Limb Spasticity Research Articles

Transcutaneous electrical acupoint stimulation for upper limb spasticity after stroke: effect andd feasibility—a randomised pilot study

ImportanceLimb spasticity is a common issue among stroke patients. Transcutaneous electrical acupoint stimulation (TEAS) is recommended as an alternative therapy for managing upper limb spasticity after stroke; however, its potential...

Clinical features and genotype in COQ4 associated hereditary spastic paraplegia: a case report and a literature reanalysis.

COQ4 mutation often leads to a fatal multi-system disease in infants. Recently, it was reported that the biallelic COQ4 variants may be a potential cause of hereditary spastic paraplegia (HSP). This study aims to describe the clinical features and genotype of the COQ4 associated hereditary spastic paraplegia (HSP). We reported a case of HSP with COQ4 variants, and a literature reanalysis was performed. Three studies with a total of 1309 patients with HSP of unknown cause were included, and 13 (1%) patients were found to have biallelic COQ4 variants. Seven patients fulfilled pure HSP, and six patients fulfilled complicated HSP. The median age of these patients was 24 years (range 15 to 65 years), and the median year of disease onset was 14 years (range 1 to 55 years). The most common clinical manifestations were lower limb spasticity (100%), hyperreflexia (100%), Babinski sign (77%), reduced muscle strength (53.8%) cerebellar ataxia (23.1%), seizures (23.1%) and dysarthria (23.1%). Including our case, 16 different variants located in exon 2, exon 4, exon 5, exon 6, exon 7 and two introns of the COQ4 gene have been identified in patients with HSP. All started CoQ10 supplementation, but follow-up was reported in only one patient. COQ4 variants were associated with childhood, adolescent, and adult onset HSP, which has a relatively mild course. The efficiency of CoQ10 supplement in patients with COQ4 associated HSP need to be classified in the future study.

Exploring New Tools in Upper Limb Rehabilitation After Stroke Using an Exoskeletal Aid: A Pilot Randomized Control Study.

Spasticity commonly occurs in individuals after experiencing a stroke, impairing their hand function and limiting activities of daily living (ADLs). In this paper, we introduce an exoskeletal aid, combined with a set of augmented reality (AR) games consisting of the Rehabotics rehabilitation solution, designed for individuals with upper limb spasticity following stroke. Our study, involving 60 post-stroke patients (mean ± SD age: 70.97 ± 4.89 years), demonstrates significant improvements in Ashworth Scale (AS) scores and Box and Block test (BBT) scores when the Rehabotics solution is employed. The intervention group showed slightly greater improvement compared to the control group in terms of the AS (-0.23, with a confidence interval of -0.53 to 0.07) and BBT (1.67, with a confidence interval of 1.18 to 2.16). Additionally, the Rehabotics solution was particularly effective for patients with more severe deficits. Patients with an AS score of 3 showed more substantial improvements, with their AS scores increasing by -1.17 ± 0.39 and BBT scores increasing by -4.83 ± 0.72. These findings underscore the potential of wearable hand robotics in enhancing stroke survivors' hand rehabilitation, emphasizing the need for further investigations into its broader applications.

From spastic paraplegia to infantile neurodegenerative disorder: Expanding the phenotypic spectrum associated with biallelic SPAST variants.

Heterozygous pathogenic variants in SPAST are known to cause Hereditary Spastic Paraplegia 4 (SPG4), the most common form of HSP, characterized by progressive bilateral lower limbs spasticity with frequent sphincter disorders. However, there are very few descriptions in the literature of patients carrying biallelic variants in SPAST. Targeted Sanger sequencing, panel sequencing and exome sequencing were used to identify the genetic causes in 9 patients from 6 unrelated families with symptoms of HSP or infantile neurodegenerative disorder. We describe 5 patients with pure HSP with a variable age of onset, mostly in infancy, and 4 patients with profound intellectual disability and progressively worsening tetrapyramidal syndrome. The patients' parents, heterozygous carriers of pathogenic SPAST variants, included both asymptomatic carriers and patients with classic forms of SPG4. Biallelic variants of SPAST may explain cases of hereditary spastic paraplegia with autosomal recessive inheritance. Furthermore, some biallelic variants may also cause psychomotor regression with an infantile neurodegenerative disorder, associated with a tetrapyramidal syndrome, a new phenotype associated with the SPAST gene.

Hereditary Spastic Paraplegia Linked to Abnormal Splicing From an AIMP1 Missense Variant.

Hereditary spastic paraplegias (HSP) are a diverse group of neurodegenerative diseases characterized by lower limb spasticity and weakness. To date, over 80 genes have been associated with HSP, but many families remain without a molecular diagnosis. In this study, linkage analysis and whole-exome sequencing (WES) were performed to identify the causal gene in a HSP family with autosomal recessive inheritance. Multipoint linkage analysis revealed a maximum significant multipoint LOD score of 4.6 on chromosome 4. WES analysis focused on this region led to the identification of a homozygous missense variant in AIMP1 (c.223G>A). Minigene assays showed that the presumed missense variant in AIMP1 caused loss of the exon 3 donor splice site. Ultimately, this led to the use of an alternative splice site within the intron and the insertion of a premature stop codon. The identification of a novel AIMP1 causal variant contributes to the growing list of HSP genes. Furthermore, it shows that, considering also previous reported cases, disruption of AIMP1 causes a spectrum of disorders ranging from intellectual disability to more complex neurodegenerative diseases.

Spasticity patterns assessment and recognition for therapeutic approaches (SPARTA) in multiple sclerosis: a multicenter epidemiological study.

Spasticity and muscle weakness are the most disabling symptoms in people with Multiple Sclerosis (pwMS), frequently affecting lower limbs and causing motor impairments, fatigue and increased risk of falls. Previous epidemiological studies on pwMS reported prevalence of spasticity and other symptoms but scarce information is available about combined patterns of muscle weakness and spasticity, symmetry and regional localization. To describe the prevalent combined patterns of muscle weakness and spasticity in pwMS in order to focus attention on their functional balance before spasticity treatment. pwMS with lower limb spasticity, 3.5 ≤ Expanded-Disability-Status Scale (EDSS) ≤ 6.5 were recruited. Data regarding muscle weakness and spasticity, symmetry and involvement of other functional systems were collected. Prevalence analysis was performed. Three-hundred pwMS were included. Muscle weakness and spasticity occurred mostly asymmetrically with a prevalence of paraparesis. Incidence of both symptoms increase with higher EDSS, particularly of muscle weakness. Twelve prevalent combined patterns were identified, with highest incidence of combinations characterized by "distal-intermediate spasticity and diffuse weakness" (29.3%), "diffuse spasticity and weakness" (13.7%), "distal spasticity and diffuse weakness" (11.7%). This study highlighted the most prevalent combined patterns of weakness and spasticity, useful in clinical practice for pwMS' assessment by supporting optimal planning of specific pharmacologic and rehabilitative treatments.

Galloway-mowat syndrome 3 (GAMOS3): a novel disease-causing variant in OSGEP gene and expansion of the clinical spectrum.

Galloway-Mowat syndrome type 3 (GAMOS3) is a rare genetic disorder with renal and neurological complications caused by pathogenic variants in the OSGEP gene. Here, we report the molecular basis and clinical features in an Iranian family. Our proband, a 10-month-old female patient, presented with microcephaly, global developmental delay, lower limb spasticity, facial dysmorphisms, and renal tubulopathy. Brain magnetic resonance imaging (MRI), electroencephalography (EEG), and laboratory tests were performed to evaluate the clinical features. WES, Sanger sequencing, computational variant analysis, and gene expression analysis were conducted to identify, validate, and evaluate the genetic cause. Additionally, I-TASSER, HADDOCK, and GROMACS tools were utilized for protein modeling, computational docking, and molecular dynamics simulation (MDS), respectively. Blood and urine tests revealed proteinuria, hypercalciuria, and hypoalbuminemia. Brain MRI detected craniosynostosis, global parenchymal atrophy, and dysgenesis of the corpus callosum. Exome sequencing identified a previously unreported homozygous variant (NM_017807.4, c.689 G > T/p.C230F) in OSGEP, demonstrating co-segregation with the condition in the family. This missense variant did not significantly change the mRNA transcription. In-silico experiments predicted that this variant would likely alter the protein's structure and impair its normal functioning. Molecular docking results indicated that this variant significantly affects the protein interactions between OSGEP and LAGE3 proteins. Furthermore, MDS findings demonstrated that the p.C230F variant induced a conformational change in the mutant structure, potentially modifying its flexibility and stability. Identification of this variant contributes to expanding the OSGEP gene variant database, establishing a solid scientific foundation for precise clinical diagnosis and treatment.

Fabrication of a novel "all in one glove"- a functional tool for oral hygiene maintenance and the assessment of its effectiveness on plaque control in spastic cerebral palsy patients.

Spastic Cerebral Palsy (CP) is a neurological disorder from non-progressive brain injury or malformation during development, severely impairing movement, coordination, reflexes, posture, balance, and motor skills. Individuals with spastic CP experience limb spasticity, complicating tasks like precise gripping, particularly with toothbrushes. This study proposed a novel "all-in-one glove" for oral hygiene, assessing its efficacy and comparing it to conventional toothbrushes for spastic CP patients. This randomized controlled trial was conducted on 30 clinically diagnosed spastic CP patients with Group 1 consisting of 15 Subjects with clinically diagnosed spastic CP with generalized gingival diseases using conventional oral hygiene techniques with weekly oral hygiene reinforcement and Group 2 consisting of 15 Subjects with clinically diagnosed spastic cerebral palsy with generalized gingival diseases using the novel "all in one glove" method for oral hygiene maintenance with weekly oral hygiene reinforcement. The Clinical Parameters assessed includes Full mouth plaque scores, Full mouth bleeding scores and OHI scores recorded at baseline, 3 and 6 months. A statistically significant reduction was observed in Full-mouth Plaque, Bleeding, and Oral Hygiene Index (OHI) scores in both the groups (48.87% & 43.285%, 31.57% & 26.66%, 57.29% & 47.37% respectively). The Group 2 exhibited a marginally higher percentage reduction in all clinical parameters compared to the Group 1 at the measured time points. The utilization of the "All in one glove" has improved the effectiveness of oral hygiene maintenance and gingival health in spastic CP individuals. [ClinicalTrials.gov], identifier, [REF/2022/06/055641].

Age and method-specific differences in the efficacy of non-invasive brain stimulation in patients’ post-stroke limb spasticity: a meta-analysis

Objective: The aim of this study was to evaluate the effectiveness of two non-invasive brain stimulation (NIBS) methods, repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS), on spasticity in post-stroke patients with respect to patient age and muscle type. Methods: This meta-analysis was performed according to the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines. PUBMED (MEDLINE), Web of Science, Cochrane Library, and ExcerptaMedica Database (EMBASE) were searched for all randomized controlled trials (RCTs) published before December 2023. Results: In patients with spasticity after stroke, both rTMS (SMD: -0.56, CI95%: -0.81, -0.31, P<0.0001) and tDCS (SMD: -0.74, CI95%: -0.89, -0.59, P=0.005) significantly reduced the modified Ashworth Scale (MAS) compared with the control group. rTMS and tDCS were more effective in patients < 60 years than those > 60 years. Both rTMS and tDCS were effective against upper limb spasticity, particularly in patients aged < 60 years. Chronicity of stroke did not affect the benefit of rTMS to reduce spasticity although tDCS was more effective at 2 months after stroke onset. The reduction in spasticity in patients with supratentorial lesions was demonstrated by tDCS. The effectiveness of rTMS in spasticity reduction was not affected by the stimulation rate, but the use of tDCS at < 2 mA significantly decreased spasticity. Anodal stimulation (tDCS) reduced spasticity after stroke, especially in patients < 60 years of age. Other therapies, such as robotic therapy, the use of virtual reality, and electroacupuncture, were less effective against spasticity than conventional physical therapy combined with tDCS. The effectiveness of rTMS in spasticity reduction was not affected by the level of development, although tDCS was more successful in developing countries. Conclusions: Our findings suggest that NIBS should consider age, methods, and muscle type when treating patients with limb spasticity after stroke.

Three-dimensional kinematic analysis can improve the efficacy of acupoint selection for post-stroke patients with upper limb spastic paresis: A randomized controlled trial.

China is seeing a growing demand for rehabilitation treatments for post-stroke upper limb spastic paresis (PSSP-UL). Although acupuncture is known to be effective for PSSP-UL, there is room to enhance its efficacy. This study explored a semi-personalized acupuncture approach for PSSP-UL that used three-dimensional kinematic analysis (3DKA) results to select additional acupoints, and investigated the feasibility, efficacy and safety of this approach. This single-blind, single-center, randomized, controlled trial involved 74 participants who experienced a first-ever ischemic or hemorrhagic stroke with spastic upper limb paresis. The participants were then randomly assigned to the intervention group or the control group in a 1:1 ratio. Both groups received conventional treatments and acupuncture treatment 5days a week for 4weeks. The main acupoints in both groups were the same, while participants in the intervention group received additional acupoints selected on the basis of 3DKA results. Follow-up assessments were conducted for 8 weeks after the treatment. The primary outcome was the Fugl-Meyer Assessment for Upper Extremity (FMA-UE) response rate (≥ 6-point change) at week 4. Secondary outcomes included changes in motor function (FMA-UE), Brunnstrom recovery stage (BRS), manual muscle test (MMT), spasticity (Modified Ashworth Scale, MAS), and activities of daily life (Modified Barthel Index, MBI) at week 4 and week 12. Sixty-four participants completed the trial and underwent analyses. Compared with control group, the intervention group exhibited a significantly higher FMA-UE response rate at week 4 (χ2=5.479, P = 0.019) and greater improvements in FMA-UE at both week 4 and week 12 (both P < 0.001). The intervention group also showed bigger improvements from baseline in the MMT grades for shoulder adduction and elbow flexion at weeks 4 and 12 as well as thumb adduction at week 4 (P=0.007, P=0.049, P=0.019, P=0.008, P=0.029, respectively). The intervention group showed a better change in the MBI at both week 4 and week 12 (P=0.004 and P=0.010, respectively). Although the intervention group had a higher BRS for the hand at week 12 (P = 0.041), no intergroup differences were observed at week 4 (all P>0.05). The two groups showed no differences in MAS grades as well as in BRS for the arm at weeks 4 and 12 (all P>0.05). Semi-personalized acupuncture prescription based on 3DKA results significantly improved motor function, muscle strength, and activities of daily living in patients with PSSP-UL. Chinese Clinical Trial Registry ChiCTR2200056216. Please cite this article as: Huang XY, Liao OP, Jiang SY, Tao JM, Li Y, Lu XY, Li YY, Wang C, Li J, Ma XP. Three-dimensional kinematic analysis can improve the efficacy of acupoint selection for post-stroke patients with upper limb spastic paresis: A randomized controlled trial. J Integr Med. 2024; Epub ahead of print.

Sustained Effect Of Neurocreative Music Therapy On Upper Limb Abilities, Spasticity, Selective Control And Quality Of Life In Cerebral Palsy: A Case Report

Abstract This case report, presents the sustained effect of Neurocreative Music Therapy (NCMT) which a uniqe music therapy approach on the upper limb in an individual with cerebral palsy (CP). Our case is a 19-year-old individual with hemiparetic CP and she was included in the 8-week NCMT application program. Before the application, a phenomenological interview was conducted in accordance with the principle of the NCMT approach, which prioritizes the needs and pleasures of the individual. Before and immediately after the 8-week NCMT application, the patient's spasticity was assessed with the Modified Ashwort Scale, selective motor control with the Selective Control of the Upper Extremity Scale, upper limb abilities in daily activities with the ABILHAND-Kids, and quality of life with the Pediatric Quality of Life Inventory CP Module 3.0. As a result of the assessments, an individual-specific music therapy program was planned and implemented. The outcome measurements made immediately after the NCMT application were repeated in the 4th and 8th weeks following the end of the application. According to the results of the scales, it was observed that spasticity decreased, selective motor control increased, upper limb abilities improved, and quality of life increased. The obtained improvements were generally maintained in the 4th week following the end of the therapy. It was observed that there was a decrease in the sustainability of the effect in the 8th week following the end of the therapy in other measurement parameters other than quality of life. As a result, we concluded that NCMT is an effective approach in the rehabilitation of individuals with CP and that its effects may be transferred to the post-rehabilitation period.

Multiple roles for TFG ring complexes in neuronal cargo trafficking.

Pathological variants in Trk-fused gene (TFG) have been implicated in a variety of neurodegenerative conditions. In particular, mutations within its amino-terminal PB1 domain have been suggested to cause hereditary spastic paraplegia (HSP), resulting in progressive lower limb spasticity and weakness. The structural basis for this effect is unknown. Here, we combine X-ray crystallography and cryo-electron microscopy to determine a structural model of TFG, demonstrating the mechanism by which it forms octameric ring complexes. A network of electrostatic and hydrophobic interactions defines the interface between protomers. Moreover, we show that mutations identified previously in HSP patients disrupt this interface, destabilizing octamers, which ultimately leads to axonopathy. Surprisingly, the impacts of these variants are not equivalent in vivo, highlighting the existence of multiple, distinct mechanisms by which TFG mutations contribute to neurodegenerative disease.

Axon demyelination and degeneration in a zebrafish spastizin model of hereditary spastic paraplegia.

Hereditary spastic paraplegias (HSPs) are a diverse set of neurological disorders characterized by progressive spasticity and weakness in the lower limbs caused by damage to the axons of the corticospinal tract. More than 88 genetic mutations have been associated with HSP, yet the mechanisms underlying these disorders are not well understood. We replicated the pathophysiology of one form of HSP known as spastic paraplegia 15 (SPG15) in zebrafish. This disorder is caused in humans by mutations in the ZFYVE26 gene, which codes for a protein called SPASTIZIN. We show that, in zebrafish, the significant reduction of Spastizin caused degeneration of large motor neurons. Motor neuron degeneration is associated with axon demyelination in the spinal cord and impaired locomotion in the spastizin mutants. Our findings reveal that the reduction in Spastizin compromises axonal integrity and affects the myelin sheath, ultimately recapitulating the pathophysiology of HSPs.

Longitudinal Goal Attainment With Repeat Injections of AbobotulinumtoxinA in Adults With Lower Limb Spasticity: Results From a Prospective Observational Study

ObjectiveTo assess longitudinal goal attainment with repeat abobotulinumtoxinA (AboBoNT-A) injections for lower limb spasticity (LLS) over 16 months. DesignProspective, longitudinal, international, multicenter, observational study (NCT04050527). SettingSpecialist neurorehabilitation centers. ParticipantsAmbulatory adults with unilateral LLS able to take ≥5 steps with/without assistance (effectiveness population, N=384). InterventionsParticipants received ≥1 AboBoNT-A treatment cycle administered in accordance with local prescribing guidelines to achieve individualized treatment goals. Main Outcome MeasuresThe primary endpoint was goal attainment as assessed using the cumulated Goal Attainment Scaling-Leg (GAS-leg) T score, across all treatment cycles for each patient. ResultsOverall, participants underwent a median of 5 lower limb injection cycles (median dose 600U, range 100-1475U) with a mean±SD injection interval of 18.3±6.1 weeks. Participants generally achieved their goals as expected over repeated cycles; the mean (95% CI) GAS-leg T score at cycle 1 baseline was 38.0 (37.7, 38.3) and the mean cumulated GAS-leg T score at 16 months was 48.2 (47.4, 48.9) (mean change from a baseline of 9.9 [9.1, 10.7]). Participants injected with a guidance technique at baseline were more likely to attain their cycle 1 primary treatment goals (odds ratio: 1.9 [95% CI 1.1, 3.1], P=.02). Overall, 56 (13.5%) participants reported ≥1 adverse event, of which 6 participants (1.4%) had a treatment-related adverse event. ConclusionsFindings from this large, international study provide evidence for the benefit of repeated cycles of AboBoNT-A for LLS. Multivariate analyses indicated that goal attainment during the first cycle was better with those injected using injection guidance than those injected without guidance.

The p.D417N variant of TUBB4A as a possible cause of hereditary spastic paraplegia: a case report

BackgroundTubulins are dimeric proteins expressed in all eukaryotic cells, serving as the fundamental building blocks of microtubule filaments. The TUBB4A gene encodes the protein β-tubulin. Mutations of TUBB4A have been associated with two neurodegenerative diseases with very different clinical characteristics: dystonia type 4 (DYT4) and Hypomyelination with Atrophy of the Basal Ganglia and Cerebellum (H-ABC). Several cases of patients with H-ABC or unclassified leukoencephalopathy show spastic ataxia with or without leukodystrophy in association with mutations in exon 5 of TUBB4A gene.Case presentationWe report the case of a 65-year-old woman who has been complaining of progressive difficulty in walking since childhood. The neurological examination revealed, among all, a spastic gait, difficulties in standing on the toes and heels, brisk deep tendon reflexes at upper limbs, clonic patellar reflexes, brisk ankle reflexes, as well as bilateral Babinski and Hoffmann sign, brisk jaw jerk and severe lower limb spasticity. NGS studies for inherited cases of spastic paraplegia revealed a novel variant of unknown significance (VUS) (c.1249A > G, p.D417N), in TUBB4A. To the best of our knowledge, this variant has not been reported in the literature or any databases in association with these diseases.ConclusionWe report the case of a patient carrying a variant of uncertain significance (VUS) of the TUBB4A gene, showing a progressive, spastic paraparesis, supporting the extension of the phenotypic spectrum up to include spastic paraplegia.

A Homoplasmic MT-TV Mutation Associated with Mitochondrial Inheritance of Hereditary Spastic Paraplegia.

Hereditary spastic paraplegia (HSP) is characterized by progressive lower limb weakness and spasticity, with unknown genetic cause in many cases. To identify novel genetic causes of HSP. Phenotypic characterization, genetic screening, transcriptome sequencing, and peroneal nerve biopsy were conducted in a Chinese HSP family. We found a homoplasmic MT-TV (mitochondrial tRNAVal) mutation, m.1661A > G, present in all affected individuals across four generations of a family with complex HSP. Fourth-generation affected individuals displayed earlier onset, likely due to presumptive anticipation, and greater symptom severity, potentially caused by decreased mitochondrial DNA (mtDNA) copy number. Upregulation of mitochondrial autophagy genes in these patients suggested that MT-TV mutations could lead to reduced mtDNA copy number. Neural biopsies revealed ultrastructural abnormalities in myelin and mitochondria. The rare MT-TV m.1661A > G mutation is associated with HSP. Variations in mtDNA copy number may play a causal role in differences among clinical phenotypes. © 2024 International Parkinson and Movement Disorder Society.

Particularities of spasticity in myelomeningocele patients.

Myelomeningocele (MMC), a congenital neural tube defect, is the most common developmental anomaly of the central nervous system (CNS). Spasticity is among the main disabling factors in these patients, affecting up to 1/5 of children. The purpose of this article is to review the current knowledge regarding spasticity in MMC patients, mainly focusing on its manifestations and management. A literature search was conducted using the PubMed database for the terms "myelomeningocele" and "spasticity." Data were collected by 5 independent investigators and then synthesized in a scoping format. Causes of spasticity in these patients include hydrocephalus, tethered cord syndrome (TCS), syringomyelia, CNS infection, and associated congenital brain and spine anomalies. Clinical manifestations include limb spasticity and neurogenic bladder. Spasticity primarily affects muscles below the neurological level and contributes to gait impairment. Besides walking ability, spasticity also severely affects functional mobility in general, self-care, and quality of life. The majority of MMC patients experience neurogenic bladder. Treatment of spasticity can be symptomatic or target its cause. Medical and surgical options are available for both limb and bladder spasticity. Regular physiotherapy and orthotics are used to prevent contractures and the early introduction of orthoses is the cornerstone of a gait training program. Neurosurgical treatment options for spasticity include nonablative and ablative procedures such as selective dorsal rhizototmy. The urodynamic pattern guides treatment strategies, with intermittent catheterization being the best treatment option for patients with underactive detrusor and overactive sphincter muscles. Given the particularities of spasticity in MMC patients, a multidisciplinary team approach and early rehabilitation programs are keys for their optimal management.

A randomized, double-blind, placebo-controlled trial of DaxibotulinumtoxinA for Injection for the treatment of upper limb spasticity in adults after stroke or traumatic brain injury.

Intramuscular injection of botulinum toxin type A is a first-line pharmacotherapy for adults with upper limb spasticity (ULS). However, reemergence of symptoms within 12 weeks of treatment is common and longer-lasting treatments are needed. To evaluate the efficacy and safety of three doses of DaxibotulinumtoxinA for Injection (DAXI) for treatment of ULS in adults with stroke or traumatic brain injury. Intramuscular injections of placebo (N = 24), DAXI 250 U (N = 22), DAXI 375 U (N = 19), or DAXI 500 U (N = 18) to the suprahypertonic muscle (SMG) and other muscle groups. Randomized, double-blind, placebo-controlled study. Twenty-six study centers across the United States. Eighty-three adult patients with ULS were randomly assigned to each treatment group and followed for up to 36 weeks. Co-primary endpoints were the Modified Ashworth Scale (MAS) score change from baseline in the designated SMG and Physician Global Impression of Change (PGIC) at Week 6. The mean changes from baseline in MAS score for the designated SMG for placebo and the DAXI 250 U, 375 U, and 500 U groups were -0.6, -0.9, -0.9, and -1.8, respectively, at Week 4 and -0.8, -0.9, -1.0, and -1.5, respectively, at Week 6. Statistically significant improvement in MAS score compared with placebo was reported only for the 500 U dose (Week 4: p < .001; Week 6: p = .049). Significant improvements in PGIC ratings compared with placebo were reported for DAXI 375 U (p = .015) and DAXI 500 U (p = .009) at Week 4 but not for any DAXI doses at Week 6. All DAXI doses were well tolerated with no trend toward more adverse events with increased dose. Results from this Phase 2 study indicate that DAXI 500 U is effective and well tolerated for treatment of adults with ULS.

Hereditary Spastic Paraparesis Mimicking Primary Progressive Multiple Sclerosis Due to CYP7B1 Gene Mutation: A Case Report

The hereditary spastic paraplegias (HSPs) are a group of disorders characterised by progressive lower limb weakness and spasticity. This report presents the a case of a 49-year-old female with spastic paraparesis, initially suspected to be primary progressive multiple sclerosis (PPMS). Genetic testing later identified two mutations in the CYP7B1 gene that was associated with the SPG5 form of HSP. This case highlights the challenge of distinguishing HSP from other chronic spinal cord diseases and emphasizes the role of genetic analysis in rare cases of spastic paraplegia.

Biallelic PI4KA Mutations Disrupt B-Cell Metabolism and Cause B-Cell Lymphopenia and Hypogammaglobulinemia.

PI4KA-related disorder is a highly clinically variable condition characterized by neurological (limb spasticity, developmental delay, intellectual disability, seizures, ataxia, nystagmus) and gastrointestinal (inflammatory bowel disease and multiple intestinal atresia) manifestations. Although features consistent with immunodeficiency (autoimmunity/autoinflammation and recurrent infections) have been reported in a subset of patients, the burden of B-cell deficiency and hypogammaglobulinemia has not been extensively investigated. We sought to describe the clinical presentation and manifestations of patients with PI4KA-related disorder and to investigate the metabolic consequences of biallelic PI4KA variants in B cells. Clinical data from patients with PI4KA variants were obtained. Multi-omics analyses combining transcriptome, proteome, lipidome and metabolome analyses in conjunction with functional assays were performed in EBV-transformed B cells. Clinical and laboratory data of 13 patients were collected. Recurrent infections (7/13), autoimmune/autoinflammatory manifestations (5/13), B-cell deficiency (8/13) and hypogammaglobulinemia (8/13) were frequently observed. Patients' B cells frequently showed increased transitional and decreased switched memory B-cell subsets. Pathway analyses based on differentially expressed transcripts and proteins confirmed the central role of PI4KA in B cell differentiation with altered B-cell receptor (BCR) complex and signalling. By altering lipids production and tricarboxylic acid cycle regulation, and causing increased endoplasmic reticulum stress, biallelic PI4KA mutations disrupt B cell metabolism inducing mitochondrial dysfunction. As a result, B cells show hyperactive PI3K/mTOR pathway, increased autophagy and deranged cytoskeleton organization. By altering lipid metabolism and TCA cycle, impairing mitochondrial activity, hyperactivating mTOR pathway and increasing autophagy, PI4KA-related disorder causes a syndromic inborn error of immunity presenting with B-cell deficiency and hypogammaglobulinemia.