Hereditary spastic paraplegia (SPG) is characterized by progressive weakness and spasticity of the lower limbs due to degeneration of corticospinal axons. There is considerable genetic heterogeneity. Inheritance is most often autosomal dominant (see 182600), but X-linked (see 312920) ... Hereditary spastic paraplegia (SPG) is characterized by progressive weakness and spasticity of the lower limbs due to degeneration of corticospinal axons. There is considerable genetic heterogeneity. Inheritance is most often autosomal dominant (see 182600), but X-linked (see 312920) and autosomal recessive (see 270800) forms occur. SPG7 shows phenotypic variability between families. Some cases are pure, whereas other are complicated with additional neurologic features (Warnecke et al., 2007).
De Michele et al. (1998) reported a large consanguineous family with autosomal recessive spastic paraplegia with age of onset between 25 and 42 years (mean 30 +/- 8 years). Abnormal gait was the presenting symptom in all cases, ... De Michele et al. (1998) reported a large consanguineous family with autosomal recessive spastic paraplegia with age of onset between 25 and 42 years (mean 30 +/- 8 years). Abnormal gait was the presenting symptom in all cases, and it was associated with leg pains in 1 patient. Weakness and extensor plantar response were absent in 1 patient with the shortest duration of disease at the time of observation. Vibration sense was frequently decreased in the lower limbs. Hypernasal and slowed speech was present in 2 patients and dysphagia in 1. Urinary urgency was present in 3 patients, scoliosis and pes cavus in 2, and pale optic disc in 2. There were no cerebellar or extrapyramidal signs in any of the 6 affected individuals (3 persons in each of 2 sibships who were related as double first cousins, having been born from brothers married to sisters). Casari et al. (1998) reported 2 affected brothers from a small village in southern Italy who showed typical signs of pure SPG with an age of onset of 26 years. Casari et al. (1998) reported a French family with autosomal recessive complicated SPG characterized by progressive weakness and spasticity of the lower limbs, decreased perception of sharp stimulation, diminished vibratory sense, and urinary incontinence. Mean age of onset was 34 years. These patients also had optic atrophy (3 of 3 examined), cortical atrophy (1 of 3 examined), and cerebellar atrophy (2 of 3 examined). Muscle biopsies showed ragged red fibers and abnormal mitochondrial structure with no reaction to cytochrome c oxidase, consistent with a defect in mitochondrial respiration. Elleuch et al. (2006) reported a Moroccan family in which 4 sibs had SPG7. Age at onset ranged from 28 to 32 years with instability and stiff legs, which rapidly progressed to lower limb spasticity and weakness with hyperreflexia. Three patients could not run, and 1 could walk only with help. All had pes cavus, but none had extensor plantar responses. One patient had nystagmus, another had cerebellar signs, and a third had bladder dysfunction; none had decreased visual acuity. Two patients had impaired sensation at the ankles. Warnecke et al. (2007) reported a consanguineous Turkish family in which 3 sibs had a complicated form of SPG7. Age at onset ranged from 10 to 25 years, with gait disturbances in 2 sibs and dysarthria in 1. Clinical features included lower limb spasticity, pyramidal signs, lower limb hyperreflexia, supranuclear palsy, nystagmus, and cerebellar dysarthria. Two of the sibs, who were more severely affected, also had ataxia and extensor plantar responses, and 1 had urinary incontinence. Neuropsychologic evaluations showed severe deficits in attention and executive function in all sibs. The more severely affected sibs also showed impaired working memory and verbal learning. However, none of the sibs reported cognitive deficits. Brain MRI showed cerebellum atrophy and mild frontal cortical atrophy. Diffusion tensor imaging showed decreased white matter in the corticospinal tracts, frontal lobes, and midbrain. There was no evidence of peripheral neuropathy or optic atrophy. Molecular analysis identified a homozygous mutation in the SPG7 gene (602783.0006). Warnecke et al. (2007) suggested that the diffuse involvement may reflect mitochondrial dysfunction.
Casari et al. (1998) found that all affected individuals from the SPG7 family reported by De Michele et al. (1998) were homozygous for a 9.5-kb deletion (602783.0003) in the SPG7 gene.
In 1 of 2 brothers ... Casari et al. (1998) found that all affected individuals from the SPG7 family reported by De Michele et al. (1998) were homozygous for a 9.5-kb deletion (602783.0003) in the SPG7 gene. In 1 of 2 brothers from a small village in southern Italy who had autosomal recessive hereditary pure spastic paraplegia, Casari et al. (1998) identified a homozygous 2-bp deletion in the paraplegin cDNA (602783.0001), resulting in a frameshift that abolished approximately 60% of the protein. In a French family with SPG, they identified homozygosity for a 1-bp insertion (602783.0002) in all affected sibs; the mother was heterozygous for the mutation. In 4 affected sibs from a Moroccan family with SPG7, Elleuch et al. (2006) identified compound heterozygosity for 2 mutations in the SPG7 gene (602783.0004-602783.0005). In 1 (0.7%) of 136 index patients with autosomal recessive SPG, Elleuch et al. (2006) identified 2 mutations in the SPG7 gene. Twenty families had at least 1 variant in the SPG7 gene that was not found in 550 control chromosomes. In 4 of these families, mutations were predicted to be highly deleterious, suggesting that they may have contributed to the phenotype. The authors identified several additional rare variants in the SPG7 gene, which were of undetermined significance. Arnoldi et al. (2008) identified 7 different SPG7 mutations (see, e.g., 602783.0007-602783.0009) in 6 (4.4%) of 135 Italian patients with spastic paraplegia. Four of the patients were heterozygous for the mutations, which fell within conserved domains of the protein and were not found in controls. In 7 of 98 Dutch patients with apparently sporadic upper motor neuron disease symptoms, Brugman et al. (2008) identified homozygosity or compound heterozygosity for 6 mutations in the SPG7 gene that were of known or probable pathogenicity. Six patients had lower limb involvement only, and 1 patient had both upper and lower limb involvement. Three patients developed cerebellar signs, including dysarthria and gait ataxia, late in the disease course. None had bulbar involvement. Two patients with pure spastic paraparesis carried a single pathogenic mutation in the SPG7 gene. Sanchez-Ferrero et al. (2013) sequenced the SPG7 gene in 285 Spanish patients with spastic paraplegia who were negative for mutations in the SPAST (604277) and ATL1 (606439) genes. Fourteen SPG7 mutations, including 12 novel mutations, were identified in 14 patients. The mutations included 2 large deletions, 5 missense changes, 4 nonsense mutations, 2 frameshift insertion/deletions, and 1 splice site mutation. Thirteen patients had only a single heterozygous mutation, suggesting a dominant effect for some SPG7 mutations. Functional studies were not performed to assess the biologic significance. An A510V (dbSNP rs61755320) substitution (602783.0012) was found in 8 patients (3%): 4 carried A510V in compound heterozygous state with another SPG7 mutation, 1 was homozygous for A510V, and 3 patients were heterozygous for A510V. The A510V substitution was also identified in 1% of controls. All patients had adult onset of the disorder, but only 35% had a complicated phenotype.
The diagnosis of spastic paraplegia 7 (SPG7) is suspected in the presence of the following:...
Diagnosis
Clinical DiagnosisThe diagnosis of spastic paraplegia 7 (SPG7) is suspected in the presence of the following:Insidiously progressive bilateral leg weaknessSpasticityDecreased vibratory sense caused by degeneration of cortical spinal axons and dorsal columnsNeurologic examination demonstrating:A pure phenotype of spastic paraplegia with hyperreflexia, extensor plantar responses, and mildly impaired vibration sensation in the distal legsIn some individuals, a complicated phenotype of spastic paraplegia including pale optic disks, ptosis, slowed speech, swallowing difficulties, subtle cognitive impairment, upper motor neuron symptoms in the arms, urinary urgency, ataxia, nystagmus, strabismus, decreased hearing, scoliosis, pes cavus, motor and sensory neuropathy, and amyotrophy [Harding 1983, De Michele et al 1998, Fink 2003, Wilkinson et al 2004, Elleuch et al 2006, Brugman et al 2008, Salinas et al 2008, Warnecke et al 2010]Family history consistent with autosomal recessive inheritanceThe diagnosis is confirmed by detection of disease-causing mutations in SPG7.TestingNeuroimagingIn a few individuals, conventional cerebral MRI may show cerebellar (or, less frequently, cortical) atrophy [De Michele et al 1998, Wilkinson et al 2004, Elleuch et al 2006, Uttner et al 2007, Warnecke et al 2007, Salinas et al 2008, Hourani et al 2009, Warnecke et al 2010]. White matter changes as detected by diffusion tensor imaging (DTI) in the frontal lobes, the corticospinal tracts, and the brain stem are specific to SPG7-HSP (hereditary spastic paraplegia) [Warnecke et al 2010]. Findings of a subtle reduction of white matter integrity in the corpus callosum of heterozygote SPG7-autosomal recessive HSP carriers may be revealed by DTI, suggesting that different HSP-related genes share a common biologic pathway leading to neurodegeneration of the corpus callosum [Warnecke et al 2010].Spinal imaging studies are useful in the differential diagnosis to exclude other anomalies of the ponto-medullary junction and of the cervical and dorsolumbar medulla. Other investigationsSpinal evoked potentials may reveal delayed prolongation of the central conduction time [Nielsen et al 2001]. Paired transcranial magnetic stimulation (TMS) may show delayed prolongation of the central motor conduction time and motor threshold in some affected individuals in lower limb muscles [Warnecke et al 2007, Warnecke et al 2010]. Intracortical inhibition seems normal in SPG7 [Nardone & Tezzon 2003]. A battery of neuropsychological tests may reveal mild impairment of visuoconstructive and executive functions in some individuals [Uttner et al 2007, Warnecke et al 2010].Molecular Genetic TestingGene. SPG7, which encodes the protein paraplegin, is the only gene in which mutations are known to cause spastic paraplegia 7 (SPG7) [Casari et al 1998].Clinical testingSequence analysis. Missense, nonsense, and splice site mutations can be detected by sequence analysis.Deletion/duplication analysis detects deletions, including the 9.5-kb deletion of exons 12-17 described by Casari et al [1998].Table 1. Summary of Molecular Genetic Testing Used in Spastic Paraplegia 7View in own windowGene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method 1Test AvailabilitySPG7Sequence analysis
Sequence variants 2100% 3ClinicalDeletion / duplication analysis 4Deletions, including the 9.5-kb deletion 51. 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. 3. The disease is defined by presence of an SPG7 mutation; therefore, the mutation detection rate is by definition 100%.4. Testing that identifies deletions/duplications not readily detectable by sequence analysis of genomic DNA; a variety of methods including quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), or targeted array GH (gene/segment-specific) may be used. A full array GH analysis that detects deletions/duplications across the genome may also include this gene/segment.5. See Table 4 (pdf).Table 3 (pdf) shows PCR primers that can be used for molecular diagnosis. Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.Testing StrategyTo confirm/establish the diagnosis in a proband requires molecular genetic testing to identify SPG7 disease-causing mutations.Sequence analysis should be performed first; If sequence analysis identifies only one or no mutations, deletion/duplication analysis may be considered. Predictive testing for at-risk asymptomatic family members requires prior identification of the disease-causing mutations in the family.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 to develop the disorder. Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutations in the family.Genetically Related (Allelic) DisordersNo other phenotypes are known to be associated with mutations in SPG7.
Spastic paraplegia 7 (SPG7) is characterized by insidiously progressive bilateral lower limb weakness and spasticity. Most affected individuals have proximal or generalized weakness in the legs and impaired vibration sense....
Natural History
Spastic paraplegia 7 (SPG7) is characterized by insidiously progressive bilateral lower limb weakness and spasticity. Most affected individuals have proximal or generalized weakness in the legs and impaired vibration sense.Onset is mostly in adulthood, although symptoms may start as early as age 11 years and as late as age 72 years [De Michele et al 1998, McDermott et al 2001, Wilkinson et al 2004].Additional features such as hyperreflexia in the arms, sphincter disturbances, spastic dysarthria, dysphagia, pale optic disks, ataxia, nystagmus, strabismus, decreased hearing, scoliosis, pes cavus, motor and sensory neuropathy, and amyotrophy may be observed [Harding 1983, De Michele et al 1998, Fink 2003, Wilkinson et al 2004, Elleuch et al 2006, Brugman et al 2008, Salinas et al 2008, Warnecke et al 2010].Progression of disease may be rapid with severe disability after eight years' duration [Elleuch et al 2006, Schüle et al 2006].Serum creatine kinase activity may be slightly above the normal range in some cases.Electromyography with nerve conduction velocities may reveal axonal sensory motor neuropathy.Muscle biopsy may shed light on the pathogenic process and reveal the following:Changes of denervation with partial reinnervationAtrophic, angulated fibers, predominantly type IIRagged-red fibers, which are positive for the histoenzymatic reaction to succinate dehydrogenase (SDH) and negative for cytochrome c oxidase (COX, the complex IV of the mitochondrial respiratory chain), indicating an oxidative phosphorylation (OXPHOS) defect [Casari et al 1998, McDermott et al 2001, Wilkinson et al 2004, Tzoulis et al 2008].
No significant differences exist between spastic paraplegia 7 (SPG7) and other types of pure autosomal dominant and autosomal recessive spastic paraplegia [Fink 2002, Fink 2003, Salinas et al 2008] (see Hereditary Spastic Paraplegia Overview for a review). However, Brugman et al [2008] reported that SPG7 mutations are a frequent cause of spastic paraplegia in individuals representing simplex cases (i.e., a single occurrence in a family) with adult-onset disease who do not have an identifiable SPG4 mutation. They also noted that SPG7 mutations are less likely to be found in adult-onset cases in which upper motor neuron symptoms (UMN) are present in the arms and in adult-onset cases with UMN symptoms involving the bulbar region....
Differential Diagnosis
No significant differences exist between spastic paraplegia 7 (SPG7) and other types of pure autosomal dominant and autosomal recessive spastic paraplegia [Fink 2002, Fink 2003, Salinas et al 2008] (see Hereditary Spastic Paraplegia Overview for a review). However, Brugman et al [2008] reported that SPG7 mutations are a frequent cause of spastic paraplegia in individuals representing simplex cases (i.e., a single occurrence in a family) with adult-onset disease who do not have an identifiable SPG4 mutation. They also noted that SPG7 mutations are less likely to be found in adult-onset cases in which upper motor neuron symptoms (UMN) are present in the arms and in adult-onset cases with UMN symptoms involving the bulbar region.Other conditions that need to be considered in the differential diagnosis of SPG7:Structural abnormalities of the brain or spinal cordAdrenomyeloneuropathy and other leukodystrophies (e.g., Krabbe disease, arylsulfatase A deficiency [metachromatic leukodystrophy]) [Bajaj et al 2002]Vitamin B12 deficiencyMultiple sclerosisTropical spastic paraplegia (caused by HTLV1 infection)Dopa-responsive dystoniaAmyotrophic lateral sclerosis (ALS) [McDermott et al 2003]Primary lateral sclerosis (PLS) [Brugman et al 2008]Arginase deficiency [Prasad et al 1997]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).SPG7, pure phenotypeSPG7, complicated phenotype
To establish the extent of disease in an individual diagnosed with spastic paraplegia 7 (SPG7), evaluation by a multidisciplinary team that includes a general practitioner, neurologist, medical geneticist, physical therapist, social worker, and psychologist should be considered....
Management
Evaluations Following Initial DiagnosisTo establish the extent of disease in an individual diagnosed with spastic paraplegia 7 (SPG7), evaluation by a multidisciplinary team that includes a general practitioner, neurologist, medical geneticist, physical therapist, social worker, and psychologist should be considered.Treatment of ManifestationsNo specific drug treatments or cures exist for SPG7.Drugs to reduce spasticity and muscle tightness include baclofen, tizanidine, dantrolene, and diazepam — preferably administered one at a time.Management of spasticity by intrathecal baclofen or intramuscular botulinum toxin injections may be an option in selected individuals [Young 1994].A combination of physical therapy and assistive walking devices are often used to reduce contractures, provide support, and promote stability.Occupational therapy is often helpful in managing activities of daily living.SurveillanceAnnual neurologic evaluation can help identify potential complications of spasticity that develop over time (e.g., contractures).Evaluation of Relatives at RiskSee Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Therapies Under InvestigationIn an SPG7 mouse model using intramuscular viral delivery of the gene to correct some of the defects, Pirozzi et al [2006] observed an improvement of neuropathologic changes and mitochondrial morphology, described by Ferreirinha et al [2004], in the peripheral nerves of parapegin-deficient mice. This approach may offer hope for future treatment strategies. Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED....
Molecular Genetics
Information 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 7: Genes and DatabasesView in own windowLocus NameGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDSPG7
SPG716q24.3Parapleginalsod/SPG7 genetic mutations HSP mutation database SPG7 homepage - Mendelian genesSPG7Data 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 7 (View All in OMIM) View in own window 602783SPG7 GENE; SPG7 607259SPASTIC PARAPLEGIA 7, AUTOSOMAL RECESSIVE; SPG7Normal allelic variants. SPG7 spans a physical distance of approximately 52 kb and is composed of 17 exons (Table 2). Pathologic allelic variants. All types of DNA alterations are observed in almost every exon or splice site. Missense mutations are the most frequent subgroup. Missense mutations and truncating mutations have been reported within the paraplegin functional domain. See Table 3 (pdf) for primers that can be used in molecular genetic testing [McDermott et al 2001; Casari, unpublished data]. To date, 26 mutations have been confirmed in SPG7 (Table 4 - pdf). Normal gene product. Paraplegin, comprising 795 amino acids, is in the AAA (ATPases associated with diverse cellular activities) family, as is spastin, encoded by SPAST, mutations in which cause SPG4, an autosomal dominant form of HSP [Hazan et al 1999] (see also Hereditary Spastic Paraplegia Overview). Paraplegin and spastin belong to different subclasses of the AAA family, since mitochondrial function of spastin has been excluded but demonstrated as a function of paraplegin.Paraplegin is ubiquitously expressed in adult and fetal human tissues and in mouse brain [Sacco et al 2010].Paraplegin shares its closest amino acid sequence homology with the yeast mitochondrial metalloproteases Afg3, Rca1, and Yme1 [Casari et al 1998, Settasatian et al 1999]. Yeast mitochondrial ATPases demonstrate both proteolytic and chaperone-like activities at the inner mitochondrial membrane, where they are involved in the assembly and degradation of proteins in the respiratory chain complex [Pearce 1999]. Two additional human genes encoding protein highly homologous to paraplegin, AFG3L2 and YME1L1, have been discovered [Banfi et al 1999, Coppola et al 2000]. The presence of two hydrophobic regions, which have the characteristics of transmembrane domains, allows identification of both paraplegin and AFG3L2 as integral membrane proteins. The AAA domain is localized in the central part of paraplegin between amino acid residues 344 and 534.Abnormal gene product. Atorino et al [2003] demonstrated that paraplegin co-assembles with a homologous protein, AFG3L2, in the mitochondrial inner membrane. The two proteins form a high molecular-weight complex that appears to be aberrant in fibroblasts of individuals affected with HSP. The inactivation of this complex causes reduced complex I activity in mitochondria that can be reversed by increased expression of wild type paraplegin. Furthermore, complementation studies in yeast demonstrate functional conservation of the human paraplegin/AFG3L2 complex with the yeast m-AAA protease and also assign proteolytic activity to this structure. A study of AFG3L2 found that null or missense Afg3l2 mouse models had marked impairment of axonal development and transport leading to neonatal death [Maltecca et al 2008]. The mice developed a severe early-onset tetraparesis and were found to have reduced myelinated fibers in the spinal cord and impaired respiratory chain complex I and III activity. The phenotype was reported to be more severe than that seen in paraplegin-deficient mice because of the higher neuronal expression of AFG3L2, but also serves to link mitochondria function with HSP. Despite coassembling in the same complex, mutations of AFG3L2 have been recently associated to a dominant form of spinocerebellar ataxia (SCA28) [Di Bella et al 2010].Biochemical analysis from two SPG7 mutation-positive individuals revealed a reduction in citrate synthase-corrected complex I and complex II/III activities in muscle and complex I activity in mitochondrial-enriched fractions from cultured myoblasts [Wilkinson et al 2004].