Spinocerebellar Ataxia, Autosomal Recessive, with Axonal Neuropathy

Alternative Names

  • SCAN1
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WHO-ICD-10 version:2010

Diseases of the nervous system

Polyneuropathies and other disorders of the peripheral nervous system

OMIM Number

607250

Mode of Inheritance

Autosomal recessive

Gene Map Locus

14q32.11

Description

Spinocerebellar ataxias (SCAs) are a group of progressive and irreversible neurological diseases affecting gait and movement coordination.  Many result from cerebellar degeneration or the impairment of a portion of the neuroaxis that contributes to cerebellar inflow or outflow.  Spinocerebellar ataxia with axonal neuropathy (SCAN1) is characterized by late-childhood-onset, recessive ataxia with peripheral axonal motor and sensory neuropathy, distal muscular atrophy, and pes cavus and stepagge gait.  All affected individuals have normal intelligence.  Diagnosis of SCAN1 is based on clinical findings, family history, MRI, and nerve conduction studies.  To date, there are only symptomatic treatments for SCAN1; physical therapy may help maintain a more active lifestyle.  The only reported SCAN1 patients are from an extended Saudi Arabian family with nine affected individuals.

Molecular Genetics

Genetic studies in the SCAN1 Saudi Arabian patients mapped the disease to chromosome 14q31 and identified a homozygous missense mutation (c.1478A>G) in the gene encoding topoisomerase I-dependent DNA damage repair enzyme (TDP1).  This mutation results in a p.His493Arg amino acid alteration. 

The mechanism underlying the pathogenesis of SCAN1 revolves around the role played by TDP1 in repairing chromosomal single-strand breaks arising independently of DNA replication from abortive topoisomerase-1 activity or oxidative stress.  In normal cells, TDP1 is part of multiprotein single-strand break repair (SSBR) complexes; however these complexes become catalytically inactive in SCAN1 cells.  Defective SSBR is thought to disrupt the maintenance of genetic integrity in postmitotic neurons leading to SCAN1.

Epidemiology in the Arab World

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Other Reports

Saudi Arabia

Takashima et al. (2002) studied the molecular bases in an extended Saudi family with nine affected members with autosomal recessive SCAN1.  All affected members had normal intelligence.  They evaluated three of the nine patients; these individuals had cerebellar ataxia and axonal neuropathy.  One of the patients had a history of seizures, and two had mid brain atrophy.  All the three patients had mild hypercholesterolemia and borderline hypoalbuminemia.  By performing a genome-wide screening and sequencing, a homozygous transition mutation (A1478G) in the TPD1 gene was found in the nine affected members, which encodes tryosyl-DNA phosphodiesterase 1. 

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