Pure or complex autosomal dominant spastic paraplegia
-Rare genetic disease
-Rare neurologic disease
Comment:
Autosomal dominant spastic paraplegia, type 4 (SPG4), a debilitating disorder of progressive spasticity and weakness of the lower limbs, results from heterozygous mutations in the SPAST gene (= ADPSP, FSP2, SPG4). Genomic deletions encompassing the final exon of SPAST may affect expression of SLC30A6, the most proximal downstream locus and a gene that has been implicated in the pathogenesis of Alzheimer disease, potentially explaining recent reports of dementia in selected SPG4 patients (PMID:21659953). Age of onset of symptoms showed a wide range from four to 61 years of age (PMID:12124993).
The SPG4 gene product spastin is a protein belonging to the AAA family of ATPases, which are associated with several cellular activities, that is believed to play a major role in microtubule dynamics. SPG4 is highly conserved across species, suggesting that the amino-acid changes, especially when present in the ATPase domain, are likely to influence protein function. Most of the mutations described are in exon 8–15, the region encoding the ATPase domain, but they have been reported in all 17 exons, except exon 4 (PMID:17594340).
The hereditary spastic paraplegias (SPG, HSP) are a group of clinically and genetically diverse inherited disorders characterized predominantly by progressive lower extremity spasticity and weakness. SPG is classified by mode of inheritance (autosomal dominant, autosomal recessive, and X-linked) ... The hereditary spastic paraplegias (SPG, HSP) are a group of clinically and genetically diverse inherited disorders characterized predominantly by progressive lower extremity spasticity and weakness. SPG is classified by mode of inheritance (autosomal dominant, autosomal recessive, and X-linked) and whether the primary symptoms occur in isolation ('uncomplicated') or with other neurologic abnormalities ('complicated'). Pure SPG4 is the most common form of autosomal dominant hereditary SPG, comprising up to 45% of cases (Svenson et al., 2001; Crippa et al., 2006). For a general phenotypic description and a discussion of genetic heterogeneity of autosomal dominant spastic paraplegia, see SPG3A (182600).
In 5 of 7 French families and in 1 large Dutch pedigree with a form of autosomal dominant familial spastic paraplegia, Hazan et al. (1994) found linkage to a locus, which they termed FSP2 (also known as SPG4), ... In 5 of 7 French families and in 1 large Dutch pedigree with a form of autosomal dominant familial spastic paraplegia, Hazan et al. (1994) found linkage to a locus, which they termed FSP2 (also known as SPG4), on chromosome 2p. This finding distinguished the disease from autosomal dominant spastic paraplegia-3 (182600), which had been mapped to chromosome 14. Age of onset in the 6 families showing linkage to 2p varied widely within families and the mean age at onset ranged from 20 to 39 years. Thus, age of onset may be a poor criterion for classifying autosomal dominant spastic paraplegia. Anticipation in the age of onset was observed in 2 of the kindreds. Durr et al. (1996) reported 12 families with autosomal dominant spastic paraplegia linked to the SPG4 locus on chromosome 2. Age of onset ranged from infancy to 63 years. The clinical expression of the disorder within a family included asymptomatic patients who were unaware of their condition, mildly affected individuals who had spastic gait but were able to walk independently, and severely affected patients who were wheelchair bound. Durr et al. (1996) commented on the extensive intra- and interfamilial clinical variation. Nielsen et al. (1998) evaluated 5 families with 2p-linked pure spastic paraplegia. In 2 families, nonprogressive 'congenital' spastic paraplegia was seen in some affected members, whereas adult-onset progressive spastic paraplegia was present in others. Low backache was reported as a late symptom by 47% of the 63 at-risk members in the 5 families. Brain and total spinal cord MRI disclosed no significant abnormalities. Nielsen et al. (1998) concluded that SPG4 is a phenotypically heterogeneous disorder, characterized by both interfamilial and intrafamilial variation. Nance et al. (1998) found striking variation in clinical features in 4 families with spastic paraplegia with linkage to chromosome 2 markers. Only mild neurologic signs were observed in some subjects. The clinical features of 1 family had previously been described by Boustany et al. (1987). Onset was generally in the third to fifth decades with an average onset age of 35 years (range, 5 to 61 years). All clearly affected patients had scissoring gait, and in all who were examined at least 2 of the following were found: extensor plantar responses, increased knee and ankle reflexes, increased tone, muscle spasms, or leg cramps. Urinary urgency or other symptoms compatible with a neurogenic bladder, leg weakness, and decreased vibration sense were present in some but not all patients. Byrne et al. (1997, 1998) presented a family with autosomal dominant hereditary spastic paraplegia and a specific form of cognitive impairment who showed linkage to the SPG4 locus on chromosome 2. The pattern of cognitive impairment in this family was characterized primarily by deficits in visual-spatial functions. Dysfunction manifested itself by difficulty in carrying out new tasks, forgetfulness, poor spatial perception, and impaired visual-motor coordination. By haplotype analysis the presence of the mutant gene was identified in an individual who, at the age of 57, had the same pattern of cognitive impairment but no spastic paraplegia. Furthermore, 6 individuals who presented with the disease haplotype had normal neurologic and neuropsychologic examinations. All 6 were below the maximal age of onset in the family, namely, 60 years. In this Irish family the cognitive impairment was considered to be a manifestation of the SPG4 gene mutation. Reid et al. (1999) investigated 35 individuals from 4 families of Welsh origin, 22 of whom had 'pure' hereditary spastic paraplegia, for the presence of subclinical cognitive impairment. They found significant reductions in scores on the Mini-Mental State Examination (MMSE) among affected individuals compared to controls. To assess whether the lower MMSE scores were restricted to subjects older than 50 years, scores for affected subjects 50 years of age or younger were compared to those of controls. A significant difference in score remained. One of the families was linked to the chromosome 2 locus, while 2 others showed linkage to none of the loci known at that time. There was no significant difference between the results of these 2 groups. McMonagle et al. (2000) compared the phenotypic expressions of autosomal dominant hereditary spastic paresis in several families with a mutation in the SPG4 gene and several families without a mutation in SPG4. In the mutation-positive group, age of onset was later, disability score was greater, progression of disease was faster, wheelchair use was greater (40.9% vs 4.8% in the mutation-excluded group), there was greater abnormal vibration sensation in the lower limbs (68.2% vs 19%), and fewer individuals were asymptomatic (18.2% vs 42.9%). Dementia was more prevalent in the mutation-positive group. McMonagle et al. (2000) emphasized the finding of cognitive impairment as a feature of SPG4 mutations. White et al. (2000) reported a patient with familial SPG4 who had clinical dementia. Postmortem neuropathologic examination showed neuronal loss and tau- (MAPT; 157140) immunoreactive neurofibrillary tangles in the hippocampus and tau-immunoreactive balloon cells in the limbic area and neocortex. Lewy bodies were present in the substantia nigra. White et al. (2000) suggested that these findings confirmed an association of dementia with SPG4. McMonagle et al. (2004) used several measures of cognitive function to assess 11 patients from 3 families in whom SPG4 was confirmed by genetic analysis or linkage. SPG4 patients scored significantly lower on the Cambridge cognitive examination (CAMCOG) (mean score of 73.5 compared to 91.7 in controls). After approximately 3 years, the patients' mean score fell to 64.4, whereas the mean control score declined slightly to 90.8. Deficits in the SPG4 patients were noted in attention, language expression, memory, and abstraction. Behavior assessment found that SPG4 patients exhibited agitation, aggression, apathy, irritability, depression, and disinhibition. Accounting for age, McMonagle et al. (2004) concluded that subtle changes in cognitive function in patients with SPG4 may begin after age 40 years, with more severe decline after age 60. Orlacchio et al. (2004) reported 32 patients from 9 families from southern Scotland with SPG4. Age at onset varied from 11 to 53 years. In addition to classic features of hereditary spastic paraplegia, 2 of the 32 patients had mental retardation and 2 other patients had a thin corpus callosum and cerebellar atrophy. All affected members had the same mutation in the SPG4 gene (604277.0014), and haplotype analysis suggested a founder effect. Orlacchio et al. (2004) reported a large Italian family in which all 16 members who had SPG4 also had congenital arachnoid cysts at the cerebellopontine angle ranging in size from 21 to 31 mm. Six patients also had mental retardation. Genetic analysis confirmed a mutation in the SPG4 gene. McDermott et al. (2006) reported a patient with SPG4 who developed walking difficulties in his late teens with deteriorating gait in his 20s; he was wheelchair-dependent at age 35. He later developed stiffness in the upper limbs, bladder dysfunction, dysarthria, and swallowing difficulties. In his 40s, he developed respiratory insufficiency and distal muscle wasting in the lower limbs. Molecular analysis identified a mutation in the SPG4 gene (S445R; 604277.0021). The findings of bulbar and respiratory involvement, as well as lower motor neuron degeneration, broadened the phenotype associated with mutations in the SPG4 gene. Orlacchio et al. (2008) reported a large 4-generation Italian family with SPG4 confirmed by genetic analysis. The mean ages at onset were 17.5 and 18.8 years for symptoms of the lower and upper limbs, respectively. There was a general impression of genetic anticipation spanning the 4 generations. All affected individuals had spasticity of the lower limbs and pyramidal tract signs such as hyperreflexia, extensor plantar responses, or both, and pes cavus. All patients also had weak intrinsic hand muscles, with severe amyotrophy most relevant in the thenar eminence. Peroneal muscle wasting was reported in five patients, and many used a cane. Other associated features included impaired vibration sensation and cognitive dysfunctions. All patients except 1 had temporal lobe epilepsy with partial complex seizures associated with hippocampal sclerosis. Murphy et al. (2009) reported a family in which 12 members had SPG4 due to a deletion of exon 17 in the SPG4 gene (Beetz et al., 2007). Cognitive assessment performed over a 7-year period found that all 4 patients who were older than 60 years developed mild to moderate cognitive decline. Two younger patients aged 48 and 40, respectively, had mild cognitive impairment. Genetic analysis of this family was unusual because 4 patients with the SPG4 deletion also carried a microdeletion in the NIPA1 gene (608145), which causes SPG6 (600363); only 2 of these 4 had cognitive impairment. Five patients with only the SPG4 deletion had cognitive impairment, including 2 who did not have clinical signs of SPG. Another family member with only the NIPA1 microdeletion lacked clinical signs of SPG or cognitive impairment at age 57. Murphy et al. (2009) concluded that SPG4 is associated with cognitive decline, and that the SPG6 microdeletion does not have a clinical phenotype in this family. Postmortem examination of the proband, who had both deletions as well as SPG and cognitive impairment, showed a markedly atrophic spinal cord with degeneration of the corticospinal tracts, and superficial spongiosis and widespread ubiquitin-positive inclusions in the neocortex and white matter.
Using the repeat expansion detection (RED) method, Nielsen et al. (1997) analyzed 21 affected individuals from 6 SPG4 Danish families with SPG linked to 2p24-p21. They found that 20 of 21 affected individuals showed CAG repeat expansions of ... Using the repeat expansion detection (RED) method, Nielsen et al. (1997) analyzed 21 affected individuals from 6 SPG4 Danish families with SPG linked to 2p24-p21. They found that 20 of 21 affected individuals showed CAG repeat expansions of the SPG4 gene (604277.0006) versus 2 of 21 healthy spouses, demonstrating a strongly statistically significant association between the occurrence of the repeat expansion and the disease. Presumably, CAG repeat expansion is involved as a dynamic mutation in SPG4. They estimated the expansion to be equal to or greater than 60 CAG repeat copies in the affected individuals. Benson et al. (1998) analyzed 20 familial spastic paraplegia families, including 4 for which there was evidence for linkage to the SPG4 region on 2p24-p21, and found that in most cases the repeat expansion detected by the RED method was due to nonpathogenic expansions of the chromosome 18q21.1 SEF2-1 locus (TCF4; 602272) or the 17q21.3 ERDA1 locus (603279). Polymorphic expansions at SEF2-1 and ERDA1 appeared frequent and can confound RED studies in the search for genes causing disorders demonstrating anticipation. In 6 SPG families, however, the CAG repeat expansion was detected in a subset of affected and at-risk individuals that did not result from expansion of either of these loci. Overall, 11 of 37 (30%) of the SPG patients with a CAG/CTG repeat expansion were unaccounted for by the SEF2-1 and ERDA1 loci, compared with 2 of 23 (9%) of the unaffected at-risk individuals and none of 19 controls. In the majority of cases the novel expansions were shorter than those previously reported. Fonknechten et al. (2000) analyzed DNA from 87 unrelated patients with autosomal dominant hereditary spastic paraplegia and detected 34 novel mutations scattered along the coding region of the SPG4 gene. They found missense (28%), nonsense (15%), and splice site point (26.5%) mutations as well as deletions (23%) and insertions (7.5%). Mean age at onset was 29 +/- 17 years, with a range of 0 to 74 years. Disease severity was highly variable among patients, and disease progression was actually faster in the late-onset group. Penetrance was age-dependent and incomplete even in older mutation carriers (85% after 40 years). Six percent of 238 mutation carriers were asymptomatic, while 20% of carriers were unaware of their symptoms. There was no difference in either age of onset or clinical severity among groups of patients with missense mutations versus truncation mutations. Svenson et al. (2001) stated that pure hereditary spastic paraplegia type 4 is the most common form of autosomal dominant hereditary SPG. They screened the spastin gene (604277) for mutations in 15 families showing linkage to the SPG4 locus and identified 11 mutations, 10 of which were novel. In 15 of 76 unrelated individuals with hereditary spastic paraplegia, Meijer et al. (2002) identified 5 previously reported mutations and 8 novel mutations in the SPG4 gene. Svenson et al. (2004) identified 2 rare polymorphisms in the SPG4 gene: ser44 to leu (S44L; 604277.0015) and pro45 to gln (P45Q; 604277.0017). In affected members of 4 SPG4 families, the presence of either the S44L or P45Q polymorphism in addition to a disease-causing SPG4 mutation (see, e.g., 604277.0016; 604277.0018) resulted in an earlier age at disease onset. Svenson et al. (2004) concluded that the S44L and P45Q polymorphisms, though benign alone, modified the SPG4 phenotype when present with another SPG4 mutation. Depienne et al. (2006) identified 19 different mutations in the SPG4 gene in 18 (12%) of 146 unrelated mostly European patients with progressive spastic paraplegia. Most of the patients had no family history of the disorder. In 13 (26%) of 50 unrelated Italian patients with pure hereditary spastic paraplegia (HSP), Crippa et al. (2006) identified 12 different mutations in the SPG4 gene, including 8 novel mutations. All 5 of the familial cases analyzed carried an SPG4 mutation, confirming that the most common form of autosomal dominant HSP is caused by mutations in this gene. Eight (18%) of 45 sporadic patients had a SPG4 mutation. No mutations were identified in 10 additional patients with complicated HSP. Genotype-phenotype correlations were not observed. In 24 (20%) of 121 probands with autosomal dominant SPG in whom mutations in the SPG4 gene were not detected by DHPLC, Depienne et al. (2007) identified 16 different heterozygous exonic deletions in the SPG4 gene using multiplex ligation-dependent probe amplification (MLPA). The deletions ranged in size from 1 exon to the whole coding sequence. The patients with deletions showed a similar clinical phenotype as those with point mutations but an earlier age at onset. The findings confirmed that haploinsufficiency of SPG4 is a major cause of autosomal dominant SPG and that exonic deletions account for a large proportion of mutation-negative SPG4 patients, justifying the inclusion of gene dosage studies in appropriate clinical scenarios. Depienne et al. (2007) stated that over 150 different pathogenic mutations in the SPG4 gene had been identified to date. Using MLPA analysis, Beetz et al. (2007) identified partial deletions of the SPG4 gene in 7 of 8 families who had been linked to the region, but in whom mutation screening had not identified mutations. The families had been previously reported by Lindsey et al. (2000), McMonagle et al. (2000), Meijer et al. (2002), and Svenson et al. (2001). The findings indicated that large genomic deletions in SPG4 are not uncommon and should be part of a workup for autosomal dominant SPG. Mitne-Neto et al. (2007) identified a heterozygous tandem duplication of exons 10 through 12 of the SPG4 gene (604277.0022) in affected individuals of a large Brazilian kindred with spastic paraplegia, originally reported by Starling et al. (2002). In this family, Starling et al. (2002) noted that there were 24 affected men and only 1 affected woman, but X-linked inheritance was ruled out. The authors found strong linkage to the SPG4 locus, but no mutations were identified in the coding region of the SPG4 gene. The results of Mitne-Neto et al. (2007) thus confirmed the diagnosis of SPG4. At the time of the latter report, 12 of 30 mutation carriers had no clinical complaints. Among these patients, 9 of 14 female carriers had no complaints, indicating sex-dependent penetrance in this family, with women being partially protected. Shoukier et al. (2009) identified SPG4 mutations in 57 (28.5%) of 200 unrelated, mostly German patients with SPG. There were 47 distinct mutations identified, including 29 novel mutations. In a review of other reported mutations, the authors found that most (72.7%) of the mutations were clustered in the C-terminal AAA domain of the SPG4 gene. However, clustering was also observed in the MIT (microtubule interacting and trafficking), MTBD (microtubule-binding domain), and an N-terminal region (residues 228 to 269). In the original cohort of 57 patients, there was a tentative genotype-phenotype correlation indicating that missense mutations were associated with an earlier onset of the disease.
The diagnosis of spastic paraplegia type 4 (SPG4; also known as SPAST-associated HSP) in a proband is based on the following:...
DiagnosisClinical DiagnosisThe diagnosis of spastic paraplegia type 4 (SPG4; also known as SPAST-associated HSP) in a proband is based on the following:Characteristic clinical symptoms of insidiously progressive bilateral leg stiffness affecting gait without (or with only mild) spasticity at rest and very mild proximal weakness, often accompanied by urinary urgency Neurologic examination demonstrating corticospinal tract deficits affecting both legs (spastic weakness, hyperreflexia, and extensor plantar responses), often accompanied by mildly impaired vibration sensation in the anklesFamily history consistent with autosomal dominant inheritance, or exclusion of known causes of spastic paraplegia in simplex cases (i.e., a single occurrence in a family)Molecular genetic testing of SPAST. Detection of disease-causing mutations or deletions in SPAST confirms the diagnosis. Note: Failure to detect a mutation/deletion does not absolutely exclude the diagnosis. Note: The presence of other signs/symptoms (complicated hereditary spastic paraplegia, HSP) does not exclude SPAST-associated HSP although it reduces its probability.Brain and spinal cord MRI is useful in identifying anomalies of the cerebro-medullary junction and the cervical and dorsolumbar medulla that are characteristic of disorders discussed in Differential Diagnosis. Most MRI investigations are uninformative for SPAST-associated HSP, but mild vermis atrophy and/or a thin corpus callosum have been occasionally reported [Nielsen et al 2004, Orlacchio et al 2004b]. Spinal atrophy was confirmed in HSP, but less pronounced in SPG4 compared with other genetic forms of HSP [Hedera et al 2005]. Cerebellar atrophy was also reported in two individuals without ataxia [Orlacchio et al 2004b] and congenital arachnoid cysts were seen in one family [Orlacchio et al 2004a]. Subtle white matter changes have been reported [Duning et al 2010] and may prove useful biomarkers of disease, but the results must be confirmed in further studies. Electromyography (EMG) with nerve conduction velocities (NCV) is used to exclude peripheral nervous system involvement, which could raise the possibility of an alternative diagnosis. Other Spinal evoked potentials may eventually reveal delayed prolongation of the central conduction time [Nielsen et al 2001]. Whether paired transcranial magnetic stimulation may help confirm the diagnosis of SPG4 remains to be determined [Nielsen et al 2001]. Motor and somatosensory evoked potentials were significantly affected in SPG4 [Sartucci et al 2007]. Whether these findings may be used as a marker for spasticity as suggested by these investigators remains to be determined.Reduced regional cerebral blood flow may be specific for SPAST-associated HSP [Scheuer et al 2005]. Proton magnetic resonance spectroscopy showed significant associations with cognitive impairment in a study of eight individuals with SPG4 [Erichsen et al 2009b]. Molecular Genetic TestingGene. SPAST, encoding the protein spastin, is the gene in which mutations are known to cause the SPG4 type of hereditary spastic paraplegia. Clinical testing Table 1. Summary of Molecular Genetic Testing Used in SPG4View in own windowGene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method 1 Test AvailabilitySPASTSequence analysisSequence variants 275%-80% 3Clinical Deletion / duplication analysis 4Exonic or multiexonic deletion or duplication20%-25% 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; typically, exonic or whole-gene deletions/duplications are not detected.3. Normal allelic variants can affect the phenotype (see Genotype-Phenotype Correlations and Molecular Genetics).4. 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.5. Exonic and multiexonic deletions and duplications account for approximately 20%-25% of SPAST mutations [Beetz et al 2006, Depienne et al 2007b].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 the diagnosis in a proband, molecular genetic testing of SPAST should be considered. Sequence analysis of SPAST should be pursed first. If a disease-causing mutation is not identified, then deletion/duplication analysis of SPAST can be done. Alternatively, sequence analysis and deletion/duplication testing can be performed in parallel. Detection of a disease-causing mutation or deletion/duplication in SPAST confirms the diagnosis. Failure to detect a mutation or deletion does not completely exclude the diagnosis although it makes it unlikely. Note: Once non-genetic causes have been excluded, testing for SPAST-associated HSP should be considered in simplex cases (i.e., individuals with no family history of spasticity), as SPAST mutations can be identified in approximately 10% of simplex cases [Depienne et al 2007a]. 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 requires prior identification of the disease-causing mutation in the family. Genetically Related (Allelic) DisordersNo other phenotypes other than those discussed in this GeneReview are known to be associated with mutations in SPAST.
The cardinal clinical feature of SPG4 (SPAST-associated HSP) is insidiously progressive bilateral lower-limb spasticity associated with frequent brisk reflexes, ankle clonus, and Babinski signs. Individuals with SPAST-associated HSP may also have increased reflexes in the upper limbs, but they are very rarely tetraspastic. More than 50% of affected individuals have proximal weakness in the lower limbs and one third have sphincter disturbances....
Natural HistoryThe cardinal clinical feature of SPG4 (SPAST-associated HSP) is insidiously progressive bilateral lower-limb spasticity associated with frequent brisk reflexes, ankle clonus, and Babinski signs. Individuals with SPAST-associated HSP may also have increased reflexes in the upper limbs, but they are very rarely tetraspastic. More than 50% of affected individuals have proximal weakness in the lower limbs and one third have sphincter disturbances.Onset is mostly in early adulthood, although symptoms may appear as early as age one year (when the child starts to walk) and as late as age 76 years [Author, personal observation]. A subset of individuals with a SPAST disease-causing mutation may remain asymptomatic their entire life [Dürr et al 1996]. SPG4 is the most frequent type of dominant hereditary spastic paraplegia in many countries; the main symptoms and findings described in the reports listed appear to be the same as those originally reported [Basri et al 2006, Crippa et al 2006, Ivanova et al 2006, Magariello et al 2006, McDermott et al 2006, Depienne et al 2007b, Erichsen et al 2007, Meijer et al 2007, Orlacchio et al 2008]. Disease severity generally worsens with the duration of the disease, although some individuals remain mildly affected all their lives. Families in which some individuals are mildly affected while others are severely affected are reported [Matsuura et al 1997, Nance et al 1998, Nielsen et al 1998, Hentati et al 2000, Lindsey et al 2000, McMonagle et al 2000, Santorelli et al 2000, Higgins et al 2001, Mead et al 2001, Svenson et al 2001, Meijer et al 2002, Depienne et al 2007b]. Wheelchair use and walking only with assistance occur in 17% and 20% of individuals, respectively. Disease progression is more rapid in individuals with late onset (age >35 years) than in those with early onset. However, Orlacchio et al [2005] studied a large family with the 906delT mutation and found a significant correlation between disability and disease duration.Other findings. The most frequent additional feature is decreased, but not abolished, vibration sense at the ankles, occurring in 33%-59% of individuals [Fonknechten et al 2000, Lindsey et al 2000, Mead et al 2001, Tallaksen et al 2003, Orlacchio et al 2004b]. Pes cavus and mild spastic dysarthria may be observed. Subtle cognitive impairment has been documented [Byrne et al 1998, Heinzlef et al 1998, Webb & Hutchinson 1998, Reid et al 1999, Byrne et al 2000, McMonagle et al 2000, White et al 2000, Tallaksen et al 2003, Erichsen et al 2007, Ribaï et al 2008, Erichsen et al 2009b], but its relation to the disease remains undetermined. Cognitive deficits appear late in the disease course and are not present in all affected members of a given family. When detected by neuropsychological testing, the impairment is often subtle, limited to executive dysfunction, and without noticeable effect on daily living. No definite correlation with the type of mutation in SPAST could be established [Erichsen et al 2007].Seizures, intellectual disability, and cerebellar ataxia are rare:Nielsen et al [2004] reported a family with SPAST-associated HSP with a variable complex phenotype including ataxia, dysarthria, unipolar depression, epilepsy, migraine, and/or cognitive impairment. Ribaï et al [2008] reported three families with SPAST-associated HSP with intellectual disability, extensive social dependence, and/or isolated psychomotor delay. Neuropathy, reported in a few affected individuals, was most probably not related to the presence of the SPAST mutation [Schulte et al 2003, Fukunaga et al 2007]. Posterior fossa abnormalities have also been reported in two unrelated families [Scuderi et al 2009], and again the relation to the presence of a SPAST mutation is unclear.A few individuals with severe dementia – one with neuronal loss, tau-immunoreactive neurofibrillary tangles in the hippocampus, and Lewy bodies in the substantia nigra on neuropathologic examination – have been reported [White et al 2000]. However, too few neuropathologic studies have been performed in persons with SPAST-associated HSP for a general picture of the distribution of cortical and medullar lesions in the disease to emerge [Tallaksen et al 2003]. In the Irish population a higher than expected rate of psychosis was found in individuals with HSP including SPG4 [McMonagle et al 2006]; however, the association with SPG4 is uncertain. Depression is reported to be frequent (41%) and unrelated to disease severity [du Montcel et al 2008].Only three individuals have been reported with lower motor neuron symptoms and/or bulbar dysfunction and respiratory insufficiency [Brugman et al 2005, Meyer et al 2005, McDermott et al 2006].These presentations remain therefore extremely rare.Restless leg syndrome may be a frequent undiagnosed associated condition with HSP, but whether this is particular to SPG4 is not known [Sperfeld et al 2007]. Bladder dysfunction remains one of the most frequent problems for affected individuals and remains largely unexplored. No significant differences between SPAST-HSP and other HSP were detected in one study of bladder disturbances in 49 affected individuals [Braschinsky et al 2010].Hand tremor has been reported in 10% of a large cohort of Dutch individuals with SPG4 [de Bot et al 2010].
The largest study comparing missense and truncating mutations found no clear genotype-phenotype correlations [Fonknechten et al 2000]....
Genotype-Phenotype CorrelationsThe largest study comparing missense and truncating mutations found no clear genotype-phenotype correlations [Fonknechten et al 2000].No significant difference in either age at onset or clinical severity exists among groups of individuals with missense or truncating mutations, although a meta-analysis demonstrated a tendency to earlier onset in individuals with missense mutations compared to those with other SPAST mutations [Yip et al 2003].The age at onset and clinical severity are highly variable for a given mutation, even in the same family. Two family members with the same mutation can have in one case a pure spastic paraparesis and in the other a complex disease. For example, Orlacchio et al [2004b] reported wide phenotypic variability with the p.Asn386Ser mutation. The intra- and interfamilial range of age at onset and disease duration was large. Some individuals had intellectual disability and others showed brain MRI abnormalities including thin corpus callosum or cerebellar atrophy [Orlacchio et al 2004b]. Svenson et al [2004] reported two rare nonsynonymous allelic variants (a nucleotide variant that results in a change of the amino acid) (c.131C>T [p.Ser44Leu] and c.134C>A [p.Pro45Gln]). Individuals who have both a SPAST pathologic variant on one allele and either a c.131C>T or c.134C>A variant on the other allele seem to have very early onset, suggesting that these alleles could modify the HSP phenotype. The allelic variant c.131C>T has a frequency of 0.6%-2% in a control population [Svenson et al 2004, McDermott et al 2006, personal communication]; c.134C>A is even rarer. Nevertheless, early onset is not restricted to individuals who have both a mutation and one of these variants. The extensive phenotypic variability in SPAST-associated HSP cannot therefore be explained exclusively by the c.131C>T and c.134C>A variants. A positive correlation between genotype and electrophysiologic phenotype has been reported [Bönsch et al 2003]. In a study using transcranial magnetic stimulation, individuals from two pedigrees with different SPAST mutations showed different degrees of disturbance in the motor system with respect to motor evoked potential amplitude, central motor conduction time, and central motor threshold [Bönsch et al 2003]. These results must be confirmed, however, with more families.
See Hereditary Spastic Paraplegia overview for a review of the differential diagnosis. In the case of a definite autosomal dominant hereditary spastic paraplegia, other types of autosomal dominant pure spastic paraplegia that need to be considered are SPG3, SPG6, SPG8, SPG10, SPG12, SPG13, SPG19, SPG31, SPG33, and SPG37. ...
Differential DiagnosisSee Hereditary Spastic Paraplegia overview for a review of the differential diagnosis. In the case of a definite autosomal dominant hereditary spastic paraplegia, other types of autosomal dominant pure spastic paraplegia that need to be considered are SPG3, SPG6, SPG8, SPG10, SPG12, SPG13, SPG19, SPG31, SPG33, and SPG37. SPG4 (SPAST-associated HSP) is the most frequently occurring form of autosomal dominant hereditary spastic paraplegia, accounting for an estimated 15%-40% of the pure dominant forms of hereditary spastic paraplegia [Meijer et al 2002, McDermott et al 2006, personal communication]. Because SPAST is the gene most commonly involved in autosomal dominant HSP (AD-HSP), it is the first and most relevant gene to be tested. With the exceptions of SPG31, SPG10, and SPG3A, no significant differences have been established between SPG4 and other types of pure dominant spastic paraplegia. Peripheral neuropathy is more frequently associated with subtypes SPG31 and SPG10 [Goizet et al 2009, Goizet et al 2011]. SPG3A, encoding atlastin, is the second most frequently involved gene in AD-HSP. Dürr et al [2004] have shown that SPG3A-related disease is a pure form of HSP associated with earlier onset than SPG4 HSP. In SPG3A, impairment of vibration sense at the ankles and increased reflexes in the upper limbs are less frequently seen than in SPG4. There are also fewer sphincter disturbances, more muscle wasting in the lower limbs, and more scoliosis in SPG3 than SPG4 [Dürr et al 2004]. As a consequence, an individual with pure and very early-onset HSP should be tested for SPG3A before being considered for testing for SPG4.In simplex cases (spasticity in one individual in a family), all possible causes of spasticity in the legs have to be considered because some non-genetic causes of spasticity are more common than SPG4. 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 in an individual diagnosed with spastic paraplegia type 4 (SPG4), the following evaluations are recommended:...
ManagementEvaluations Following Initial DiagnosisTo establish the extent of disease in an individual diagnosed with spastic paraplegia type 4 (SPG4), the following evaluations are recommended:Neuro-urologic examination is advised for individuals who have sphincter disturbances.Whether neuropsychological testing should be performed to assess the cognitive impairment frequently reported in individuals with SPG4 remains unclear. So far, no consensus exists on the type of tests that should be performed, the timing of the tests, and the purpose. Considering that cognitive impairment is often absent or is detectable only by neuropsychological testing, one should be wary of increasing the burden of individuals with SPG4, and probably only recommend further testing when required by the affected individual. Electrophysiologic investigations may be advisable in case of pain and/or edema in the lower limbs to evaluate for associated neuropathy. Neuropathy (not a feature of SPG4 per se) may occur in individuals with SPG4 for other reasons and should be investigated and adequately treated. Because of the underlying HSP the neuropathy may remain undiagnosed if routine investigations are not conducted.Spinal MRI examination to exclude any additional degenerative disorder can be considered if unusual symptoms or pain are present.A thorough examination for associated restless legs syndrome (RLS) also appears to be warranted [Sperfeld et al 2007]. Medical genetics consultation is appropriate.Treatment of ManifestationsCare by a multidisciplinary team that includes a general practitioner, neurologist, medical geneticist, physiotherapist, physical therapist, social worker, and psychologist should be considered. Symptomatic treatment includes use of the following:Antispastic drugs for leg spasticity Anticholinergic antispasmodic drugs for urinary urgency Regular physiotherapy for stretching of spastic muscles. Stretching should be done manually at all levels (hips, knees, ankles) and preceded by heat conditioning.Botulinum toxin and intrathecal baclofen can be proposed when oral drugs are ineffective and spasticity is severe and disabling. One open-label study with botulinum toxin injections showed an increase in gait velocity in persons with HSP after six months [Rousseaux et al 2007]. Urodynamic evaluation should be performed early in all affected individuals complaining of urgency or other problems, such as voiding difficulties, urine retention, and/or frequent urinary infections. Such symptoms should be monitored and treated according to individual needs and disease evolution. At the present time there is no consensus on treatment of sphincter disturbances (both urinary and anal) and management remains therefore symptomatic [Braschinsky et al 2010]. Prevention of Secondary ComplicationsFollow-up of the sphincter disturbances is important to prevent bladder dysfunction. Early regular physiotherapy can prevent contractures to a certain extent. Intensive and early physiotherapy delays the development of symptoms related to spasticity and prolongs the ability to walk [Author, personal observation]. In children orthopedic treatment and botulinum toxin injections may also contribute to better ambulatory function. More systematic studies are, however, needed to confirm these observations. SurveillanceSpecialized outpatient evaluations are suggested every six months to update medications and physical rehabilitation. Evaluation of Relatives at Risk See 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.Other A double-blind crossover trial with gabapentin did not show improvement of spasticity in persons with SPG4 [Scheuer et al 2007].
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 4: Genes and DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDSPAST2p22.3Spastinalsod/SPAST genetic mutations ALS mutation database HSP mutation database SPAST homepage - Mendelian genesSPASTData 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 4 (View All in OMIM) View in own window 182601SPASTIC PARAPLEGIA 4, AUTOSOMAL DOMINANT; SPG4 604277SPASTIN; SPASTNormal allelic variants. SPAST spans approximately 90 kb and is composed of 17 exons (NM_014946.3). The coding region contains very few normal allelic variants.One synonymous polymorphism (c.879G>A) located in exon 6 is found in about 1.5%-2% of persons of Northern European origin [Author, personal data]. A nonsynonymous polymorphism (c.1292G>A;p.Arg431Gln) was reported only once, in the spouse of an affected individual [Meijer et al 2002]. The status of this variant remains unknown. Svenson et al [2004] reported two rare nonsynonymous allelic variants (c.131C>T and c.134C>A) in a control population with frequencies of 0.6% and 0.2%, respectively. The SPAST: c.131T and SPAST: c.134A heterozygous alleles were shown to segregate independently of the disease in two families and independently of a heterozygous disease-causing mutation in another family. The variant c.131C, which serine at reside 44, could theoretically be phosphorylated by a proline-directed serine/threonine cyclin-dependent kinase (Cdk). Individuals who have a documented SPAST disease-causing mutation on one allele and either a c.131T or c.134A variant on the other allele seem to have very early-onset disease, suggesting that these alleles could modify the HSP phenotype [Svenson et al 2004]. (see Genotype-Phenotype Correlations) SPAST undergoes alternate splicing with variable inclusion of exon 4. No mutations have been reported in exon 4, however, suggesting that the isoform lacking exon 4 is the predominant functional form of spastin in the adult nervous system. This transcript variant is NM_199436.1. (See Table A, Gene Symbol)Table 2. Selected SPAST Allelic Variants View in own windowClass of Variant AlleleDNA Nucleotide Change (Alias 1)Protein Amino Acid ChangeReference Sequences Normalc.131C>T (C256T)p.Ser44Leu 2NM_014946.3 NP_055761.2c.134C>A (C259A)p.Pro45Gln 2c.879G>A (1004G>A)p.Pro293ProPathologicc.334G>Ap.Glu112Lysc.1157A>Gp.Asn386SerSee 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 conventions2. Rare alleles that may modify the HSP phenotypePathologic allelic variantsAll types of DNA alterations are observed: missense, nonsense, and splice site mutations, small deletions and insertions, and rare large-scale deletions. Recurrent mutations in SPAST are exceptional.Point mutations include nonsense mutations (~10%), splice site mutations (~26%), small deletions (~22%) or insertions (~11%) creating a frameshift, and missense mutations (31%). With the exception of missense variants, most pathologic point mutations result in premature termination codons (PTC). The corresponding mRNA is likely recognized and degraded via the nonsense-mediated mRNA decay (NMD), with the exception of truncating mutations located in exon 17. With only rare exceptions, missense mutations are located in the AAA cassette (see Normal gene product).Normal gene product. SPAST encodes a 616-amino acid protein that is a putative nuclear member of the AAA (ATPases associated with diverse cellular activities) protein family named spastin. SPAST is ubiquitously expressed in adult and fetal human tissues, showing slightly higher expression in the fetal brain. SPAST undergoes alternate splicing with variable inclusion of exon 4 (NM_199436.1). No mutations have been reported in exon 4, however, suggesting that the protein isoform NP_955468.1 of this transcript is the predominant functional form of spastin in the adult nervous system. Paraplegin, encoded by SPG7 (mutations in which cause SPG7, an autosomal recessive form of HSP), is also a member of the AAA family (see Hereditary Spastic Paraplegia Overview). These proteins share very little homology outside the AAA motif and spastin belongs to another AAA subclass as do paraplegin and other related metalloproteinases. This subclass includes katanin, a microtubule-severing protein. The AAA domain of spastin is located in the C terminus of the protein between amino acids 342 and 599. Immunohistochemical studies on post mortem human brain revealed that spastin is widely expressed in the neurons of the central nervous system, including the cortex and striatum [Wharton et al 2003]. Distal degeneration of long tracts in the spinal cord is associated with a microglial reaction. Observations are consistent with an alteration of the cytoskeleton in the motor system as well as a tau-pathology outside the motor system.Subcellular localization of spastin is dual. Overexpressed full-length spastin proteins are found in the cytoplasm or the perinuclear area of cell lines [Errico et al 2002, McDermott et al 2003], while the endogenous protein is at least partly located in the nucleus of HeLa cells and mouse motor neurons [Charvin et al 2003]. Wharton et al [2003] confirmed on post mortem human brain that spastin showed both cytoplasmic and nuclear expression in neurons. In pyramidal neurons of the motor cortex and in immortalized motor neurons, spastin is localized to the synaptic terminals and growth cones [Wharton et al 2003]. A synaptic localization of spastin has also been shown for its Drosophila ortholog [Sherwood et al 2004, Trotta et al 2004]. Claudiani et al [2005] have shown that two spastin isoforms of 68 and 60 kd, respectively, were synthesized from the SPAST mRNA through usage of two different translational start sites. The 60-kd isoform is predominantly nuclear whereas the 68-kd, full-length isoform contains two nuclear export signals that efficiently drive export to the cytoplasm and is therefore mostly cytoplasmic. [Claudiani et al 2005]. The situation is further complicated by alternative splicing of exon 4, resulting in the presence of minor exon 4-deleted versions of the long and short isoforms [Svenson et al 2001, Sanderson et al 2006]. To date no mutation has been reported in exon 4, suggesting that the isoform lacking exon 4 is the predominant functional form of spastin in the brain. However, controversial experimental data exist regarding the isoform that is more abundant in the brain and spinal cord [Claudiani et al 2005, Solowska et al 2008]; further study is therefore necessary to determine which isoform is really relevant to the disorder.It is now well established that spastin plays a role in microtubule dynamics. Overexpression of spastin promotes microtubule disassembly in cellular models [Errico et al 2002], indicating that spastin acts as a microtubule-severing protein such as katanin, an AAA protein of the same subfamily that contributes to the regulation of microtubule length and dynamics during mitosis and meiosis. Furthermore, Ciccarelli et al [2003] identified a region of approximately 80 amino acids in the N terminus of spastin that they named MIT (for microtubule-interacting and trafficking molecules domain); the region is also shared by spartin, the protein mutated in the Amish type of hereditary spastic paraplegia (Troyer syndrome). This region corresponds to a domain present in several proteins, all of which are implicated in endosomal trafficking models [Ciccarelli et al 2003]. These observations led to the proposition that spastin plays a role in intracellular organelle trafficking via its interaction with the microtubule cytoskeleton.Abnormal gene product. Haploinsufficiency has been postulated on the basis of the observation of reduced spastin mRNA in individuals with premature protein termination [Bürger et al 2000]. The level of spastin mRNA has been tested and found to be reduced, probably as a consequence of RNA instability. Reduced levels of functional spastin are not well tolerated, since two leaky splice site mutations that create both wild type and aberrant splice variants are pathogenic. Approaches have thus been developed to reproduce haploinsufficiency: loss of function of Drosophila spastin, either by RNAi or knock-out, affected the morphology and function of the neuromuscular synapse by modulating microtubule dynamics in synaptic terminals [Sherwood et al 2004, Trotta et al 2004]. More recently, mice in whom Spast was deleted were reported to develop progressive axonal degeneration restricted to the central nervous system, associated with a late and mild motor deficit [Tarrade et al 2006]. The degenerative process, slightly observable in heterozygous mice but increased in homozygous mice, is characterized by focal axonal swellings and abnormal accumulation of organelles and cytoskeletal components. Mutant cortical neurons develop neurite swellings associated with focal impairment of retrograde transport in culture. These defects occur near the growth cone, in a region characterized by the transition between stable microtubules and dynamic microtubules, confirming that spastin deficiency has a major impact on neurite maintenance and transport [Tarrade et al 2006].The finding that SPAST mutations in the AAA domain lead to constitutive binding to microtubules suggests a dominant-negative effect [Errico et al 2002]. McDermott et al [2003] have shown that the abnormal interaction of mutant spastin with microtubules results in a change in the distribution of intracellular organelles such as mitochondria or peroxisomes. The impairment of microtubule-dependent organelle transport could thus be responsible for the degeneration of long corticospinal axons underlying the pathogenesis of hereditary spastic paraplegia [McDermott et al 2003]. However, the aforementioned results were obtained by overexpression of mutant and wild type spastin fusion proteins, mostly in cell lines, which may not be the appropriate model to mimic the defects in pyramidal tract neurons in affected individuals. In contrast to a peptide from the short spastin isoform, the expression of a peptide from the full-length isoform in cultured neurons altered normal axonal growth and inhibited fast axonal transport. These results could be consistent with a “gain-of-function” mechanism underlying HSP [Solowska et al 2008]. However, the mutation spectrum in SPAST, which includes mostly mutations introducing premature termination codons and leading to degradation of the mRNA by nonsense-mediated decay, argues in favor of haploinsufficiency (i.e., disease occurs once the level of functional spastin falls below a critical level) rather than a dominant negative effect [Patrono et al 2002, Schickel et al 2007]. This hypothesis is further supported by the observation that spastin down-regulation has a negative impact on the assembly rate of microtubules and that spastin depletion alters the development of primary hippocampal neurons leading to abnormal neuron morphology, dystrophic neurites, and axonal growth defects [Riano et al 2009].