Recessive Spastic Ataxia Of Charlevoix-Saguenay Research Articles

Thickened Retinal Nerve Fiber Layer Without Hypermyelination in Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay

Purpose: To report the retinal findings in a patient with autosomal recessive spastic ataxia of Charlevoix-Saguenay. Methods: A case was evaluated. Results: A 16-year-old male patient with a known diagnosis of autosomal recessive spastic ataxia of Charlevoix-Saguenay was referred for evaluation of retinal hypermyelination given its frequent association with the condition. The patient was asymptomatic with a best-corrected visual acuity of 20/20. Optical coherence tomography of the peripapillary retinal nerve fiber layer (RNFL) showed bilateral thickening in each eye (average thicknesses: 180 µm, right eye; 177 µm, left eye). An examination showed no myelinization of the RNFL. Conclusions: Most studies to date describe RNFL thickening secondary to hypermyelination as a characteristic finding in autosomal recessive spastic ataxia of Charlevoix-Saguenay. This case provides evidence that this thickening may be a result of hypertrophy rather than hypermyelination. Further investigation is needed to define the pathophysiologic cause of RNFL thickening in autosomal recessive spastic ataxia of Charlevoix-Saguenay.

Neuropathy in ARSACS is demyelinating but without typical nerve enlargement in nerve ultrasound.

To specify peripheral nerve affection in autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) by correlating high-resolution nerve ultrasound and nerve conduction studies. We assessed a cohort of 11 ARSACS patients with standardized nerve conduction studies and high-resolution ultrasound of peripheral nerves and compared nerve ultrasound findings to a healthy control group matched for age, sex, size and weight. Mean age of patients was 39.0 (± 14.1) years and disease duration at assessment 30.6 (± 12.5) years. All patients presented with a spasticity, ataxia and peripheral neuropathy. Neuropathy appeared to be primarily demyelinating in 9/11 cases and was not classifiable in 2/11 cases due to not evocable potentials. Nerve ultrasound revealed a normal ultrasound pattern sum score (UPSS) in each ARSACS patient and no significant nerve enlargement compared to the control group. Peripheral neuropathy in ARSACS showed primarily demyelinating rather than axonal characteristics and presented without nerve enlargement. As demyelinating neuropathies do commonly present enlarged nerves we recommend further genetic testing of the SACS gene in patients who present with this combination of demyelinating neuropathy without nerve enlargement. ARSACS cases that initially presented only with neuropathy without spasticity or ataxia and therefore were misdiagnosed as Charcot-Marie-Tooth disease are supporting this suggestion.

Toward a Better Understanding of Walking Speed in Ataxia of Charlevoix-Saguenay: a Factor Exploratory Study.

Mobility limitations, including a decrease in walking speed, are major issues for people with autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS). Improving our understanding of factors influencing walking speed in ARSACS may inform the development of future interventions for gait rehabilitation and contribute to better clinical practices. The objective of the study was to identify the factors influencing the self-selected walking speed in adults with ARSACS. The dependent variable of this cross-sectional study was the self-selected speed and the factors (independent variables) were age, sex, balance, balance confidence, knee flexion and extension cocontraction indexes, lower limb coordination, passive range of motion of ankle dorsiflexion, knee and hip extension, and global spasticity. Multiple regression models were used to assess the relationships between walking speed and each factor individually. Six factors were significantly associated with walking speed and thus included in regression models. The models explained between 42.4 and 66.5% of the total variance of the self-selected walking speed. The factors that most influence self-selected walking speed are balance and lower limb coordination. In order of importance, the other factors that also significantly influence self-selected walking speed are ankle dorsiflexion range of motion, lower limb spasticity, knee extension range of motion, and confidence in balance. Balance and lower limb coordination should be targeted in rehabilitation interventions to maintain walking ability and functional independence as long as possible. The six factors identified should also be included in future studies to deepen our understanding of walking speed.

Widening the clinical, radiological and genetic spectrum of autosomal recessive ataxia of Charlevoix-Saguenay in Indian patients.

Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS), classically presenting as a triad of early-onset cerebellar ataxia, lower extremity spasticity and peripheral neuropathy, is caused by mutations in SACS gene which encodes the protein sacsin. To provide new insight into the occurrence of SACS mutations in South India. Patients with three cardinal features of ARSACS-peripheral neuropathy, cerebellar ataxia, and pyramidal tract signs were included. Nine patients were clinically identified and genetically evaluated. Mutation screening of SACS by targeted sequencing of 40 recessive ataxia genes panel by next-generation sequencing was conducted. Additional investigations included magnetic resonance imaging (MRI), fundoscopy, optical coherence tomography (OCT) and nerve conduction studies (NCS). Functional disability was assessed by the Spinocerebellar Degeneration Functional Score. Two hundred and fifteen cerebellar ataxia patients were screened, and 9 patients with cerebellar ataxia with spasticity, peripheral neuropathy and MRI brain characteristics, consistent with a clinical diagnosis of ARSACS were identified, of which 7 patients were identified to have mutation in the SACS gene and are detailed hereafter. Age of presentation ranged from 20 to 55years (29.8 ± 11.9) with a mean disease duration of 12.7years (SD-7.65, range 5-22years). All except one had onset of symptoms in the form of an ataxic gait noticed before 20years of age. Additional features were subnormal intelligence (4/7), slow and hypometric saccades (1/7), seizures (1/7), kyphoscoliosis (1/7) and dysmorphic facies (1/7). SDFS was 3 in 5/7 patients signifying moderate disability with independent ambulation. MRI showed cerebellar atrophy with predominant atrophy of the superior vermis (7/7), horizontal linear T2 hypointensities in the pons(7/7), hyperintensities where lateral pons merges with the middle cerebellar peduncle (MCP) (7/7) well seen in fluid-attenuated inversion recovery (FLAIR) images, thickening of MCP (3/7), symmetric lateral thalamic hyperintensities (6/7), posterior fossa arachnoid cyst (4/7),thinning of posterior mid-body of corpus callosum (7/7), marginal mineralisation of the basal ganglia (7/7), bilateral parietal atrophy (7/7) and thinning of corticospinal tract on diffusion tensor imaging (DTI) (7/7). We identified pathogenic homozygous frameshift mutations in the SACS gene in six patients (including two siblings), while one patient had a heterozygous pathogenic deletion. This is the largest series of genetically confirmed ARSACS patients from India highlighting the clinical, ophthalmological, imaging and genetic features of this cohort.

A SACS deletion variant in Great Pyrenees dogs causes autosomal recessive neuronal degeneration.

ARSACS (autosomal recessive spastic ataxia of Charlevoix-Saguenay) is a human neurological disorder characterized by progressive cerebellar ataxia and peripheral neuropathy. A recently recognized disorder in Great Pyrenees dogs is similarly characterized by widespread central nervous system degeneration leading to progressive cerebellar ataxia and spasticity, combined with peripheral neuropathy. Onset of clinical signs occurred in puppies as young as 4 months of age, with slow progression over several years. A multi-generation pedigree suggested an autosomal recessive mode of inheritance. Histopathology revealed consistent cerebellar Purkinje cell degeneration, neuronal degeneration in brainstem nuclei, widespread spinal cord white matter degeneration, ganglion cell degeneration, inappropriately thin myelin sheaths or fully demyelinated peripheral nerve fibers, and normal or only mild patterns of denervation atrophy in skeletal muscles. Genome-wide single nucleotide polymorphism (SNP) genotype data was collected from 6 cases and 26 controls, where homozygosity mapping identified a 3.3Mb region on CFA25 in which all cases were homozygous and all controls were either heterozygous or homozygous for alternate haplotypes. This region tagged the SACS gene where variants are known to cause ARSACS. Sanger sequencing of SACS in affected dogs identified a 4bp deletion that causes a frame shift and truncates 343 amino acids from the C terminus of the encoded sacsin protein (p.Val4244AlafsTer32). Our clinical and histopathological descriptions of this canine disorder contribute to the description of human ARSACS and represents the first naturally occurring large animal model of this disorder.

Restoring calcium homeostasis in Purkinje cells arrests neurodegeneration and neuroinflammation in the ARSACS mouse model.

Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay (ARSACS) is caused by mutations in SACS gene encoding sacsin, a huge protein highly expressed in cerebellar Purkinje cells (PCs). ARSACS patients, as well as mouse models, display early degeneration of PCs, but the underlying mechanisms remain unexplored, with no available treatments.In this work, we demonstrated aberrant calcium (Ca2+) homeostasis and its impact on PC degeneration in ARSACS. Mechanistically, we found pathological elevation in Ca2+-evoked responses in Sacs-/- PCs, as the result of defective mitochondria and ER trafficking to distal dendrites and strong downregulation of key Ca2+ buffer-proteins. Alteration of cytoskeletal linkers, that we identified as specific sacsin interactors, likely account for faulty organellar trafficking in Sacs-/- cerebellum.Based on this pathogenetic cascade, we treated Sacs-/- mice with Ceftriaxone, a repurposed drug which exerts neuroprotection by limiting neuronal glutamatergic stimulation, and thus Ca2+ fluxes into PCs. Ceftriaxone treatment significantly improved motor performances of Sacs-/- mice, at both pre- and post-symptomatic stages. We correlated this effect to restored Ca2+ homeostasis, which arrests PC degeneration and attenuates secondary neuroinflammation. These findings disclose new key steps in ARSACS pathogenesis and support further optimization of Ceftriaxone in pre-clinical and clinical settings for the treatment of ARSACSpatients.

Responsiveness of the Scale for the Assessment and Rating of Ataxia and Natural History in 884 Recessive and Early Onset Ataxia Patients.

The Scale for the Assessment and Rating of Ataxia (SARA) is the most widely applied clinical outcome assessment (COA) for genetic ataxias, but presents metrological and regulatory challenges. To facilitate trial planning, we characterize its responsiveness (including subitem-level relations to ataxia severity and patient-focused outcomes) across a large number of ataxias, and provide first natural history data for several of them. Subitem-level correlation and distribution-based analysis of 1,637 SARA assessments in 884 patients with autosomal recessive/early onset ataxia (370 with 2-8 longitudinal assessments) were complemented by linear mixed effects modeling to estimate progression and sample sizes. Although SARA subitem responsiveness varied between ataxia severities, gait/stance showed a robust granular linear scaling across the broadest range (SARA < 25). Responsiveness was diminished by incomplete subscale use at intermediate or upper levels, nontransitions ("static periods"), and fluctuating decreases/increases. All subitems except nose-finger showed moderate-to-strong correlations to activities of daily living, indicating that metric properties-not content validity-limit SARA responsiveness. SARA captured mild-to-moderate progression in many genotypes (eg, SYNE1-ataxia: 0.55 points/yr, ataxia with oculomotor apraxia type 2: 1.14 points/yr, POLG-ataxia: 1.56 points/yr), but no change in others (autosomal recessive spastic ataxia of Charlevoix-Saguenay, COQ8A-ataxia). Whereas sensitivity to change was optimal in mild ataxia (SARA < 10), it substantially deteriorated in advanced ataxia (SARA > 25; 2.7-fold sample size). Use of a novel rank-optimized SARA without subitems finger-chase and nose-finger reduces sample sizes by 20 to 25%. This study comprehensively characterizes COA properties and annualized changes of the SARA across and within a large number of ataxias. It suggests specific approaches for optimizing its responsiveness that might facilitate regulatory qualification and trial design. ANN NEUROL 2023.

Natural History of Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay: a 4-Year Longitudinal Study.

Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is a neurologic disorder with generally well-known clinical manifestations. However, few studies assessed their progression rate using a longitudinal design. This study aimed to document the natural history of ARSACS over a 4-year period in terms of upper and lower limb functions, balance, walking capacity, performance in daily living activities, and disease severity. Forty participants were assessed on three occasions over 4 years. Participant performance was reported in raw data as well as in percentage from reference values to consider the normal aging process. Severe balance and walking capacity impairments were found, with a significant performance decrease over the 4 years. Balance reached a floor score of around 6 points on the Berg Balance Scale for participants aged >40 years, while other participants lost about 1.5 points per year. The mean loss in walking speed was 0.044 m/s per year and the mean decrease in the distance walked in 6 min was 20.8 m per year for the whole cohort. Pinch strength, balance, walking speed, and walking distance decreased over time even when reported in percentage from reference values. Major impairments and rapid progression rates were documented in the present study for upper limb coordination, pinch strength, balance, and walking capacity in the ARSACS population. A progression rate beyond the normal aging process was observed. These results provide fundamental insights regarding the disease prognosis that will help to better inform patients, develop specific rehabilitation programs, and improve trial readiness.

In Vitro Characterization of Motor Neurons and Purkinje Cells Differentiated from Induced Pluripotent Stem Cells Generated from Patients with Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay.

Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is an early-onset neurodegenerative disease mainly characterized by spasticity in the lower limbs and poor muscle control. The disease is caused by mutations in the SACS gene leading in most cases to a loss of function of the sacsin protein, which is highly expressed in motor neurons and Purkinje cells. To investigate the impact of the mutated sacsin protein in these cells in vitro, induced pluripotent stem cell- (iPSC-) derived motor neurons and iPSC-derived Purkinje cells were generated from three ARSACS patients. Both types of iPSC-derived neurons expressed the characteristic neuronal markers β3-tubulin, neurofilaments M and H, as well as specific markers like Islet-1 for motor neurons, and parvalbumin or calbindin for Purkinje cells. Compared to controls, iPSC-derived mutated SACS neurons expressed lower amounts of sacsin. In addition, characteristic neurofilament aggregates were detected along the neurites of both iPSC-derived neurons. These results indicate that it is possible to recapitulate in vitro, at least in part, the ARSACS pathological signature in vitro using patient-derived motor neurons and Purkinje cells differentiated from iPSCs. Such an in vitro personalized model of the disease could be useful for the screening of new drugs for the treatment of ARSACS.

Digital health metrics reveal upper limb impairment profiles in ARSACS

ObjectiveAdults with autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) often present with reduced upper limb coordination affecting their independence in daily life. Previous studies in ARSACS identified reduced performance in clinical assessments requiring fine and gross dexterity as well as prehension. However, the kinematic and kinetic aspects underlying reduced upper limb coordination in ARSACS have not been systematically investigated yet. In this work, we aimed to provide a detailed characterization of alterations in upper limb movement patterns and hand grip forces in 57 participants with ARSACS. MethodsWe relied on a goal-directed technology-aided assessment task, which provides eight previously validated digital health metrics describing movement efficiency, smoothness, speed, and grip force control. ResultsFirst, we observed that 98.3% of the participants were impaired in at least one of the metrics, that all metrics are significantly impaired on a population level, and that grip force control during precise manipulations is most commonly and strongly impaired. Second, we identified high inter-participant variability in the kinematic and kinetic impairment profiles, thereby capturing different clinical profiles subjectively observed in this population. Lastly, abnormal goal-directed task performance in ARSACS could be best explained by reduced movement speed, efficiency, and especially force control during precise manipulations, while abnormal movement smoothness did not have a significant effect. InterpretationThis work helped to refine the clinical profile of ARSACS and highlights the need for characterizing individual kinematic and kinetic impairment profiles in clinical trials in ARSACS.

Research advance on the pathogenesis of autosomal recessive spastic ataxia of Charlevoix-Saguenay

Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is a rare and early-onset neurodegenerative disease caused by variants of the SACS gene which maps to chromosome 13q11 and encodes sacsin protein. Sacsin is highly expressed in large motor neurons, in particular cerebellar Purkinje cells. This article has provided a review for the structure and function of sacsin protein and the mechanisms underlying abnormalities of sacsin in ARSACS disease.

A rehabilitation program to increase balance and mobility in ataxia of Charlevoix-Saguenay: An exploratory study.

Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is characterized by balance impairment and mobility limitations, which both increase the risk of falling. The objective of this study was to explore the effects of a rehabilitation program aimed at increasing trunk and lower limb motor control on balance and walking abilities, and accomplishment of activities of daily living. In this exploratory study, a group-supervised rehabilitation program was performed three times a week for 8 weeks (two sessions at a rehabilitation gym and one pool session). Outcome measures included the Ottawa Sitting Scale, Berg Balance Scale, modified Activities-specific Balance Confidence Scale, 30-Second Chair Stand Test, 10-Meter Walk Test, Barthel Index, and Scale for the Assessment and Rating of Ataxia. Significant improvements in balance, trunk control, maximal and self-selected walking speed difference, ataxia severity and accomplishment of specific activities of daily living were noted for the whole group at the end of the program. At the individual level, all participants improved beyond the standard error of measurement in at least two outcome measures. Also, most participants reported many perceived improvements related to balance, posture and functional mobility. This study provides encouraging results on the effects of a rehabilitation program for ambulatory people with ARSACS. Group intervention could have a positive impact on their daily lives and improve the health care service offered to this population. Future studies with larger sample sizes including control groups and other forms of ataxia are necessary to validate our results to generalize them.

Multi-omic profiling reveals the ataxia protein sacsin is required for integrin trafficking and synaptic organization.

Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is a childhood-onset cerebellar ataxia caused by mutations in SACS, which encodes the protein sacsin. Cellular ARSACS phenotypes include mitochondrial dysfunction, intermediate filament disorganization, and progressive death of cerebellar Purkinje neurons. It is unclear why the loss of sacsin causes these deficits or why they manifest as cerebellar ataxia. Here, we perform multi-omic profiling in sacsin knockout (KO) cells and identify alterations in microtubule dynamics and mislocalization of focal adhesion (FA) proteins, including multiple integrins. Deficits in FA structure, signaling, and function can be rescued by targeting PTEN, a negative regulator of FA signaling. ARSACS mice possess mislocalization of ITGA1 in Purkinje neurons and synaptic disorganization in the deep cerebellar nucleus (DCN). The sacsin interactome reveals that sacsin regulates interactions between cytoskeletal and synaptic adhesion proteins. Our findings suggest that disrupted trafficking of synaptic adhesion proteins is a causal molecular deficit in ARSACS.

I.15 Neuromuscular Disorders with Founder Effects in French Canada: why, where and how they contribute to the NMD field

The French settlers of North America during the French Regime (1604-1763) were few and sparse on a vast continent. Understanding the early pioneer period and the subsequent growth of their descendants is key to explain the higher regional prevalence of certain Neuromuscular Disorders (NMD) in Canada. We will review the genetic impact of the various population bottlenecks that shaped the French Canadian gene pool. We will present a history of the identification of NMD with Canadian regional founder effects to emphasize how these large cohorts played a role in gene identification. Using oculopharyngeal muscular dystrophy (OPMD) as a prototype of FC founder diseases, we will chart how large FC cohorts disproportionally continue to contribute to our knowledge of these conditions. Myotonic muscular dystrophy type 1 (DM1) and Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay (ARSACS) will also be discussed to underline the value of large cohort characterizations for granular clinical phenotyping and natural history studies. Lastly, we will discuss the contribution of rare recessive mutations and dominant mutations with variable prevalence to the identification of novel mutations relying on the mixed European and First Nation backgrounds of the French Canadian population.

Clinical and genetic characterization of a Taiwanese cohort with spastic paraparesis combined with cerebellar involvement.

Hereditary spastic paraplegias (HSPs) are a heterogeneous group of neurodegenerative disorders clinically characterized by progressive lower-limb spasticity. Cerebellar ataxia commonly co-occurs with complicated HSPs. HSP with concurrent cerebellar ataxia has significant clinical and genetic overlaps with hereditary cerebellar ataxia (HCA) and other inherited neurological diseases, adding to the challenge of planning genetic testing for the disease. In this study, we characterized clinical features of a cohort of 24 patients (male/female: 15/9) from 22 families who presented spastic paraparesis combined with cerebellar involvement, with a median disease onset age 20.5 (range 5–53) years. Aside from the core phenotype, 18 (75%) patients had additional neuropsychiatric and systemic manifestations. A stepwise genetic testing strategy stratified by mode of inheritance, distinct neuroimaging features (e.g., thin corpus callosum), population-specific prevalence and whole-exome sequencing was utilized to investigate the genetic etiology. Causative mutations in up to 10 genes traditionally related to HSP, HCA and other neurogenetic diseases (autosomal recessive spastic ataxia of Charlevoix-Saguenay, neurodegeneration with brain iron accumulation, and progressive encephalopathy with brain atrophy and thin corpus callosum) were detected in 16 (73%) of the 22 pedigrees. Our study revealed the genetic complexity of HSP combined with cerebellar involvement. In contrast to the marked genetic diversity, the functions of the causative genes are restricted to a limited number of physiological themes. The functional overlap might reflect common underlying pathogenic mechanisms, to which the corticospinal tract and cerebellar neuron circuits may be especially vulnerable.

First report of spastic ataxia of Charlevoix-Saguenay cases in Mexico. Novel SACS gene mutations identified

Introduction and objectivesSpinocerebellar ataxia autosomal recessive (SCAR) represents a heterogeneous chronic and progressive neurological diseases group. They usually occur at an early age in a progressive manner. Diagnosis is complex due to phenotypic overlap. SCARs account for more than 50% of all ataxia cases of genetic origin, with a prevalence of 3–4/100 000. According to international published series, Friedreich's ataxia (FA) is the most common. In Mexico, more than 90% of patients with suspected SCAR remain without etiologic diagnosis after ruling out FA and acquired causes of ataxia. Our main goal was to reach a diagnosis using genomic tools in this group of patients. Materials and methodsAt the National Institute of Genomic Medicine, we used next-generation sequencing as a diagnostic tool in 4 patients with a clinical diagnosis of SCAR to identify and classify etiologic variants responsible for this group of disorders. ResultsTwo novel pathogenic variants were identified in the SACS gene, and the diagnosis of autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) was established. ConclusionsThis is the first report of spastic ataxia of Charlevoix-Saguenay cases in Mexico.

The ARSACS disease protein sacsin controls lysosomal positioning and reformation by regulating microtubule dynamics

Autosomal recessive spastic ataxia of Charlevoix-Saguenay is a fatal brain disorder featuring cerebellar neurodegeneration leading to spasticity and ataxia. This disease is caused by mutations in the SACS gene that encodes sacsin, a massive 4579-amino acid protein with multiple modular domains. However, molecular details of the function of sacsin are not clear. Here, using live cell imaging and biochemistry, we demonstrate that sacsin binds to microtubules and regulates microtubule dynamics. Loss of sacsin function in various cell types, including knockdown and KO primary neurons and patient fibroblasts, leads to alterations in lysosomal transport, positioning, function, and reformation following autophagy. Each of these phenotypic changes is consistent with altered microtubule dynamics. We further show the effects of sacsin are mediated at least in part through interactions with JIP3, an adapter for microtubule motors. These data reveal a new function for sacsin that explains its previously reported roles and phenotypes.

Integrative Organelle-Based Functional Proteomics: In Silico Prediction of Impaired Functional Annotations in SACS KO Cell Model.

Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is an inherited neurodegenerative disease characterized by early-onset spasticity in the lower limbs, axonal-demyelinating sensorimotor peripheral neuropathy, and cerebellar ataxia. Our understanding of ARSACS (genetic basis, protein function, and disease mechanisms) remains partial. The integrative use of organelle-based quantitative proteomics and whole-genome analysis proposed in the present study allowed identifying the affected disease-specific pathways, upstream regulators, and biological functions related to ARSACS, which exemplify a rationale for the development of improved early diagnostic strategies and alternative treatment options in this rare condition that currently lacks a cure. Our integrated results strengthen the evidence for disease-specific defects related to bioenergetics and protein quality control systems and reinforce the role of dysregulated cytoskeletal organization in the pathogenesis of ARSACS.

Cannabis use in patients with Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay

Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay (ARSACS) is an early-onset cerebellar ataxia with often presence of peripheral sensorimotor neuropathy and lower limb spasticity. Recently, the presence of pain has been associated with ARSACS in a quarter of the population in relation to spasms and neuropathic pain. However, limited therapeutic options available to patients and the occurrence of persistent symptoms despite treatment with the usual pharmacologic agents have led to exploring cannabis as a potential alternative. The aim of this study was to characterize the profile of cannabis use among patients with ARSACS. Phone interviews were conducted to document current or former cannabis use. Reasons of cannabis use and the characteristics of use were also investigated. Among the 50 study participants, 18% currently used cannabis, 40% reported at least one occurrence of cannabis use and 42% reported having never used cannabis. A greater proportion of patients with regular cannabis use reported chronic pain in comparison to those who never used. Although less frequent than ataxia, spasticity, muscle cramps or muscle spasms, which were independently reported by more than half of the studied sample, chronic pain was notably present in 30% of participants. While our study did not assess the therapeutic effects of cannabis, our results highlight that there is a potential role for cannabis and cannabinoids in the management of multiple ARSACS-associated symptoms and that agents modulating the endocannabinoid system need to be properly investigated.

Genetic origin of patients having spastic paraplegia with or without other neurologic manifestations

BackgroundHereditary spastic paraplegia (HSP) is a group of neurodegenerative diseases characterized by lower-limb spastic paraplegia with highly genetic and clinical heterogeneity. However, the clinical sign of spastic paraplegia can also be seen in a variety of hereditary neurologic diseases with bilateral corticospinal tract impairment. The purpose of this study is to identify the disease spectrum of spastic paraplegia, and to broaden the coverage of genetic testing and recognize clinical, laboratorial, electrophysiological and radiological characteristics to increase the positive rate of diagnosis.MethodsTwenty-seven cases were screened out to have definite or suspected pathogenic variants from clinically suspected HSP pedigrees through HSP-associated sequencing and/or expanded genetic testing. One case was performed for enzyme detection of leukodystrophy without next-generation sequencing. In addition, detailed clinical, laboratorial, electrophysiological and radiological characteristics of the 28 patients were presented.ResultsA total of five types of hereditary neurological disorders were identified in 28 patients, including HSP (15/28), leukodystrophy (5/28), hereditary ataxia (2/28), methylmalonic acidemia/methylenetetrahydrofolate reductase deficiency (5/28), and Charcot-Marie-tooth atrophy (1/28). Patients in the HSP group had chronic courses, most of whom were lower limbs spasticity, mainly with axonal neuropathy, and thinning corpus callosum, white matter lesions and cerebellar atrophy in brain MRI. In the non-HSP groups, upper and lower limbs both involvement was more common. Patients with homocysteine remethylation disorders or Krabbe’s disease or autosomal recessive spastic ataxia of Charlevoix-Saguenay had diagnostic results in laboratory or imaging examination. A total of 12 new variants were obtained.ConclusionsHSP had widespread clinical and genetic heterogeneity, and leukodystrophy, hereditary ataxia, Charcot-Marie-Tooth atrophy and homocysteine remethylation disorders accounted for a significant proportion of the proposed HSP. These diseases had different characteristics in clinical, laboratorial, electrophysiological, and radiological aspects, which could help differential diagnosis. Genetic analysis could ultimately provide a clear diagnosis, and broadening the scope of genetic testing could improve the positive rate of diagnosis.