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Abstract Details

Genotype-Phenotype Associations in Hereditary Spastic Paraplegia (HSP): A Systematic Review and Individual-level Data Meta-analysis
Movement Disorders
P12 - Poster Session 12 (12:00 PM-1:00 PM)
3-015
To investigate genotype-phenotype associations in hereditary spastic paraplegia (HSP) with a focus on movement disorders.
HSP is a rare genetically-driven disorder associated with mutations in >80 loci designated SPGs (SPastic parapleGia). The clinical hallmark of HSP is progressive spastic paraparesis due to degeneration of the corticospinal tracts. It is increasingly recognized that the phenotypic spectrum of HSPs can extend to include other neurologic features, including movement disorders.
We performed a systematic individual participant data (IPD)-level meta-analysis by retrieving publications from Medline/EMBASE/Web of Science from 1990 to June 2018 on HSP with a SPG genotype. Studies were included only if individual-level information was accessible and at least one movement disorder was reported for that genotype. Out of 21,957 hits, 192 manuscripts with a total of 1,413 HSP cases were eligible. Genotype-phenotype associations were analyzed and compared between two HSP groups: manifested with (HSP-MD, n=767) or without (HSP-nMD, n=646) a movement disorder.
The HSP-MD group had an older age-of-onset (20.5±16.0 vs. 17.1±14.2 yr,p<0.001) and less frequent autosomal dominant inheritance (7.6% vs. 30.1%,p<0.001). SPG7 (29.1%) and SPG11 (32.3%) were the most frequent genotypes in HSP-MD and HSP-nMD groups, respectively. HSP-MD patients with SPG7 had higher prevalence of later onset during adulthood (82.9% vs. 8.5%,p<0.001), ataxia (96.8% vs. 70.6%, OR=12.6(5.2-30.7),p<0.001), extraocular movement disturbances (52.7% vs. 24.5%, OR=3.4(2.1-5.5),p<0.001) and seizure (11.7% vs. 3.5%, OR=3.7(1.3-9.9),p=0.007) compared to those with SPG11. SPG11 mutants were more frequently associated with consanguinity (65.1% vs. 31.3%, OR=4.1(1.3-12.9),p=0.012), parkinsonism (11.2% vs. 1.6%, OR=7.8(2.2-27.2),p<0.001), dystonia (10.5% vs. 2.1%, OR=5.4(1.7-16.6),p=0.001), peripheral neuropathy (60.1% vs. 5.3%, OR=26.9(13.1-55.2),p<0.001), and cognitive dysfunction (80.4% vs. 10.6%, OR=34.5(18.5-64.2),p<0.001).
This systematic IPD-level meta-analysis provides, to our knowledge, the largest data on genotype-phenotype associations in HSP. Several clinically relevant phenotypic differences were found between various genotypes in demographic and neurologic features, which can possibly facilitate diagnosis in resource-limited settings.   
Authors/Disclosures
Seyed-Mohammad Fereshtehnejad, MD, PhD (University of British Columbia)
PRESENTER 		Dr. Fereshtehnejad has nothing to disclose.
Philip Saleh, MD (Baycrest Health Sciences Centre) No disclosure on file
Neha Patel, MD (University of Toronto) No disclosure on file
Suvorit S. Bhowmick, MD (Vadodara Institute of Neurological Sciences) No disclosure on file
Gerard Raimon Saranza, MD Dr. Saranza has nothing to disclose.
No disclosure on file
Lorraine Kalia, MD, PhD, FRCPC Dr. Kalia has received personal compensation in the range of $0-$499 for serving as a Consultant for Cure Ventures. Dr. Kalia has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Ipsen. Dr. Kalia has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Knight Therapeutics. Dr. Kalia has received personal compensation in the range of $500-$4,999 for serving as a Consultant for UCB. Dr. Kalia has received personal compensation in the range of $5,000-$9,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for IOS Press/Sage Publications. The institution of Dr. Kalia has received research support from Canadian Institutes of Health Research. The institution of Dr. Kalia has received research support from Natural Sciences and Engineering Research Council of Canada. The institution of Dr. Kalia has received research support from Michael J. Fox Foundation for Parkinson's Research. The institution of Dr. Kalia has received research support from Cure Parkinson's. The institution of Dr. Kalia has received research support from Krembil Foundation. Dr. Kalia has received intellectual property interests from a discovery or technology relating to health care.