Abstract Details

Title Disruption of spermatogenesis and infertility in Ataxia with Oculomotor Apraxia Type 2 (AOA2)

Topic Movement Disorders

Presentation(s) P4 - Poster Session 4 (5:30 PM-6:30 PM)

Poster/Presentation
Number 1-003

Objective To assess whether disruption of senataxin, encoded by the SETX gene, leads to defective spermatogenesis and sterility in men, we evaluated patients with ataxia with oculomotor apraxia type 2 (AOA2), an autosomal recessive adolescent-onset cerebellar ataxia caused by loss-of-function mutation of the SETX gene.

Background Ataxia with oculomotor apraxia type 2 (AOA2) is a rare autosomal recessive cerebellar ataxia characterized by adolescent onset, progressive cerebellar atrophy, axonal sensorimotor neuropathy, oculomotor apraxia in a majority of patients, and elevated serum alpha-fetoprotein. AOA2 is caused by mutation of the SETX gene which encodes senataxin, a DNA/RNA helicase involved in transcription regulation, RNA processing, DNA repair, and genome stability. While neurological signs are the hallmark of AOA2, extra-neurological features related to reproductive function abnormalities in females have been reported for this disease. Disruption of senataxin in rodents led to defective spermatogenesis and sterility in males suggesting a key role for senataxin in male germ cell survival.

Design/Methods

We assessed hormonal levels, sperm production, and testicular pathology in 5 patients with AOA2 and compared the findings to those of Setx knockout mice.

Results Sperm production was impaired in all patients assessed (3/3, 100%). Analyses of testicular biopsies from an AOA2 patient recapitulate features of the histology seen in Setx knockout mice, strongly suggesting an underlying mechanism centering on DNA-damage-mediated germ cell apoptosis.

Conclusions Here we report the first clinical and cellular evidence of impaired spermatogenesis in AOA2 patients. These findings support a role for senataxin in human reproductive function and highlight a novel clinical feature of AOA2 that extends the extra-neurological roles of senataxin. This raises an important reproductive counselling issue for clinicians, and fertility specialists should be aware of SETX mutations as a possible diagnosis in young male patients presenting with oligospermia or azoospermia since infertility may presage the later onset of neurological manifestations in some individuals.

Authors/Disclosures
Brent L. Fogel, MD, PhD, FAAN (UCLA Neurology) PRESENTER	Dr. Fogel has received personal compensation in the range of $0-$499 for serving as an officer or member of the Board of Directors for National Ataxia Foundation. Dr. Fogel has received personal compensation in the range of $0-$499 for serving as an officer or member of the Board of Directors for Ataxia Global Initiative. Dr. Fogel has received personal compensation in the range of $0-$499 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Neurology Today. Dr. Fogel has received personal compensation in the range of $0-$499 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Neurology Genetics. Dr. Fogel has received personal compensation in the range of $0-$499 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Frontiers in Genetics. Dr. Fogel has received personal compensation in the range of $0-$499 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Genes. Dr. Fogel has received personal compensation in the range of $0-$499 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Neuromarkers. The institution of Dr. Fogel has received research support from the National Institutes of Health. The institution of Dr. Fogel has received research support from the National Ataxia Foundation. The institution of an immediate family member of Dr. Fogel has received research support from the National Institutes of Health, the National Science Foundation, and the Department of Defense. The institution of Dr. Fogel has received research support from US Department of Defense .
	No disclosure on file
	No disclosure on file
	No disclosure on file
	No disclosure on file
	No disclosure on file
	No disclosure on file

��ɫ��

��ɫ��