding the alpha-tocopherol transfer protein [Ouahchi et al 1995, Cavalier et al 1998]. 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).

ManagementEvaluations Following Initial DiagnosisTo 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 ManifestationsProstheses, walking aids, and wheelchairs are helpful for mobility depending on disabilities.Physical therapy may be helpful in maintaining a more active lifestyle.SurveillanceRoutine visits to a neurologist are appropriate.Agents/Circumstances to AvoidExposure 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 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. Note: There may not be clinical trials for this disorder.

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. Spinocerebellar Ataxia with Axonal Neuropathy, Autosomal Recessive: Genes and DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDTDP114q32​.11Tyrosyl-DNA phosphodiesterase 1TDP1 homepage - Mendelian genesTDP1Data 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 Spinocerebellar Ataxia with Axonal Neuropathy, Autosomal Recessive (View All in OMIM) View in own window 607198TYROSYL-DNA PHOSPHODIESTERASE 1; TDP1 607250SPINOCEREBELLAR ATAXIA, AUTOSOMAL RECESSIVE, WITH AXONAL NEUROPATHY; SCAN1Molecular Genetic PathogenesisTDP1 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 mutation 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 mutation or a functional equivalent. Therefore, the p.His493Arg mutant isoform of TDP1 has both loss of function and dominant gain of function activity. The autosomal recessive inheritance of a mutation 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]. Normal allelic variants. None confirmed to date Pathologic allelic variants. Only the c.1478A>G TDP1 missense mutation has been associated with SCAN1 [Takashima et al 2002]. (See Table 2.)Table 2. Selected TDP1 Pathologic Allelic Variants View in own windowDNA Nucleotide ChangeProtein Amino Acid ChangeReference Sequencesc.1478A>Gp.His493ArgNM_018319​.3
NP_060789​.2See Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). 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 mutation 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].