SPG3A Mutations Research Articles

The Natural History of Motor, Cognitive Development and Mood in Early Onset Hereditary Spastic Paraplegias (S34.001)

<h3>Objective:</h3> To study the natural history of motor, cognitive development and mood in early onset hereditary spastic paraplegias herein called e-HSP. <h3>Background:</h3> e-HSP is a heterogeneous group of ultra-rare genetic diseases with the uniting clinical feature of lower limb spasticity and weakness presenting in childhood. However, little is known of the early development and psychological manifestations of e-HSP. Here we outline 87 patients with e-HSP and their early childhood development, cognitive function and mood. <h3>Design/Methods:</h3> Retrospective analysis of 87 genetically confirmed e-HSP patients, the majority with SPG4 and SPG3A mutations. Patients were consented and clinical information was collected at each clinic visit including developmental history, school performance and mood. Patients and families were contacted or met with in person to validate missing data points. <h3>Results:</h3> Two thirds of patients with e-HSP were found to have average to high cognitive function and perform well academically. Even 50% of patients who also had a confounding diagnosis of a neurodevelopmental or learning disorder were able to enroll in regular and advanced placement courses in school. 25% of patients had attention deficit disorder. Many of the patients had reported experiencing sadness around their diagnosis and 25% of patients reported being diagnosed with an emotional disorder such as anxiety or depression. Within SPG3A, 8/18 required assistance with long distances including a walker or wheelchair. Within SPG4, patients with de novo mutations showed a severe early developmental disorder. However, no genetic differences could be discerned in patients who had motor progression to walker or wheelchair use. Other mutations of SPG were included in this cohort but limited n-values confounded analysis on specific mutations. <h3>Conclusions:</h3> For the majority of e-HSP patients, motor disorder is the predominant disease feature, but patients should be screened for attention deficit, anxiety, and depression. <b>Disclosure:</b> Dr. Christie has nothing to disclose. Ms. Marvel has nothing to disclose.

SPG3A (ATL1) gene mutations in Taiwanese patients with apparently sporadic pure spastic paraplegia

Background: Hereditary spastic paraplegias (HSP) are degenerative disorders that are clinically and genetically heterogeneous. The SPG3A (ATL1) mutations accounted for approximately 10% of the autosomal dominant HSP cases, and have been identified as de novo mutations sometimes.

High frequency of SPG4 in Taiwanese families with autosomal dominant hereditary spastic paraplegia.

BackgroundHereditary spastic paraplegias (HSPs) are a group of neurodegenerative diseases characterized by progressive spasticity and weakness of the lower limbs. SPG4, SPG3A and SPG31 are the three leading causes of autosomal dominant (AD) HSPs.MethodsA total of 20 unrelated AD-HSP families were recruited for clinical and genetic assessment. Detection of mutations in SPG4, SPG3A and SPG31 genes was conducted according to a standard protocol. Genotype-phenotype correlations and determinants for disease severity and progression were analyzed.ResultsMutations in the SPG4 gene (SPAST) were detected in 18 (90%) of the AD-HSP families. Mutations in SPG4, SPG3A and SPG31 genes were not detected in the remaining two families. Considerable variations in clinical features were noted, even for mutation carriers from the same family. Mutations causing complete loss of the spastin AAA cassette were associated with earlier onset of disease (20 ± 18 years) compared with those with preservation of partial or total AAA cassette (32 ± 19 years, p = 0.041). For those with SPG4 mutations, disease severity was related to the patients’ current age, and the progression rate of disease was positively correlated with age at onset.ConclusionsSPG4 accounts for most of the AD-HSP cases in Taiwanese, with a frequency significantly higher than in other populations. SPAST mutations which predict complete loss of the spastin AAA cassette were associated with an earlier onset of disease.Electronic supplementary materialThe online version of this article (doi:10.1186/s12883-014-0216-x) contains supplementary material, which is available to authorized users.

Spg3a Mutation Co-Segregates with Hereditary Spastic Paraplegia Phenotype Whereas SPG31 Duplication Does Not

Spg3a Mutation Co-Segregates with Hereditary Spastic Paraplegia Phenotype Whereas SPG31 Duplication Does Not

Mitochondrial DNA polymorphisms/haplogroups in hereditary spastic paraplegia

Mitochondrial dysfunction could contribute to the development of spastic paraplegia. Among others, two of the genes implicated in hereditary spastic paraplegia encoded mitochondrial proteins and some of the clinical features frequently found in these patients resemble those observed in patients with mitochondrial DNA (mtDNA) mutations. We investigated the association between common mtDNA polymorphisms and spastic paraplegia. The ten mtDNA polymorphisms that defined the common European haplogroups were determined in 424 patients, 19% with a complicated phenotype. A rare haplogroup was associated with the disease in patients without a SPG3A, SPG4, or SPG7 mutation. Allele 10398G was more frequent among patients with a pure versus complicated phenotype. This mtDNA polymorphism was previously associated with the risk of developing other neurodegenerative diseases. In conclusion, some mtDNA polymorphisms could contribute to the development of spastic paraplegia or act as modifiers of the phenotype.

Expansion of the phenotypic spectrum of SPG6 caused by mutation in NIPA1

BackgroundHereditary spastic paraplegia type 6 (SPG6) is caused by mutations in the NIPA1 gene, this is a rare cause of HSP, until now, all the affected individuals reported displayed “pure” spastic paraplegia. ObjectivesTo analyze the genotype/phenotype correlation of mutations so far described in NIPA1. MethodsEighty-six Chinese Han HSP patients were investigated for SPG6 mutations by direct sequencing of the NIPA1 gene. ResultsOne heterozygous missense mutation c.316G>C/p.G106R was identified in a complicated form of ADHSP family with peripheral nerves disease, and SPG6 mutation in our sample accounted for 3.6% (1/28) of ADHSP families and 1.1% (1/86) of non-ARHSP patients who were negative for SPG4, SPG3A and SPG31 mutations. ConclusionsWe report the first complicated case of SPG6 in the world by the presence of peripheral neuropathy, which extends the phenotype initially described.

Hereditary Spastic Paraplegia Associated With Axonal Neuropathy: A Novel Mutation of SPG3A in a Large Family

Spastic paraplegia Type 3A is an autosomal-dominant pure or uncomplicated hereditary spastic paraplegia. It is caused by mutations in SPG3A, the only gene associated with this condition. We identified a novel mutation, c.1040T>C (p. M347T), in a family with axonal neuropathy in addition to spastic paraplegia. This expands the spectrum of neurologic complications associated with SPG3A and highlights the importance of long-term follow-up and neurological surveillance in this patient population.

Late-onset hereditary spastic paraplegia with thin corpus callosum caused by a new SPG3A mutation

Mutations in the SPG3A gene cause the most frequent autosomal dominant (AD) type of pure hereditary spastic paraplegia (HSP) with very early onset [1, 2]. Here, we report a novel disease-associated mutation in the SPG3A gene in an immigrant South African Zulu family with ADHSP and atypical clinical characteristics. Individuals were clinically evaluated by two neurologists with a proven experience in HSPs (A.O., G.B.). The proband (Fig. 1a, II:3) was a 68-year-old male. He had had progressive walking disturbance from the age of 56 years and a hoist had been required from the age of 66 years. A recent neurological examination disclosed moderate disease severity (SPRS [3] score 35/52) and mild mental retardation (WAIS-R IQ [4] score 62). Furthermore, the patient reported urinary incontinence due to sphincter incompetence. Brain MRI showed a thin corpus callosum (TCC) without cerebellar involvement or white matter abnormalities (Fig. 1b). The spinal cord MRI demonstrated no abnormal signal intensity or atrophy. Similar clinical features, including a late-onset of the disease (55 ± 5.6 years, mean ± SD), mental impairment and the occurrence of TCC, were observed in the other family members (Table 1). After informed consent was given by participants, genomic DNA was isolated from blood samples and subject to linkage analyses at all currently known ADHSP loci (OMIM web site: http://www.ncbi.nlm.nih.gov/omim). HSP gene sequences were studied by direct sequencing. The PCR-RFLP method was used for segregation analysis as described previously [5]. Significant two-point lod scores were obtained at the microsatellite markers of the SPG3A region (Zmax = 4.11 for D14S269 at h = 0.0), while linkage to the other known ADHSP loci was excluded. Sequence analysis of SPG3A demonstrated a novel heterozygous change in exon 12 (c.1246 C[T), resulting in the change of amino acid arginine to cysteine at codon 416 (R416C). The PCR-RFLP analyses showed that all affected family members carried the mutation in SPG3A, while the unaffected members did not (Fig. 1). The mutation was absent in 400 control chromosomes from unrelated South African Zulu individuals. In addition, sequence analyses of the known genes causing HSP with mental retardation and TCC (SPG1, SPG7, SPG11, SPG15 and SPG21) showed no pathological nucleotide changes. We detected a novel R416C missense mutation in a South African Zulu family with ADHSP. The genetic variation fell on exon 12, in accordance with the literature indicating a frequency of 35% for SPG3A mutations in this exon [2], and the R416C amino acid change could exert its pathogenic effect by generating an aberrant secondary A. Orlacchio (&) P. Montieri C. Babalini F. Gaudiello G. Bernardi Laboratorio di Neurogenetica, Centro Europeo di Ricerca sul Cervello (CERC), Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Santa Lucia, 64 Via del Fosso di Fiorano, 00143 Rome, Italy e-mail: a.orlacchio@hsantalucia.it

The effect of HSP-causing mutations in SPG3A and NIPA1 on the assembly, trafficking, and interaction between atlastin-1 and NIPA1

Despite its genetic heterogeneity, hereditary spastic paraplegia (HSP) is characterized by similar clinical phenotypes, suggesting that a common biochemical pathway underlies its pathogenesis. In support of this hypothesis, we used a combination of immunoprecipitation, confocal microscopy, and flow cytometry to demonstrate that two HSP-associated proteins, atlastin-1 and NIPA1, are direct binding partners, and interestingly, that the endogenous expression and trafficking of these proteins is highly dependant upon their coexpression. In addition, we demonstrated that the cellular distribution of atlastin-1:NIPA1 complexes was dramatically altered by HSP-causing mutations, as missense mutations in atlastin-1 (R239C and R495W) and NIPA1 (T45R and G106R) caused protein sequestration in the Golgi complex (GC) and endoplasmic reticulum (ER), respectively. Moreover, we demonstrated that HSP-causing mutations in both atlastin-1 and NIPA1 reduced axonal and dendritic sprouting in cultured rat cortical neurons. Together, these findings support the hypothesis that NIPA1 and atlastin-1 are members of a common biochemical pathway that supports axonal maintenance, which may explain in part the characteristic degeneration of long spinal pathways observed in patients with HSP.

Complex phenotype in an Italian family with a novel mutation in SPG3A

Mutations in the SPG3A gene represent a significant cause of autosomal dominant hereditary spastic paraplegia with early onset and pure phenotype. We describe an Italian family manifesting a complex phenotype, characterized by cerebellar involvement in the proband and amyotrophic lateral sclerosis-like syndrome in her father, in association with a new mutation in SPG3A. Our findings further widen the notion of clinical heterogeneity in SPG3A mutations.

Hereditary spastic paraplegia and axonal motor neuropathy caused by a novel SPG3A de novo mutation

Mutations in the SPG3A gene (atlastin protein) cause approximately 10% of autosomal-dominant hereditary spastic paraplegia. Most patients with an SPG3A mutation present with a pure phenotype and early-onset disease, although complicated forms with peripheral neuropathy are also reported. We report a new heterozygous S398F mutation in exon 12 of the SPG3A gene causing a very early-onset spastic paraplegia in association with motor axonal neuropathy in a 4-year-old girl resembling diplegic cerebral palsy.

Novel SPG3A and SPG4 Mutations in Two Patients With Silver Syndrome

Hereditary spastic paraplegia encompasses a group of disorders that are characterized by progressive lower extremity weakness and spasticity. We describe two patients with Silver phenotype including one with a novel SPG4 (Spastin) mutation and a second with a known SPG 4 mutation (previously unassociated with this phenotype) and a concomitant previously unreported mutation in SPG3A (Atlastin). These cases suggest that Silver syndrome may be associated with a wider variety of genotypes than previously described.

Extending the clinical spectrum of SPG3A mutations to a very severe and very early complicated phenotype

Extending the clinical spectrum of SPG3A mutations to a very severe and very early complicated phenotype

Hereditary Spastic Paraplegia 3A Associated With Axonal Neuropathy

To study the frequency and distribution of mutations in SPG3A in a large cohort of patients with hereditary spastic paraplegia. We screened a large cohort of 182 families and isolated cases with pure or complex hereditary spastic paraplegia phenotypes, which were negative for mutations in SPG4. In 12 probands (6.6%), we identified 12 different SPG3A mutations (11 missense and 1 insertion/frameshift) of which 7 were novel and 3 were de novo. We found incomplete penetrance in 1 family (G482V). In most cases, SPG3A mutations were associated with an early age at onset (mean, 3 y); however, in 1 family (R495W mutation), symptoms started later (mean, 14 y) with clear intrafamilial variability (8-28 y). Six patients with an SPG3A mutation (F151S, Q191R, M408T, G469A, R495W) originating from 5 unrelated families presented with a complex form of hereditary spastic paraplegia associated with a neuropathy (17%). Our electrophysiological and pathological findings confirmed an axonal sensory-motor neuropathy. There was no correlation between the genotype and the presence of a neuropathy. We conclude that mutations in SPG3A represent an important cause of patients in the overall hereditary spastic paraplegia population. SPG3A is more often associated with a neuropathy than previously assumed. Therefore, patients with a bipyramidal syndrome and a neuropathy should be screened for mutations in SPG3A.

A SPG3A mutation with a novel foot phenotype of hereditary spastic paraplegia in a Chinese Han family

A SPG3A mutation with a novel foot phenotype of hereditary spastic paraplegia in a Chinese Han family

Mutations in the SPG3A gene encoding the GTPase atlastin interfere with vesicle trafficking in the ER/Golgi interface and Golgi morphogenesis

Mutations in SPG3A causing autosomal dominant pure spastic paraplegia led to identification of atlastin, a new dynamin-like large GTPase. Atlastin is localized in the endoplasmic reticulum, the Golgi, neurites and growth cones and has been implicated in neurite outgrowth. To investigate whether it exerts its activity in the early secretory system, we expressed normal and mutant atlastin in cell culture. Pathogenic mutations in the GTPase domain interfered with the maturation of Golgi complexes by preventing the budding of vesicles from the endoplasmic reticulum, whereas mutations in other regions of the protein disrupted fission of endoplasmic reticulum-derived vesicles or their migration to their Golgi target. Atlastin, therefore, plays a role in vesicle trafficking in the ER/Golgi interface. Furthermore, atlastin partially co-localized with proteins of the p24/emp/gp25L family that regulate vesicle budding and trafficking in the early secretory pathway, and co-immunoprecipitated p24, suggesting a functional relationship that should be further explored.

Genetic and structural analyses suggest that a novel SPG3A mutation causes severe phenotypes of hereditary spastic paraplegia

Hereditary spastic paraplegia (HSP) is a group of neurodegenerative diseases. The genotypes and phenotypes of HSP are extremely heterogenous. SPG3A is one of the identified genes underlying HSP, and codes for a GTPase, atlastin. Mutations in SPG3A are currently believed to be associated with early onset and mild phenotypes. And most structural predictions could not detect gross changes in the mutant protein. However, in a severely affected HSP family we have identified a novel SPG3A mutation, c.1228G>A (p.G410R), in a Tibetan kindred. The mutation occurred at the highly conserved nucleotide and co-segregated with the disease, and was absent in the control subjects. Structural predictions showed that the Tibetan mutation occurred at the linking part between the guanylate-binding protein domain (GB, the ball region) and the transmembrane helices (TM, the rod region) at the start point of an α-helix, which may disrupt the helix, and cause changes in the overall structure of the transmembrane region of the molecule. Our results indicate that severe phenotypes can also arise from SPG3A mutations and the linking part of the guanylate-binding protein domain and the transmembrane helices might be crucial in determining the severity of the disease. This paper not only presents the first SPG3A mutational report from the Chinese population, but also provides potential evidence for a possible correlation between the severity of the phenotypes of HSP with the extension of the changes in the protein structures of atlastin.

De Novo Occurrence of Novel SPG3A/Atlastin Mutation Presenting as Cerebral Palsy

Mutations in the SPG3A gene (atlastin protein) cause approximately 10% of autosomal-dominant hereditary spastic paraplegia. For many subjects with an SPG3A mutation, spastic gait begins in early childhood and does not significantly worsen even over many years. Such subjects resemble those with spastic diplegic cerebral palsy. To date, only 9 SPG3A mutations have been reported. To analyze the SPG3A coding sequence in an individual with childhood-onset spastic gait, who, prior to the birth of her similarly affected child, had no previous family history of hereditary spastic paraplegia. The SPG3A coding sequence was analyzed in DNA samples from the proband, her affected child, her unaffected parents, and control subjects by polymerase-chain-reaction amplification of each exon followed by direct DNA sequencing. Seventeen microsatellite polymorphisms were amplified and analyzed to confirm reported paternity. We identified a novel SPG3A mutation (L157W) in the proband and her affected child. This mutation was absent in the proband's unaffected parents. Results of microsatellite polymorphism analysis were consistent with paternity as reported. These results indicate that this novel SPG3A mutation arose de novo in the proband. We report the de novo occurrence of a novel SPG3A mutation in a subject with childhood-onset, nonprogressive, spastic diplegia who had no previous family history of hereditary spastic paraplegia until the birth of her similarly affected son. Although rare, the occurrence of a de novo hereditary spastic paraplegia gene mutation must be considered in subjects with spastic diplegic cerebral palsy for whom no other cause is identified. This is extremely important for correct genetic counseling because recurrence risk may be as high as 50% when a mutation is detected.

SPG3A is the most frequent cause of hereditary spastic paraplegia with onset before age 10 years

Seven families with six different SPG3A mutations were identified among 106 with autosomal dominant hereditary spastic paraplegia (HSP). Two mutations were novel (T162P, C375R). SPG3A was twice as frequent as SPG4 in patients with onset before age 10 years (31.8%). Later onset was not observed. The phenotype was pure HSP, but disease duration was longer than in non-SPG3A/SPG4 patients, leading ultimately to greater handicap.

Atlastin1 Mutations Are Frequent in Young-Onset Autosomal Dominant Spastic Paraplegia

Hereditary spastic paraplegias are disorders that are very heterogeneous, both clinically and genetically. The atlastin1 gene has recently been implicated in SPG3A, a form of autosomal dominant pure spastic paraplegia. Atlastin1 mutations have been identified in 8 families so far. To determine the relative frequency, phenotype, and mutation spectrum of SPG3A in patients with pure autosomal dominant spastic paraplegia and onset before age 20 years. We sequenced the atlastin1 gene in a large series of patients (31 families) in which mutations in the spastin gene, corresponding to the frequent SPG4 locus, had previously been excluded. The phenotype was compared with 126 SPG4 patients. We identified 12 families (39%) including 34 patients with 9 different missense atlastin1 mutations, 7 of which are newly described. The main clinical characteristic of these SPG3A patients was pure spasticity with very young onset of symptoms (mean age, 4.6 +/- 3.9 years) and slow progression. However, additional signs such as decreased vibration sense and wasting in lower limbs, sphincter disturbances, and scoliosis were found in a minority of patients. In addition, several gene carriers were clinically affected but still asymptomatic (n = 5) or had no clinical signs (n = 2), indicating incomplete penetrance. Compared with patients from other families meeting the same diagnostic criteria (43 patients) and families with SPG4 (126 patients), the major form of autosomal dominant spastic paraplegia, SPG3A patients had earlier symptom onset, less frequently increased reflexes in the upper limbs, decreased vibration sense in the lower limbs, and fewer sphincter disturbances, but more frequently observed wasting in the lower limbs and scoliosis. These particularities, as well as frequent abnormal motor evoked potentials, could help identify patients to be screened for atlastin1 gene mutations. This study enables us to estimate the frequency of the SPG3A mutations in France at 39% in families with young-onset autosomal dominant spastic paraplegia after exclusion of SPG4 cases. So far, most mutations have been private, although they were all found in exons 7, 8, 12, and 13. These exons should be given priority when performing molecular diagnoses for SPG3A.