HSP Patients Research Articles

Investigating the comparative effect of vitamin D level with the type of complications in Henoch Schönlein purpura and Kawasaki disease

Introduction and objectivesHenoch Schönlein purpura (HSP) and Kawasaki disease (KD) are two main inflammatory diseases among childhood vasculitis. Considering the anti-inflammatory effects of 25-hydroxyvitamin D3, we decided to investigate the association of serum 25-hydroxy vitamin D3 level with the type and severity of these conditions. Materials and methodsThe present study was performed as a historical cohort of 254 affected children with KD and HSP vasculitis. The required data were extracted, using a researcher-made questionnaire from patients’ electronic file, and then they were analyzed after collecting information of the patients. ResultsIn HSP group, 54% of participants were boys. Similarly, in KD group, boys were more affected than girls. The comparative 25-hydroxyvitamin vitamin D3 level in HSP patients with and without renal involvement (P=0.02), hematuria (P=0.14), and in two groups with and without heart disease, and also with and without coronary artery dilatation in KD patients (P<0.001) were significant. Discussion and conclusionsThe findings showed that insufficient level of vitamin D3 were significantly associated with the exacerbation of complications of both diseases, and therefore it seems that vitamin D deficiency can be an effective predictive factor of severity in HSP and KD patients.

Associations of MEFV gene variants, IL-33, and sST2 with the risk of Henoch-Schönlein purpura in children

ObjectiveHenoch-Schönlein purpura (HSP) is the most common systemic vasculitis in children. HSP is a multifactorial inflammatory disease, but its pathogenesis is still unclear. The pathogenicity of familial Mediterranean fever gene (MEFV) variants in HSP remains controversial. The objective of this study was to evaluate relationships between MEFV variants and susceptibility to HSP and their associations with clinical outcomes. We also investigated levels of IL-33 and soluble suppression of tumorigenicity 2 (sST2) in children with HSP and their clinical significance. MethodsWe selected 100 children with HSP as the case group. The control group consisted of 50 children who visited the hospital for physical health examinations. All subjects were screened for MEFV gene exon mutations, and levels of IL-33 and sST2 were measured. ResultsThe frequency of MEFV variants was significantly greater in HSP patients than in healthy controls. The variant with the highest frequency was E148Q. The frequency of the C allele of the MEFV variant E148Q was 32 % in HSP patients and 18 % in controls (P-adjust = 0.04). Patients with the MEFV E148Q variant had more frequent joint involvement and recurrent purpura and higher levels of IL-33 and C-reactive protein (CRP). Levels of IL-33 and sST2 in children with HSP were significantly higher than those in the control group, and the sST2/IL-33 ratio in children with HSP was unbalanced (P-adjust <0.05). Logistic regression analysis revealed the presence of E148Q and an unbalanced sST2/IL-33 ratio to be independent risk factors for HSP. ConclusionThe results of this study suggest that the MEFV variant E148Q is associated with HSP susceptibility in Chinese children and that carriers of the variant may have more severe clinical manifestations and greater inflammatory responses. E148Q and the sST2/IL-33 ratio may play important roles in the pathogenesis of HSP.

IL-4-secreting CD40L+ MAIT cells support antibody production in the peripheral blood of Heonch-Schönlein purpura patients.

Here, we explored the phenotype and function of MAIT cells in the peripheral blood of patients with HSP. Blood samples from HSP patients and HDs were assessed by flow cytometry and single-cell RNA sequencing to analyze the proportion, phenotype, and function of MAIT cells. Th-cytokines in the serum of HSP patients were analyzed by CBA. IgA in cocultured supernatant was detected by CBA to analyze antibody production by B cells. The percentage of MAIT cells in HSP patients was significantly reduced compared with that in HDs. Genes related to T cell activation and effector were up-regulated in HSP MAIT cells, indicating a more activated phenotype. In addition, HSP MAIT cells displayed a Th2-like profile with the capacity to produce more IL-4 and IL-5, and IL-4 was correlated with IgA levels in the serum of HSP patients. Furthermore, CD40L was up-regulated in HSP MAIT cells, and CD40L+ MAIT cells showed an increased ability to produce IL-4 and to enhance IgA production by B cells. Our data demonstrate that MAIT cells in HSP patients exhibit an activated phenotype. The enhanced IL-4 production and CD40L expression of MAIT cells in HSP patients could take part in the pathogenesis of HSP.

The therapeutic effects of physical treatment for patients with hereditary spastic paraplegia: a narrative review

BackgroundHereditary spastic paraplegia (HSP) encompass a variety of neurodegenerative disorders that are characterized by progressive deterioration of walking ability and a high risk for long-term disability. The management of problems associated with HSP, such as stiffness, deformity, muscle contractures, and cramping, requires strict adherence to recommended physiotherapy activity regimes. The aim of this paper is to conduct a critical narrative review of the available evidence focusing exclusively to the therapeutic advantages associated with various forms of physical therapy (PT) in the context of HSP, emphasizing the specific benefit of every distinct approach in relation to muscle relaxation, muscle strength, spasticity reduction, improvement of weakness, enhancement of balance, posture, walking ability, and overall quality of life.MethodsTo conduct a literature review, the databases PubMed, Scopus, and DOAJ (last access in June 2023) were searched.ResultsThe PubMed search returned a total of 230 articles, Scopus returned 218, and DOAJ returned no results. After screening, the final list included 7 papers on PT treatment for HSP patients.ConclusionElectrostimulation, magnetotherapy, hydrotherapy, PT, robot-assisted gait training, and balance rehabilitation have the potential to increase lower extremity strength and decrease spasticity in HSP patients.

Automated assessment of foot elevation in adults with hereditary spastic paraplegia using inertial measurements and machine learning

BackgroundHereditary spastic paraplegias (HSPs) cause characteristic gait impairment leading to an increased risk of stumbling or even falling. Biomechanically, gait deficits are characterized by reduced ranges of motion in lower body joints, limiting foot clearance and ankle range of motion. To date, there is no standardized approach to continuously and objectively track the degree of dysfunction in foot elevation since established clinical rating scales require an experienced investigator and are considered to be rather subjective. Therefore, digital disease-specific biomarkers for foot elevation are needed.MethodsThis study investigated the performance of machine learning classifiers for the automated detection and classification of reduced foot dorsiflexion and clearance using wearable sensors. Wearable inertial sensors were used to record gait patterns of 50 patients during standardized 4 times 10 m walking tests at the hospital. Three movement disorder specialists independently annotated symptom severity. The majority vote of these annotations and the wearable sensor data were used to train and evaluate machine learning classifiers in a nested cross-validation scheme.ResultsThe results showed that automated detection of reduced range of motion and foot clearance was possible with an accuracy of 87%. This accuracy is in the range of individual annotators, reaching an average accuracy of 88% compared to the ground truth majority vote. For classifying symptom severity, the algorithm reached an accuracy of 74%.ConclusionHere, we show that the present wearable gait analysis system is able to objectively assess foot elevation patterns in HSP. Future studies will aim to improve the granularity for continuous tracking of disease severity and monitoring therapy response of HSP patients in a real-world environment.

Stiffness changes in internal rotation muscles of the shoulder and its influence on hemiplegic shoulder pain.

Hemiplegic shoulder pain (HSP) is a common complication in patients with stroke. The pathogenesis of HSP is complex, and muscle hypertonia, especially the hypertonia of internal rotation muscles of the shoulder, may be one of the important causes of shoulder pain. However, the relationship between muscle stiffness and HSP has not been well studied. The purpose of this study is to explore the correlations between the stiffness of internal rotation muscles and clinical symptoms in patients with HSP. A total of 20 HSP patients and 20 healthy controls were recruited for this study. The stiffness of internal rotation muscles was quantified using shear wave elastography, and Young's modulus (YM) of the pectoralis major (PM), anterior deltoid (AD), teres major ™, and latissimus dorsi (LD) were measured. Muscle hypertonia and pain intensity were evaluated using the Modified Ashworth Scale (MAS) and Visual Analog Scale (VAS), respectively. The mobility of the shoulder was evaluated using the Neer score. The correlations between muscle stiffness and the clinical scales were analyzed. YM of internal rotation muscles on the paretic side was higher than that of the control group in the resting and passive stretching positions (P < 0.05). YM of internal rotation muscles on the paretic side during passive stretching was significantly higher than that at rest (P < 0.05). YM of PM, TM, and LD during passive stretching were correlated with MAS (P < 0.05). In addition, the YM of TM during passive stretching was positively correlated with VAS and negatively correlated with the Neer score (P < 0.05). Increased stiffness of PM, TM, and LD was observed in patients with HSP. The stiffness of TM was associated with pain intensity of the shoulder and shoulder mobility.

Proteome analysis reveals novel serum biomarkers for Henoch-Schönlein purpura in Chinese children

PurposeHenoch-Schönlein purpura (HSP) is diagnosed based on characteristic skin changes. This study aimed to identify the serum biomarkers of HSP in children. Experimental designWe performed proteomic analysis of serum samples from 38 paired pre- and posttherapy HSP patients and 22 healthy controls using a combination of magnetic bead-based weak cation exchange and MALDI-TOF MS. ClinProTools was used to screen the differential peaks. Then, LC–ESI–MS/MS was performed to identify the proteins. ELISA was used to verify the expression of whole protein in the serum of 92 HSP patients, 14 peptic ulcer disease (PUD) patients and 38 healthy controls, which were prospectively collected. Finally, logistic regression analysis was performed to analyze the diagnostic value of the above predictors and existing clinical indicators. ResultsSeven potential HSP serum biomarker peaks (m/z:1228.95, m/z:1781.22, m/z:1468.43, m/z:1619.53, m/z:1868.41, m/z:1694.05, m/z:1743.25) with higher expression in the pretherapy group and one peak (m/z:1947.41) with lower expression in the pretherapy group were all identified as peptide regions of albumin (ALB), complement C4-A precursor (C4A), tubulin beta chain (TUBB), isoform 1 of fibrinogen alpha chain (FGA), and ezrin (EZR). The expression of identified proteins was validated by ELISA. Multivariate logistic regression analysis showed that serum C4A EZR and ALB were independent risk factors for HSP, serum C4A and lgA were independent risk factors for HSPN, and serum D-dimer was an independent risk factor for abdominal HSP. Conclusions and clinical relevanceThese findings revealed the specific etiology of HSP from the perspective of serum proteomics. The identified proteins might serve as potential biomarkers for HSP and HSPN diagnoses. SignificanceHenoch-Schönlein purpura (HSP) is the most common systemic vasculitis in children, and its diagnosis depends primarily on characteristic skin changes. Early diagnosis of non-rash patients is difficult, especially for abdominal and renal types (Henoch-Schönlein purpura nephritis, HSPN). HSPN has poor outcomes, is diagnosed based on urinary protein and/or haematuria, and cannot be detected early in HSP. Patients with an earlier diagnosis of HSPN appear to have better renal outcomes. Our plasma proteomic analysis of HSP in children revealed that HSP patients could be distinguished from healthy controls and peptic ulcer disease patients using complement C4-A precursor (C4A), ezrin, and albumin. C4A and IgA could distinguish HSPN from HSP in the early stages, and D-dimer was a sensitive index used to distinguish abdominal HSP; identifying these biomarkers could promote the early diagnosis of HSP, especially pediatric HSPN and abdominal HSP, thereby improving precision therapy.

Hemoperfusion and intravenous immunoglobulins for refractory gastrointestinal involvement in pediatric Henoch-Schönlein purpura: a single-center retrospective cohort study

BackgroundHenoch-Schönlein purpura (HSP) with refractory gastrointestinal (GI) symptoms is always difficult to handle because of its resistance to supportive therapies and glucocorticoid. This study aimed to evaluate the efficacy of hemoperfusion (HP) and intravenous immunoglobulins (IVIG) therapies in this population.MethodsSixty-four HSP patients with refractory GI involvement (R-GI group) and 64 cases with mild GI symptoms (control group) were retrospectively analyzed in our center from March 2016 to October 2019. In R-GI group, 42 cases (subgroup A) were treated with IVIG and steroid, 13 cases (subgroup B) used HP and steroid, 9 cases (subgroup C) executed a combination of IVIG, HP and steroid. Demographic characteristics, clinical features, laboratory indexes and treatment outcomes were recorded. t-test, One-way ANOVA, Mann-Whitney U test, and multivariate logistic regression were used in comparing differences among subgroups and predicting independent risk factors.ResultsCompared with the control group, R-GI cases experienced higher risk of renal involvement (P = 0.000), more steroid exposure (P = 0.000), six times expenses (P = 0.000) and 2.3 times length of hospitalization (P = 0.000). The independent risk factors of R-GI group were elevated neutrophils (OR 1.250 [95% CI 1.130-1.383]) and the percentage of B lymphocytes (OR 1.100 [95% CI 1.026-1.179]) as well as decreased IgG (OR 0.847 [95% CI 0.732-0.98]). In R-GI group, increased age (OR 1.039 [95% CI 1.016-1.062]) and IgM (OR 5.994 [95% CI 1.403-27.611]) were verified to be risk factors of HSP nephritis. All three subgroups could alleviate the symptoms effectively. Compared with those in subgroup A, patients in subgroup B were elder (P = 0.004), had less relapse (P = 0.002), steroid exposure (P = 0.033) and expenses (P = 0.031), more significant decrease of WBC (P = 0.026) after treatment.ConclusionThe HSP with refractory GI involvement had much higher risk of medical burden and renal involvement. Both IVIG and HP therapies could ameliorate refractory GI symptoms efficiently. HP therapy tended to reduce the relapse, costs and steroid exposure in its audiences who were cooperated and with stable hemodynamics, while IVIG had better use in younger children.

Investigating KIF1A mutations in a Taiwanese cohort with hereditary spastic paraplegia

BackgroundHereditary spastic paraplegia (HSP) is a heterogeneous group of inherited neurodegenerative disorders characterized by slowly progressive lower limbs spasticity and weakness. HSP type 30 (SPG30) is a HSP subtype caused by mutations in the kinesin family member 1A gene (KIF1A) and could be either autosomal dominantly or recessively inherited. The aim of this study was to investigate the clinical and genetic features of KIF1A mutations in a Taiwanese HSP cohort. MethodsMutational analysis of KIF1A was performed in 242 unrelated Taiwanese patients of Han Chinese ethnicity with clinically suspected HSP using targeted resequencing panel covering the entire coding regions of KIF1A. Clinical, electrophysiological and neuroimaging features of the HSP patients carrying a KIF1A mutation were characterized. ResultsThree different KIF1A mutations were identified in three patients with autosomal dominantly inherited HSP. Among them, KIF1A p.E19K was a novel mutation. The patient harboring KIF1A p.G321D presented with pure HSP, while the individuals carrying KIF1A p.E19K or p.R316Q manifested complex HSP with additional axonal sensorimotor polyneuropathy. The patients carrying KIF1A p.R316Q also had thoracic cord atrophy, thin corpus callosum and white matter hyperintensity. ConclusionSPG30 accounts for 1.2% (3/242) of patients in the Taiwanese HSP cohort, suggesting that it is an uncommon HSP subtype in Taiwan. This study delineates the clinical and genetic features of SPG30 in Taiwan and provides useful information for the diagnosis and management of SPG30, especially in patients of Han Chinese descent.

AP4B1-associated hereditary spastic paraplegia: Expansion of clinico-genetic phenotype and geographic range

BackgroundHereditary spastic paraplegias (HSP) are a group of neurodegenerative diseases that present with weakness and stiffness in the lower limb muscles and lead to progressive neurological decline. Bi-allelic loss-of-function variants in genes that encode subunits of the adaptor protein complex 4 (AP-4) lead to complex HSP. This study aimed to identify causative genetic variants in consanguineous families with HSP from Azerbaijan and Pakistan. MethodsWe performed a thorough clinical and neuroradiological characterization followed by exome sequencing in 7 patients from 3 unrelated families. Segregation analysis was subsequently performed by Sanger sequencing. ResultsWe describe 7 patients (4 males, 2–31 years of age) with developmental delay and spasticity.Similar to the previously reported cases with AP4B1-associated HSP, cases in the present report besides spasticity in the lower limbs had additional features including microcephaly, facial dysmorphism, infantile hypotonia, and epilepsy. The imaging findings included thin corpus callosum, white matter loss, and ventriculomegaly. ConclusionIn this study, we report 7 novel cases of HSP caused by bi-allelic variants in AP4B1 in Azerbaijani and Pakistani families. Our observations will help clinicians observe and compare common and unique clinical features of AP4B1-associated HSP patients, further improving our current understanding of HSP.

Large single-centre cohort of HSP patients in UK: advantages of deep pheno- typing and longitudinal follow-up

AimTo identify clinical, radiological and instrumented gait correlates predictive of natural history in a cohort of HSP patients.BackgroundHSP is a rare heterogeneous group of neurodegenerative disorders. We present our experi- ence managing a large cohort of HSP patients in the regional centre for HSP. We believe Sheffield Teaching Hospitals to have the largest cohort in the North of England.Methodology and ResultsOur cohort comprises 426 patients, 246 male (57.7%) of which 290 were geneti- cally characterized. The commonest mutation is in SPASTIN (SPG4, 38.3%), whilst REEP1 (SPG31) and SPG11 mutations make up 3.1% and 2.1% respectively. Sheffield also holds the largest cohort of SPG7 patients in the UK (n=54) accounting for 18.6% of genetic HSP. The remainder have mutations in KIF5A, Atlastin, WASHC5, KIAA0196, NIPA1, ARSACS, CYP27A1, CYP7B1, AP4S1, GBA2 and L1CAM. Over 240 patients have had detailed MR imaging which has identified novel features in HSP. Repeated instrumented gait monitoring and cognitive assessments have shown novel clinical markers suggesting disease progression.ConclusionFor rare disorders like HSP, specialised clinics optimise comprehensive longitudinal clinical and radiological data collection for large cohorts. This develops local expertise and helps identify novel radiological and clinically relevant biomarkers, enabling better patient care.klprice1@sheffield.ac.uk

A clinical and genetic study of SPG31 in Japan.

SPG31 is an autosomal dominant hereditary spastic paraplegia caused by pathogenic variants in the receptor expression-enhancing protein 1 (REEP1) gene. We analyzed 488 DNA samples from unrelated HSP patients collected by Japan Spastic Paraplegia Research Consortium and found 15 Japanese SPG31 families. We investigated each family and found a total of 25 individuals with REEP1 variants (comprising 22 patients and three asymptomatic carriers). Fourteen REEP1 variants (five missense, three nonsense, four frameshift, one splice site, and one large deletion) including 11 novel ones were detected. Seventy percent of the patients (14 of 20) showed a pure form and the others (6 of 20) showed a complicated form with peripheral neuropathy. Fifty percent of the patients had neurological symptoms before the age of 10 and 20% of them at age 41-50. The mean age of onset was 19.6 ± 18.7 (from 5 to 67, n = 15) years for males and 32.8 ± 24.7 (from 4 to 60, n = 5) years for females. Although the difference was not statistically significant (p = 0.38, Mann-Whitney U test), males tended to have an earlier age of onset. Moreover, all three asymptomatic carriers were female. We investigated additional factors as to phenotypic appearance in one family with apparent intrafamilial variability in age at onset and clinical severity, but no additional factors including gene variants could be found. This is the first report of clinical and genetic findings of SPG31 in Japan, which may lead to further studies of the genotype-phenotype correlation of SPG31.

Detection of spinal long fiber tract degeneration in HSP: Improved diffusion tensor imaging

Spinal diffusion tensor imaging (sDTI) is still a challenging technique for selectively evaluating anatomical areas like the pyramidal tracts (PT), dorsal columns (DC), and anterior horns (AH) in clinical routine and for reliably quantifying white matter anisotropy and diffusivity. In neurodegenerative diseases, the value of sDTI is promising but not yet well understood.The objective of this prospective, single-center study was to evaluate the long fiber tract degeneration within the spinal cord in normal aging (n = 125) and to prove its applicability in pathologic conditions as in patients with molecular genetically confirmed hereditary spastic paraplegias (HSP; n = 40), a prototypical disease of the first motor neuron and in some genetic variants with affection of the dorsal columns. An optimized monopolar Stejskal-Tanner sequence for high-resolution, axial sDTI of the cervical spinal cord at 3.0 T with advanced standardized evaluation methods was developed for a robust DTI value estimation of PT, DC, and AH in both groups.After sDTI measurement at C2, an automatic motion correction and an advanced semi-automatic ROI-based, standardized evaluation of white matter anisotropy and diffusivity was performed to obtain regional diffusivity measures for PT, DC, and AH. Reliable and stable sDTI values were acquired in a healthy population without significant decline between age 20 and 65. Reference values for PT, DC, and AH for fractional anisotropy (FA), mean diffusivity (MD), and radial diffusivity (RD) were established.In HSP patients, the decline of the long spinal fiber tracts could be demonstrated by diffusivity abnormalities in the pyramidal tracts with significantly reduced PTFA (p < 0.001), elevated PTRD (p = 0.002) and reduced PTMD (p = 0.003) compared to healthy controls. Furthermore, FA was significantly reduced in DCFA (p < 0.001) with no differences in AH. In a genetically homogeneous subgroup of SPG4 patients (n = 12) with affection of the dorsal columns, DCRD significantly correlated with the overall disease severity as measured by the Spastic Paraplegia Rating Scale (SPRS) (r = − 0.713, p = 0.009).With the most extensive sDTI study in vivo to date, we showed that axial sDTI combined with motion correction and advanced data post-processing strategies enables robust measurements and is ready to use, allowing recognition and quantification of disease- and age-related changes of the PT, DC, and AH. These results may also encourage the usage of sDTI in other neurodegenerative diseases with spinal cord involvement to explore its capability as selective biomarkers.

Altered Functional Connectivity and Sensory Processing in Blepharospasm and Hemifacial Spasm: Coexistence and Difference.

Background: Blepharospasm (BSP) and hemifacial spasm (HFS) are both facial hyperkinesia however BSP is thought to be caused by maladaptation in multiple brain regions in contrast to the peripherally induced cause in HFS. Plausible coexisting pathophysiologies between these two distinct diseases have been proposed.Objectives: In this study, we compared brain resting state functional connectivity (rsFC) and quantitative thermal test (QTT) results between patients with BSP, HFS and heathy controls (HCs).Methods: This study enrolled 12 patients with BSP, 11 patients with HFS, and 15 HCs. All subjects received serial neuropsychiatric evaluations, questionnaires determining disease severity and functional impairment, QTT, and resting state functional MRI. Image data were acquired using seed-based analyses using the CONN toolbox.Results: A higher cold detection threshold was found in the BSP and HFS patients compared to the HCs. The BSP and HFS patients had higher rsFC between the anterior cerebellum network and left occipital regions compared to the HCs. In all subjects, impaired cold detection threshold in the QTT of lower extremities had a correlation with higher rsFC between the anterior cerebellar network and left lingual gyrus. Compared to the HCs, increased rsFC in right postcentral gyrus in the BSP patients and decreased rsFC in the right amygdala and frontal orbital cortex in the HFS subjects were revealed when the anterior cerebellar network was used as seed.Conclusions: Dysfunction of sensory processing detected by the QTT is found in the BSP and HSP patients. Altered functional connectivity between the anterior cerebellar network and left occipital region, especially the Brodmann area 19, may indicate the possibility of shared pathophysiology among BSP, HFS, and impaired cold detection threshold. Further large-scale longitudinal study is needed for testing this theory in the future.

HSP Nephritis in Children, Clinical Behavior, Renal Involvement and Remedy

Introduction: Childhood HSP is a systemic vasculitis of diverse clinical features with a favorable prognosis but renal involvement in HSP can cause chronic kidney disease (CKD) in children which is preventable in most cases if diagnosed and referred early. Aim of the study: To determine the occurrence ratio of HSP in children, its clinical behavior, renal involvement, and possible remedies. Methods: Medical records of 31 HSP patients were evaluated in the Nephrology and Rheumatology department of Dhaka Shishu (Children) Hospital from July 2017 to December 2019. Epidemiological data, clinical and laboratory findings were reviewed. The treatment for each patient was recorded including supportive care antihypertensive, ACE inhibitor, and immunosuppressive drug. Result: Most children affected during winter and spring (29%). Mean duration of disease 21.19 ±11.54 days. The mean age was 8.63±2.53 yrs. The mean age of renal involvement was 9.5 years. Male-female ratio 5.7:2. Almost all children (96.8%) presented with a rash. Abdominal pain was noted in 74.19% of patients. Joint pain was reported in 51.6% of patients. Renal involvement was presented in 58% of patients commonly in the form of proteinuria (58.6%) and hematuria (48.4%). 9 (29%) patients developed acute kidney injury (AKI). Occasional complications include convulsion, intestinal obstruction, septicemia, and pneumonia. Lab analysis showed thrombocytosis in 54% of patients, leukocytosis in 61% of patients, hypo-albuminemia in 58% of patients. C3 low in 29% patients. A kidney biopsy was done in 10 patients. IgA deposition and mesangial cell proliferation were the most common pathology. Regarding treatment, 12 patients were treated with methylprednisolone and MMF. 8 patients go into remission after taking only oral prednisolone. 6 patients took ACE inhibitor and 2 patients need dialysis. The majority of children (90.3%) achieved remission, though 2 patients died during admission. Conclusion: Present literature .....

SPG9A with the new occurrence of an ALDH18A1 mutation in a CMT1A family with PMP22 duplication: case report

BackgroundALDH18A1 mutations lead to delta-1-pyrroline-5-carboxylate-synthetase (P5CS) deficiency, which is a urea cycle-related disorder including SPG9A, SPG9B, autosomal dominant cutis laxa-3 (ADCL3), and autosomal recessive cutis laxa type 3A (ARCL3A). These diseases exhibit a broad clinical spectrum, which makes the diagnosis of P5CS deficiency difficult. We report here a rare Japanese family including both patients with an ALDH18A1 mutation (SPG9A) and ones with CMT1A.Case presentationA Japanese family included five patients with the CMT phenotype and five with the HSP phenotype in four generations. The patients with the HSP phenotype showed a pure or complicated form, and intrafamilial clinical variability was noted. Genetically, FISH analysis revealed that two CMT patients had a PMP22 duplication (CMT1A). Exome analysis and Sanger sequencing revealed five HSP patients had an ALDH18A1 heterozygous mutation of c.755G > A, which led to SPG9A. Haplotype analysis revealed that the ALDH18A1 mutation must have newly occurred. To date, although de novo mutations of ALDH18A1 have been described in ADCL3A, they were not mentioned in SPG9A in earlier reports. Thus, this is the first SPG9A family with a de novo mutation or the new occurrence of gonadal mosaicism of ALDH18A1. Analysis of serum amino acid levels revealed that two SPG9A patients and two unaffected family members had low citrulline levels and one had a low level of ornithine.ConclusionsSince the newly occurring ALDH18A1 mutation, c.755G > A, is the same as that in two ADHSP families and one sporadic patient with SPG9A reported previously, this genomic site might easily undergo mutation. The patients with the c.755G > A mutation in our family showed clinical variability of symptoms like in the earlier reported two families and one sporadic patient with this mutation. Further studies are required to clarify the relationship between the amino acid levels and clinical manifestations, which will reveal how P5CS deficiency influences disease phenotypes including ARCL3A, ADCL3, SPG9B, and SPG9A.

The characteristics of video capsule endoscopy in pediatric Henoch\u2013Sch\xf6nlein purpura with gastrointestinal symptoms

BackgroundHenoch–Schönlein purpura (HSP) is a systemic small-vessel vasculitis also named IgA vasculitis that commonly affects the gastrointestinal tract. The video capsule endoscopy (VCE) characteristics of pediatric HSP patients are rarely reported.MethodsPatients diagnosed with HSP and analyzed by VCE examination at our hospital from February 2010 to January 2020 are enrolled. The clinical features, laboratory findings, and the characteristics of VCE findings are studied.ResultsThere are 30 patients enrolled in this investigation from February 2010 to January 2020. The mean age of these patients is 96.9 ± 35.8 months, and the most frequent finding of VCE is mucosal erosion, which account for 79.3% of the patients, and followed by mucosal erythema or petechia accounted for 69% of the patients. Regarding the disease location detected by endoscopy, jejunum is the most common involved part of the gastrointestinal tract in pediatric HSP patients. All the patients had the jejunum involved except in one patient the VCE did not pass through the pylorus. One third of the patients involved the descending portion of duodenum. No side effect is observed in this study.ConclusionsVCE may be an excellent adjust tool for evaluation of the gastrointestinal tract in children with abdominal symptoms without typical purpura in suspected pediatric HSP patients. VCE appears to be superior to esophagogastroduodenoscopy in detecting small intestinal lesions of HSP and has an excellent safety profile.

Decreased glycolysis induced dysfunction of NK cells in Henoch-Schonlein purpura patients

BackgroundHenoch-Schonlein purpura (HSP) is the most common systemic vasculitis of the childhood. However, its mechanisms and pathogenesis still need more exploration. Natural killer (NK) cells are innate lymphocytes, and there is a growing appreciation that cellular metabolism is important in determining the immune responsiveness of lymphocytes. Thus, we aimed to analyze the NK cells phenotype and explore the association between glucose metabolism and NK cells function in HSP patients.ResultsA total number of 64 HSP patients and 34 healthy children were included. The HSP patients were divided into two groups according to whether accompanied with nephritis or not. NK cells in HSP patients without nephritis showed a reduced frequency in peripheral blood, a down-regulated expression of activating receptors both NKp30 and NKp46, and an attenuated cytotoxic function against tumor cells. In addition, the function impairment of NK cells was shown to exacerbate in HSPN. Our data further revealed an aberrant metabolic reprogramming of NK cells in HSP patients. Upon stimulation with cytokines (IL-15, IL-12 and IL-2), NK cells from healthy controls switched to an elevated glycolysis rate to support their effector function. By contrast, the glycolysis rate of activated NK cells in HSP group was not significantly up-regulated from the resting level possibly owing to the inhibition of mTORC1.ConclusionsOur study found that HSP patients were accompanied with dysfunction of NK cells. We concluded that the dysfunction of NK cells in HSP patients was induced with a decreased glycolysis rate and suggested that metabolic reprogramming of NK cells might be a player in the pathogenesis of HSP.

A novel SPAST gene mutation identified in a Chinese family with hereditary spastic paraplegia

BackgroundHereditary spastic paraplegia is a heterogeneous group of clinically and genetically neurodegenerative diseases characterized by progressive gait disorder. Hereditary spastic paraplegia can be inherited in various ways, and all modes of inheritance are associated with multiple genes or loci. At present, more than 76 disease-causing loci have been identified in hereditary spastic paraplegia patients. Here, we report a novel mutation in SPAST gene associated with hereditary spastic paraplegia in a Chinese family, further enriching the hereditary spastic paraplegia spectrum.MethodsWhole genomic DNA was extracted from peripheral blood of the 15 subjects from a Chinese family using DNA Isolation Kit. The Whole Exome Sequencing of the proband was analyzed and the result was identified in the rest individuals. RaptorX prediction tool and Protein Variation Effect Analyzer were used to predict the effects of the mutation on protein tertiary structure and function.ResultsSpastic paraplegia has been inherited across at least four generations in this family, during which only four HSP patients were alive. The results obtained by analyzing the Whole Exome Sequencing of the proband exhibited a novel disease-associated in-frame deletion in the SPAST gene, and this mutation also existed in the rest three HSP patients in this family. This in-frame deletion consists of three nucleotides deletion (c.1710_1712delGAA) within the exon 16, resulting in lysine deficiency at the position 570 of the protein (p.K570del). This novel mutation was also predicted to result in the synthesis of misfolded SPAST protein and have the deleterious effect on the function of SPAST protein.ConclusionIn this case, we reported a novel mutation in the known SPAST gene that segregated with HSP disease, which can be inherited in each generation. Simultaneously, this novel discovery significantly enriches the mutation spectrum, which provides an opportunity for further investigation of genetic pathogenesis of HSP.

Clinical characteristics of Taiwanese patients with Hereditary spastic paraplegia type 5.

ObjectivesTo investigate the clinical, electrophysiological, neuroimaging characteristics and genetic features of SPG5 in Taiwan.MethodsMutational analysis of the coding regions of CYP7B1 was performed by utilizing targeted resequencing analysis of the 187 unrelated Taiwanese HSP patients. The diagnosis of SPG5 was ascertained by the presence of biallelic CYP7B1 mutations. The SPG5 patients received clinical, electrophysiological, and neuroimaging evaluations. Disease severity was assessed by using the Spastic Paraplegia Rating Scale (SPRS) and the disability score. Two microsatellite markers as well as 18 single‐nucleotide polymorphism (SNP) markers flanking CYP7B1 were genotyped to assess the founder effect of the CYP7B1 p.R112* mutation.ResultsNineteen SPG5 patients from 17 families were identified. They typically presented an insidious onset progressive spastic paraparesis with proprioception involvement beginning at age 8 to 40 years. Their MRIs often showed white matter abnormalities in bilateral occipito‐parietal regions, spinal cord atrophy, and mild cerebellar atrophy. Six different mutations in CYP7B1 were recognized, including three novel ones (p.N131Ifs*4, p.A295V, and p.L439R). CYP7B1 p.R112* was the most common mutation and present in 88.2% of the 17 SPG5 pedigrees. The patients with homozygous CYP7B1 p.R112* mutations had a milder clinical severity. Detailed haplotype analyses demonstrated a shared haplotype in the 25 individuals carrying at least one single allele of CYP7B1 p.R112*, suggesting a founder effect.InterpretationThis study delineates the distinct clinical and genetic features of SPG5 in Taiwan and provides useful information for the diagnosis and management of SPG5, especially in patients of Chinese descent.