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 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.

Note: It is the policy of GeneReviews to include in GeneReviews™ chapters any clinical uses of testing available from laboratories listed in the GeneTests™ Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

Genetically Related (Allelic) Disorders

No other phenotypes are known to be associated with mutations in TDP1.

Natural History

The 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 Correlations

Homozygous 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.

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.

Other

Genetics clinics, staffed by genetics professionals, provide information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.

See Consumer Resources for disease-specific and/or umbrella support organizations for this disorder. These organizations have been established for individuals and families to provide information, support, and contact with other affected individuals.

Mode of Inheritance

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

Risk to Family Members

This section is written from the perspective that molecular genetic testing for this disorder is available on a research basis only and, results should not be used for clinical purposes. This perspective may not apply to families using custom mutation analysis. —ED.

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 disease-causing mutation.

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 using molecular genetic techniques is not offered because it is not clinically available.

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, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals. See for a list of laboratories offering DNA banking.

Prenatal Testing

No laboratories offering molecular genetic testing for prenatal diagnosis of SCAN1 are listed in the GeneTests™ Laboratory Directory. However, prenatal testing may be available for families in which the disease-causing mutation has been identified. For laboratories offering custom prenatal testing, see .

Preimplantation genetic diagnosis (PGD) may be available for families in which the disease-causing mutations have been identified. For laboratories offering PGD, see .

Note: It is the policy of GeneReviews to include in GeneReviews™ chapters any clinical uses of testing available from laboratories listed in the GeneTests™ Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

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 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.)

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].

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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

• 26 April 2012 (me) Comprehensive update posted live

• 22 October 2007 (me) Review posted to live Web site

• 26 September 2007 (cfb) Original submission