Novel mutation of SPG4 gene in a Chinese family with hereditary spastic paraplegia:A case report

BACKGROUND Hereditary spastic paraplegia(HSP)is a group of neurogenetic diseases of the corticospinal tract,accompanied by distinct spasticity and weakness of the lower extremities.Mutations in the spastic paraplegia type 4(SPG4)gene,encoding the spastin protein,are the major cause of the disease.This study reported a Chinese family with HSP caused by a novel mutation of the SPG4 gene.CASE SUMMARY A 44-year-old male was admitted to our hospital for long-term right lower limb weakness,leg stiffness,and unstable walking.His symptoms gradually worsened,while no obvious muscle atrophy in the lower limbs was found.Neurological examinations revealed that the muscle strength of the lower limbs was normal,and knee reflex hyperreflexia and bilateral positive Babinski signs were detected.Members of his family also had the same symptoms.Using mutation analysis,a novel heterozygous duplication mutation,c.1053dupA,p.(Gln352Thrfs*15),was identified in the SPG4 gene in this family.CONCLUSION A Chinese family with HSP had a novel mutation of the SPG4 gene,which is autosomal dominant and inherited as pure HSP.The age of onset,sex distribution,and clinical manifestations of all existing living patients in this family were analyzed.The findings may extend the current knowledge on the existing mutations in the SPG4 gene.

Proteolipid protein 1 gene sequencing of hereditary spastic paraplegia

PCR amplification and sequencing of whole blood DNA from an individual with hereditary spastic paraplegia, as well as family members, revealed a fragment of proteolipid protein 1 （PLP1） gene exon 1, which excluded the possibility of isomer 1 expression for this family. The fragment sequence of exon 3 and exon 5 was consistent with the proteolipid protein 1 sequence at NCBI. In the proband samples, a PLP1 point mutation in exon 4 was detected at the basic group of position 844, T→C, phenylalanine→leucine. In proband samples from a male cousin, the basic group at position 844 was C, but gene sequencing signals revealed mixed signals of T and C, indicating possible mutation at this locus. Results demonstrated that changes in PLP1 exon 4 amino acids were associated with onset of hereditary spastic paraplegia.

Verification of the Validity of the NPT Treatment in Hereditary Spastic Paraplegia: An Investigation Performed by Application of Random Matrix Theory

We have applied the Random Matrix Theory in order to examine the validity of the NPT treatment in HSP. We have investigated the pathology examining the sEMG recorded signal for about eight minutes. We have performed standard electromyographic investigations as well as we have applied the RMT method of analysis. We have investigated the sEMG signals before and after the NPT treatment. The application of a so robust method as the RMT evidences that the NPT treatment was able to induce a net improvement of the disease respect to the pathological status before NPT.

A novel candidate locus on chromosome 11p14.1-p11.2 for autosomal dominant hereditary spastic paraplegia

Background Hereditary spastic paraplegia （HSP） is a group of inherited neurodegenerative disorders with the shared characteristics of slowly progressive spasticity and weakness of the lower limbs. Thirteen loci for autosomal dominant HSP have been mapped. Methods A Chinese family with HSP was found in the Shandong province and Inner Mongolia Autonomous Region of China and genomic DNA of all 19 family members was isolated. After exclusion of known autosomal dominant loci, a genome wide scan and linkage analysis were performed. Results The known autosomal dominant loci of SPG3A, SPG4, SPG6, SPG8, SPG9, SPG10, SPG12, SPG13, SPG17, SPG19, SPG29, SPG31 and SPG33 were excluded by linkage analysis. The results of a genome wide scan demonstrated candidate linkage to a locus on chromosome 11 p14.1-p11.2, over an 18.88 cM interval between markers D11 S1324 and D11 S1933. A maximal, two point LOD score of 2.36 for marker D11S935 at a recombination fraction （e） of 0 and a multipoint LOD score of 2.36 for markers D11S1776, D11S1751, D11S1392, D11S4203, D11S935, D11S4083, and D11S4148 at θ=0, suggest linkage to this locus. Conclusion The HSP neuropathy in this family may represent a novel genetic entity, which will facilitate discovery of this causative gene.

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

Hereditary spastic paraplegia （HSP） （MIM#182600） is a group of heterogeneous neurodegenerative disorders, with 35 underlying loci recognized by the HGNC （HUGO Gene Nomenclature Committee; http：//www.gene.ucl.ac.uk/nomenclature/） and 10 identified genes （ http ： //www. gene. ucl. ac. uk/cgi-bin/nomenc lature/ searchgenes.pl plus NIPA1, last search July 2006）. The mode of inheritance may be autosomal dominant, autosomal recessive or X-linked. Among these, autosomal dominant spastic paraplegia （AD-HSP） is the most common type, accounting for 70%-80% of all families. The disease is characterized by lower limb spasticity, hyperreflexia, progressive spastic gait and an extensor plantar response. Pes cavus is one of the commonly reported foot phenotypes.

Clinical features of hereditary spastic paraplegia with thin corpus callosum: report of 5 Chinese cases

Background Hereditary spastic paraplegia is a clinically and genetically heterogeneous group of neurodegenerative disorders of the motor system, characterized by slowly progressive spasticity and weakness of the lower extremities. This study was conducted to investigate the clinical features of hereditary spastic paraplegia with thin corpus callosum (HSP-TCC). Methods Clinical data from five patients and thirty-five previously published case reports of HSP-TCC were analyzed retrospectively. Results Most patients were adolescents at the onset of the disease, presenting with spastic paraparesis of the lower limbs and mental impairment. Some patients also had other clinical features, including spasticity of the upper limbs, cerebellar ataxia, and sensory disturbances. Cranial MRIs of the five patients revealed an extremely thin corpus callosum, sometimes with widened cerebral sulci and ventricles, as well as with cerebellar and cerebral atrophy. Conclusion The main clinical features of HSP-TCC include slowly progressive spastic paraplegia, mental impairment during the second decade of life, and an extremely thin corpus callosum as shown on cranial MRIs.

Clinical features and genetic spectrum in Chinese patients with recessive hereditary spastic paraplegia

Background:Although many causative genes of hereditary spastic paraplegia(HSP)have been uncovered in recent years,there are still approximately 50% of HSP patients without genetically diagnosis,especially in autosomal recessive(AR)HSP patients.Rare studies have been performed to determine the genetic spectrum and clinical profiles of recessive HSP patients in the Chinese population.Methods:In this study,we investigated 24 Chinese index AR/sporadic patients by targeted next-generation sequencing(NGS),Sanger sequencing and multiplex ligation-dependent probe amplification(MLPA).Further functional studies were performed to identify pathogenicity of those uncertain significance variants.Results:We identified 11 mutations in HSP related genes including 7 novel mutations,including two(p.V1979_L1980delinsX,p.F2343 fs)in SPG11,two(p.T55 M,p.S308 T)in AP5Z1,one(p.S242N)in ALDH18A1,one(p.D597fs)in GBA2,and one(p.Q486X)in ATP13A2 in 8 index patients and their family members.Mutations in ALDH18A1,AP5Z1,CAPN1 and ATP13A2 genes were firstly reported in the Chinese population.Furthermore,the clinical phenotypes of the patients carrying mutations were described in detail.The mutation(p.S242 N)in ALDH18A1 decreased enzyme activity of P5CS and mutations(p.T55 M,p.S308 T)in AP5Z1 induced lysosomal dysfunction.Conclusion:Our results expanded the genetic spectrum and clinical profiles of AR-HSP patients and further demonstrated the efficiency and reliability of targeted NGS diagnosing suspected HSP patients.

Novel Mutations in Endoplasmic Reticulum Lipid Raft-associated Protein 2 Gene Cause Pure Hereditary Spastic Paraplegia Type 18

Hereditary spastic paraplegia type 18 （HSP18） is a complicated form ofautosomal recessive HSP characterized by progressive weakness and spasticity of the lower extremities,dysarthria,and cognitive decline. In the year 2011,HSP18,also known as Spastic Paraplegia 18 （SPG18）,was firstly identified due to a candidate gene endoplasmic reticulum lipid raft-associated protein 2 （ERLIN2） on chromosome 8pl 1.2 in one Saudis family.During the past 5 years,another two families with SPG18 due to ERLIN2 mutations have been reported presenting with complicated phenotype. Here,we reported a patient born in a nonconsanguineous family who possessed an autosomal recessive pure form of HSP owing to novel mutations in ERLIN2.Patient was characterized by late-onset spasticity of lower extremities without significant speech involvement or cognitive disability.

Hereditary spastic paraplegia type 56:what a mouse can tell-a narrative review

Hereditary spastic paraplegia type 56(SPG56-HSP)is a rare autosomal recessive disorder caused by loss of function mutations in CYP2U1,leading to an early-onset limbs spasticity,often complicated by additional neurological or extra-neurological manifestations.Given its low prevalence,the molecular bases underlying SPG56-HSP are still poorly understood,and effective treatment options are still lacking.Recently,through the generation and characterization of the SPG56-HSP mouse model,we were able to take few important steps forward in expanding our knowledge of the molecular background underlying this complex disease.Leveraging the Cyp2u1-/-mouse model we were able to identify several new diagnostics biomarkers(vitamin B2,coenzyme Q,neopterin,and interferon-alpha),as well as to highlight the key role played by the folate pathway in SPG56-HSP pathogenesis,providing a potential treatment option.In this review,we discuss the major role played by the Cyp2u1-/-model in dissecting clinical and biological aspects of the disease,opening the way to a series of new research paths ranging from clinical trials,biomarker testing,and to the expansion of the underlying genetic and molecular,emphasizing how basic mouse model characterization could contribute to advance research in the context of rare disorders.

Receptor expression-enhancing protein 1 gene （SPG31） mutations are rare in Chinese Han patients with hereditary spastic paraplegia

Hereditary spastic paraplegia （HSP）, also known as familial spastic paraparesis or Stumpell-Lorrain disease, is a large group of inherited, heterogeneous neurologic disorders caused by the degeneration of corticospinal axons. The prevalence is estimated at 3-10 cases per 100000 people in Europe, and is uncertain in other continents. Most patients have the same core features, which are characterized by spastic gait, lower limb hypertonicity, hyperreflexia, extensor-plantar responses, muscle weakness, and occasionally decreased vibration sense at the ankles, bladder dysfunction, pes cavus, or scoliosis.

Spastin and alsin protein interactome analyses begin to reveal key canonical pathways and suggest novel druggable targets

Developing effective and long-term treatment strategies for rare and complex neurodegenerative diseases is challenging. One of the major roadblocks is the extensive heterogeneity among patients. This hinders understanding the underlying disease-causing mechanisms and building solutions that have implications for a broad spectrum of patients. One potential solution is to develop personalized medicine approaches based on strategies that target the most prevalent cellular events that are perturbed in patients. Especially in patients with a known genetic mutation, it may be possible to understand how these mutations contribute to problems that lead to neurodegeneration. Protein–protein interaction analyses offer great advantages for revealing how proteins interact, which cellular events are primarily involved in these interactions, and how they become affected when key genes are mutated in patients. This line of investigation also suggests novel druggable targets for patients with different mutations. Here, we focus on alsin and spastin, two proteins that are identified as “causative” for amyotrophic lateral sclerosis and hereditary spastic paraplegia, respectively, when mutated. Our review analyzes the protein interactome for alsin and spastin, the canonical pathways that are primarily important for each protein domain, as well as compounds that are either Food and Drug Administration–approved or are in active clinical trials concerning the affected cellular pathways. This line of research begins to pave the way for personalized medicine approaches that are desperately needed for rare neurodegenerative diseases that are complex and heterogeneous.

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 genotypephenotype 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.

Characterization of the Drosophila Atlastin Interactome Reveals VCP as a Functionally Related Interactor

At least 25 genes,many involved in trafficking,localisation or shaping of membrane organelles,have been identified as causative genes for the neurodegenerative disorder hereditary spastic paraplegia（HSP）.One of the most commonly mutated HSP genes,atlastin-1, encodes a dynamin-like GTPase that mediates homotypic fusion of endoplasmic reticulum（ER） membranes.However,the molecular mechanisms of atlastin-1-related membrane fusion and axonopathy remain unclear.To better understand its mode of action,we used affinity purification coupled with mass spectrometry to identify protein interactors of atlastin in Drosophila.Analysis of 72 identified proteins revealed that the atlastin interactome contains many proteins involved in protein processing and transport,in addition to proteins with roles in mRNA binding,metabolism and mitochondrial proteins.The highest confidence interactor from mass spectrometry analysis, the ubiquitin-selective AAA-ATPase valosin-containing protein（VCP）,was validated as an atlastin-interacting protein,and VCP and atlastin showed overlapping subcellular distributions.Furthermore,VCP acted as a genetic modifier of atlastin：loss of VCP partially suppressed an eye phenotype caused by atlastin overexpression,whereas overexpression of VCP enhanced this phenotype.These interactions between atlastin and VCP suggest a functional relationship between these two proteins,and point to potential shared mechanisms between HSP and other forms of neurodegeneration.