HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Figures Only Full Text Full Text (PDF) Data Supplement Correspondence: Submit a response Alert me when this article is cited Alert me when Correspondence are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Mintchev, N. Articles by Christodoulou, K. Search for Related Content PubMed Articles by Mintchev, N. Articles by Christodoulou, K. Related Collections All Clinical Neurology All Neuromuscular Disease Amyotrophic lateral sclerosis All Genetics

A novel ALS2 splice-site mutation in a Cypriot juvenile-onset primary lateral sclerosis family

From The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus.

Address correspondence and reprint requests to Dr. Kyproula Christodoulou, Neurogenetics Department, The Cyprus Institute of Neurology and Genetics, 6 International Airport Avenue, Ayios Dhometios, 2370 Nicosia, Cyprus roula{at}cing.ac.cy

Background: Primary lateral sclerosis (PLS) is a rare neurodegenerative disease that affects the upper motor neurons of the CNS. Juvenile-onset PLS (JPLS) is inherited in an autosomal recessive mode and is also found in sporadic cases. A consanguineous Cypriot family with three affected individuals presenting with JPLS was identified and studied.

Methods: Patients were clinically evaluated and samples were taken from consenting family members. All available family members were genotyped and linkage analysis at marker loci spanning the wider region of the ALS2 gene was performed. Selected exons of the ALS2 gene were sequenced and RNA analysis was performed using available lymphoblastoid cell lines from the proband.

Results: All affected individuals presented in the second year of life with progressive upper motor neuron dysfunction, affecting both bulbar and extremity muscles. Severity was variable, with two of the patients remaining ambulatory in the second and fifth decade of life while the third one was never able to walk. A novel ALS2 homozygous c.2980-2A>G mutation at the splice acceptor site of intron 17 was identified and its effect was confirmed at the RNA level.

Conclusions: This novel ALS2 splice-site mutation is causing the loss of exon 18 in the transcript which results in a frameshift after exon 17. This frameshift most probably introduces a stop codon seven amino acids further down the new reading frame (p.993fsX7) and is expected to lead to a premature stop in exon 19 thus leading to a truncated protein after translation.

Abbreviations: ALS = amyotrophic lateral sclerosis; AR = autosomal recessive; bp = base pair; CMAP = compound muscle action potential amplitudes; IAHSP = infantile-onset ascending hereditary spastic paraplegia; JALS = juvenile-onset ALS; JPLS = juvenile-onset PLS; NCS = nerve conduction studies; ND = not done; PLS = primary lateral sclerosis; SSEP = somatosensory evoked potentials; UMN = upper motor neurons; VEP = visual evoked potentials.

Supplemental data at www.neurology.org

Disclosure: The authors report no disclosures.

Received June 5, 2008. Accepted in final form September 18, 2008.