A novel homozygous variant in ATL1 associated with early onset spastic paraplegia 3A: Further evidence for autosomal recessive inheritance.

Spastic paraplegia 3A (SPG3A) has long been considered as an autosomal dominant disorder till the report in 2014 and 2016 of two consanguineous Arabic families, showing that ATL1 mutations may cause autosomal recessive paraplegia. Here, a third report of a consanguineous Arabic family with recessive SPG3A is described. Exome sequencing reveals homozygosity for a novel likely pathogenic ATL1 splice donor variant (c.522+1G>T) in an affected 5-year-old infant whereas the parents, heterozygous carriers, are asymptomatic. The infant's phenotype is consistent with an early onset complicated SPG3A with severe progressive spasticity of the lower limbs and intellectual disability.

Copy number variations in SPAST and ATL1 are rare among Brazilians.

Copy number variations (CNV) may represent a significant proportion of SPG4 and SPG3A diagnosis, the most frequent autosomal dominant subtypes of hereditary spastic paraplegias (HSP). We aimed to assess the frequency of CNVs in SPAST and ATL1 and to update the molecular epidemiology of HSP families in southern Brazil. A cohort study that included 95 Brazilian index cases with clinical suspicion of HSP was conducted between April 2011 and September 2022. Multiplex Ligation Dependent Probe Amplification (MLPA) was performed in 41 cases without defined diagnosis by different massive parallel sequencing techniques (MPS). Diagnosis was obtained in 57/95 (60%) index cases, 15/57 (26.3%) being SPG4. Most frequent autosomal recessive HSP subtypes were SPG7 followed by SPG11, SPG76 and cerebrotendinous xanthomatosis. No CNVs in SPAST and ATL1 were found. Copy number variations are rare among SPG4 and SPG3A families in Brazil. Considering the possibility of CNVs detection by specific algorithms with MPS data, we consider that this is likely the most cost-effective approach to investigate CNVs in these genes in low-risk populations, with MLPA being reserved as an orthogonal confirmatory test.

Reduced penetrance of an eastern French mutation in ATL1 autosomal-dominant inheritance (SPG3A): extended phenotypic spectrum coupled with brain 18F-FDG PET.

ATL1-related spastic paraplegia SPG3A is a pure form of hereditary spastic paraplegia. Rare complex phenotypes have been described, but few data concerning cognitive evaluation or molecular imaging of these patients are available. We relate a retrospective collection of patients with SPG3A from the Neurology Department of Nancy University Hospital, France. For each patient were carried out a 18F-FDG PET (positron emission tomography), a electromyography (EMG), a sudoscan®, a cerebral and spinal cord MRI (magnetic resonance imaging) with measurement of cervical and thoracic surfaces, a neuropsychological assessment. The present report outlines standardised clinical and paraclinical data of five patients from two east-France families carrying the same missense pathogenic variation, NM_015915.4(ATL1): c.1483C > T p.(Arg495Trp) in ATL1. Mean age at onset was 14 ± 15.01 years. Semi-quantitatively and in comparison to healthy age-matched subjects, PET scans showed a significant cerebellar and upper or mild temporal hypometabolism in all four adult patients and hypometabolism of the prefrontal cortex or precuneus in three of them. Sudoscan® showed signs of small fibre neuropathy in three patients. Cervical and thoracic patients' spinal cords were significantly thinner than matched-control, respectively 71 ± 6.59mm2 (p = 0.01) and 35.64 ± 4.35mm2 (p = 0.015). Two patients presented with a dysexecutive syndrome. While adding new clinical and paraclinical signs associated with ATL1 pathogenic variations, we insist here on the variable penetrance and expressivity. We report small fibre neuropathy, cerebellar hypometabolism and dysexecutive syndromes associated with SPG3A. These cognitive impairments and PET findings may be related to a cortico-cerebellar bundle axonopathy described in the cerebellar cognitive affective syndrome (CCAS).

Clinical and genetic aspects of hereditary spastic paraplegia in patients from Turkey.

OBJECTIVES: Hereditary spastic paraplegias (HSPs) are a heterogenous group of rare neurodegenerative disorders that present with lower limb spasticity. It is known as complicated HSP if spasticity is accompanied by additional features such as cognitive impairment, cerebellar syndrome, thin corpus callosum, or neuropathy. Most HSP families show autosomal dominant (AD) inheritance. On the other hand, autosomal recessive (AR) cases are also common because of the high frequency of consanguineous marriages in our country. This study aimed to investigate the clinical and genetic aetiology in a group of HSP patients. PATIENTS AND METHODS: We studied 21 patients from 17 families. Six of them presented with recessive inheritance. All index patients were screened for ATL1 and SPAST gene mutations to determine the prevalence of the most frequent types of HSP in our cohort. Whole exome sequencing was performed for an AD-HSP family, in combination with homozygosity mapping for five selected AR-HSP families. RESULTS: Two novel causative variants were identified in PLP1 and SPG11 genes, respectively. Distribution of HSP mutations in our AD patients was found to be similar to European populations. CONCLUSION: Our genetic studies confirmed that clinical analysis can be misleading when defining HSP subtypes. Genetic testing is an important tool for diagnosis and genetic counselling. However, in the majority of AR HSP cases, a genetic diagnosis is not possible.

Disease-Causing Variants in the ATL1 Gene Are a Rare Cause of Hereditary Spastic Paraplegia among Czech Patients.

Variants in the ATL1 gene have been repeatedly described as the second most frequent cause of hereditary spastic paraplegia (HSP), a motor neuron disease manifested by progressive lower limb spasticity and weakness. Variants in ATL1 have been described mainly in patients with early onset HSP. We performed Sanger sequencing of all coding exons and adjacent intron regions of the ALT1 gene in 111 Czech patients with pure form of HSP and additional Multiplex-Ligation Probe Analysis (MLPA) testing targeting the ATL1 gene in 56 of them. All patients except seven were previously tested by Sanger sequencing of the SPAST gene with negative results. ATL1 diagnostic testing revealed only five missense variants in the ATL1 gene. Four of them are novel, but we suppose only two of them to be pathogenic and causal. The remaining variants are assumed to be benign. MLPA testing in 56 of sequence variant negative patients revealed no gross deletion in the ATL1 gene. Variants in the ATL1 gene are more frequent in patients with early onset HSP, but in general the occurrence of pathogenic variants in the ATL1 gene is low in our cohort, less than 4.5% and less than 11.1% in patients with onset before the age of ten. Variants in the ATL1 gene are a less frequent cause of HSP among Czech patients than has been previously reported among other populations.

Patients with complex and very-early-onset ATL1-related spastic paraplegia offer insights on genotype/phenotype correlations and support for autosomal recessive forms of SPG3A.

Spastic paraplegia type 3A (SPG3A) is the second most common form of hereditary spastic paraplegia (HSP). This autosomal-dominant-inherited motor disorder is caused by heterozygous variants in the ATL1 gene which usually presents as a pure childhood-onset spastic paraplegia. Affected individuals present muscle weakness and spasticity in the lower limbs, with symptom onset in the first decade of life. Individuals with SPG3A typically present a slow progression and remain ambulatory throughout their life. Here we report three unrelated individuals presenting with very-early-onset (before 7 months) complex, and severe HSP phenotypes (axial hypotonia, spastic quadriplegia, dystonia, seizures and intellectual disability). For 2 of the 3 patients, these phenotypes led to the initial diagnosis of cerebral palsy (CP). These individuals carried novel ATL1 pathogenic variants (a de novo ATL1 missense p.(Lys406Glu), a homozygous frameshift p.(Arg403Glufs*3) and a homozygous missense variant (p.Tyr367His)). The parents carrying the heterozygous frameshift and missense variants were asymptomatic. Through these observations, we increase the knowledge on genotype-phenotype correlations in SPG3A and offer additional proof for possible autosomal recessive forms of SPG3A, while raising awareness on these exceptional phenotypes. Their ability to mimic CP also implies that genetic testing should be considered for patients with atypical forms of CP, given the implications for genetic counseling.

[A case of spastic paraplegia with SPG4 and SPG3 associated mutations]. / Sluchai spasticheskoi paraplegii s mutatsiyami v genakh dvukh form: SPG4 i SPG3.

A rare case of autosomal dominant spastic paraplegia in a 36-year-old female with two reported earlier mutations of most common spastic paraplegia forms: SPG4 (mutation p.Cys28Leufs*20 in SPAST gene) and SPG3 (mutation p.Val405Met in ATL1 gene) is presented. The mutations detected by massively parallel sequencing (MPS) panel were inherited from affected mother and clinically unaffected father, respectively. The proband, her 61-year-old mother and deceased grandfather had 'uncomplicated' paraplegia with onset in 4th decade. The 67-year-old father had no even minimal subclinical signs of the disease and no affected relatives, detection of his low-penetrating ATL1 mutation was unexpected. MPS methods are the most informative for identifying a patient and/or family members with a combined hereditary neurological pathology, especially a combination of similar forms of heterogeneous groups, such as spastic paraplegia.

Circ-ATL1 silencing reverses the activation effects of SIRT5 on smooth muscle cellular proliferation, migration and contractility in intracranial aneurysm by adsorbing miR-455.

BACKGROUND: Alterations in vascular smooth muscle cells (VSMCs) contribute to the pathogenesis of intracranial aneurysms (IAs). However, molecular mechanisms underlying these changes remain unknown. The present study aimed to characterize the molecular mechanisms underlying VSMC-mediated IAs. METHODS: Expression of the circular RNA circ-ATL1 and microRNA miR-455 was detected in IAs by RT-qPCR. Interactions between circ-ATL1, miR-455 and SIRT5 were examined by luciferase reporter analysis and RT-qPCR. The regulatory roles of circ-ATL1, miR-455 and SIRT5 in VSMC migration, proliferation and phenotypic modulation were also examined by CCK8, Transwell® migration and western blot assays. RESULTS: Biochemical and bioinformatic techniques were used to demonstrate that circ-ATL1 and miR-455 participated in disparate biological processes relevant to aneurysm formation. Clinically, increased expression of circ-ATL1 and downregulated miR-455 expression were observed in IA patients compared with healthy subjects. Silencing of circ-ATL1 led to suppression of VSMC migration, proliferation and phenotypic modulation. Both SIRT5 and miR-455 were found to be downstream targets of circ-ATL1. SIRT5 upregulation or miR-455 inhibition reversed the inhibitory effects induced by circ-ATL1 silencing on VSMC proliferation, migration and phenotypic modulation. We found that VSMC phenotypic modulation by circ-ATL1 upregulation and miR-455 downregulation had a critical role in the development and formation of AIs. Specifically, circ-ATL1 downregulation reversed IA formation. CONCLUSION: Our data provide the theoretical basis for future studies on potential clinical treatment and prevention of IAs.

Atractylenolide I inhibits EMT and enhances the antitumor effect of cabozantinib in prostate cancer via targeting Hsp27.

Objective: To investigate the effect of Hsp27 and the inhibitory effect of Atractylenolide I (ATL-1) on the proliferation of prostate cancer cell DU145 and PC-3. Methods: MTT assay was used to detect the inhibitory effect of silencing Hsp27 and ATL-1 on DU145 and PC-3 proliferation of prostate cancer cells. TUNEL detected the apoptosis rate of prostate cancer cell DU145 and PC-3 after silencing Hsp27 and ATL-1 treated. qRT-PCR was used to detect the changes of apoptosis related genes caspase-3, PARP, Bax and Bcl-2 in prostate cancer cell DU145 and PC-3 after the effect of silencing Hsp27 and ATL-1 treated. At the same time, the antitumor effect of ATL-1 combined with cabozantinib was analyzed. Results: Hsp27 was highly expressed in human prostate cancer. MTT assay showed that ATL-1 inhibited the proliferation of prostate cancer cells DU145 and PC-3 compared with the control group. TUNEL results showed that silencing Hsp27 and ATL-1 treated could significantly promote the apoptosis of prostate cancer cells DU145 and PC-3 compared with the control group. qRT-PCR results showed that compared with the control group, ATL-1 could promote the expression of caspase-3, PARP and Bax in DU145 and PC-3 prostate cancer cells. Inhibition of Hsp27 by ATL-1 reduced cell viability and induced apoptosis. ATL-1 inhibits the antitumor effect of Hsp27 - enhanced cabozantinib. Hsp27 regulates eIF4E and mediates cell protection. Conclusion: Silencing Hsp27 inhibits EMT. ATL-1 can inhibit the malignant evolution of prostate cancer cells by inhibiting Hsp27/eIF4E. ATL-1 also enhanced chemosensitization of cabozantinib in prostate cancer.

Clinical and genetic characterization of hereditary spastic paraplegia type 3A in Taiwan.

AIM: To investigate the clinical and genetic features of hereditary spastic paraplegia (HSP) type 3A (SPG3A) in Taiwan. METHODS: Mutational analysis of the ATL1 gene was performed for 274 unrelated Taiwanese HSP patients. The diagnosis of SPG3A was ascertained by the presence of a heterozygous pathogenic mutation in ATL1. The SPG3A patients received clinical, electrophysiological, and neuroimaging evaluations. Disease severity was assessed by using Spastic Paraplegia Rating Scale (SPRS) and disability score. Nineteen single nucleotide polymorphism (SNP) markers flanking ATL1 were genotyped for haplotype analysis of ATL1 p.R416C mutation. RESULTS: Eighteen SPG3A patients from 11 families were identified. They typically presented a pure form HSP phenotype with disease onset ranging from age 1-68 years. Five heterozygous ATL1 mutations were identified, including p.R239C, p.V253I, p.Y336H, p.P342R and p.R416C. ATL1 p.R416C was the most common mutation and presented in five SPG3A pedigrees. Haplotype analyses demonstrated a shared haplotype in the 12 individuals carrying a p.R416C allele. CONCLUSION: SPG3A accounts for 4% (11 out of 274) of HSP in the Taiwanese cohort. Patents with the ATL1 p.R416C mutation in Taiwan may descend from a common ancestor. This study defines the clinical and genetic features of SPG3A in Taiwan and provides useful information for the diagnosis and management, especially in patients of Han Chinese descent.

Lipoxin-Induced Phenotypic Changes in CD115+LY6Chi Monocytes TAM Precursors Inhibits Tumor Development.

During tumor development, the spleen acts as an extra-medullar reservoir of LY6Chi inflammatory monocytes, which can migrate toward tumor to differentiate into tumor-associated macrophage (TAMs), renewing the TAM population. In the tumor microenvironment, pro-inflammatory macrophages (M1) acquire anti-inflammatory and pro-tumor (M2) characteristics favoring tumor development. We previously demonstrated that lipoxins, a family of pro-resolving lipid mediators, restored in vitro the cytotoxic M1-like properties of TAMs. Objective: In this study, we have investigated in vivo the cellular mechanisms underlying the anti-tumor property of lipoxins. Methods: Fourteen days after inducing B16-F10 melanoma tumors, mice received one single dose of ATL-1 (1 µg/i.v.), a lipoxin A4 analog. After further 7 days, blood and bone-marrow were collected, tumors and spleens were removed, and TAMs and blood monocytes were isolated. Results: While the population of LY6Chi monocytes was increased in non-treated tumor-bearing mice, the treatment with ATL-1 diminished the population of LY6Chi monocytes in spleen, blood and bone marrow, decreasing macrophage infiltration into the tumor and reducing the M2 markers expression on TAMs. Importantly, those effects were accompanied by an impairment of tumor growth and improved survival of tumor-bearing mice. The data evidence the anti-tumor mechanism of ATL-1, by decreasing the availability of TAM-precursor monocytes and changing TAMs profile in vivo, impairing tumor progression. ATL-1 may become a new tool in cancer control.

Novel ATL1 mutation in a Chinese family with hereditary spastic paraplegia: A case report and review of literature.

BACKGROUND: Hereditary spastic paraplegias (HSPs) refer to a group of heterogeneous neurodegenerative diseases characterized by lower limbs spasticity and weakness. So far, over 72 genes have been found to cause HSP (SPG1-SPG72). Among autosomal dominant HSP patients, spastic paraplegia 4 (SPG4/SPAST) gene is the most common pathogenic gene, and atlastin-1 (ATL1) is the second most common one. Here we reported a novel ATL1 mutation in a Chinese spastic paraplegia 3A (SPG3A) family, which expands the clinical and genetic spectrum of ATL1 mutations. CASE SUMMARY: A 9-year-old boy with progressive spastic paraplegia accompanied by right hearing loss and mental retardation for five years was admitted to our hospital. Past history was unremarkable. The family history was positive, and his grandfather and mother had similar symptoms. Neurological examinations revealed hypermyotonia in his lower limbs, hyperreflexia in knee reflex, bilateral positive Babinski signs and scissors gait. The results of blood routine test, liver function test, blood glucose test, ceruloplasmin test and vitamin test were all normal. The serum lactic acid level was significantly increased. The testing for brainstem auditory evoked potential demonstrated that the right side hearing was impaired while the left was normal. Magnetic resonance imaging showed mild atrophy of the spinal cord. The gene panel test revealed that the proband carried an ATL1 c.752A>G p.Gln251Arg (p.Q251R) mutation, and Sanger sequencing confirmed the existence of family co-segregation. CONCLUSION: We reported a novel ATL1 Q251R mutation and a novel clinical phenotype of hearing loss in a Chinese SPG3A family.

Clinical features and genotype-phenotype correlation analysis in patients with ATL1 mutations: A literature reanalysis.

BACKGROUND: The hereditary spastic paraplegias (HSPs) are a group of clinically and genetically heterogeneous disorders. Approximately 10% of the autosomal dominant (AD) HSPs (ADHSPs) have the spastic paraplegia 3A (SPG3A) genotype which is caused by ATL1 gene mutations. Currently there are more than 60 reported ATL1 gene mutations and the genotype-phenotype correlation remains unclear. The study aims to investigate the genotype-phenotype correlation in SPG3A patients. METHODS: We performed a reanalysis of the clinical features and genotype-phenotype correlations in 51 reported studies exhibiting an ATL1 gene mutation. RESULTS: Most HSPs-SPG3A patients exhibited an early age at onset (AAO) of <10 years old, and showed an autosomal dominant pure spastic paraplegia. We found that 14% of the HSPs-SPG3A patients presented complicated phenotypes, with distal atrophy being the most common complicated symptom. The AAO of each mutation group was not statistically significant (P > 0.05). The mutational spectrum associated with ATL1 gene mutation is wide, and most mutations are missense mutations, but do not involve the functional motif of ATL1 gene encoded atlastin-1 protein. CONCLUSIONS: Our findings indicate that there is no clear genotype-phenotype correlation in HSPs-SPG3A patients. We also find that exons 4, 7, 8 and 12 are mutation hotspots in ATL1 gene.

Molecular spectrum of the SPAST, ATL1 and REEP1 gene mutations associated with the most common hereditary spastic paraplegias in a group of Polish patients.

Hereditary spastic paraplegias (HSPs) consist of a heterogeneous group of genetically determined neurodegenerative disorders. Progressive lower extremity weakness and spasticity are the prominent features of HSPs resulting from retrograde axonal degeneration of the corticospinal tracts. Three genetic types, SPG3 (ATL1), SPG4 (SPAST) and SPG31 (REEP1), appear predominantly and may account for up to 50% of autosomal dominant hereditary spastic paraplegias (AD-HSPs). Here, we present the results of genetic testing of the three mentioned SPG genetic types in a group of 216 unrelated Polish patients affected with spastic paraplegia. Molecular evaluation was performed by multiplex ligation-dependent probe amplification (MLPA) and DNA sequencing. Nineteen novel mutations: 13 in SPAST, 4 in ATL1 and 2 in REEP1, were identified among overall 50 different mutations detected in 57 families. Genetic analysis resulted in the identification of molecular defects in 54% of familial and 8.4% of isolated cases. Our research expanded the causative mutations spectrum of the three most common genetic forms of HSPs found in a large cohort of probands originating from the Central Europe.

Mutational spectrum of the SPAST and ATL1 genes in Korean patients with hereditary spastic paraplegia.

Hereditary spastic paraplegia (HSP) is a genetically heterogeneous group of diseases characterized by insidiously progressive lower-extremity weakness and spasticity. Spastic paraplegia 4 (SPAST) is the most common type of uncomplicated autosomal dominant HSP (40% of such cases), and spastic paraplegia 3A (ATL1) is the second most common. Here, we conducted mutational analysis of the SPAST and/or ATL1 genes in 206 unrelated patients with HSP. DNA sequencing and multiplex ligation-dependent probe amplification was used to analyze SPAST or ATL1 pathogenic variants. To confirm splice-site pathogenic variants, mRNA transcripts were analyzed by reverse transcription-polymerase chain reactions and sequencing. Among the 52 patients with medical records and SPAST or ATL1 gene pathogenic variants or novel unclassified variants, 50 showed spasticity or weakness in their lower extremities. We identified 16 known and 18 novel SPAST pathogenic variants and 2 known and a novel splicing pathogenic variants in ATL1. We also identified 4 unclassified SPAST variants in 5 patients and an unclassified ATL1 variant in 1 patient. Further, a novel leaky-splicing variant (c.1537-11A>G) was found in SPAST, which caused skipping of exon 13 or exons 13-14. Among the 206 unrelated patients with HSP, SPAST or ATL1 pathogenic variants and potentially pathogenic variants were identified in 52 patients, a low pathogenic variant rate compared to previous results. Results from our study suggest that other genes may be involved in HSP in the Korean population.

Novel mutation in the ATL1 with autosomal dominant hereditary spastic paraplegia presented as dysautonomia.

SPG3A, which is the second most common type of autosomal dominant hereditary spastic paraplegia (HSP), is caused by mutations in the atlastin GTPase 1 gene, ATL1. We report a case of a patient who presented as dysautonomia and had a novel splicing mutation c.35-3C>T in exon 2 of the ATL1. Orthostatic intolerance, urinary symptoms, hyperreflexia in the biceps and knee jerk, and decreased proprioception in both limbs were observed on neurological examinations. We tested the autonomic function and performed genetic tests for the SPG4 and SPG3A forms of HSP. This case is a genetically confirmed HSP with a novel mutation in SPG3A, and extends the phenotype of SPG3A.

Mutation analysis of SPAST, ATL1, and REEP1 in Korean Patients with Hereditary Spastic Paraplegia.

BACKGROUND AND PURPOSE: Hereditary spastic paraplegia (HSP) is a genetically heterogeneous group of neurodegenerative disorders that are characterized by progressive spasticity and weakness of the lower limbs. Mutations in the spastin gene (SPAST) are the most common causes of HSP, accounting for 40-67% of autosomal dominant HSP (AD-HSP) and 12-18% of sporadic cases. Mutations in the atlastin-1 gene (ATL1) and receptor expression-enhancing protein 1 gene (REEP1) are the second and third most common causes of AD-HSP, respectively. METHODS: Direct sequence analysis was used to screen mutations in SPAST, ATL1, and REEP1 in 27 unrelated Korean patients with pure and complicated HSP. Multiplex ligation-dependent probe amplification was also performed to detect copy-number variations of the three genes. RESULTS: Ten different SPAST mutations were identified in 11 probands, of which the following 6 were novel: c.760A>T, c.131C>A, c.1351_1353delAGA, c.376_377dupTA, c.1114A>G, and c.1372A>C. Most patients with SPAST mutations had AD-HSP (10/11, 91%), and the frequency of SPAST mutations accounted for 66.7% (10/15) of the AD-HSP patients. No significant correlation was found between the presence of the SPAST mutation and any of the various clinical parameters of pure HSP. No ATL1 and REEP1 mutations were detected. CONCLUSIONS: We conclude that SPAST mutations are responsible for most Korean cases of genetically confirmed AD-HSP. Our observation of the absence of ATL1 and REEP1 mutations needs to be confirmed in larger series.

Clinical and genetic analyses of 3 pedigrees with hereditary spastic paraplegia / 中华神经医学杂志

Objective To analyze the clinical manifestations and genetic mutations in 3 pedigrees with hereditary spastic paraplegia (HSP).Methods Three pedigrees diagnosed as having HSP in our hospital from January 2014 to November 2015,were chosen;the clinical manifestations,electrophysiology and imaging features of the patients in these three families were analyzed.Genomic DNA was extracted from peripheral venous blood,and the targeted gene capturing was employed to identify the disease-causing genes of these patients.Results The patients from the first family was familiar HSP,and the main clinical features were progressive lower limbs weakness and abnormal gait without cognitive impairment;the patients from the second family were familiar HSP and those from the third family were HSP without family history,and the main clinical features of the two pedigrees were slowly progressive spastic paraplegia and cognitive impairment.In addition,thin corpus callosum was visible in MR imaging of family three.Genetic testing showed the first family presented with a known mutation c.715C＞T ofA TL1 exon 7 and the loci co-segregated in the family.The second family presented with novel compound heterozygous mutations in the SPG11 gene:c.3099_3103delGTTTG mutation of exon 17and c3817 3818insTGA mutation of exon 22;novel compound heterozygous mutations in the SPG11 gene in the third family were detected as follows:c.6194C ＞G mutation of exon 32 and c.5121+1C＞T splicing mutation ofintro 29.Conclusions Four novel mutations in SPG11 gene and one known mutation in A TL1 gene are found,which enriches the known HSP mutation types.Targeted gene capture is an efficient and rapid tool for identifying the causation of some complex and genetically heterogeneous neurodegenerative diseases.

Mutation analysis of SPAST, ATL1, and REEP1 in Korean Patients with Hereditary Spastic Paraplegia

BACKGROUND AND PURPOSE: Hereditary spastic paraplegia (HSP) is a genetically heterogeneous group of neurodegenerative disorders that are characterized by progressive spasticity and weakness of the lower limbs. Mutations in the spastin gene (SPAST) are the most common causes of HSP, accounting for 40-67% of autosomal dominant HSP (AD-HSP) and 12-18% of sporadic cases. Mutations in the atlastin-1 gene (ATL1) and receptor expression-enhancing protein 1 gene (REEP1) are the second and third most common causes of AD-HSP, respectively. METHODS: Direct sequence analysis was used to screen mutations in SPAST, ATL1, and REEP1 in 27 unrelated Korean patients with pure and complicated HSP. Multiplex ligation-dependent probe amplification was also performed to detect copy-number variations of the three genes. RESULTS: Ten different SPAST mutations were identified in 11 probands, of which the following 6 were novel: c.760A>T, c.131C>A, c.1351_1353delAGA, c.376_377dupTA, c.1114A>G, and c.1372A>C. Most patients with SPAST mutations had AD-HSP (10/11, 91%), and the frequency of SPAST mutations accounted for 66.7% (10/15) of the AD-HSP patients. No significant correlation was found between the presence of the SPAST mutation and any of the various clinical parameters of pure HSP. No ATL1 and REEP1 mutations were detected. CONCLUSIONS: We conclude that SPAST mutations are responsible for most Korean cases of genetically confirmed AD-HSP. Our observation of the absence of ATL1 and REEP1 mutations needs to be confirmed in larger series.