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spinocerebellar ataxia with axonal neuropathy (SCAN1)

SCAN1 is an autosomal recessive disorder caused by a specific point mutation (c.1478A>G, p.H493R) in the tyrosyl DNA phosphodiesterase (TDP1) gene.
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. All affected individuals had normal intelligence. 
Diagnosis is based on clinical findings, family history, MRI, and nerve conduction studies (NCS)/EMG. TDP1 is the only gene known to be associated with SCAN1. 

Functional and genetic studies suggest that this mutation, which disrupts the active site of the TDP1 enzyme, causes disease by a combination of decreased catalytic activity and stabilization of the normally transient covalent TDP1‑DNA intermediate. This covalent reaction intermediate can form during the repair of stalled topoisomerase I‑DNA (TOP1) adducts or oxidatively damaged bases at the 3′ end of the DNA at a strand break. However, our current understanding of the biology of Tdp1 function in humans is limited and does not allow us to fully elucidate the disease mechanism.

ABREVIATION(S):
SCAN1

TYPE: psychomotor impairment, neurodegenerative disease

Related patway(s): base excision repair (BER)

DNAtraffic protein(s) related to disease: TDP1

OMIM: 607250

Last modification date: Aug. 17, 2011