Hereditary spastic paraplegia (HSP) is a severe neurodegenerative movement disorder, the underlying pathophysiology of which remains poorly understood. Mounting evidence has suggested that iron ...homeostasis dysregulation can lead to motor function impairment. However, whether deficits in iron homeostasis are involved in the pathophysiology of HSP remains unknown. To address this knowledge gap, we focused on parvalbumin-positive (PV
) interneurons, a large category of inhibitory neurons in the central nervous system, which play a critical role in motor regulation. The PV
interneuron-specific deletion of the gene encoding transferrin receptor 1 (TFR1), a key component of the neuronal iron uptake machinery, induced severe progressive motor deficits in both male and female mice. In addition, we observed skeletal muscle atrophy, axon degeneration in the spinal cord dorsal column, and alterations in the expression of HSP-related proteins in male mice with
deletion in the PV
interneurons. These phenotypes were highly consistent with the core clinical features of HSP cases. Furthermore, the effects on motor function induced by
ablation in PV
interneurons were mostly concentrated in the dorsal spinal cord; however, iron repletion partly rescued the motor defects and axon loss seen in both sexes of conditional
mutant mice. Our study describes a new mouse model for mechanistic and therapeutic studies relating to HSP and provides novel insights into iron metabolism in spinal cord PV
interneurons and its role in the regulation of motor functions.
Iron is crucial for neuronal functioning. Mounting evidence suggests that iron homeostasis dysregulation can induce motor function deficits. Transferrin receptor 1 (TFR1) is thought to be the key component in neuronal iron uptake. We found that deletion of
in parvalbumin-positive (PV
) interneurons in mice induced severe progressive motor deficits, skeletal muscle atrophy, axon degeneration in the spinal cord dorsal column, and alterations in the expression of hereditary spastic paraplegia (HSP)-related proteins. These phenotypes were highly consistent with the core clinical features of HSP cases and partly rescued by iron repletion. This study describes a new mouse model for the study of HSP and provides novel insights into iron metabolism in spinal cord PV
interneurons.
Background and purpose
White matter (WM) damage is the main target of hereditary spastic paraplegia (HSP), but mounting evidence indicates that genotype‐specific grey matter (GM) damage is not ...uncommon. Our aim was to identify and compare brain GM and WM damage patterns in HSP subtypes and investigate how gene expression contributes to these patterns, and explore the relationship between GM and WM damage.
Methods
In this prospective single‐centre cohort study from 2019 to 2022, HSP patients and controls underwent magnetic resonance imaging evaluations. The alterations of GM and WM patterns were compared between groups by applying a source‐based morphometry approach. Spearman rank correlation was used to explore the associations between gene expression and GM atrophy patterns in HSP subtypes. Mediation analysis was conducted to investigate the interplay between GM and WM damage.
Results
Twenty‐one spastic paraplegia type 4 (SPG4) patients (mean age 50.7 years ± 12.0 SD, 15 men), 21 spastic paraplegia type 5 (SPG5) patients (mean age 29.1 years ± 12.8 SD, 14 men) and 42 controls (sex‐ and age‐matched) were evaluated. Compared to controls, SPG4 and SPG5 showed similar WM damage but different GM atrophy patterns. GM atrophy patterns in SPG4 and SPG5 were correlated with corresponding gene expression (ρ = 0.30, p = 0.008, ρ = 0.40, p < 0.001, respectively). Mediation analysis indicated that GM atrophy patterns were mediated by WM damage in HSP.
Conclusions
Grey matter atrophy patterns were distinct between SPG4 and SPG5 and were not only secondary to WM damage but also associated with disease‐related gene expression.
Clinical trial registration no. NCT04006418.
Background and purpose
Hereditary spastic paraplegias (HSPs) comprise a group of inherited neurodegenerative disorders characterized by progressive spasticity and weakness. Botulinum toxin has been ...approved for lower limb spasticity following stroke and cerebral palsy, but its effects in HSPs remain underexplored. We aimed to characterize the effects of botulinum toxin on clinical, gait, and patient‐reported outcomes in HSP patients and explore the potential of mobile digital gait analysis to monitor treatment effects and predict treatment response.
Methods
We conducted a prospective, observational, multicenter study involving ambulatory HSP patients treated with botulinum toxin tailored to individual goals. Comparing data at baseline, after 1 month, and after 3 months, treatment response was assessed using clinical parameters, goal attainment scaling, and mobile digital gait analysis. Machine learning algorithms were used for predicting individual goal attainment based on baseline parameters.
Results
A total of 56 patients were enrolled. Despite the heterogeneity of treatment goals and targeted muscles, botulinum toxin led to a significant improvement in specific clinical parameters and an improvement in specific gait characteristics, peaking at the 1‐month and declining by the 3‐month follow‐up. Significant correlations were identified between gait parameters and clinical scores. With a mean balanced accuracy of 66%, machine learning algorithms identified important denominators to predict treatment response.
Conclusions
Our study provides evidence supporting the beneficial effects of botulinum toxin in HSP when applied according to individual treatment goals. The use of mobile digital gait analysis and machine learning represents a novel approach for monitoring treatment effects and predicting treatment response.
Voluntary movement is a fundamental way in which animals respond to, and interact with, their environment. In mammals, the main CNS pathway controlling voluntary movement is the corticospinal tract, ...which encompasses connections between the cerebral motor cortex and the spinal cord. Hereditary spastic paraplegias (HSPs) are a group of genetic disorders that lead to a length-dependent, distal axonopathy of fibres of the corticospinal tract, causing lower limb spasticity and weakness. Recent work aimed at elucidating the molecular cell biology underlying the HSPs has revealed the importance of basic cellular processes — especially membrane trafficking and organelle morphogenesis and distribution— in axonal maintenance and degeneration.
After reviewing this article, the participant should be able to: 1. Understand the anatomy and pathophysiology of spinal cord injury and the resulting upper and lower motor neuron syndromes. 2. ...Recognize who may benefit from nerve transfers. 3. Understand the role of history, examination, imaging, and electrodiagnostics in the determination of time-sensitive lower motor neuron injury versus non-time-sensitive upper motor neuron injury. 4. Outline the surgical options and perioperative care for those undergoing nerve transfer and the expected outcomes in restoring shoulder, elbow, wrist, and hand function.
This article outlines how to localize and differentiate upper motor neuron from combined upper and lower motor neuron injury patterns in spinal cord injury by means of detailed history, physical examination, imaging, and electrodiagnostic studies to formulate appropriate surgical plans to restore function in this complex population.
Paraplegia remains one of the major complications of contemporary open thoracoabdominal aortic aneurysm (TAAA) repair. Intraoperative motor-evoked potentials (MEPs) act as a surrogate measure for ...spinal cord homeostasis. The purpose of this study was to evaluate the results of intraoperative neuromonitoring in contemporary TAAA repair and its association with postoperative spinal cord ischemia (SCI).
Patients who underwent open type 2 or 3 TAAA or completion aortic repair using intraoperative neuromonitoring were identified between May 2006 and November 2023. Patient demographics, comorbidities, indication for the procedure, procedural details, and outcomes were recorded. The groups were divided based on type of repair, and univariate statistics were then used to evaluate the association of these metrics vs the type of repair.
Seventy-nine patients underwent open type 2 (N = 41) and 3 (N = 23) TAAA and completion aortic (N = 15; open in 14 and endovascular in 1) repairs by a single surgeon. The cohort was predominantly male (N = 48, 60.8%) with a mean age of 52.5 ± 16.2 years. There was a high incidence of hypertension (N = 53, 67.1%), smoking history (N = 42, 53.1%), and connective tissue disorders (N = 37, 46.8%). Operative indications included dissection-related (N = 50, 63.3%) and degenerative (N = 26, 32.9%) TAAA and dissection-related malperfusion (N = 3, 3.8%). Left heart bypass was often (N = 73, 92.4%) used for distal aortic perfusion, and cerebrospinal fluid drainage (N = 77, 97.5%) was a common adjunct. MEPs were classified as no change (N = 43, 54.4%), reversible change (N = 26, 32.9%), irreversible change (N = 4, 5.1%), and unreliable (N = 6, 7.6%). MEP changes were predominantly bilateral (N = 70, 88.6%) and occurred most often during repair of the abdominal aortic segment (N = 13, 16.5%). The median number of replaced vertebral levels was associated with MEP changes (P = .013). SCI was only observed in repairs greater than 6 replaced vertebral levels with an overall frequency of 17.7%. It was most prevalent in completion aortic repairs (26.7%). Immediate and delayed SCI occurred in 10.1% and 7.6% of patients, respectively; it was most commonly (71.8%) reversible. Permanent paraplegia occurred in four patients (5.1%), with equal immediate and delayed onsets. MEPs demonstrated poor sensitivity (53.9%) and specificity (62.3%) for SCI; however, there was a high negative predictive value (86.4%) in this population. In-hospital mortality occurred in five (6.3%) patients.
No changes in intraoperative MEPs are highly predictive of spinal cord homeostasis. The number of replaced vertebral levels and previous aortic repair should guide intraoperative neuroprotective measures including intercostal reimplantation and should take precedence over intraoperative monitoring, especially when MEP changes occur.
1. NAME OF DISEASE (SYNONYMS): Pontocerebellar hypoplasia type 9 (PCH9) and spastic paraplegia-63 (SPG63). 2. OMIM# OF THE DISEASE: 615809 and 615686. 3. NAME OF THE ANALYSED GENES OR DNA/CHROMOSOME ...SEGMENTS: AMPD2 at 1p13.3. 4. OMIM# OF THE GENE(S): 102771.
Task-specific locomotor training has been promoted to improve walking-related outcome after incomplete spinal cord injury (iSCI). However, there is also evidence that lower extremity strength ...training might lead to such improvements. The aim of this randomized cross-over pilot study was to compare changes in a broad spectrum of walking-related outcome measures and pain between robot-assisted gait training (RAGT) and strength training in patients with chronic iSCI, who depended on walking assistance. We hypothesized that task-specific locomotor training would result in better improvements compared to strength training.
Nine participants with a chronic iSCI were randomized to group 1 or 2. Group 1 received 16 sessions of RAGT (45 min each) within 4 weeks followed by 16 sessions of strength training (45 min each) within 4 weeks. Group 2 received the same interventions in reversed order. Main outcome measures were the 10 m Walk Test (10MWT) at preferred and maximal speed. Furthermore, we assessed several measures such as walking speed under different conditions, balance, strength, and 2 questionnaires that evaluate risk of falling and pain. Data were collected at baseline, between interventions after 4 weeks, directly after the interventions and at follow-up 6 months after the interventions. Pain was assessed repeatedly throughout the study.
There were no significant differences in changes in scores between the 2 interventions, except for maximal walking speed (10MWT), which improved significantly more after strength training than after RAGT. Pain reduced after both interventions.
In patients with chronic iSCI dependent on walking assistance, RAGT was not more effective in improving walking-related outcome compared to lower extremity strength training. However, the low sample size limits generalizability and precision of data interpretation.
This study was registered at Clinicaltrials.gov (NCT01087918).
Spastic paraplegia type 7 (SPG7) is one of the most common hereditary spastic paraplegias. SPG7 mutations most often lead to spastic paraparesis (HSP) and/or hereditary cerebellar ataxia (HCA), ...frequently with mixed phenotypes. We sought to clinically and genetically characterize a Spanish cohort of SPG7 patients. Patients were recruited from our HCA and HSP cohorts. We identified twenty-one patients with biallelic pathogenic SPG7 mutations. Mean age at onset was 37.4 years (SD ± 14.3). The most frequent phenotype was spastic ataxia (57%), followed by pure spastic paraplegia (19%) and complex phenotypes (19%). Isolated patients presented with focal or multifocal dystonia, subclinical myopathy or ophthalmoplegia. p.Ala510Val was the most frequent pathogenic variant encountered. Compound heterozygous for p.Ala510Val displayed younger onset (p < 0.05) and more complex phenotypes (p < 0.05) than p.Ala510Val homozygotes. Two novel variants were found: p.Lys559Argfs*33 and p.Ala312Glu. In conclusion, spastic ataxia is the most common phenotype found in Spanish patients. Nonetheless, SPG7 analysis should also be considered in patients with less frequent clinical findings such as dystonia or ophthalmoplegia especially when these symptoms are associated with mild spastic ataxia.
•Spastic ataxia is the main phenotype found in our Spanish population.•p.Ala510Val compound heterozygotes had more complex phenotypes than homozygotes.•SPG7 may be an under-recognized cause of inherited movement disorders.•Further studies are needed to understand the heritability of single heterozygotes.
The aim of this study is to provide a comprehensive characterization of a large Estonian family spanning five generations with seventeen individuals affected by spastic paraplegia associated with a ...novel variant in the receptor expression-enhancing protein-1 (REEP1) gene.
Comprehensive clinical evaluation, neuroimaging, and neurophysiological studies were performed on six patients who provided oral and written consent. Whole-exome sequencing was performed on the index case. Targeted carrier testing was done in all other available affected and at-risk relatives.
Four individuals presented with pure spastic paraplegia, with onset from early childhood to adult age. None had bladder or bowel dysfunction. Two subjectively asymptomatic mutation carriers displayed pyramidal signs on examination. Imaging of the neuroaxis was normal in three patients, three had MRI findings interpreted as unrelated. Motor evoked potential (MEP) was abnormal in five; the patient with the longest disease duration had additional somatosensory evoked potential (SSEP) abnormalities. The novel splice-site variant, c.32 + 1G > C in the REEP1 gene, found in the index case, co-segregates with disease in the family. Expressivity in this family is variable.
Our findings are in keeping with previous descriptions of the SPG31 spectrum. The phenotype associated with splice variants is not necessarily more severe than other conventional REEP1 variants. As for other forms of familial spastic paraplegias, the factors modulating variable expressivity in SPG31 are still unknown.
•A novel c.32 + 1G > C REEP1 variant in a large Estonian family with a simple form of spastic paraplegia.•Variable disease expressivity in the family and the REEP1 variant is predicted to affect splicing.•Neuroimaging of the brain and spinal cord was normal.•SSEP was abnormal in the patient with longest disease duration.
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