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Spinocerebellar Ataxia with Axonal Neuropathy

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Prevalence of clinical parameters (%)

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Pubmed id number as a reference Organ system affected
Number of patients in the reference Percent affected patients (Between 0 and 1, eg. 0.1 = 10%)
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List of symptoms

Symptom/sign Organ system Percent affected Pubmed id Added on(yyyy-mm-dd) Edit/add reference
Ataxia nervous 100 % 12244316 2011-10-19
Nephropathy nervous 100 % 12244316 2011-10-02
Hypercholesterolemia digestive 100 % 12244316 2011-10-02
Hypoalbuminemia digestive 100 % 12244316 2011-10-02
Neuropathy nervous 100 % 12244316 2011-10-26
Cerebellar atrophy nervous 67 % 12244316 2011-10-26
Seizures nervous 33 % 12244316 2011-10-02
Demyelination nervous 33 % 12244316 2011-10-02

List of references:

Mutation of TDP1, encoding a topoisomerase I-dependent DNA damage repair enzyme, in spinocerebellar ataxia with axonal neuropathy.
Hiroshi Takashima, Cornelius F Boerkoel, Joy John, Gulam Mustafa Saifi, Mustafa A M Salih, Dawna Armstrong, Yuxin Mao, Florante A Quiocho, Benjamin B Roa, Masanori Nakagawa, David W Stockton, James R Lupski,

Tyrosyl-DNA phosphodiesterase 1 (TDP1) repairs covalently bound topoisomerase I-DNA complexes and is essential for preventing the formation of double-strand breaks that result when stalled topoisomerase I complexes interfere with DNA replication in yeast. Here we show that a deficiency of this DNA repair pathway in humans does not predispose to neoplasia or dysfunctions in rapidly replicating tissues, but instead causes spinocerebellar ataxia with axonal neuropathy (SCAN1) by affecting large, terminally differentiated, non-dividing neuronal cells. Using genome-wide linkage mapping and a positional candidate approach in a Saudi Arabian family affected with autosomal recessive SCAN1, we identified a homozygous mutation in TDP1 (A1478G) that results in the substitution of histidine 493 with an arginine residue. The His493 residue is conserved in TDP1 across species and is located in the active site of the enzyme. Protein modeling predicts that mutation of this amino acid to arginine will disrupt the symmetric structure of the active site. We propose that loss-of-function mutations in TDP1 may cause SCAN1 either by interfering with DNA transcription or by inducing apoptosis in postmitotic neurons.

Nature genetics - Oct 2002

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