Pure or complex autosomal recessive spastic paraplegia
-Rare genetic disease
-Rare neurologic disease
Rare genetic intellectual deficit with developmental anomaly
-Rare genetic disease
Rare intellectual deficit with developmental anomaly
-Rare neurologic disease
Comment:
Hereditary spastic paraplegias (HSPs) are clinically and genetically highly heterogeneous. SPG11 (ALS5, CMT2X, KIAA1840) is presumably the most frequent type of autosomal recessive HSP and accounts for about 20% of cases. If the typical phenotype, especially thin corpus callosum and cognitive impairment are present, SPG11 is as frequent as 59% in autosomal recessive or apparently sporadic HSP patients. SPG11 usually manifests in the first three decades of life (PMID:22266886). The SPG11 phenotype may be mild and uncomplicated or variably associated with intellectual disability, dysarthria, nystagmus, upper extremity weakness and extrapyramidal features. In some cases the clinical picture can be similar to a slowly progressive juvenile ALS and it may also present as Kjellin syndrome with childhood onset spastic paraplegia, retinopathy, dementia and distal muscular atrophy. A TCC (thin corpus callosum) is a very characteristic finding in SPG11 and has been proposed to be the best phenotypic predictor of this form of HSP (Schüle et al., 2009). However, this finding is neither constant nor specific since this abnormality can be observed in other SPG genetic subtypes (PMID:26937357).
For SPG11 mutations compare also "Autosomal recessive Charcot Marie Tooth disease type 2X".
Hereditary spastic paraplegia (SPG or HSP) is characterized by progressive weakness and spasticity of the lower limbs due to degeneration of corticospinal axons. SPG11 is a form of complicated SPG, in that it has neurologic features in addition ... Hereditary spastic paraplegia (SPG or HSP) is characterized by progressive weakness and spasticity of the lower limbs due to degeneration of corticospinal axons. SPG11 is a form of complicated SPG, in that it has neurologic features in addition to spasticity. For a discussion of genetic heterogeneity of autosomal recessive HSP, see SPG5A (270800), which has been mapped to chromosome 8p12-q13.
Nakamura et al. (1995) reported 2 families with autosomal recessive hereditary spastic paraplegia, mental impairment, and thin corpus callosum. In the first family, 3 affected brothers had onset in the second decade of gait disturbance resulting in wheelchair ... Nakamura et al. (1995) reported 2 families with autosomal recessive hereditary spastic paraplegia, mental impairment, and thin corpus callosum. In the first family, 3 affected brothers had onset in the second decade of gait disturbance resulting in wheelchair use by age 21 years. All 3 patients had an IQ less than 60. Other features included lower limb spasticity, slight ataxia, and mild sensory impairment. Three sisters from a second family, in which the parents were first cousins, had similar features to the affected brothers in the first family. Brain CT and MRI of 4 patients showed mild frontal and temporal cortical atrophy, mild ventricular dilatation, and widening of the frontal longitudinal fissure. All patients had a markedly thin corpus callosum which was not consistent with a degenerative process and was distinct from congenital agenesis (ACC; 217990) and partial agenesis (e.g., 304100) of the corpus callosum. Peripheral nerve biopsies showed decreased numbers of myelinated fibers, axonal degeneration, and abnormal Schwann cell inclusions. Ueda et al. (1998) reported 2 Japanese sibs with SPG11 who showed thalamic glucose hypometabolism on positron emission tomography (PET) scan. Winner et al. (2004) reported 2 German sisters with SPG11. The more severely affected sister had onset at age 24 years of a slowly progressive spastic paraplegia with increasing urinary urge incontinence and slow cognitive decline. Both sisters were obese, whereas no other family members were overweight. Serial MRIs showed a tendency toward progressive atrophy of the rostral corpus callosum, as well as symmetric white matter lesions. Transcranial stimulation showed a lack of transcallosal inhibition, and PET scan showed cortical and thalamic hypometabolism that decreased further within 4 years. Combined axonal loss and demyelinating sensory neuropathy were also present. No mutations were identified in the SLC12A6 gene (604878), which is mutated in agenesis of the corpus callosum with peripheral neuropathy (ACCPN; 218000). Casali et al. (2004) reported 18 patients from 12 Italian families with HSP-TCC; 2 of the families were consanguineous. The clinical phenotype was homogeneous, with gait difficulties beginning at a median age of 13 years (range 4 to 20 years) and progressing to loss of ambulation within approximately 10 years. Neurologic features included spasticity, pyramidal signs, hyperreflexia, and severe mental deterioration. MRI studies showed thin corpus callosum in all patients and periventricular white matter changes in 15 of 18 patients. Lossos et al. (2006) reported 2 consanguineous Arab-Israeli families in which 2 sibs in each family had autosomal recessive HSP-TCC. All patients had onset of clinical symptoms during the second decade of life, with cognitive decline preceding gait disturbance by 2 to 5 years. Cardinal signs included pseudobulbar dysarthria, spastic paraparesis with lower limb hyperreflexia, upper limb hyperreflexia, extensor plantar responses, and distal amyotrophy. Brain imaging of 1 affected sib from each family showed thin corpus callosum, white matter abnormalities, and mild frontal atrophy. Two of 3 patients examined had mild axonal peripheral neuropathy. Two affected sibs in 1 family were obese. Stevanin et al. (2007) reviewed the features of autosomal recessive hereditary spastic paraplegia with thin corpus callosum (ARHSP-TCC). Cognitive impairment is first noticed in childhood and progresses insidiously to severe functional disability of a frontal type over a period of 10-20 years (Nakamura et al., 1995; Winner et al., 2004). Some affected individuals develop a pseudobulbar involvement, with dysarthria, dysphagia, and upper limb spasticity, associated with bladder dysfunction and signs of predominantly axonal, motor, or sensorimotor peripheral neuropathy. PET scan shows cortical and thalamic glucose hypometabolism. MRI shows thin corpus callosum that predominates in the rostral third, with hyperintensities in periventricular white matter and cerebral cortical atrophy predominating in the frontal region. Del Bo et al. (2007) reported 27-year-old Italian opposite-sex dizygotic twins with autosomal recessive SPG11. The sibs had onset of ataxia and cognitive impairment at ages 12 and 15 years, respectively. The disorder progressed rapidly, leading to spastic paraplegia, dysarthria, and peripheral neuropathy. Both were wheelchair-bound in their early twenties. Brain MRI showed thin corpus callosum and cortical atrophy in both sibs. Both parents were healthy and came from the same small town in Sicily but denied consanguinity. Genetic analysis identified a homozygous mutation in the SPG11 gene (733delAT; 610844.0004). Hehr et al. (2007) reported clinical details of 18 patients from 9 families with genetically confirmed SPG11. Several of the families had previously been reported by Olmez et al. (2006). The mean age at onset of walking impairment was 16 years (range, 8 to 31). Patients had predominantly lower limb paresis with proximal spasticity and hyperreflexia with extensor plantar responses. The gait was slow, spastic, and slightly ataxic. Dysarthria was noted in 85% of patients, and amyotrophy of the hypothenar and thenar muscles was commonly present. General mental impairment of varying degrees was present in 83%, and was associated with hypometabolism of the frontal cortex and thalamus on PET scan. MRI performed in at least 1 member of each family showed rostral atrophy of the corpus callosum and supratentorial white matter changes. Peripheral nerve biopsy showed hypomyelination of large fibers and loss of unmyelinated fibers, consistent with a clinical picture of mixed axonal and demyelinating polyneuropathy. Evidence also suggested disturbed axonal transport. The long-term course of 1 patient followed for 10 years showed progression of the disorder. Hehr et al. (2007) concluded that the disease process in SPG11 affects the corticospinal tract, major corticocortical connections via the corpus callosum, and the peripheral nervous system, and likely involves impaired axonal transport. Samaranch et al. (2008) reported 4 Spanish patients with SPG11 confirmed by genetic analysis. All had some degree of mental retardation and a thin corpus callosum on brain imaging. The 3 older individuals had spastic paraparesis since late childhood and decreased brain metabolism on PET studies, predominantly in the thalamus and paracentral cortex of the hemispheres. Samaranch et al. (2008) postulated that the thalamic dysfunction may contribute to impaired attention. - Clinical Variability Crimella et al. (2009) identified homozygous or compound heterozygous mutations in the SPG11 gene in 4 (40%) of 10 patients with SPG and thin corpus callosum and in 3 (8.5%) of 35 patients with SPG without thin corpus callosum. The molecular findings were consistent with a loss-of-function mechanism. Orlen et al. (2009) reported 5 patients from 4 unrelated families with 5 truncating mutations in the SPG11 gene (see, e.g., 610844.0007-610844.0009). Two patients had delayed psychomotor development, 2 had onset at ages 3 and 4 years, respectively, and 1 had onset at age 14 years. Four patients were wheelchair-bound in the third or fourth decades; the fifth patient was only 14 at the time of the study and had a milder phenotype overall. The 4 older patients (ages 29 to 48) had lower limb spasticity, hyperreflexia with extensor plantar responses, sphincter disturbances, amyotrophy of the hands or calves, thin corpus callosum, cerebral atrophy, and periventricular white matter changes. All patients had some degree of cognitive dysfunction or mental retardation. Three were obese. An unusual finding in the 4 older patients was progressive central retinal degeneration, which was reminiscent of the phenotype for Kjellin syndrome (SPG15; 270700). Orlen et al. (2009) concluded that central retinal degeneration may be a previously unrecognized late-onset feature of this disorder.
Stevanin et al. (2007) analyzed 18 genes in the 3.2-cM SPG11 candidate interval by direct sequencing of all exons and their splicing sites, and identified 10 mutations in the KIAA1840 gene (610844) in 11 families. The KIAA1840 gene, ... Stevanin et al. (2007) analyzed 18 genes in the 3.2-cM SPG11 candidate interval by direct sequencing of all exons and their splicing sites, and identified 10 mutations in the KIAA1840 gene (610844) in 11 families. The KIAA1840 gene, encoding spatacsin, is expressed ubiquitously in the nervous system but most prominently in the cerebellum, cerebral cortex, hippocampus, and pineal gland. The mutations were either nonsense or insertions or deletions leading to a frameshift, suggesting a loss-of-function mechanism. All mutations were in the homozygous state except in 2 kindreds, in which affected individuals were compound heterozygous. Only 2 mutations were found in more than 1 pedigree: R2034X (604360.0001) in 3 consanguineous North African kindreds, and a 5-bp deletion in exon 3 (604360.0002) in 2 Portuguese families. The SPG11 gene appears to be the one most frequently responsible for ARHSP-TCC. Only a single family (8%) in the cohort studied by Stevanin et al. (2007) did not have a mutation in SPG11, indicating that there is at least one other responsible gene. On the other hand, whether the SPG11 gene accounts for other clinical phenotypes of ARHSP remained to be determined. Spastic paraplegias are believed to result from a dying back of exons. Mitochondrial metabolism, endosomal and trans-Golgi trafficking and axonal transport have been implicated in several HSPs (Crosby and Proukakis, 2002). Although the function of spatacsin remains unknown, the experimental evidence that it is expressed in all tissues and is highly conserved among species suggests that it has an essential biologic function. The possible presence of at least one transmembrane domain suggested that spatacsin may be a receptor or transporter. In 18 patients from 9 unrelated families with SPG11, Hehr et al. (2007) identified 11 different mutations, including 10 novel mutations, in the SPG11 gene (see, e.g., 610844.0005-610844.0006) in the homozygous or compound heterozygous state. Four of the families were consanguineous, including 3 Turkish families initially reported by Olmez et al. (2006). Mutations were distributed throughout the entire spatacsin gene without obvious clustering. Bauer et al. (2009) used high-resolution comparative genomic hybridization (HRCGH) to identify deletions in the SPG11 gene in 3 patients with SPG11 in whom only 1 mutant SPG11 allele had been identified by gene sequencing. HRCGH analysis suggested heterozygous genomic deletion in all 3 patients; however, quantitative PCR confirmed an 8.23-kb deletion in only 1 patient. The 8.23-kb deletion resulted in loss of exons 31 to 34 and was also found in the proband's affected sister and their unaffected father. The clinical features in the brother and sister did not differ from those of patients with point mutations.
Boukhris et al. (2009) identified a molecular basis for hereditary spastic paraplegia in 13 (34.2%) of 38 unrelated families from southern Tunisia with the disorder. The most common forms of SPG were SPG11 in 7 (18.4%) families and ... Boukhris et al. (2009) identified a molecular basis for hereditary spastic paraplegia in 13 (34.2%) of 38 unrelated families from southern Tunisia with the disorder. The most common forms of SPG were SPG11 in 7 (18.4%) families and SPG15 (270700) in 4 (10.5%) families. SPG4 (182601) and SPG5 (270800) were present in 1 family each.
The basic phenotype of spastic paraplegia type 11 (SPG11), caused by mutations in SPG11, is homogeneous and includes progressive spasticity and weakness of the lower limbs with the following associating signs [Shibasaki et al 2000, Casali et al 2004, Winner et al 2004, Lossos et al 2006, Olmez et al 2006, Stevanin et al 2006, Winner et al 2006, Del Bo et al 2007, Hehr et al 2007, Stevanin et al 2007b, Stevanin et al 2008, Denora et al 2009]:...
DiagnosisClinical DiagnosisThe basic phenotype of spastic paraplegia type 11 (SPG11), caused by mutations in SPG11, is homogeneous and includes progressive spasticity and weakness of the lower limbs with the following associating signs [Shibasaki et al 2000, Casali et al 2004, Winner et al 2004, Lossos et al 2006, Olmez et al 2006, Stevanin et al 2006, Winner et al 2006, Del Bo et al 2007, Hehr et al 2007, Stevanin et al 2007b, Stevanin et al 2008, Denora et al 2009]:Frequent findingsMild intellectual disability with learning difficulties in childhood and/or progressive cognitive declineAxonal, motor, or sensorimotor peripheral neuropathyPseudobulbar involvement with dysarthria and/or dysphagiaIncreased reflexes in the upper limbs Less frequent findings:Cerebellar signs (ataxia or ocular signs including nystagmus and/or saccadic pursuit)Retinal degeneration (Kjelling syndrome) [Puech et al 2011]Pes cavusScoliosisExtrapyramidal signs such as parkinsonism [Anheim et al 2009]TestingBrain and spinal cord MRI. The following MRI findings help distinguish SPG11 from other forms of hereditary spastic paraplegia (HSP), since 60% to 80% of individuals with mutations in SPG11 have these MRI findings [Del Bo et al 2007, Hehr et al 2007, Stevanin et al 2007b, Stevanin et al 2008, Denora et al 2009]:Thinning of the corpus callosum (TCC) is an almost constant feature in SPG11, except in some individuals with short disease duration [Stevanin et al 2008]. In most affected individuals, thinning of corpus callosum appears to be non-progressive [Hehr et al 2007] but this point is debated [Rajakulendran et al 2011]. TCC is not specific to SPG11 (see Differential Diagnosis). Cortical atrophy is frequently observed. White matter hyperintensities are also often associated [Del Bo et al 2007, Hehr et al 2007, Stevanin et al 2007b, Stevanin et al 2008, França et al 2012]: Periventricular, confluent leukoencephalopathy increases in severity with disease duration in individuals reported to have an SPG11 mutation [Hehr et al 2007, Stevanin et al 2008]. Note: Change in leukoencephalopathy does not always parallel the clinical course. In mild cases, only frontal and occipital periventricular hyperintensities are seen. Atrophy of both the brain stem and the cerebellum can be observed [Stevanin et al 2006, Stevanin et al 2007b]. The basal ganglia and spinal cord are usually spared. Electromyography (EMG) and nerve conduction velocities (NCVs) frequently show signs of axonal sensorimotor neuropathy. These signs are more frequently observed when disease duration exceeds ten years. In a few cases, anterior horn cell abnormalities have been noted [Stevanin et al 2007b, Stevanin et al 2008]. Sural nerve biopsies have shown loss of unmyelinated nerve fibers and accumulation of pleomorphic membranous material in unmyelinated axons [Hehr et al 2007]. Molecular Genetic TestingGene. SPG11 (previously known as KIAA1840 or FLJ21439) is the only gene in which mutations are known to cause SPG11 [Stevanin et al 2007b]. Clinical testing Table 1. Summary of Molecular Genetic Testing Used in Spastic Paraplegia Type 11View in own windowGene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method 1Test AvailabilitySPG11 Sequence analysis Sequence variants 2, 3>90% 4 ClinicalSequence analysis of select exonsSequence variants in select exons 5UnknownDeletion / duplication analysis 6Partial- and whole-gene deletions 7Unknown 71. 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. Small intragenic deletions/insertions and nonsense and splice-site mutations. A missense variant has also been reported as a possible mutation (c.4046T>A) but its consequence remains unknown [Denora et al 2009] See Molecular Genetics, Pathologic allelic variants.4. Failure to detect a mutation on sequence analysis does not definitely exclude the diagnosis because (a) the full spectrum of abnormalities in SPG11 has not yet been established and (b) other kinds of mutations (e.g., exonic, multiexonic, or whole-gene deletions and/or large genomic rearrangements) may be identified in the future and require other detection methods.5. Exons sequenced may vary by laboratory.6. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.7. Crimella et al [2009] identified a 2.6-kb deletion of SPG11 as one of two mutations in affected individuals in one family. The deletion results from a large intragenic rearrangement. Bauer et al [2009] and Denora et al [2009] also identified individuals with large gene deletions of 8.2 and 9 kb, respectively. Stevanin et al [2010] reported that 11% of the mutations in SPG11 are rearrangements detectable by MLPA.Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.Information on specific allelic variants may be available in Molecular Genetics (see Table A. Genes and Databases and/or Pathologic allelic variants).Testing StrategyTo confirm/establish of the diagnosis in a proband. Detection of mutations or rearrangements in SPG11 is the only way to confirm the diagnosis of SPG11. Sequence analysis should be performed first; if only one or no mutations are identified deletion/duplication analysis can be considered.Note: The best clinical predictors of an SPG11 mutation are lower-limb spasticity, atrophy of the corpus callosum, and either intellectual disability or cognitive impairment in individuals with onset in the first to third decade. The presence of other features such as peripheral neuropathy and white matter hyperintensities on MRI increases the chance of finding an SPG11 mutation [Stevanin et al 2008]. Carrier testing for at-risk relatives requires prior identification of the disease-causing mutations in the family. Note: Carriers are heterozygotes for this autosomal recessive disorder and are not at risk of developing the disorder.Prenatal diagnosis for at-risk pregnancies requires prior identification of the disease-causing mutations in the family. Genetically Related (Allelic) DisordersTo date, no other phenotypes are known to be associated with SPG11 mutations.
Onset of spastic paraplegia type 11 (SPG11) occurs mainly during infancy or adolescence (age 1-31 years) and is characterized in most cases by gait disorders or less frequently by intellectual disability [Stevanin et al 2007b, Stevanin et al 2008]. ...
Natural HistoryOnset of spastic paraplegia type 11 (SPG11) occurs mainly during infancy or adolescence (age 1-31 years) and is characterized in most cases by gait disorders or less frequently by intellectual disability [Stevanin et al 2007b, Stevanin et al 2008]. Approximately ten years after onset, most affected individuals have the complete clinical picture of SPG11, including progressive lower-limb spasticity, atrophy of the corpus callosum with intellectual disability, and/or progressive cognitive decline. Most affected individuals become wheelchair bound one or two decades after disease onset [Stevanin et al 2008]. Cognitive decline with low Mini Mental State Evaluation (MMSE) scores, found in the majority of affected individuals, worsens with time and includes severe short-term memory impairment, emotional lability, childish behavior, reduced verbal fluency, and attention deficit indicative of executive dysfunction [Stevanin et al 2006, Hehr et al 2007, Stevanin et al 2008]. Psychiatric problems with behavioral disturbances are observed. Most individuals with SPG11 display little concern over the progression of their motor disease [Stevanin et al 2006]. All these findings correlate with the frontal atrophy detected on follow-up brain MRI. Intellectual disability, found in all individuals with early onset, is characterized by learning difficulties in childhood and low IQ. Eye findings can include the following:Macular excavation or degeneration as reported in the Kjellin syndrome [Orlén et al 2009, Puech et al 2011] Strabismus Cerebellar ocular signs such as abnormal saccadic pursuit and nystagmus in individuals with the longest disease duration Visual evoked potentials with increased latencies and decreased amplitudes [Del Bo et al 2007, Stevanin et al 2008] Additional features are severe weakness, dysarthria, distal or generalized muscle wasting, and less frequently, pes cavus, scoliosis, parkinsonism, and orthostatic hypotension. Individuals with the longest disease duration may have swallowing difficulties [Stevanin et al 2008].
See Hereditary Spastic Paraplegia (HSP) Overview. The relative frequency of spastic paraplegia 11 (SPG11) varies according to phenotype. SPG11 accounts for: ...
Differential DiagnosisSee Hereditary Spastic Paraplegia (HSP) Overview. The relative frequency of spastic paraplegia 11 (SPG11) varies according to phenotype. SPG11 accounts for: 4.5% of persons with spastic paraplegia and cognitive impairment without TCC but with white matter hyperintensities (one family reported by Stevanin et al [2008]); Up to 59% of persons with simplex or autosomal recessive early-onset progressive spasticity with mild intellectual disability and/or cognitive decline associated with TCC [Stevanin et al 2008, Denora et al 2009]. Because the phenotype of progressive spasticity with mild intellectual disability and/or cognitive decline associated with TCC accounts for one third of autosomal recessive spastic paraplegia [França et al 2007] and because SPG11 is a common cause of this phenotype, SPG11 should account for approximately 21% of all autosomal recessive HSP [Stevanin et al 2008]. No instances of pure spastic paraplegia associated with an SPG11 mutation have been reported to date [personal data]. Lower motor neuron degeneration may mimic amyotrophic lateral sclerosis (ALS) when wasting is marked as reported by Stevanin et al [2008], Orlacchio et al [2010], and Daoud et al [2012]. Upper motor neuron degeneration with spasticity can be seen in a non-genetic disorder called primary lateral sclerosis.Other spastic paraplegias in which TCC (referred to as AR-HSP-TCC) is observed:SPG15 [Hughes et al 2001, Hanein et al 2008]. No clinical features could discriminate between SPG11 and SPG15 [Goizet et al 2009, Schüle et al 2009]. SPG21 [Simpson et al 2003] SPG32 [Stevanin et al 2007a] SPG18 with epilepsy [Al-Yahyaee et al 2006] SPG4 [Orlacchio et al 2004]; occasionalSPG7 [Coutinho et al 1999]; occasionalSPG49 [Tesson et al 2012]; occasionalSPG54 [Schuurs-Hoeijmakers et al 2012]SPG47 [Bauer et al 2012]Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).
To establish the extent of disease and needs in an individual diagnosed with spastic paraplegia type 11 (SPG11), the following evaluations are recommended:...
ManagementEvaluations Following Initial DiagnosisTo establish the extent of disease and needs in an individual diagnosed with spastic paraplegia type 11 (SPG11), the following evaluations are recommended:Neuropsychological testing to assess the cognitive impairment and decline Neuro-urologic examination for those with sphincter disturbance Electrophysiologic investigations (e.g., ENMG, VEP, SEP) Medical genetics consultationTreatment of ManifestationsNo specific drug treatment or cures exist for SPG11.Care by a multidisciplinary team that may include a general practitioner, neurologist, medical geneticist, physiotherapist, physical therapist, social worker, and psychologist should be considered. Symptomatic treatment to reduce pyramidal hyperactivity in the lower limbs includes the following:Physiotherapy for stretching of the spastic muscles to prevent contractures Anti-spastic drugs such as baclofen and tizanidine Botulin toxin and intrathecal baclofen, which can be considered when oral drugs are ineffective and spasticity is severe and disabling When sphincter disturbances become a problem, urodynamic evaluation should be performed in order to adapt treatment and monitor follow-up. Anticholinergic drugs are indicated for urinary urgency. Psychiatric manifestations should be treated in accordance with standard practice. Prevention of Secondary ComplicationsFollow-up of sphincter disturbances is important to prevent bladder dysfunction and infection. Early regular physiotherapy helps to prevent contractures.SurveillanceSpecialized outpatient clinic evaluations are suggested every six months to adjust medication and physical rehabilitation.Brain MRI can be used to follow the atrophy of the corpus callosum, cerebellum, and brain stem, and to monitor increases in the size and intensity of white matter hyperintensities. Regular electrophysiologic investigations (e.g., ENMG, VEP, SEP) are recommended to follow the extent of the disease.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.
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED....
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 Type 11: Genes and DatabasesView in own windowLocus NameGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDSPG11SPG1115q21.1SpatacsinSPG11 homepage - Mendelian genesSPG11Data 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 Type 11 (View All in OMIM) View in own window 604360SPASTIC PARAPLEGIA 11, AUTOSOMAL RECESSIVE; SPG11 610844SPG11 GENE; SPG11Normal allelic variants. See Table 2. Human SPG11 contains 40 exons spanning 101 kb of genomic DNA. Table 2. Selected SPG11 Normal Allelic Variants View in own windowExon/ IntronDNA Nucleotide Change (Alias 1)Protein Amino Acid Change 2 Frequency Reference SequencesIn Individuals with HSPIn ControlsExon 4c.808G>Ap.Val270Ile1.5%2.3%NM_025137.3 NP_079413.3Exon 6c.1388T>Cp.Phe463Ser47%51%Exon 19c.3420G>Ap.=2.3%3.3%Exon 39c.7023C>Tp.=1.5%7.1%Intron 37c.6843+62C>T (IV37+62C>T)--ND 3 NDIntron 7c.1603-141A>C (IV7-141A>C)--NDNDIntron 7c.1603-139A>G (IV7-139A>G)--NDNDStevanin et al [2008] See 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 conventions 2. p.= indicates that no effect on protein level is expected3. ND = not donePathologic allelic variants. More than 100 different truncating mutations have been identified to date [Del Bo et al 2007, Hehr et al 2007, Stevanin et al 2007b, Stevanin et al 2008, Bauer et al 2009, Boukhris et al 2009, Crimella et al 2009, Denora et al 2009, Stevanin et al 2010]. They are distributed throughout SPG11 from exon 1 to exon 39 (see Table 3; pdf). A missense variant has also been reported as a possible mutation (NM_025137.3:c.4046T>A; NP_079413.3:p.Phe1349Tyr); its effect remains unknown [Denora et al 2009] Normal gene product. The full-length transcript encodes a predicted protein of 2443 amino acids of unknown function, called spatacsin (for spasticity with thin or atrophied corpus callosum syndrome protein) [Stevanin et al 2007b]. The sequence of spatacsin is strongly conserved through evolution with orthologues in mammalians and other vertebrates: human spatacsin shares 85% identity with the homologous protein in dog, 76% and 73% with the mouse and rat homologues, and 59% with the chicken homologue, all of similar sizes. Neither the gene nor the predicted protein that it encodes in many species shows any significant sequence similarity to known cDNA or protein sequences. The spatacsin protein interacts with the SPG15 and SPG48 protein products [Słabicki et al 2010] and is an accessory protein of the adaptor protein 5 complex [Hirst et al 2011], consistent with its presence along microtubules [Murmu et al 2011].Abnormal gene product. With the exception of one variant of uncertain clinical significance (c.4046T>A) [Denora et al 2009], all pathologic allelic variants identified to date in SPG11 predict truncation of the protein, suggesting that pathogenicity results from loss of function of the spatacsin protein. Indeed, reduced spg11 function in zebrafish led to abnormal development of motor neurons [Southgate et al 2010, Martin et al 2012].