SETX mutations are a frequent genetic cause of juvenile and adult onset cerebellar ataxia with neuropathy and elevated serum alpha-fetoprotein.
OBJECTIVE
Ataxia with oculomotor apraxia defines a group of genetically distinct recessive ataxias including ataxia-telangectasia (A-T, ATM gene), ataxia with oculomotor apraxia type 1 (AOA1, APTX gene) and type 2 (AOA2, SETX gene). Although, a few unique clinical features differentiate each of these forms, the patients also share common clinical signs, such as the presence of cerebellar atrophy, sensorimotor axonal neuropathy, and elevated alpha-fetoprotein (AFP) serum level.


METHODS
We selected 22 Italian patients from 21 families, presenting progressive cerebellar ataxia, axonal neuropathy, and elevated serum AFP. We screened the coding regions of ATM, APTX and SETX genes for point mutations by direct sequencing or DHPLC, and searched genomic rearrangements in SETX by MLPA analysis. In selected cases, quantification of ATM and senataxin proteins was performed by Western blot. Clinical, neurophysiological, and neuroimaging data were collected.


RESULTS
Thirteen patients (12 families) carried SETX mutations (AOA2, 57%), two were mutated in ATM (A-T), and three in APTX (AOA1). In three remaining patients, we could not find pathogenic mutations, and in one case we found, in homozygosis, the SETX p.K992R polymorphism (population frequency 1-2%). In AOA2 cases, we identified 14 novel and three reported SETX mutations. Signs at onset were gait ataxia and facial dyskinesia, and the age ranged between 11 and 18 years. None had obvious oculomotor apraxia at the latest examination (age 14-45 years). The patient carrying the p.K992R SETX polymorphism had a phenotype similar to that of the diagnosed AOA2 patients, while the other three undiagnosed subjects had a very late onset and a few distinguishing clinical features.


CONCLUSIONS
We describe a large series of 13 AOA2 Italian patients. The phenotype was consistent with previous descriptions of AOA2, except for a higher frequency of strabism, and for the absence of oculomotor apraxia. In our survey ~60% of juvenile-to-adult cases with cerebellar ataxia, sensorimotor neuropathy and increased AFP are due to mutations in the SETX gene, and a smaller percentage to APTX and ATM gene mutations.
Unit of Genetics of Neurodegenerative and Metabolic Diseases, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy.
Lorenzo
L
Nanetti
Simona
S
Cavalieri
Viviana
V
Pensato
Alessandra
A
Erbetta
Davide
D
Pareyson
Marta
M
Panzeri
Giovanna
G
Zorzi
Carlo
C
Antozzi
Isabella
I
Moroni
Cinzia
C
Gellera
Alfredo
A
Brusco
Caterina
C
Mariotti
D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D000368:Aged; D001072:Apraxias / Q000235:genetics / Q000473:pathology; D001260:Ataxia Telangiectasia / Q000235:genetics / Q000473:pathology; D002524:Cerebellar Ataxia / Q000235:genetics* / Q000473:pathology* / Q000151:congenital; D004265:DNA Helicases; D005190:Family; D005260:Female; D006801:Humans; D034141:Hypoalbuminemia / Q000235:genetics / Q000473:pathology; D007558:Italy; D008297:Male; D008875:Middle Aged; D064251:Multifunctional Enzymes; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D020365:RNA Helicases / Q000235:genetics*; D055815:Young Adult; D000509:alpha-Fetoproteins / Q000378:metabolism
D064251:Multifunctional Enzymes; D000509:alpha-Fetoproteins; C484368:SETX protein, human; D004265:DNA Helicases; D020365:RNA Helicases