Diving deep: zebrafish models in motor neuron degeneration research.

In the dynamic landscape of biomedical science, the pursuit of effective treatments for motor neuron disorders like hereditary spastic paraplegia (HSP), amyotrophic lateral sclerosis (ALS), and spinal muscular atrophy (SMA) remains a key priority. Central to this endeavor is the development of robust animal models, with the zebrafish emerging as a prime candidate. Exhibiting embryonic transparency, a swift life cycle, and significant genetic and neuroanatomical congruencies with humans, zebrafish offer substantial potential for research. Despite the difference in locomotion-zebrafish undulate while humans use limbs, the zebrafish presents relevant phenotypic parallels to human motor control disorders, providing valuable insights into neurodegenerative diseases. This review explores the zebrafish's inherent traits and how they facilitate profound insights into the complex behavioral and cellular phenotypes associated with these disorders. Furthermore, we examine recent advancements in high-throughput drug screening using the zebrafish model, a promising avenue for identifying therapeutically potent compounds.

Management of Cerebrospinal Fluid Leak After Intrathecal Baclofen Pump Procedures in Adolescents With Cerebral Palsy: A Retrospective Study.

STUDY OBJECTIVE:  Epidural blood patches (EBPs) are frequently performed in children with cerebral palsy (CP) to manage post-dural puncture headache (PDPH) due to cerebrospinal fluid (CSF) leak after intrathecal baclofen pump (ITBP) placement or replacement procedures. The purpose of our study was to review the incidence and management of CSF leak following ITBP placement or replacement procedures in children with CP. The study was a retrospective review of 245 patients representing 310 surgical cases of baclofen pump insertion (n=141) or reinsertion (n=169) conducted at a 125-bed children's hospital with prominent specialty orthopedics surgical cases. MEASUREMENTS:  Demographic and clinical information was obtained from the anesthesia pain service database on all new ITBP placement and subsequent replacements over an eight-year period. MAIN RESULTS:  The overall incidence of CSF leak in our population was 16% (50 of 310) and 18% (25 of 141) with a new ITBP placement. Children with diplegia were associated with a threefold risk of developing CSF leak. Of patients who developed CSF leak (n=50), 68% (n=34) were successfully treated conservatively, while 32% (n=16) required EBPs. EBPs were successful in 87.5% (14 of 16) of patients at relieving PDPH on the first attempt.  Conclusions: CSF leak is a known problem after ITBP placement and replacement. Most patients were successfully treated with conservative management and EBPs were successful in patients failing conservative therapy. Diagnosing PDPH in non-verbal patients can be challenging.

Intramedullary Spinal Epidermoid Cyst-A Rare Cause of Spastic Paraparesis.

Spinal intramedullary epidermoids are rare intramedullary lesions of the spinal cord. They may be congenital or acquired with the congenital type often associated with spinal dysraphism and other spinal anomalies. The clinical presentation depends on the level of the involvement of the spinal cord. Management of these lesions is surgical excision. We report a case of intramedullary spinal epidermoid who presented with spastic paraparesis.

Novel Machine Learning Analysis Algorithm of DNA Methylation Patterns Identifies Cerebral Palsy with Concurrent Epilepsy.

Background: Spastic cerebral palsy, the most common pediatric-onset disabling condition with an estimated prevalence of 0.2% in children, is a complex condition characterized by stiff movement, muscle contractures, and abnormal gait that can diminish quality of life. Spastic CP accounts for approximately 83% of all CP cases and frequently co-occurs with other complex conditions, like epilepsy. An estimated 42% of spastic CP cases have co-occurring epilepsy. Unfortunately, CP is often difficult to diagnose. Although most children with CP are born with it or acquire it immediately after birth, many are not identified until after 19 months of age with CP diagnosis often not confirmed until 5 years of age. New bioinformatic approaches to identify CP earlier are needed. Recent studies indicate that altered DNA methylation patterns associated with CP may have diagnostic value. The potential confounding effects of co-occurrent epilepsy on these patterns are not known. We evaluated machine learning classification of CP patients with or without co-occurring epilepsy. Results: Whole blood samples were collected from 30 study participants diagnosed with epilepsy (n=4), spastic CP (n=10), both (n=8), or neither (n=8). A novel Support-Vector-Machine learning algorithm was developed to identify methylation loci that have ability to classify CP from controls in the presence or absence of epilepsy. This algorithm was also employed to measure classification ability of identified methylation loci. After preprocessing of data, isolation of important methylation loci was performed in a binary comparison between CP and controls, as well as in a 4-way scheme, encapsulating epilepsy diagnoses. The classification ability was similarly assessed. CP Classification performance was evaluated with and without inclusion of epilepsy as a feature. Median F1 scores were 0.67 in 4-class comparison, and 1.0 in the binary classification, outperforming Linear-Discriminant-Analysis (0.57 and 0.86, respectively). Conclusion: This novel algorithm was able to classify study participants with spastic CP and/or epilepsy from controls with significant performance. The algorithm shows promise for rapid identification in methylation data of diagnostic methylation loci. In this model, Support Vector Machines outperformed Linear Discriminant Analysis in classification. In the evaluation of epigenetics-based diagnostics for CP, epilepsy may not be a significant confounding factor.

Mobile digital gait analysis captures effects of botulinum toxin in hereditary spastic paraplegia.

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.

Unexpected complexity in the molecular diagnosis of spastic paraplegia 11.

BACKGROUND: Spastic paraplegia 11 (SPG11) is the most prevalent form of autosomal recessive hereditary spastic paraplegia, resulting from biallelic pathogenic variants in the SPG11 gene (MIM *610844). METHODS: The proband is a 36-year-old female referred for genetic evaluation due to cognitive dysfunction, gait impairment, and corpus callosum atrophy (brain MRI was normal at 25-years-old). Diagnostic approaches included CGH array, next-generation sequencing, and whole transcriptome sequencing. RESULTS: CGH array revealed a 180 kb deletion located upstream of SPG11. Sequencing of SPG11 uncovered two rare single nucleotide variants: the novel variant c.3143C>T in exon 17 (in cis with the deletion), and the previously reported pathogenic variant c.6409C>T in exon 34 (in trans). Whole transcriptome sequencing revealed that the variant c.3143C>T caused exon 17 skipping. CONCLUSION: We report a novel sequence variant in the SPG11 gene resulting in exon 17 skipping, which, along with a nonsense variant, causes Spastic Paraplegia 11 in our proband. In addition, a deletion upstream of SPG11 was identified in the patient, whose implication in the phenotype remains uncertain. Nonetheless, the deletion apparently affects cis-regulatory elements of the gene, suggesting a potential new pathogenic mechanism underlying the disease in a subset of undiagnosed patients. Our findings further support the hypothesis that the origin of thin corpus callosum in patients with SPG11 is of progressive nature.

Hemiplegic (unilateral) cerebral palsy in northern Stockholm: Intellectual disability and epilepsy.

PURPOSE: The purpose of this study was to describe intellectual disability and its association with epilepsy and brain imaging, in a population-based group of children with hemiplegic (unilateral) cerebral palsy, previously investigated and published in 2020. MATERIALS AND METHODS: Forty-seven children of school age in northern Stockholm, fulfilling the Surveillance of Cerebral Palsy in Europe-criteria of hemiplegic (unilateral spastic) cerebral palsy, were invited to participate in the study. Twenty-one children consented to participate. A WISC (Wechsler Intelligence Scale for Children)-test was performed by an experienced psychologist. RESULTS: In the study population of twenty-one children, 57 % (n 12) displayed uneven cognitive profiles, 38 % (n 8) intellectual disability and 62 % (n 13) had a normal IQ. 43 % (n 9) developed epilepsy. Children with extensive brain lesions had more severe intellectual disability. CONCLUSIONS: In this study intellectual disability and/or epilepsy were associated with the type and extent of the underlying brain lesion. Intellectual disability and uneven cognitive profiles were common. We therefore recommend individual cognitive assessment to ensure an optimal school start.

Two new cases with the UBQLN2 gene mutation in Han Chinese.

Variations in the UBQLN2 gene are associated with a group of diseases with X-linked dominant inheritance and clinical phenotypes of amyotrophic lateral sclerosis (ALS) and/or frontal temporal lobe dementia (FTD). Cases with UBQLN2 variations have been rarely reported worldwide. The reported cases exhibit strong clinical heterogeneity. Here, we report two adult-onset cases with UBQLN2 variations in Han Chinese. Whole exome sequencing revealed the hemizygous P506S (c.1516C > T) and the heterozygous P509S variation (c.1525C > T), both of which were located within the hotspot mutation region. The patient with the P506S variation was a 24-year-old male. The clinical feature was spastic paraplegia without lower motor neuron damage. The patient's mother was an asymptomatic heterozygote carrier with skewed X-chromosome inactivation. The patient with the P509S variation was a 63-year-old female. Clinical features included ALS and parkinsonism. 18F-fluorodopa PET-CT revealed presynaptic dopaminergic deficits in bilateral posterior putamen. These cases further highlight the clinical heterogeneity of UBQLN2 cases.

Hepatic myelopathy neurological complication of chronic liver disease: two case reports.

BACKGROUND: Hepatic myelopathy is a very rare neurological complication of chronic liver disease. Patients habitually present with progressive pure motor spastic paraparesis. This neurological dysfunction is almost always due to cirrhosis and portocaval shunt, either surgical or spontaneous. CASES REPORT: We report two cases of a 57-year-old man and a 37-year-old woman with progressive spastic paraparesis linked to cirrhosis and portal hypertension. The two patients are of Tunisian origin (north Africa). Magnetic resonance imaging of the spinal cord of two patients was normal, while brain magnetic resonance imaging showed a T2 hypersignals of the pallidums. These signs, in favor of hepatic encephalopathy in the two patients with cirrhosis with isolated progressive spastic paraparesis without bladder or sensory disorders, help to retain the diagnosis of hepatic myelopathy. CONCLUSION: Hepatic myelopathy is a severe and debilitating neurological complication of chronic liver disease. The pathogenesis is misunderstood and seems to be multifactorial, including the selective neurotoxic role both of ammonia and other pathogenic neurotoxins. Usually a pathological brain magnetic resonance imaging showing a hepatic encephalopathy was documented, contrasting with a normal spinal cord magnetic resonance imaging that contributed to diagnosis of hepatic myelopathy. Conservative therapies such as ammonia-lowering measures, diet supplementation, antispastic drugs, and endovascular shunt occlusion show little benefit in improving disease symptoms. Liver transplantation performed at early stage can prevent disease progression and could probably allow for recovery.

Proteomics and lipidomic analysis reveal dysregulated pathways associated with loss of sacsin.

Introduction: Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is a rare incurable neurodegenerative disease caused by mutations in the SACS gene, which codes for sacsin, a large protein involved in protein homeostasis, mitochondrial function, cytoskeletal dynamics, autophagy, cell adhesion and vesicle trafficking. However, the pathogenic mechanisms underlying sacsin dysfunction are still largely uncharacterized, and so attempts to develop therapies are still in the early stages. Methods: To achieve further understanding of how processes are altered by loss of sacsin, we used untargeted proteomics to compare protein profiles in ARSACS fibroblasts versus controls. Results: Our analyses confirmed the involvement of known biological pathways and also implicated calcium and lipid homeostasis in ARSACS skin fibroblasts, a finding further verified in SH-SY5Y SACS -/- cells. Validation through mass spectrometry-based analysis and comparative quantification of lipids by LC-MS in fibroblasts revealed increased levels of ceramides coupled with a reduction of diacylglycerols. Discussion: In addition to confirming aberrant Ca2+ homeostasis in ARSACS, this study described abnormal lipid levels associated with loss of sacsin.

Evaluation of the long-term effect of selective tibial neurotomy for the treatment of spastic foot using a personal goal-centered approach.

OBJECTIVE: The objective of this study was to evaluate the long-term effectiveness of selective tibial neurotomy (STN) for the treatment of the spastic foot using a goal-centered approach. METHODS: Between 2011 and 2018, adult patients with a spastic foot (regardless of etiology) who received STN followed by a rehabilitation program were included. The primary outcome was the achievement of individual goals defined preoperatively (T0) and compared at 1-year (T1) and 5-year (T5) follow-up by using the Goal Attainment Scaling methodology (T-score). The secondary outcomes were the presence of spastic deformities (equinus, varus, and claw toes), modified Ashworth scale (MAS) score for the targeted muscles, and modified Rankin Scale (mRS) score at T0, T1, and T5. RESULTS: Eighty-eight patients were included. At T5, 88.7% of patients had achieved their goals at least "as expected." The mean T-score was significantly higher at T1 (62.5 ± 9.5) and T5 (60.6 ± 11.3) than at T0 (37.9 ± 2.8) (p < 0.0001), and the difference between T1 and T5 was not significant (p = 0.2). Compared to T0, deformities (equinus, varus, and claw toes; all p < 0.0001), MAS score (p < 0.0001), and mRS score (p < 0.0001) were significantly improved at T1 and T5. Compared to T1, MAS score increased slightly only at T5 (p = 0.05) but remained largely below the preoperative value. There was no difference between T1 and T5 regarding other clinical parameters (e.g., deformities, walking abilities, mRS score). CONCLUSIONS: This study found that STN associated with a postoperative rehabilitation program can enable patients to successfully achieve personal goals that are sustained within a 5-year follow-up period.

HTLV-1/2 infection in Italy: a narrative review of epidemiological studies.

The human T-cell leukemia virus type 1 (HTLV-1) was first described in 1980. It is spread in highly endemic regions in the world, such as the Southwestern part of Japan, sub-Saharan Africa and South America, Caribbean, Middle East, and Australo-Melanesia regions. HTLV-1 causes adult T cell leukemia and is associated with many inflammatory conditions, most notably HTLV-1-associated myelopathy/tropic spastic paraparesis. HTLV-2, first isolated in 1982, was recognized as a common infection in intravenous drug users, but a clear association with disease remains elusive. The first estimate of HTLV-1-positive individuals worldwide, in 1993, was around 10-20 millions. Due to the lack of global population-based prevalence studies, this is considered an underestimate at the moment. Furthermore, HTLV-1 prevalence in Europe is impacted by changing migration flows. Particularly, no data on HTLV-1 prevalence in the general population in Italy are available. Here, we report a systematic literature review of studies conducted in Italy on HTLV-1/2 from 1980 to 2023. Based on the criteria we adopted a total of 426 publications were found (64 reviews, 99 epidemiological, and 263 translational studies). The contents of some representative publications are summarized and discussed. Moreover, an approximate estimation of about 26,000 HTLV-1 positive foreigners living in Italy was obtained from updated data of foreigners from each single country officially registered as resident in Italy and from data on HTLV-1 prevalence among the general population in the corresponding countries.

Autosomal Recessive Spastic Paraplegia and Psychomotor Retardation With or Without Seizures: A Case Report From Saudi Arabia.

Spastic paraplegia and psychomotor retardation with or without seizures (SPPRS) is a rare neurodevelopmental disorder associated with autosomal recessive mutations in the HACE1 gene. This case report presents the clinical features and genetic analysis of an 11-month-old girl and her sister with SPPRS, making it the third reported case in the Middle East and the second in Saudi Arabia. The patient exhibited hypotonia, global developmental delay, speech delay, swallowing difficulties, and recurrent respiratory infections. A homozygous pathogenic variant in the HACE1 gene (p.R664*) was identified through genetic analysis, confirming the diagnosis of SPPRS. This case report emphasizes the importance of considering variations in clinical presentation, especially in rare disorders where only a few cases are reported. Further research and case studies are needed to better understand the complete phenotypic spectrum of SPPRS and its complications.

Selective voluntary motor control influences knee joint torque, work and power in children with spastic cerebral palsy.

BACKGROUND: Children with spastic cerebral palsy (CP) have damage to the corticospinal tracts that are responsible for selective motor control (SMC). Force, velocity and timing of joint movement are related biomechanical features controlled by the corticospinal tracts (CSTs) that are important for skilled movement. RESEARCH QUESTION: Does SMC influence knee joint biomechanics in spastic CP? METHODS: In this prospective study, relationships between SMC and knee biomechanics (peak torque, total work, average power) across a range of velocities (0-300 deg/s) were assessed using an isokinetic dynamometer in 23 children with spastic CP. SMC was assessed using Selective Control Assessment of the Lower Extremity (SCALE). Logistic and linear regression models were used to evaluate relationships between SCALE and biomechanical measures. RESULTS: The ability to produce knee torque diminished with increasing velocity for both Low (0-4 points) and High (5-10 points) SCALE limb score groups (p < 0.01). More knees in the High group produced extension torque at 300 deg/s (p < 0.05) and flexion torque at 30, 90,180, 240 and 300 deg/s (p < 0.05). The ability to produce torque markedly decreased above 180 deg/s for Low group flexion. For knees that produced torque, significant positive correlations between SCALE limb scores and joint torque (0 and 120 deg/s), work (120 deg/s) and power (120 deg/s) were found (p < 0.05). Greater knee torque, work and power for the High group was found for the extensors at most velocities and the flexors for up to 120 deg/s (p < 0.05). Few Low group participants generated knee flexor torque above 120 deg/s limiting comparisons. SIGNIFICANCE: Biomechanical impairments found for children with low SMC are concerning as skilled movements during gait, play and sport activities occur at high velocities. Differences in SMC should be considered when designing individualized assessments and interventions.

Digital Gait Outcomes for Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay (ARSACS): Discriminative, Convergent, and Ecological Validity in a Multicenter Study (PROSPAX).

BACKGROUND: With treatment trials on the horizon, this study aimed to identify candidate digital-motor gait outcomes for autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS), capturable by wearable sensors with multicenter validity, and ideally also ecological validity during free walking outside laboratory settings. METHODS: Cross-sectional multicenter study (four centers), with gait assessments in 36 subjects (18 ARSACS patients; 18 controls) using three body-worn sensors (Opal, APDM) in laboratory settings and free walking in public spaces. Sensor gait measures were analyzed for discriminative validity from controls, and for convergent (ie, clinical and patient relevance) validity by correlations with SPRSmobility (primary outcome) and Scale for the Assessment and Rating of Ataxia (SARA), Spastic Paraplegia Rating Scale (SPRS), and activities of daily living subscore of the Friedreich Ataxia Rating Scale (FARS-ADL) (exploratory outcomes). RESULTS: Of 30 hypothesis-based digital gait measures, 14 measures discriminated ARSACS patients from controls with large effect sizes (|Cliff's δ| > 0.8) in laboratory settings, with strongest discrimination by measures of spatiotemporal variability Lateral Step Deviation (δ = 0.98), SPcmp (δ = 0.94), and Swing CV (δ = 0.93). Large correlations with the SPRSmobility were observed for Swing CV (Spearman's ρ = 0.84), Speed (ρ = -0.63), and Harmonic Ratio V (ρ = -0.62). During supervised free walking in a public space, 11/30 gait measures discriminated ARSACS from controls with large effect sizes. Large correlations with SPRSmobility were here observed for Swing CV (ρ = 0.78) and Speed (ρ = -0.69), without reductions in effect sizes compared with laboratory settings. CONCLUSIONS: We identified a promising set of digital-motor candidate gait outcomes for ARSACS, applicable in multicenter settings, correlating with patient-relevant health aspects, and with high validity also outside laboratory settings, thus simulating real-life walking with higher ecological validity. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

A novel SPAST gene splicing variant (c.1617-2A>C) in a heterozygous carrier with hereditary spastic paraplegia.

Hereditary spastic paraplegia (HSP) is a group of genetically heterogenous neurodegenerative disorders characterized by progressive spasticity and weakness of lower limbs. We report a novel splicing variant (c.1617-2A>C) of the SPAST gene in a heterozygous carrier from an Italian family with autosomal dominant HSP. The case study describes a pure form of spastic paraparesis with the cardinal clinical features of SPG4. The novel variant affects a canonical splice site and is likely to disrupt RNA splicing. We conclude that the c.1617-2A>C substitution is a null variant, which could be classified as pathogenic; its penetrance should be further investigated.

DDHD2 promotes lipid droplet catabolism by acting as a TAG lipase and a cargo receptor for lipophagy.

Mutations in the DDHD2 (DDHD domain containing 2) gene cause autosomal recessive spastic paraplegia type 54 (SPG54), a rare neurodegenerative disorder characterized by the early childhood onset of progressive spastic paraplegia. DDHD2 is reported as the principal brain triacylglycerol (TAG) lipase whose dysfunction causes massive lipid droplet (LD) accumulation in the brains of SPG54 patients. However, the precise functions of DDHD2 in regulating LD catabolism are not yet fully understood. In a recent study, we demonstrate that DDHD2 interacts with multiple members of the Atg8-family proteins (MAP1LC3/LC3s, GABARAPs), which play crucial roles in lipophagy. DDHD2 possesses two LC3-interacting region (LIR) motifs that contribute to its LD-eliminating activity. Moreover, DDHD2 enhances the colocalization between LC3B and LDs to promote lipophagy. LD·ATTEC, a compound that tethers LC3 to LDs to enhance their macroautophagic/autophagic clearance, effectively counteracts DDHD2 deficiency-induced LD accumulation. These findings provide insights into the dual functions of DDHD2 as a TAG lipase and cargo receptor for lipophagy in neuronal LD catabolism, and also suggest a potential therapeutic approach for treating SPG54 patients.