HSP Patients Research Articles

AB0013 Lack of Association between IL6 Gene and Henoch-SchÖNlein Purpura

BackgroundHenoch-Schönlein purpura (HSP) is the most common type of primary small-sized blood vessel vasculitis in children and a rare entity in adults [1]. Although the etiology of HSP remains unknown,...

Hereditary spastic paraparesis in adults. A clinical and genetic perspective from Tuscany

ObjectiveHereditary spastic paraparesis or paraplegias (HSPs) are a group of neurogenetic conditions with prominent involvement of the pyramidal tracts. Aim of this study is the clinical and molecular characterization of a cohort of patients with HSP. Moreover, we aim to study the minimum prevalence of HSP in our area and to propose a schematic diagnostic approach to HSP patients based on the available data from the literature. MethodsRetrospective/perspective study on the subjects with clinical signs and symptoms indicative of pure or complicated HSP, in whom other possible diagnosis were excluded by appropriate neuroradiological, neurophysiologic and laboratory studies, who have been evaluated by the Neurogenetic Service of our Clinic in last two years (2011-2012). Results45 patients were identified. The minimum prevalence of HSP in our area was of about 2.17-3.43/100,000. The SF-36 (quality of life) and SPRS (disease progression) scores were inversely related; the time-saving, four-stage scale of motor disability could predict the SPRS scores with a high statistical significance, and we encourage its use in HSP. Our study confirms SPG4 as the major cause of HSP. All SPG4 patients had a pure HSP phenotype, and the dominant inheritance was evident in the great majority of these subjects. SPG7 was the second genetic cause. Other genotypes were rarer (SPG10, SPG11, SPG17). ConclusionExact molecular diagnosis will allow a more accurate patient counseling and, hopefully, will lead to specific, targeted, therapeutic options for these chronic, still incurable diseases.

Apoptosis of human umbilical vein endothelial cells (HUVEC) induced by IgA1 isolated from Henoch-Schonlein purpura children

It had been shown that apoptosis of vascular endothelial cells played an important role in the pathogenesis of HSP. The present study was designed to investigate the apoptosis of vascular endothelial cells induced by isolated IgA1 from sera of HSP patients. HUVEC were cultured in 3 different types of media with IgA1 from HSP patients, normal healthy children and simply medium (blank control). Serum IgA1 was purified by jacalin affinity chromatography. The rates of apoptosis in HUVEC incubated with IgA1 were determined by the TUNEL method and flow cytometry, respectively. The expression of bax/bcl-2 and p53 was detected with the methods of Real-time PCR and Westernblot, respectively. The results showed that the apoptosis rate of HUVEC by IgA1 isolated from HSP patients was higher than that the normal controls (14.77±2.23% vs 9.97±1.48%) and blank controls (14.77±2.23% vs 2.25±0.77%) (P <0.01). Moreover the rate of HUVEC by IgA1 from normal healthy children was higher than the blank controls (9.97±1.48% vs 2.25±0.77%) (P <0.01). In addition, the bax and P53 expression were up-regulated and the Bcl-2 expression was down-regulated in HUVEC co-cultured with IgA1 isolated from HSP patients for 24 hours. These findings suggested that IgA1 from HSP patients could induce the apoptosis of HUVEC, which might be related to the vascular endothelial injury of HSP.

AB0039 TH17 cells are effective in defining the severity of HSP nephritis

BackgroundHenoch-Schönlein Purpura (HSP) is the most frequent vasculitis of childhood and mainly affects vessels of the skin, gastrointestinal system and kidneys. Kidney involvement is an important factor for morbidity and...

A patient-derived stem cell model of hereditary spastic paraplegia with SPAST mutations

SUMMARYHereditary spastic paraplegia (HSP) leads to progressive gait disturbances with lower limb muscle weakness and spasticity. Mutations in SPAST are a major cause of adult-onset, autosomal-dominant HSP. Spastin, the protein encoded by SPAST, is a microtubule-severing protein that is enriched in the distal axon of corticospinal motor neurons, which degenerate in HSP patients. Animal and cell models have identified functions of spastin and mutated spastin but these models lack the gene dosage, mutation variability and genetic background that characterize patients with the disease. In this study, this genetic variability is encompassed by comparing neural progenitor cells derived from biopsies of the olfactory mucosa from healthy controls with similar cells from HSP patients with SPAST mutations, in order to identify cell functions altered in HSP. Patient-derived cells were similar to control-derived cells in proliferation and multiple metabolic functions but had major dysregulation of gene expression, with 57% of all mRNA transcripts affected, including many associated with microtubule dynamics. Compared to control cells, patient-derived cells had 50% spastin, 50% acetylated α-tubulin and 150% stathmin, a microtubule-destabilizing enzyme. Patient-derived cells were smaller than control cells. They had altered intracellular distributions of peroxisomes and mitochondria and they had slower moving peroxisomes. These results suggest that patient-derived cells might compensate for reduced spastin, but their increased stathmin expression reduced stabilized microtubules and altered organelle trafficking. Sub-nanomolar concentrations of the microtubule-binding drugs, paclitaxel and vinblastine, increased acetylated α-tubulin levels in patient cells to control levels, indicating the utility of this cell model for screening other candidate compounds for drug therapies.

Functional MRI of the cortical sensorimotor system in patients with hereditary spastic paraplegia

The study aimed to use functional magnetic resonance imaging to ascertain changes in sensorimotor system function in patients with hereditary spastic paraplegia and to correlate it with severity of spasticity and paresis. Tartu University Hospital, Tartu, Estonia. Nine patients with autosomal-dominant pure HSP and 14 age- and sex-matched healthy controls were investigated with a 1.5T fMRI scanner during flexion/extension of the right-hand fingers and right ankle. Images were analysed with a general linear model and Statistical Parametrical Mapping software. Highest Z-scores were identified from probability maps, and weighted laterality indices were calculated using combined bootstrap/histogram analysis; these were correlated with clinical severity of spasticity and paresis. During hand movements, clusters located in contralateral primary sensorimotor and premotor areas activated in both controls and patients. Bilateral activation occurred in the supplementary motor area, parietal operculum and cerebellum (predominantly ipsilateral). During the ankle task, bilateral activation was noted in the primary sensorimotor area, supplementary motor area and cerebellum. Activation clusters in HSP patients were smaller than those in controls in the sensorimotor area, especially during the ankle task, and more pronounced ipsilaterally in cerebellum both during hand and ankle motor tasks. Spasticity was significantly associated with contralateral activation in the sensory area and correlated negatively with the highest Z-scores in Brodmann areas 1-2-3 and 4. Our results suggest changes in cortical sensorimotor network function in patients with HSP compared with healthy subjects. Lower activation in patients might reflect damage to the corticospinal tract, be influenced by compensatory mechanisms, and/or be a reflection of neurorehabilitation.

C1GALT1 polymorphisms are associated with Henoch–Schönlein purpura nephritis

Henoch-Schönlein purpura nephritis (HSPN) is the most serious long-term complication of Henoch-Schönlein purpura and aberrant galactosylation of IgA1 plays a role in its development. However, the precise role of genetic factors contributing to the abnormal IgA1 galactosylation remains unknown. In order to examine the effects of C1GALT1 gene encoding core 1 β1,3-galactosyltransferase, an important role in the β1,3 glycosylation of IgA1, on HSPN susceptibility, we conducted a case-control association genetic study in 269 HSP and 61 HSPN in China. Five tagging SNPs, SNP1(-734 C/T), SNP4(-465A/G), SNP6(-330 G/T), SNP7(-292 C/-), and SNP8(1365 G/A) in C1GALT1 were studied using single-locus and haplotype-based multilocus analysis. Our results demonstrated that 1365 G allele frequency was significantly higher in HSPN patients than in HSP patients without nephritis (0.459 vs 0.331, p = 0.0008, adjusted p' = 0.004) with an odds ratio (OR) = 1.716, 95%CI 1.151-2.560). The GG genotype of 1,365 G/A was significantly different in HSP without nephritis and HSPN (p = 0.008, adjusted p'' = 0.04). We did not observe statistically significant differences in haplotype frequencies between HSPN and HSP patients. In conclusion, our study suggested that the 1365 G/A polymorphism of the C1GALT1 gene may contribute to HSPN development.

Analysis of 100 HSP Exomes and Characterization of Mutations in Known Autosomal Dominant Genes (P05.166)

Objective: Comprehensive screening of all known autosomal dominant HSP genes in a large cohort of patients. Background Hereditary spastic paraplegias comprise a group of clinically and genetically heterogeneous neurodegenerative disorders that share the common clinical feature of lower limb spastic paraplegia. Ten genes causing autosomal dominant HSP are known to date, together explaining about 60% of cases. Knowledge about frequency of HSP subtypes and genotype-phenotype correlation is limited by the fact that most screenings so far are biased due to phenotypic pre-selection of the study cohort or inhomogeneous a priori genetic diagnostic testing. Design/Methods: We have screened a large cohort of autosomal dominant HSP patients for mutations in the most common HSP genes, including SPG3, SPG4 and SPG31. Mutation negative samples (n=100) were examined by whole exome sequencing. Sanger sequencing and segregation analysis were used to validate results. Results: More than hundred rare conserved coding variants were identified in known autosomal dominant HSP genes. The variants were further evaluated in regard to functional impact and segregation. Mutations in several rare autosomal dominant HSP genes as well as unusual phenotypes in patients with mutations in known HSP genes are described, including mutations in KIF5A, RTN2 and SETX. Conclusions: We have developed an advanced pipeline for analysis of known autosomal dominant HSP genes using whole exome sequencing. A comprehensive overview over mutational and phenotypic spectrum of autosomal dominant HSP is given. About 30% of autosomal dominant HSP cases cannot be explained by mutations in currently known autosomal dominant HSP genes, indicating the need for further studies to discover new HSP disease genes. Supported by: The National Institute of Health (grants 1R01NS072248-01 and 1 R01 NS352767) and the German HSP-Selbsthilfegruppe e.V. Disclosure: Dr. Schuele has nothing to disclose. Dr. Gonzalez has nothing to disclose. Dr. Powell has nothing to disclose. Dr. Klimpe has nothing to disclose. Dr. Klebe has nothing to disclose. Dr. Otto has nothing to disclose. Dr. Klopstock has received personal compensation for activities with Gerson Lehrman Group as a consultant. Dr. Speziani has nothing to disclose. Dr. Young has nothing to disclose. Dr. Schoels has received research support from Deutsche Forschungsgemeinschaft, German Research Council, Leukonet, mitoNET, EUROSPA, RISCA, and the HSP-Selbsthilfegruppe Deutschland eV. Dr. Zuchner has received license fee payments from Athena Diagnostics.

Stem Cell Gene Mutation and MTHFR C677T Variants Increased“Risk” in Acute Myeloid Leukemia Patients

1.1. Aim To assess the prevalence of MEFV mutations in Caucasian children with Henoch-Schi?½nlein purpura (HSP) and to investigate a possible association between the two diseases in a population with presumably low incidence of familial Mediterranean fever (FMF). 1.2. Methods One hundred and two children diagnosed with HSP between January 2002 and February 2009 were included in the study. Clinical data were obtained from medical charts. Children were tested for 6 common MEFV mutations. To find out the carrier rate of mutations in MEFV gene in Slovenian population a control group of 105 apparently healthy adults was screened. 1.3. Results Heterozygous MEFV gene mutations were found in 6% of children with HSP and in 7% of apparently healthy adults. The most common allelic variants found in both groups were as follows: V726A in 5 participants, K695R in 4 participants, E148Q in 3 participants and M694V in 1 participant. No significant differences in HSP clinical picture between the group of children with and without mutations in MEFV were found. HSP patients with MEFV mutations were younger than patients without MEFV mutations. 1.4. Conclusion In contrast to previously published researches, MEFV mutations are not more frequent in children with HSP comparing to apparently healthy population and have no influence on the clinical presentation of HSP.

Structural and metabolic damage in brains of patients with SPG11-related spastic paraplegia as detected by quantitative MRI

The goal of this work was to assess brain structural and metabolic abnormalities of subjects with SPG11 and their relevance to clinical disability by using quantitative magnetic resonance (MR) metrics. Autosomal recessive hereditary spastic paraplegia (AR-HSP) with thin corpus callosum and cognitive decline is a complex neurological disorder caused by mutations in the SPG11 gene in most cases. Little is known about the process leading to corticospinal and white matter degeneration. We performed conventional MRI/MR spectroscopic imaging ((1)H-MRSI) examinations in 10 HSP patients carrying an SPG11 mutation and in 10 demographically matched healthy controls (HC). We measured in each subject cerebral white matter hyperintensities (WMHs), normalized global and cortical brain volumes, and (1)H-MRSI-derived central brain levels of N-acetylaspartate (NAA) and choline (Cho) normalized to creatine (Cr). Clinical disability was assessed according to patients' autonomy in walking. Conventional MRI showed WMHs in all patients. Global brain volumes were lower in patients than in HC (p < 0.001). Decreased values were diffusely found also in cortical regions (p < 0.01). On (1)H-MRSI, NAA/Cr values were lower in SPG11 patients than in HC (p = 0.002). Cho/Cr values did not differ between patients and HC. Cerebral volume decreases and NAA/Cr in the corona radiata correlated closely with increasing disability scores (p < 0.05). Quantitative MR measures propose that widespread structural and metabolic brain damage occur in SPG11 patients. The correlation of these MR metrics with measures of patients' disease severity suggests that they might represent adequate surrogate markers of disease outcome.

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.

High Prevalence of Sinusitis in Children with Henoch-Schönlein Purpura

We evaluated the prevalence and the types of infectious foci in oral as well as ear, nose, and throat diseases, and we examined incidence of renal involvement with active treatment for focal infection in children with Henoch-Schönlein Purpura. A total of 96 children who presented at Aichi Children's Health and Medical Center and were diagnosed as having HSP were evaluated for infectious foci in the ear, nose, throat, and oral cavities. Seventy-one of 96 children (74.0%) had some type of infectious lesion, such as sinusitis or tonsillitis, and the prevalence of sinusitis was the highest (51 cases, 53.7%). In 44 HSP patients without renal involvement at the first examination, the incidence of nephritis was lower (13.6%) than in previous reports (17–54%) due to our aggressive intervention for infectious foci.

Study the allergic purpura association witll Helicobacter pylori infection

Objective To study the relationship between allergic purpura and Helicobacter pylori infection and direct therapy.Methods From December 2007 to December 2009 120 cases at the undergraduate treated of HSP patients had HP-IgG antibody been tested,and serum Hp-IgG-positive patients were randomly divided into two groups,A group on the basis of conventional therapy to give anti-Hp therapy,B group only conventional treatment,cured patients were followed up for 6 months.Results 120 case with The percentage of HpIgG-positive is 67.5% ,Hp-IgG-positive HSP patients given conventional therapy on the basis of anti-Hp therapy,there are high efficiency and low recurrence rate.Conclusion Helicobacter pylori infection in the pathogenesis of allergic purpura is one important factor,anti-HP therapy is conducive to the rehabilitation of HSP. Key words: Helicobacter pylori infection; Allergic purpura

Whole brain‐based analysis of regional white matter tract alterations in rare motor neuron diseases by diffusion tensor imaging

Different motor neuron disorders (MNDs) are mainly defined by the clinical presentation based on the predominance of upper or lower motor neuron impairment and the course of the disease. Magnetic resonance imaging (MRI) mostly serves as a tool to exclude other pathologies, but novel approaches such as diffusion tensor imaging (DTI) have begun to add information on the underlying pathophysiological processes of these disorders in vivo. The present study was designed to investigate three different rare MNDs, i.e., primary lateral sclerosis (PLS, N = 25), hereditary spastic paraparesis (HSP, N = 24), and X-linked spinobulbar muscular atrophy (X-SBMA, N = 20), by use of whole-brain-based DTI analysis in comparison with matched controls. This analysis of white matter (WM) impairment revealed widespread and characteristic patterns of alterations within the motor system with a predominant deterioration of the corticospinal tract (CST) in HSP and PLS patients according to the clinical presentation and also in patients with X-SBMA to a lesser degree, but also WM changes in projections to the limbic system and within distinct areas of the corpus callosum (CC), the latter both for HSP and PLS. In summary, DTI was able to define a characteristic WM pathoanatomy in motor and extra-motor brain areas, such as the CC and the limbic projectional system, for different MNDs via whole brain-based FA assessment and quantitative fiber tracking. Future advanced MRI-based investigations might help to provide a fingerprint-identification of MNDs.

Unique spectrum of spast variants in Estonian HSP patients: presence of benign missense changes but lack of exonic rearrangements

Unique spectrum of spast variants in Estonian HSP patients: presence of benign missense changes but lack of exonic rearrangements

Functional evaluation of paraplegin mutations by a yeast complementation assay

An autosomal recessive form of hereditary spastic paraplegia (AR-HSP) is primarily caused by mutations in the SPG7 gene, which codes for paraplegin, a subunit of the hetero-oligomeric m-AAA protease in mitochondria. In the current study, sequencing of the SPG7 gene in the genomic DNA of 25 unrelated HSP individuals/families led to the identification of two HSP patients with compound heterozygous mutations (p.G349S/p.W583C and p.A510V/p.N739KfsX741) in the coding sequence of the SPG7 gene. We used a yeast complementation assay to evaluate the functional consequence of novel SPG7 sequence variants detected in the HSP patients. We assessed the proteolytic activity of hetero-oligomeric m-AAA proteases composed of paraplegin variant(s) and proteolytically inactive forms of AFG3L2 (AFG3L2(E575Q) or AFG3L2(K354A)) upon expression in m-AAA protease-deficient yeast cells. We demonstrate that the newly identified paraplegin variants perturb the proteolytic function of hetero-oligomeric m-AAA protease. Moreover, commonly occurring silent polymorphisms such as p.T503A and p.R688Q could be distinguished from mutations (p.G349S, p.W583C, p.A510V, and p.N739KfsX741) in our HSP cohort. The yeast complementation assay thus can serve as a reliable system to distinguish a pathogenic mutation from a silent polymorphism for any novel SPG7 sequence variant, which will facilitate the interpretation of genetic data for SPG7.

Japan spastic paraplegia research consortium (JASPAC)

Japan Spastic Paraplegia Research Consortium (JASPAC), a nationwide clinical and genetic survey of patients with HSP in Japan, was started from 2006 as a project of the Research Committee for Ataxic Diseases of the Ministry of Health, Labor and Welfare, Japan. To date (October 4, 2010), 321 index patients with HSP have been registered from 40 prefectures in Japan. We are now performing molecular testing for the HSP patients using direct sequencing (SPG4, SPG31, and ARSACS), comparative genomic hybridization (CGH) array (SPG1/2/3A/4/5/6/7/8/10/11/13/15/17/20/21/31/33/39/42/ABCD1/alsin/SACS), and resequencing microarray (SPG1/2/3A/4/5/6/7/8/10/11/13/17/20/21/31/33/ABCD1). In 144 Japanese ADHSP families, SPG4 was the most common form, accounting for 47%, followed by SPG31 (4%), SPG3A (3%), SPG8 (1%), and SPG10 (1%). The results of molecular testing will be applicable to patients in terms of improved positive diagnosis, follow-up, and genetic counseling. Since approximately 40% of ADHSP remain unknown, we will perform high-throughput linkage analyses using SNP HiTLink (SNP High Throughput Linkage analysis system) for the identification of loci for disease-associated genes. Meanwhile, preliminary data showed that SPG11 and ARSACS were common in Japanese ARHSP families. JASPAC will contribute to elucidate the spectrum of clinical features and mutations, genotype/phenotype correlations, pathophisiology in various HSP phenotypes.

Bladder dysfunction in hereditary spastic paraplegia: what to expect?

BackgroundHereditary spastic paraplegia (HSP) comprises a group of rare neurodegenerative disorders characterised by progressive spasticity and hyperreflexia of the legs. Neurogenic bladder dysfunction is a well recognised problem in patients...

115. Health-related quality of life decreases with disease severity in German HSP patients

115. Health-related quality of life decreases with disease severity in German HSP patients

Screening of hereditary spastic paraplegia patients for alterations at NIPA1 mutational hotspots

Mutations in NIPA1 cause hereditary spastic paraplegia type 6 (SPG6 HSP). Sequencing of the whole gene has revealed alterations of either of two nucleotides in eight of nine SPG6 HSP families reported to date. By analysing CpG methylation, we provide a mechanistic explanation for a mutational hotspot to underlie frequent alteration of one of these nucleotides. We also developed PCR RFLP assays to detect recurrent NIPA1 changes and screened 101 independent HSP patients, including 45 index patients of autosomal dominant HSP families. Our negative finding in this cohort for which several other causes of HSP had been excluded suggests NIPA1 alterations at mutational hotspots to be less frequent than previously thought. Nevertheless, the assays introduced represent a valid pre-screen easily implementable in the molecular diagnosis of HSP.