Sporadic Spastic Paraplegia Research Articles

KIF1A-related autosomal dominant spastic paraplegias (SPG30) in Russian families

BackgroundSpastic paraplegia type 30 (SPG30) caused by KIF1A mutations was first reported in 2011 and was initially considered a very rare autosomal recessive (AR) form. In the last years, thanks to the development of massive parallel sequencing, SPG30 proved to be a rather common autosomal dominant (AD) form of familial or sporadic spastic paraplegia (SPG),, with a wide range of phenotypes: pure and complicated. The aim of our study is to detect AD SPG30 cases and to examine their molecular and clinical characteristics for the first time in the Russian population.MethodsClinical, genealogical and molecular methods were used. Molecular methods included massive parallel sequencing (MPS) of custom panel ‘spastic paraplegias’ with 62 target genes complemented by familial Sanger sequencing. One case was detected by the whole -exome sequencing.ResultsAD SPG30 was detected in 10 unrelated families, making it the 3rd (8.4%) most common SPG form in the cohort of 118 families. No AR SPG30 cases were detected. In total, 9 heterozygous KIF1A mutations were detected, with 4 novel and 5 known mutations. All the mutations were located within KIF1A motor domain. Six cases had pure phenotypes, of which 5 were familial, where 2 familial cases demonstrated incomplete penetrance, early onset and slow relatively benign SPG course. All 4 complicated cases were caused by novel mutations without familial history. The phenotypes varied from severe in two patients (e.g. lack of walking, pronounced mental retardation) to relatively mild non-disabling symptoms in two others.ConclusionAD SPG30 is one of the most common forms of SPG in Russia, the disorder has pronounced clinical variability while pure familial cases represent a significant part.

Striatal Dopaminergic Functioning in Patients with Sporadic and Hereditary Spastic Paraplegias with Parkinsonism

Sporadic spastic paraplegia (SSP) and hereditary spastic paraplegia (HSP) belong to a clinical and genetically heterogeneous group of disorders characterized by progressive spasticity and weakness in the lower extremities. The symptoms are associated with pyramidal tract dysfunction and degeneration of the corticospinal tracts. Parkinsonism is uncommon in SSP/HSP patients. However, both disorders are associated with damage to the nigrostriatal dopaminergic system. In the present study, the clinical features of patients with SSP/HSP were investigated, and nigrostriatal dopaminergic binding potential was assessed using dopamine transporter (DAT) single-photon emission computer tomography (SPECT). Nine patients with spastic paraplegia participated in the present study. The subjects underwent DAT SPECT using the agent [2-[[2-[[[3-(4-chlorophenyl)-8-methyl-8-azabicyclo[3,2,1]oct-2-yl]methyl](2-mercaptoethyl)amino]ethyl]amino]ethanethiolato (3-)-N2,N20,S2,S20]oxo-[IR-(exo-exo)])-[99mTc]technetium ([99mTc]TRODAT-1). The [99mTc]TRODAT-1 SPECT images of five patients appeared normal, whereas the images of four patients revealed reduced striatal ligand uptake. Among the four patients with reduced uptake, two had parkinsonism, and one exhibited periodic limb movements and restless leg syndrome. Our DAT SPECT imaging study shows that reduced DAT density may be observed in patients with parkinsonism. The results of the present study offer an explanation for the spectrum of spastic paraplegia symptoms and the progression of the disorder.

Amplicon‐based high‐throughput pooled sequencing identifies mutations in CYP7B1 and SPG7 in sporadic spastic paraplegia patients

Hereditary spastic paraplegia (HSP) is a neurodegenerative disorder defined clinically by progressive lower limb spasticity and weakness. HSP is a genetically highly heterogeneous condition with at least 46 gene loci identified so far, involving X-linked, autosomal recessive (AR) and autosomal dominant inheritance. For correct diagnosis, molecular testing is essential because clinical parameters by themselves are not reliable to differentiate HSP forms. The purpose of this study was to establish amplicon-based high-throughput genotyping for AR-HSP. A sample of 187 index cases with apparently sporadic or recessive spastic paraplegia were analyzed by applying an array-based amplification strategy. Amplicon libraries of the CYP7B1-(SPG5) and SPG7-gene were generated followed by a pooled next-generation sequencing (NGS) approach. We identified three SPG5 and seven SPG7 patients. All had one homozygous or two heterozygous mutations. In total, 20 distinct mutations (CYP7B1,n = 4and SPG7,n = 16) including two novel CYP7B1 mutations (p.G51R and p.E211KfsX3) and eight novel SPG7 mutations (p.Leu8delinsLeuLeu, p.W29X, p.R139X, p.R247X, p.G344D, p.Leu346_Leu347ins11, p.R398X and p.R398Q) were detected by this comprehensive genetic testing. Our study illustrates how amplicon-based NGS can be used as an efficient tool to study genotypes and mutations in large patient cohorts and complex phenotypes.

Four novel SPG3A/atlastin mutations identified in autosomal dominant hereditary spastic paraplegia kindreds with intra‐familial variability in age of onset and complex phenotype

Mutation of the atlastin gene (SPG3A) is responsible for approximately 10% of autosomal dominant hereditary spastic paraplegia (AD-HSP) cases. The goal of this study was to identify novel disease causing atlastin mutations. Atlastin nucleotide variations were detected by direct sequencing of all 14 exons in 70 autosomal dominant (AD), 16 single sibship and 14 sporadic spastic paraplegia patients. Six mis-sense mutations (four of which were novel) were identified in six unrelated AD-HSP kindreds in exons 4, 7 and 8 of the atlastin gene. One kindred with a novel mutation showed variability in clinical phenotype and age of onset. Mutations are predicted to decrease GTPase activity, cause morphological abnormalities of the endoplasmic reticulum and prevent maturation of the Golgi complex resulting in impaired vesicle trafficking. Our study significantly adds to the spectrum of mutations and clinical phenotype of SPG3A. We advocate that all spastin mutation negative AD-HSP kindreds should be screened for pathogenic atlastin mutations regardless of age of onset or phenotypic complexity.

Sporadically occurring neurologic disease

Spastic paraplegia as the primary neurologic syndrome occurs as a manifestly inherited disorder (hereditary spastic paraplegia [HSP]1) and in subjects with no known family history (apparently sporadic spastic paraplegia [ASSP]). Other than the family history, there are no clinical parameters that reliably distinguish “hereditary” from “apparently sporadic” spastic paraplegia. Typically, ASSP is a transitional diagnosis applied for a number of years until 1) a pathogenic mutation in an HSP gene is identified or a family history emerges, and the diagnosis is then changed to HSP; 2) the disorder progresses to involve upper extremities, speech, and swallowing, and the diagnosis is then changed to primary lateral sclerosis; 3) another etiology is identified (e.g., amyotrophic lateral sclerosis). Nonetheless, for many subjects, despite adequate family size and structure and reliable family history, the disorder remains “apparently sporadic” and serial examinations over many years document insidiously progressive neurologic deficits largely confined to corticospinal tracts affecting the lower extremities, often associated with urinary urgency, and sometimes associated with mild decrease in distal lower extremity vibratory sensation. This is …

Four mutations of the spastin gene in Japanese families with spastic paraplegia

Hereditary spastic paraplegia (HSP) is a group of genetically heterogeneous neurodegenerative disorders characterized by slowly progressive spasticity and weakness of the lower limbs. HSP is caused by failure of development or selective degeneration of the corticospinal tracts, which contain the longest axons in humans. The most common form of HSP is caused by mutations of the spastin gene (SPAST), located on chromosome 2p21-p22, which encodes spastin, one of the ATPases associated with diverse cellular activities (AAA). In this study, we detected four causative mutations of SPAST among 14 unrelated patients with spastic paraplegia. Two missense mutations (1447A-->G, 1207C-->G) and two deletion mutations (1465delT, 1475-1476delAA) were located in the AAA cassette region. Three of these four mutations were novel. Previous reports and our results suggest that the frequency of SPAST mutations is higher among Japanese patients with autosomal dominant HSP, although SPAST mutations are also observed in patients with sporadic spastic paraplegia.

Objective assessment of gait after intrathecal baclofen in hereditary spastic paraplegia

Sirs: Sporadic spastic paraplegia (SSP) and hereditary spastic paraplegia (HSP) are heterogeneous neurodegenerative disorders. On physical examination spasticity of the lower limbs is often predominant, whereas paraparesis may be mild [1, 2]. The gait disorder of SSP/HSP patients which is the cardinal source of disability in these patients has been recently characterized [3]. The treatment of spastic paraplegia is symptomatic and limited to oral antispastic drugs and physiotherapy. In 1984 Penn [4] showed that intrathecal baclofen (ITB) could alleviate spinal cord spasticity. The efficacy of ITB on spasticity has been proven in several studies [5, 6]. In these studies ITB was used as a symptomatic treatment to reduce painful spasm and muscle contractions in mostly wheelchair bound patients. However, SSP/HSP patients are often able to walk even in advanced stages of their disease. Therefore, ITB therapy in SSP/HSP has the special requirement of reducing spasticity but preserving gait function. So far most clinical trials on spasticity rely on rating scales such as the modified “Ashworth Scale of Spasticity” (ASH), which may not adequately reflect the functional benefit in gait in SSP/HSP patients. In the particular case of ITB therapy for SSP/HSP the indication for an ITB pump implantation should moreover be based on the global clinical impression of gait improvement after an ITB test injection. Unfortunately, there are no scientific operational data to test the functional benefit of ITB in SSP/HSP. Here we describe the clinical effect of ITB in 10 patients, who were all treated with oral antispastic drugs and ongoing physiotherapy. Additionally we tested the usefulness of a three-dimensional movement analysis system for the selection of candidates for an ITB pump implantation. The gait of 10 SSP/HSP patients before and after a testing dose of 25 or 50 μg ITB was examined with this method, which is described elsewhere in detail [7]. In cooperation with the responsible physiotherapists we clinically distinguished responders (group 1; n = 5) from non responders (group 2; n = 5) based on the global clinical impression of gait improvement after ITB. Group 1 was recommended for an ITB pump implantation, whereas group 2 was not. With respect to spastic tone SSP/HSP patients showed a significant reduction of the ASH after ITB (p = 0.014). These result are comparable to the study of Penn et al. who analysed the effect of ITB via an implanted pump system [6]. We found an increased gait velocity accompanied by larger step length and a reduced step width after ITB in all patients, but no significant change in other kinematic gait parameters at a self chosen comfortable speed. Additionally, gait analysis was also performed with a fixed velocity of 1 km/h to eliminate the variable influence of speed. Under this condition group 1 presented an increased range of motion (ROM) of the ankle angle. Furthermore group 1 showed a reduction of the minimum knee angle as shown in a patient in Fig. 1. Gait parameters alone, however, did not allow us to separate clinical responders and non responders. An ITB pump implantation was performed in three of the five screened patients of group 1. Two patients did not opt for ITB owing to subjective unsteadiness and weakness in the lower extremities. We were able to collect follow up gait analysis data of two patients under chronic ITB. Both patients showed an effect of chronic ITB (mean dosage 60 μg/day), which was equivalent to the effect of the test bolus (Fig. 2). In conclusion, our findings show that ITB is a potential treatment option in SSP/HSP. However, only 50 % of our patients were recommended for a pump implantation. Therefore it can be assumed that all patients showed a variable effect of ITB that was probably too strong and a formerly existing weakness was unmasked by the ITB in some patients. In the quantitative gait analysis an improvement of gait was documented in the gait velocity and the step length. However, gait analysis alone was not able to discriminate between clinical responders and non-responders. This may be due to the relatively small number of investigated patients. If so, in the individual patient the clinical examination of gait before and after bolus injection of ITB in a multidisciplinary assessment by a neurologist and physiotherapists experienced with gait disorders is decisive and cannot be replaced by a technical assessment alone.

A clinical, genetic and biochemical study of SPG7 mutations in hereditary spastic paraplegia.

Mutations in the SPG7 gene, encoding the mitochondrial protein paraplegin, were the first to be identified in autosomal recessive hereditary spastic paraplegia (ARHSP). Four different SPG7 mutations have been described so far in association with both pure and complicated HSP phenotypes. Muscle biopsies from the most severely affected patients have shown histological evidence of an oxidative phosphorylation defect. We identified six ARHSP kindreds, in whom linkage to SPG7 could not be excluded, and 29 sporadic spastic paraplegia patients. The 17 exons and flanking regions of the SPG7 gene were screened for mutations using a combination of single-stranded conformation polymorphism (SSCP) analysis and sequencing. Three patients were found to carry compound heterozygous SPG7 mutations, comprising five novel and one previously described mutation. Muscle biopsies from two SPG7 mutation patients did not show any histological evidence of an oxidative phosphorylation defect. However, biochemical analysis revealed a reduction in citrate synthase-corrected complex I and complex II/III activities in muscle and complex I activity in mitochondrial-enriched fractions from cultured myoblasts, suggesting that either a primary or a secondary defect of respiratory chain function may play an important role in the pathogenesis of the disease.