DiagnosisClinical DiagnosisHereditary spastic paraplegia 8 (SPG8) is diagnosed in individuals with the following [Reid et al 1999, Rocco et al 2000]:“Pure” spastic paraplegia of the lower limbs (i.e., hyperreflexia and occasionally clonus without other neurologic findings)Onset in the 20s and 30sMutation in KIAA0196Molecular Genetic TestingGene. KIAA0196, encoding the protein strumpellin, is the only gene in which mutation is known to cause hereditary SPG8.Clinical testingSequence analysis. Sequence analysis of all exons and exon/intron junctions should detect 100% of point mutations and small insertions and deletions [Valdmanis et al 2007]. Of the six families that map to the SPG8 locus [Hedera et al 1999], five families were evaluated and found to have a KIAA0196 mutation [Valdmanis et al 2007].Table 1. Summary of Molecular Genetic Testing Used in Spastic Paraplegia 8View in own windowGene Symbol Test MethodMutations DetectedMutation Detection Frequency by Test Method ^{1Test AvailabilityKIAA0196Sequence analysis of coding regions and exon/intron junctionsSequence variants 25/5 3Clinical1. The ability of the test method used to detect a mutation that is present in the indicated gene2. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected.3. Valdmanis et al [2007]Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.Testing StrategyTo establish the diagnosis in a proband, molecular genetic testing is necessary to identify a disease-causing mutation in KIAA0196.Predictive testing for at-risk asymptomatic adult family members requires prior identification of the disease-causing mutation in the family.Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family.Genetically Related (Allelic) DisordersNo other phenotypes are known to be associated with germline mutations in KIAA0196.KIAA0196 is overexpressed in prostate cancer [Porkka et al 2004].}

Natural HistorySpastic paraplegia 8 (SPG8) is characterized by progressive lower-limb spasticity (hyperreflexia and extensor plantar reflexes). Affected individuals also demonstrate weakness, a minor component that is probably secondary to reduced mobility.Some affected individuals have urinary urgency that usually becomes apparent at the same time as the spasticity.Decreased vibration sense is an additional finding on neurologic examination [Depienne et al 2007].Intra- and interfamilial phenotypic variability is high. In one family, age of onset was between ages 18 and 26 years [Rocco et al 2000]; in another family the age of onset was between ages 35 and 53 years [Valdmanis et al 2007].SPG8 is typically more severe than other types of hereditary spastic paraplegia, with affected individuals usually becoming wheelchair bound in their 30s and 40s [Rocco et al 2000]:Onset is between ages 18 and 59 years [Hedera et al 1999, Reid et al 1999, Rocco et al 2000]. In one family of 15 affected individuals, insidiously progressive spastic paraparesis began between ages 22 and 60 years (average: 37.2 years). Ten of the 15 were wheelchair bound by age 40 years [Hedera et al 1999].In one large family, SPG8 had more wheelchair-dependent family members (6 of 15) than observed in other types of autosomal dominant hereditary spastic paraplegia [Reid et al 1999].Neuroimaging. In one moderately affected individual MRI showed significant atrophy of the thoracic spinal cord as determined by cross-sectional area measurements [Hedera et al 1999].Other studies. The following are normal:Sensory examinationCerebrospinal fluid Electrophysiologic studies:Nerve conduction velocityElectromyographySomatosensory evoked potentialsMuscle biopsy [Hedera et al 1999, Rocco et al 2000]

Genotype-Phenotype CorrelationsThe number of mutations reported to date is too small to draw any genotype-phenotype correlations.

Differential DiagnosisSee Hereditary Spastic Paraplegia Overview.Hereditary spastic paraplegia 8 (SPG8) is indistinguishable clinically from other forms of autosomal dominant hereditary spastic paraplegia. In the absence of a KIAA0196 mutation, the following conditions should be considered: SPG3A, SPG4, SPG6, SPG10, SPG12, SPG13, and SPG19. See Table 2 (pdf) for the different genes and loci identified for HSP. Of note, SPG3A and SPG4 can account for as much as 50% of autosomal dominant hereditary spastic paraplegia.Individuals who represent simplex cases (i.e., occurrence only in one individual in a family) may have other non-hereditary spastic paraplegia disorders including the following:Amyotrophic lateral sclerosis (ALS)Primary lateral sclerosis (PLS)Tropical spastic paraplegia (caused by HTLV1 infection)Multiple sclerosisTumors in and around the spinal cordMutation of PSEN1 (the gene encoding presenilin 1) in individuals who later develop Alzheimer disease type 3

ManagementEvaluations Following Initial DiagnosisTo establish the extent of disease in an individual diagnosed with spastic paraplegia 8 (SPG8), the following evaluations are recommended:Neurologic examinationUrodynamic evaluationTreatment of ManifestationsNo cures or specific drug treatments exist for hereditary spastic paraplegia. An approach to management of spasticity is reviewed by Young [1994]:Daily regimen of physical therapy directed toward improving cardiovascular fitness, maintaining and improving muscle strength and gait, and reducing spasticity is recommended.Occupational therapy, assistive walking devices, and ankle-foot orthotics are often used.Antispasmodic drugs (e.g., baclofen, BOTOX^®, dantrolene, tizanidine), used one at a time, are usually helpful, especially early in the disease course. Baclofen can be tried first, and can be used with an intrathecal pump in some cases. The entire therapeutic range of doses in all four drugs is used. The drugs are administered before sleep if nocturnal cramps are problematic, otherwise three to four times per day. These drugs alleviate symptoms by decreasing cramps and making leg muscles less tight, which can facilitate walking. It usually takes a few days for their effects to become evident. No significant toxicity limits their use.SurveillanceThe following are appropriate:Regular neurologic examinations to evaluate disease progression.Referral to a urologist for urodynamic testing and follow-up when symptoms appear.Evaluation of Relatives at RiskSee Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Therapies Under InvestigationSearch ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Molecular GeneticsInformation in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.Table A. Spastic Paraplegia 8: Genes and DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDKIAA01968q24​.13StrumpellinHSP mutation database
KIAA0196 homepage - Mendelian genesKIAA0196Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for Spastic Paraplegia 8 (View All in OMIM) View in own window 603563SPASTIC PARAPLEGIA 8, AUTOSOMAL DOMINANT; SPG8 610657KIAA0196 GENE; KIAA0196Normal allelic variants. KIAA0196 has 28 exons and spans a genomic interval of 60 kb. Its mRNA contains 3925 nucleotides. No alternative transcripts or pseudogenes have been identified for this gene.Pathologic allelic variants. See Table 3. All KIAA0196 mutations identified to date are missense mutations. They appear in the middle of the gene in exons 11 (p.Asn471Asp), 14 (p.Leu619Phe), and 15 (p.Val626Phe). The p.Val626Phe mutation has been found in four families from North America and Britain, suggesting that it is a recurrent mutation [Valdmanis et al 2007].Table 3. KIAA0196 Pathologic Allelic Variants Discussed in This GeneReviewView in own windowDNA Nucleotide Change
(Alias ¹)Protein Amino Acid ChangeReference Sequencesc.1411A>G
(1491A>G)p.Asn471AspNM_014846​.3
NP_055661​.3c.1857G>T
(1937G>C)p.Leu619Phec.1876G>T
(1956G>T)p.Val626PheSee Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org).1. Variant designation that does not conform to current naming conventionsNormal gene product. KIAA0196 encodes an 1159-amino-acid protein. The protein contains one spectrin repeat and one highly conserved domain of unknown significance [Valdmanis et al 2007]. The spectrin domain is involved in interaction with the cytoskeletal matrix of the cell and can facilitate binding to other spectrin-repeat-containing proteins. KIAA0196 is expressed in all tissues; northern blot analysis indicates that the mRNA is present in many regions of the brain [Valdmanis et al 2007].Abnormal gene product. The missense mutations in KIAA0196 are expressed as amino acid substitutions in the abnormal protein and likely result in an abnormal function. As expected for missense mutations, the abnormal protein apparently is not truncated as demonstrated by Western blot analysis [Author, personal data]. The p.Asn471Asp mutation is present in the spectrin-binding domain, indicating that the interaction of this domain with the spectrin protein or some other as-yet unidentified protein may be important.