http://www.sickkids.ca/genome-diagnostics January 2016 HEREDITARY SPASTIC PARAPLEGIA

Hereditary spastic paraplegias (HSPs) comprise a genetically and clinically heterogeneous For More Information group of neurodegenerative disorders characterized by lower limb spasticity and weakness with hyperreflexia and extensor plantar responses. HSP is estimated to affect 1 in 20,000 Spastic Paraplegia individuals in the European population, and can also occur in individuals of other ethnic Foundation backgrounds. Clinically, HSPs can be divided into two main groups: uncomplicated (pure) http://www.sp-foundation.org/ and complicated (complex) forms. Pure HSPs are characterized by spasticity in the lower 1-877-773-4483 limbs; whereas complex HSPs are characterized by the presence of additional neurological or non-neurological features. The age of symptom onset, rate of symptom GeneReviews: HSP progression, and extent of disability are variable both within and between HSP families. http://www.ncbi.nlm.nih.gov/ books/NBK1509/ GENETICS TEST METHODS SickKids Genomic The genetics of HSP are complex and Diagnostics Laboratory:  Complete sequencing of the coding different modes of inheritance (autosomal www.sickkids.ca/genome- region and flanking intron/exon dominant, autosomal recessive and X-linked diagnostics boundaries of the genes listed below. recessive) have been described. The three This is done via NGS of the targeted To locate a genetics center targeted Next-Generation Sequencing (NGS) gene panels. Testing can be near you: panels at our laboratory include genes requested for one, two or all three associated with all modes of inheritance (see Canadian Association of panels based on the suspected mode table below). Genetic Counsellors (CAGC): of inheritance. Please refer to our “A http://www.cagc-accg.ca BEFORE MOLECULAR TESTING Guide to Next-Generation Sequencing” information sheet National Society of Genetic For a patient where a clinical diagnosis of available on our website, for further Counselors (NSGC): HSP is suspected, the following tests should details. http://www.nsgc.org be undertaken first, to exclude other causes:  Exon targeted dosage analysis is 1. An MRI of the brain and spinal cord to rule available using an oligonucleotide out structural causes of progressive spasticity microarray platform.

2. Biochemical testing of Vitamin B12, Vitamin E, very long chain fatty acids, lysosomal work-up, plasma amino acids and serum lipoprotein analysis INTERPRETATION OF If the above tests are negative, proceed TEST RESULTS 1. Current molecular testing with molecular testing for HSP. may not detect all possible Genetic testing may reveal one or more mutations for this disease. A WHO SHOULD BE TESTED? variants in the HSP genes, which negative test does not rule out  Individuals clinically suspected of being should be interpreted in the context of the possibility of HSP. affected with HSP the suspected inheritance pattern, clinical findings, family history and other 2. The clinical course or severity of symptoms cannot be  The relatives of a proband with identified experimental data. predicted by molecular analysis. pathogenic variant(s) in an HSP-associated gene Please refer to our “A Guide to 3. Test results should be Interpreting Sequence Variations” interpreted in the context of  Pregnancies at increased risk due to a information sheet available on our web- clinical findings, family history family history of HSP site, for further details. and other laboratory data. 4. This test was developed Panel (version 2) Genes and its performance characteristics validated by the Autosomal Recessive ALDH18A1, ALS2, AP4B1, AP4E1, AP4M1, AP4S1, AP5Z1, Molecular Genetics Laboratory (34 genes) C10orf2, C12orf12, CYP2U1, CYP7B1, DDHD1, DDHD2, at the Hospital for Sick ENTPD1, ERLIN1, ERLIN2, FA2H, GBA2, GJC2, KIF1A, Children. It has not been KIF1C, NT5C2, PGAP1, PNPLA6, POLG, SACS, SPG11, cleared or approved by the SPG20, SPG21, SPG7, TECPR2, VPS37A, ZFYVE26 U.S. Food and Drug Administration. The FDA has determined that such Autosomal Dominant ALDH18A1, ATL1, BSCL2, C10orf2, HSPD1, KIAA0196, clearance or approval is not (15 genes) KIF5A, NIPA1, POLG, POLG2, REEP1, SPAST, RTN2, necessary. This test is used for SLC33A1, SETX clinical purposes. X-Linked Recessive L1CAM, PLP1, SLC16A2 (3 genes) OMG1620F/05