Pure or complex autosomal dominant spastic paraplegia
-Rare genetic disease
-Rare neurologic disease
Comment:
Hereditary spastic paraplegia (HSP), which is a clinically and genetically heterogeneous group of conditions, has pathological features of retrograde degeneration of the longest nerve fibers in the corticospinal tracts and posterior column. The clinical hallmark of HSP is gradual and progressive spastic weakness of the lower extremities associated with variable degrees of impaired vibration sensation, autonomic dysfunction of the bladder, and occasional anal sphincter hyperactivity. SPG4 caused by SPAST mutations is the most common type of autosomal dominant HSP, followed by SPG3A, which is caused by mutations in the atlastin GTPase 1 gene, ATL1 (AD-FSP, FSP1, GBP3, HSN1D, SPG3, SPG3A, atlastin1). The clinical feature of SPG3A is early-onset progressive spastic weakness in the lower extremities (PMID:24969372).
The hereditary spastic paraplegias are a group of clinically and genetically diverse disorders characterized by progressive, usually severe, lower extremity spasticity; see reviews of Fink et al. (1996) and Fink (1997).
SPG is classified according to ... The hereditary spastic paraplegias are a group of clinically and genetically diverse disorders characterized by progressive, usually severe, lower extremity spasticity; see reviews of Fink et al. (1996) and Fink (1997). SPG is classified according to both the mode of inheritance (autosomal dominant, autosomal recessive (see 270800), and X-linked (see 303350)) and whether progressive spasticity occurs in isolation ('uncomplicated SPG') or with other neurologic abnormalities ('complicated SPG'), including optic neuropathy, retinopathy, extrapyramidal disturbance, dementia, ataxia, ichthyosis, mental retardation, and deafness. The major neuropathologic feature of autosomal dominant, uncomplicated SPG is axonal degeneration that is maximal in the terminal portions of the longest descending and ascending tracts (crossed and uncrossed corticospinal tracts to the legs and fasciculus gracilis, respectively). Spinocerebellar fibers are involved to a lesser extent. Since the description of 'pure' hereditary spastic paraparesis of late onset by Strumpell (1904), many 'complicated' forms of the disorder have been reported and the question as to whether a 'pure' form exists has been raised off and on. Probably in large part because of their exceptional length, the pyramidal tracts are unusually vulnerable to both acquired and genetic derangement. Although a majority of reported families have displayed recessive inheritance, 10 to 30% of families have a dominant pattern and in fact recessive inheritance of a 'pure' spastic paraplegia may be rare. - Genetic Heterogeneity of Autosomal Dominant Spastic Paraplegia In addition to SPG3A, which is caused by mutation in the ALT1 gene on chromosome 14q22, other forms of autosomal dominant spastic paraplegia for which the molecular basis is known include SPG4 (182601), caused by mutation in the SPAST gene (604277) on 2p22-p21; SPG6 (600363), caused by mutation in the NIPA1 gene (608145) on 15q11.1; SPG8 (603563), caused by mutation in the KIAA0196 gene (610657) on 8q24; SPG10 (604187), caused by mutation in the KIF5A gene (602821) on 12q13; SPG12 (604805), caused by mutation in the RTN2 gene (603183) on 19q13; SPG13 (605280), caused by mutation in the SSPD1 gene (118190) on 2q33.1; SPG31 (610250), caused by mutation in the REEP1 gene (609139) on 2p11.2; and SPG33 (610244), caused by mutation in the ZFYVE27 gene (610243) on 10q24.2. Autosomal dominant spastic paraplegia has been mapped to chromosomes 10q (SPG9; 601162), 9q (SPG19; 607152), 1p31-p21 (SPG29; 609727), 12q23-q24 (SPG36; 613096), 8p21.1-q13.3 (SPG37; 611945), 4p16-p15 (SPG38; 612335), and 11p14.1-p11.2 (SPG41; 613364).
Schule et al. (2006) presented a 13-item scale designed to rate functional impairment in pure forms of spastic paraplegia. The scale measures items including walking distance, gait quality, maximum gait speed, spasticity, weakness, and pain. The scale can ... Schule et al. (2006) presented a 13-item scale designed to rate functional impairment in pure forms of spastic paraplegia. The scale measures items including walking distance, gait quality, maximum gait speed, spasticity, weakness, and pain. The scale can be performed in an outpatient setting, requires no special equipment, and was found to be a reliable and valid measure of disease severity.
In the Amish of Lancaster County, Pa., a kindred with affected members in 3 generations was observed (McKusick, 1965). In this closed community the origin of the de novo mutation could be identified with considerable certainty. The disease ... In the Amish of Lancaster County, Pa., a kindred with affected members in 3 generations was observed (McKusick, 1965). In this closed community the origin of the de novo mutation could be identified with considerable certainty. The disease was early in onset but very slowly progressive or even static. This same type of congenital stationary familial paraplegia was described in 7 members of 2 generations by Hohmann (1957). In contrast to the early-onset, static form of disease in the Amish family, a family with many affected members I have studied on Deer Isle, Maine, had onset in the second or third decade and steady progression of neurologic defect (Thurmon and Walker, 1971). Schwarz and Liu (1956) reported several families including one originally reported by Bayley (1897) which in 1956 contained 22 affected persons in 6 generations. Aagenaes (1959) described a family with 31 cases in 4 generations. Prognosis for life was good. Histopathologic changes were found bilaterally in the lateral corticospinal tracts in the thoracic cord and in the fasciculus gracilis. The confusion of the spinocerebellar degenerations is illustrated by the fact that some members of Aagenaes' family had ataxia in addition to spastic paraplegia. Behan and Maia (1974) studied 6 families. In 2 cases autopsy studies were performed. They concluded that distal axonal degeneration of the long ascending and descending tracts in the spinal cord is characteristic. McLeod et al. (1977) found no abnormality of motor and sensory nerve conduction in 10 persons in 3 families. In one family 4 generations were affected, in a second, 3 generations, and in a third 2 brothers were affected, possibly with the X-linked form. Sack et al. (1978) described affected members of 6 generations of a kindred. Onset was in the fourth decade or later, with symptoms of progressive gait difficulties, lower limb spasticity, and weakness. No sensory cerebellar and cranial nerve changes were associated. Anatomic changes in 1 affected person studied at autopsy were confined to the lateral corticospinal tracts and the fasciculus gracilis. Opjordsmoen and Nyberg-Hansen (1980) described a family from northern Norway with spastic paraplegia and type III syndactyly (fusion of fingers 4 and 5). The two traits were transmitted together through 3 generations and 9 affected persons. The spastic paraplegia was of unusual type: neurogenic bladder was the earliest manifestation. Indeed, the spastic paraplegia easily escaped attention. Are these two genes linked? Harding (1981) reviewed 22 families with 'pure' spastic paraplegia and found autosomal dominant inheritance in 19 and autosomal recessive in 3. She identified 2 forms on the basis of age of onset: type I with onset mainly before age 35 years; type II with onset usually after age 35 years. Cooley et al. (1990) identified 71 affected individuals in 7 generations of a New England family; of these they examined 17 cases. Onset occurred at or before 3 years of age with involvement limited to the lower limbs. They suggested that although in the first year of life the physical examination is normal, in the second year long tract signs are evident on examination and there is a rapid increase in spasticity followed by a delay in walking. Crutches are occasionally necessary in the teens and often necessary after the age of 18. No progression of spasticity was observed after age 7. Cooley et al. (1990) reviewed the medical records of 25 family members and examined 16 of them. They felt that children free of signs by age 3 years could be assumed to be unaffected. They further suggested that early, aggressive, habilitative intervention may result in more functional ambulation for the youngest family members. No significant progression was observed after 3 years of age. Scheltens et al. (1990) described a Dutch family with 15 affected members in 3 generations. Onset of clinical signs was in the fourth or fifth decade. The disease was mild; only a few of the affected persons became chairbound late in life. Mild sphincter disturbances were noted in 6 patients. There were no sensory changes. Polo et al. (1993) described the genetic and clinical features of 46 patients in 9 families. Inheritance was autosomal dominant in 7, but was thought to be autosomal recessive in 2. The evidence for recessive inheritance was the occurrence in males and females in one generation with consanguineous parents (see 270800). Among the dominant kindreds, 5 corresponded to type I with onset before 35 years and 2 to type II with onset over 35 years. Irrespective of genetic type, serial evaluation demonstrated that the main symptom was slowly progressive spastic gait, extremely variable in severity, associated in some patients with decreased vibratory sense and micturition disorders (generally as late features). Among dominant families, the disease tended to be more severe in late-onset cases. No patient had symptoms in the upper limbs and plantar responses were flexor in 6 symptomatic patients. Durr et al. (1994) studied 23 families with pure autosomal dominant spastic paraplegia and found a unimodal distribution of age of onset. The clinical manifestations of early-onset and late-onset patients were not significantly different. There was no evidence of anticipation or imprinting. Spasticity, sphincter disturbance, decreased vibratory sense, and muscle weakness increased with disease duration. Except for 1 family with electrophysiologic evidence of an axonal neuropathy, there were no clinical features by which the families could be distinguished. Schady and Smith (1994) reported a large kindred transmitting typical 'pure' hereditary spastic paraplegia and found electrophysiologic evidence of a sensory polyneuropathy, with normal motor nerve conduction velocities. Sural nerve biopsies demonstrated severe loss of large diameter fibers and relative preservation of small myelinated and nonmyelinated fibers. Members of this family had previously been shown to have delayed central motor conduction (Schady et al., 1991). The mild sensory changes, the absence of mutilating ulcers, and the dominant mode of inheritance clearly distinguished the disorder in this family from autosomal recessive hereditary sensory neuropathy with spastic paraplegia (256840). Although the sensory changes were subclinical and therefore may have been missed in other cases of 'pure' hereditary spastic paraplegia, the authors speculated that HSP with abnormal sensory action potentials may be a distinct entity. In their own studies of 17 kinships with HSP (Schady et al., 1991; Schady and Sheard, 1990), they had found only 2 other patients with abnormal sensory action potentials. Thurmon et al. (1999) restudied the large Deer Isle, Maine family reported by Thurmon and Walker (1971). Analysis of age of onset was found to be consistent with anticipation in this family. The findings were considered consistent with an unstable trinucleotide repeat occurring primarily in the female germline. On reexamination they were impressed with variable spasticity and Babinski responses. Indeed, spasticity was said not to be a prominent aspect of the disorder; most affected relatives exhibited leg paralysis, with little or no spasticity. Only individuals with long duration of the disorder (more than 22 years) typically manifested a combination of paraplegic gait, hyperreflexia, and Babinski sign. One patient was thought to have been homozygous for the mutation. He was affected with spastic quadriplegia and mental retardation and died at the age of 11.5 years of pneumonia. The parents were consanguineous. The father was known to be affected at the time of report in 1971; since that time the boy's mother had become affected. In a family with 6 members affected with a very early onset severe form of spastic paraplegia, Dalpozzo et al. (2003) identified a heterozygous mutation in the SPG3A gene (606439.0006). All affected members had onset in infancy with delayed motor milestones, gait impairment, spastic paraparesis, distal atrophy, and lower limb weakness. Because of the very early onset, the first patients were misdiagnosed with cerebral palsy, and the index patient (mother of 5 affected members) was unaware that she had a genetically transmissible disease. Two patients had the unusual sign of mild hand atrophy. Durr et al. (2004) identified mutations in the atlastin gene in 12 of 31 (39%) families in France with early-onset autosomal dominant SPG. Mean age at onset was 4.6 years (range, birth to 14 years). The overall clinical phenotype was of a pure spastic gait disorder. Scoliosis was present in 22% of patients, mild pes cavus in 15%, and brisk upper limb reflexes in 10%. Sensation was not impaired, and only 13% of patients reported decreased vibration sense in the ankles. Two patients had postural tremor in the upper limbs. One family showed incomplete penetrance. Rainier et al. (2006) reported a mother and son with SPG3A confirmed by the finding of a mutation in the SPG3A gene (L157W; 606439.0008). Genetic analysis of family members indicated that the mutation occurred de novo in the mother. The mother was a 34-year-old woman with uncomplicated nonprogressive spastic paraplegia since infancy who was originally diagnosed with spastic diplegic cerebral palsy. She was correctly diagnosed with SPG after her son developed similar clinical symptoms at age 10 months. Both patients showed brisk lower limb reflexes, clonus, and spastic gait with normal bulbar and upper limb function, normal bowel and urinary control, and normal intelligence. Rainier et al. (2006) emphasized the importance of the correct diagnosis of SPG for genetic counseling because the recurrence risk may be as high as 50%. Ivanova et al. (2007) identified SPG3A mutations in 12 (6.6%) of 182 European or Australian probands with spastic paraplegia. Mean age at onset in SPG3A probands was 3 years. In the 12 probands and 24 affected family members, age of onset was before 10 years of age, except in 1 family with mean onset of 14 years and notable variability (range, 8 to 28 years). In addition to typical features of SPG, 6 (17%) of 36 affected individuals had an axonal, predominantly motor peripheral polyneuropathy, confirmed by pathologic and electrophysiologic studies. The 6 patients with neuropathy originated from 5 unrelated families, and 4 of these patients had pes cavus. - Clinical Variability Orlacchio et al. (2011) reported a 3-generation Zulu family from South Africa with an unusual form of late-onset SPG3A. The 68-year-old proband presented with progressive walking difficulties at age 56, and required a walking aid since age 66. He had mild mental retardation (IQ of 62), urinary incontinence, and thin corpus callosum without cerebellar involvement or white matter abnormalities. Inheritance was clearly autosomal dominant. Other affected family members had a similar disease course, with late onset (range, 38-51 years), spasticity restricted to the lower limbs, mental impairment, and thin corpus callosum on brain imaging. Genomewide linkage analysis followed by direct sequencing identified a heterozygous mutation in exon 12 of the ATL1 gene in affected individuals (R416C; 606439.0013).
Zhao et al. (2001) analyzed 5 autosomal dominant hereditary spastic paraplegia kindreds showing linkage to the SPG3A locus on 14q. They identified an obligate recombinant individual, permitting a reduction of the interval containing the SPG3A locus to 2.7 ... Zhao et al. (2001) analyzed 5 autosomal dominant hereditary spastic paraplegia kindreds showing linkage to the SPG3A locus on 14q. They identified an obligate recombinant individual, permitting a reduction of the interval containing the SPG3A locus to 2.7 cM, and screened candidate genes in this interval for disease-causing mutations (Rainier et al., 2001). Zhao et al. (2001) reported the identification of disease-specific missense mutations in a novel gene, SPG3A (ATL1; 606439), in affected individuals from these 5 SPG3A-linked kindreds. SPG3A is expressed predominantly in the central nervous system. It does not have homology to genes that cause other forms of HSP. By contrast, the peptide encoded by SPG3A, termed atlastin, shows significant homology with several GTPases, particularly guanylate-binding protein-1 (GBP1; 600411), which maps to chromosome 1 and is a member of the dynamin family of large GTPases. The hereditary spastic paraplegia in the families of the SPG3A variety is characterized by early onset (before age 10 and usually before age 5 years). In an Italian family with HSP characterized by a mean age of onset of 8.3 years and progressive lower extremity weakness and spasticity, Muglia et al. (2002) identified a mutation in the ATL1 gene (606439.0004), which resulted in an arg217-to-gln substitution in a conserved area of GTPases. Abel et al. (2004) identified mutations in the ATL1 gene (see, e.g., 606439.0001) in affected members of the families reported by Hazan et al. (1993) and Gispert et al. (1995). Namekawa et al. (2006) stated that 19 mutations in the ATL1 gene had been identified in 40 different families. More than 90% of the mutations were located in exons 4 (12.5%), 7 (27.5%), 8 (17.5%), and 12 (35%). They identified mutations in the ATL1 gene in 7 (13.5%) of 52 families with autosomal dominant SPG with onset before age 20 years and 7 (31.8%) of 22 families with onset before age 10 years. Among a total of 106 mostly European families, no ATL1 mutations were identified in patients with onset after age 10 years. ATL1 mutations were twice as frequent as SPAST (604277) mutations in patients with onset before age 10 years. Rainier et al. (2006) stated that SPG3A accounts for approximately 10% of dominantly inherited, uncomplicated SPG. Ivanova et al. (2007) identified 12 different heterozygous ATL1 mutations in 12 (6.6%) of 182 European or Australian probands with spastic paraplegia. Seven mutations were novel, and 3 were de novo.
In a nationwide survey of Japanese patients, Hirayama et al. (1994) estimated the prevalence of all forms of spinocerebellar degeneration to be 4.53 per 100,000; of these, 3.9% were thought to have hereditary spastic paraplegia.
Spastic paraplegia 3A (SPG3A) is one of the hereditary spastic paraplegias (HSPs), a group of neurodegenerative disorders characterized by progressive bilateral and mostly symmetric lower extremity weakness and spasticity resulting from axonal degeneration of corticospinal tracts, diminished vibration sense caused by impairment of dorsal columns, and urinary bladder hyperactivity. ...
DiagnosisClinical Diagnosis Spastic paraplegia 3A (SPG3A) is one of the hereditary spastic paraplegias (HSPs), a group of neurodegenerative disorders characterized by progressive bilateral and mostly symmetric lower extremity weakness and spasticity resulting from axonal degeneration of corticospinal tracts, diminished vibration sense caused by impairment of dorsal columns, and urinary bladder hyperactivity. The diagnosis of SPG3A, one of the specific genetic types of HSP, can only be established by molecular testing of ATL1, the gene associated with SPG3A, because of the significant overlap between the age of onset and severity of the disease among the various types of HSP (see Hereditary Spastic Paraplegia).Molecular Genetic TestingGene. ATL1 (formerly known as SPG3A), encoding the protein atlastin-1, is the only gene known to be associated with spastic paraplegia 3A. Clinical testingTable 1. Summary of Molecular Genetic Testing Used In Spastic Paraplegia 3AView in own windowGene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method 1Test AvailabilityATL1Sequence analysis/mutation scanning 2Sequence variants 3~100%Clinical Deletion/duplication analysis 4Exonic and whole-gene deletions 5Unknown1. The ability of the test method used to detect a mutation that is present in the indicated gene2. Sequence analysis and mutation scanning of the entire gene can have similar mutation detection frequencies; however, mutation detection rates for mutation scanning may vary considerably among laboratories depending on the specific protocol used.3. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations.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 chromosomal microarray analysis (gene/segment-specific) may be used. A full chromosomal microarray analysis that detects deletions/duplications across the genome may also include this gene/segment.5. One ATL1 deletion involving exon 4 has been reported [Sulek et al 2011].Interpretation of test resultsFor issues to consider in interpretation of sequence analysis results, click here.Failure to detect a pathologic ATL1 sequence variant cannot absolutely exclude the diagnosis of SPG3A because the frequency of mutations involving non-coding regions (introns and promoter region) is unknown. Testing Strategy To confirm/establish the diagnosis in a probandGenotype/phenotype correlation in persons with hereditary spastic paraplegia (HSP) has a low sensitivity; the diagnosis of SPG3A can be established only by molecular genetic testing. Individuals with HSP with a clear family history of autosomal dominant transmission are typically tested for several genes causing autosomal dominant HSP (AD HSP) (see Differential Diagnosis). Individuals with early-onset AD HSP may initially be tested for SPG3A only, followed by testing for other genes commonly associated with AD HSP if a pathologic ATL1 sequence variant is not identified.The yield of molecular genetic testing of ATL1 in persons with who are simplex cases (i.e., a single occurrence in a family) is unknown, but molecular genetic testing should be considered if acquired causes of spastic paraparesis have been eliminated [Rainier et al 2006].Predictive testing for at-risk asymptomatic adult family members requires prior identification of the disease-causing mutation in the family.Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family.Genetically Related (Allelic) Disorders SPG3A is allelic with hereditary sensory neuropathy type ID (HSN ID), which is an axonal form of autosomal dominant hereditary motor and sensory neuropathy distinguished by prominent sensory loss that leads to painless injuries. Missense mutation in ATL1 was identified in a single family with HSN I; other known HSN I-associated genes were excluded as the cause of polyneuropathy [Guelly et al 2011].
Spastic paraplegia 3A (SPG3A) is characterized by clinical findings that tend to be more homogenous than other forms of AD HSP [Zhao et al 2001, Durr et al 2004, Hedera et al 2004]. The average age of onset is four years. More than 80% of reported individuals manifest spastic gait before the end of the first decade of life. The rate of progression is slow; wheelchair-dependency or need for an assistive walking device is relatively rare. ...
Natural History Spastic paraplegia 3A (SPG3A) is characterized by clinical findings that tend to be more homogenous than other forms of AD HSP [Zhao et al 2001, Durr et al 2004, Hedera et al 2004]. The average age of onset is four years. More than 80% of reported individuals manifest spastic gait before the end of the first decade of life. The rate of progression is slow; wheelchair-dependency or need for an assistive walking device is relatively rare. Although it has been suggested that SPG3A is a neurodevelopmental rather than a neurodegenerative disorder, recent identification of individuals with adult-onset SPG3A argues strongly against this hypothesis [Sauter et al 2004, Zhu et al 2006]. Persons with adult onset of SPG3A also tend to experience slower progression of their clinical symptoms. Most persons with early-onset SPG3A have a “pure” or uncomplicated” HSP phenotype. However, complex HSP phenotypes with axonal motor neuropathy and/or distal amyotrophy (like that observed in the Silver syndrome phenotype) have also been reported [Scarano et al 2005, Ivanova et al 2007, Salameh et al 2009]. Signs seen less frequently in SPG3A than in other HSPs include the following [Durr et al 2004]:Hyperreflexia of the upper extremitiesImpairment of vibration sensation at the ankles Urinary sphincter hyperactivity Signs seen more frequently in SPG3A than in other HSPs are pes cavus deformities and scoliosis; however, the presence of these findings may be attributable to the earlier age of onset rather than the specific form of HSP.
Most persons with mutations in ATL1 and early-onset disease have point missense mutations clustered around the GTPase binding domain. ...
Genotype-Phenotype Correlations Most persons with mutations in ATL1 and early-onset disease have point missense mutations clustered around the GTPase binding domain. Although some ATL1 mutations associated with late-onset HSP are insertional mutations in the C-terminus of the gene that result in a premature truncation of the protein, adult-onset disease has also been observed with missense mutations in the GTPase binding domain [Tessa et al 2002, Sauter et al 2004].
HSP is a progressive condition with a gradual worsening of spasticity and weakness of the lower extremities. Overall, the age of onset, disease severity, and rate of progression differ among different types of AD HSP; there is also a considerable variability within the same genetic forms of HSP. ...
Differential DiagnosisHSP is a progressive condition with a gradual worsening of spasticity and weakness of the lower extremities. Overall, the age of onset, disease severity, and rate of progression differ among different types of AD HSP; there is also a considerable variability within the same genetic forms of HSP. For a general discussion of the differential diagnosis of spastic paraplegia/paraparesis syndrome, see Hereditary Spastic Paraplegia Overview. While the association of infantile or early (age <10 years) onset and mutations in ATL1 has been confirmed by many studies, this genotype-phenotype correlation is not sufficient for the specific diagnosis of SPG3A on clinical grounds alone and an early age of onset can be seen in other types of AD HSP. Overall, a low specificity of genotype/phenotype correlations in AD HSP requires the molecular diagnosis of a specific type of HSP.SPG3A needs to be differentiated from other forms of AD HSP, such as BSCL2-related neurologic disorders, in which the Silver syndrome phenotype can be observed. [Salameh et al 2009].SPG3A needs to be differentiated from other forms of AD HSP with possible early age of onset.Additional considerations for SPG3A include a diplegic form of cerebral palsy (CP) because of the majority of such patients tend to have very early onset of the symptoms and a slow progression, which may suggest a static clinical course [Rainier et al 2006]. The presence of a positive family history with an affected parent typically does not present any diagnostic dilemmas. However, incomplete penetrance or a de novo mutation may lead to the diagnosis of diplegia caused by periventricular leukomalacia or perinatal hypoxic-ischemic injury. Normal pre- and perinatal history and unremarkable neuroimaging should prompt a consideration of HSP, including SPG3A.SPG4, the most common type of AD HSP, may occasionally present in infancy, although it tends to have a more progressive course [Blair et al 2007].SPG6, caused by mutations in NIPA1, may occasionally also manifest in infancy [Bien-Willner et al 2006]. This is probably the most aggressive form of AD HSP, leading to wheelchair dependency in a relatively short period of time. SPG10, caused by mutations in KIF5A (encoding kinesin 5A), is probably the second most common cause of early onset AD HSP. Axonal motor neuropathy is common [Reid et al 2002].SPG42, caused by mutation in SLC33A1, may also start in the first decade of life and has a mild, minimally progressive clinical course. Pes cavus and distal amyotrophy are common [Lin et al 2008]. This form of HSP has been reported in a single family.
To establish the extent of disease in an individual diagnosed with spastic paraplegia 3A (SPG3A), the following evaluations may be indicated:...
ManagementEvaluations Following Initial Diagnosis To establish the extent of disease in an individual diagnosed with spastic paraplegia 3A (SPG3A), the following evaluations may be indicated:Orthopedic evaluation in persons with early onset of SPG3A who have developed musculoskeletal complications including scoliosis or foot deformitiesPhysical and occupational therapy evaluation in children with early onset of disease Urologic evaluation in persons with prominent urinary bladder hyperactivityElectromyography and nerve conduction studies in persons with associated axonal neuropathy or neurogenic pain in the lower extremities caused by possible lumbo-sacral radiculopathy secondary to lumbar hyperlordosis and degenerative vertebral changes Treatment of ManifestationsTherapy for spasticity, distal weakness, and urinary bladder dysfunction, the primary manifestations of SPG3A, is symptomatic.Spasticity can be treated with:Oral baclofen or tizanidine Chemodenervation with botulinum A or B toxins; may be tried in those who do not tolerate oral antispasticity medicationsIntrathecal baclofen pump; a good alternative for patients who improve on oral baclofen but cannot tolerate a therapeutic dose because of systemic adverse effects Each of the above therapies should be combined with intensive physical therapy focused on stretching and strengthening exercises. The role of surgical therapy for spasticity (including hamstring and heel cord lengthening and release of the adductor longus) remains unknown, but such treatment should be considered if contractures appear. See also Prevention of Secondary Complications. Distal weakness, typically affecting foot dorsiflexion, can be ameliorated by ankle-foot orthoses; referral to orthotic services may be helpful. Urinary urgency can be treated with anticholinergic antispasmodic drugs. Prevention of Secondary ComplicationsMusculoskeletal abnormalities including muscle tendon contractures, scoliosis, and foot deformities are the secondary complications most likely to occur, resulting from long-standing spasticity and weakness. Intense and regular therapy for spasticity, including physiotherapy, can delay and minimize the appearance of these complications. The higher incidence of orthopedic problems in patients with SPG3A may be related to early age of onset and these patients should be followed by an orthopedist if problems are present.Urinary bladder incontinence can be a secondary complication of a neurogenic bladder and urologic care may be needed. Patients with advanced disease may experience falls with a risk of traumatic injury. A walking aid (cane, walker, or wheelchair) may need to be considered in patients experiencing falls. SurveillanceThere is no consensus regarding the frequency of clinical follow-up visits, but every person with HSP should be reevaluated once or twice a year to identify new complications early and to initiate aggressive therapy as indicated. Agents/Circumstances to AvoidDantrolene should be avoided in persons who are ambulatory as it may induce irreversible weakness, which can adversely interfere with overall mobility. 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.
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 3A: Genes and DatabasesView in own windowLocus NameGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDSPG3AATL114q22.1Atlastin-1HSP mutation database ATL1 homepage - Leiden Muscular Dystrophy pagesATL1Data 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 3A (View All in OMIM) View in own window 182600SPASTIC PARAPLEGIA 3, AUTOSOMAL DOMINANT; SPG3A 606439ATLASTIN GTPase 1; ATL1Normal allelic variants. ATL1 is 73 kb in length and spans from nucleotide position 51,026,743 to 51,099,782. Transcript variants encoding two different isoforms with 13 or 14 transcribed exons have been found for this gene. Complementary DNA length varies from 2,74 bp to 2,812 bp for different variants. Both synonymous and non-synonymous single polymorphisms (benign allelic variants) have been identified (see Table 2).Table 2. Selected ATL1 Normal Allelic Variants View in own windowDNA Nucleotide ChangeReference SNP NumberProtein Amino Acid ChangeReference Sequencesc.84A>Grs35014209NA 1NG_009028.1 NM_015915.4 NP_056999.2 Q5R4P1.2c.129C>Grs17850684p.Asp43Gluc.351G>A rs1060197NAc.578T>Grs17850683p.Phe193Cysc.621G>Ars35629585NAc.1222A>Grs28939094 p.Met408ValSee Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www.hgvs.org). 1. Not applicablePathologic allelic variants. Most of mutations in ATL1 are unique and no obvious hot spots for recurrent mutations have been identified [Durr et al 2004]. One genomic deletion of exon 4 has been reported [Sulek et al 2011].Table 3. Selected ATL1 Pathologic Allelic Variants View in own windowDNA Nucleotide Change (Alias 1) Protein Amino Acid Change (Alias 1)Reference Sequencesc.1243C>Tp.Arg415Trp 2NM_015915.3 NP_056999.2c.467C>T (635C>T)p.The156Ilec.715C>T (884C>T)p.Arg239Cysc.773A>G (942A>C)p.His258Argc.479T>G (638T>C)p.Leu157Trpc.1270dupA (1688insA)p.Ile424Asnfs*16 (522Stop)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 conventions2. Low penetrance allele (see Penetrance) Normal gene product. ATL1 encodes a 558-amino acid protein named atlastin-1 belonging to the subclass of GTPases called dynamins. Dynamins play a role in vesicle transport, especially in the process of recycling of the vesicles. The protein has two transmembrane domains and also contains the GTP binding domain with a catalytic activity [Zhu et al 2003]. Atlastin-1 is predominantly expressed in the pyramidal neurons giving the origin to the pyramidal tracts, which undergo axonal degeneration in patients with HSP. It localizes predominantly to the endoplasmatic reticulum (ER) and Golgi complex but is also found in other subcellular compartments, including the axonal growth cones [Zhu et al 2003, Zhu et al 2006]. Atlastin-1 plays an important role in the formation of the tubular ER network, where it may coordinate the interaction between microtubules and the tubular ER network [Hu et al 2009, Park et al 2010]. Atlastin-1 also interacts with spastin, which causes the most common form of AD HSP and is known to function as a microtubule-severing protein [Sanderson et al 2006]. Abnormal gene product. Most disease-causing missense mutations in ATL1 are clustered around the GTPase domain, resulting in reduction of catalytic activity. However, it is still not clear whether SPG3A results from a loss of atlastin-1 function: a dominant-negative effect of mutant protein forms on a wild type of atlastin-1 has also been suggested. Atlastin-1 forms tetrameric complexes and heterocomplexes of wild type and mutant atlastin-1 molecules may inactivate the normal function of wild type atlastin-1, consistent with a dominant-negative effect [Zhu et al 2003]. Expression of HSP-causing mutations of atlastin-1 results in abnormal connectivity of ER complex and these ER-shaping defects may represent a novel neuropathogenic mechanism [Hu et al 2009]. Additionally, atlastin-1 appears to be enriched in neuronal growth cones, and knockdown of atlastin-1 expression was found to impair axonal elongation [Zhu et al 2006].