Canine RNF170 Single Base Deletion in a Naturally Occurring Model for Human Neuroaxonal Dystrophy.

BACKGROUND: Neuroaxonal dystrophy (NAD) is a group of inherited neurodegenerative disorders characterized primarily by the presence of spheroids (swollen axons) throughout the central nervous system. In humans, NAD is heterogeneous, both clinically and genetically. NAD has also been described to naturally occur in large animal models, such as dogs. A newly recognized disorder in Miniature American Shepherd dogs (MAS), consisting of a slowly progressive neurodegenerative syndrome, was diagnosed as NAD via histopathology. OBJECTIVES: To describe the clinical and pathological phenotype together with the identification of the underlying genetic cause. METHODS: Clinical and postmortem evaluations, together with a genome-wide association study and autozygosity mapping approach, followed by whole-genome sequencing. RESULTS: Affected dogs were typically young adults and displayed an abnormal gait characterized by pelvic limb weakness and ataxia. The underlying genetic cause was identified as a 1-bp (base pair) deletion in RNF170 encoding ring finger protein 170, which perfectly segregates in an autosomal recessive pattern. This deletion is predicted to create a frameshift (XM_038559916.1:c.367delG) and early truncation of the RNF170 protein (XP_038415844.1:(p.Ala123Glnfs*11)). The age of this canine RNF170 variant was estimated at ~30 years, before the reproductive isolation of the MAS breed. CONCLUSIONS: RNF170 variants were previously identified in human patients with autosomal recessive spastic paraplegia-85 (SPG85); this clinical phenotype shows similarities to the dogs described herein. We therefore propose that this novel MAS NAD could serve as an excellent large animal model for equivalent human diseases, particularly since affected dogs demonstrate a relatively long lifespan, which represents an opportunity for therapeutic trials. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Pseudodominance in RFC1-Spectrum Disorder.

Cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS) and disease spectrum is an autosomal recessive disorder associated with biallelic repeat expansion (RE) in the RFC1 gene. A high carrier frequency in the healthy population determines the possibility of having affected members in two consecutive generations. We describe pseudodominance in two families affected with RFC1 disorder (10 affected, 5 oligo/asymptomatic individuals). In Family A, after the 75-year-old index case was diagnosed with CANVAS, the 73-year-old wife decided to undergo screening for carrier testing. Although she did not report any symptoms, she resulted positive for the biallelic AAGGG RE thus leading to a diagnosis in the asymptomatic offspring as well and revealing a pseudodominant pattern of inheritance. In Family B pseudodominance was suspected after the identification of the RFC1 RE in the proband affected by sensitive neuropathy because of a positive family history for undetermined polyneuropathy in the mother. The post-mortem identification of the RFC1 RE in a sample specimen from the deceased mother, who had been under our care, allowed the solution of a "cold case". Our report suggests that pseudodominance is a confounding phenomenon to consider in RFC1-spectrum disorder and genetic counselling is instrumental in families with affected individuals.

Digenic FLNA and UCHL1 variants resulting in a complex phenotype.

AIM: X-linked variants in Filamin A (FLNA) are associated with the Ehlers-Danlos-syndrome-variant form of periventricular heterotopia, and autosomal dominant variants in ubiquitin C-terminal hydrolase L1 (UCHL1) are associated with a late-onset spastic ataxia, peripheral neuropathy and optic atrophy. Here we present a rare case involving both a novel heterozygous whole-gene deletion of UCHL1 and a heterozygous frameshift variant in the FLNA gene resulting in a complex phenotype. METHODS: A 67-year-old female with a confirmed pathogenic variant in the FLNA gene, resulting in an enlarged aorta and joint pains, presented with a 4-year history of severe sensory ataxia, upper motor neuron signs, eye movement abnormalities and severe sensory loss. RESULTS: Neurophysiology including Somatosensory-evoked potentials confirmed the sensory loss as predominantly preganglionic with denervation. Genetic testing revealed a digenic cause of her complex presentation, confirming a pathogenic frameshift variant in the FLNA gene and a heterozygous loss of function deletion in the UCHL1 gene. CONCLUSIONS: To the best of our knowledge, this is the first case with concomitant pathogenic variants in the FLNA and UCHL1 genes which explain the complex phenotype. The severe preganglionic sensory loss is also a rare finding and expands the phenotype of UCHL1 variants.

Imbalance and gait impairment in Parkinson's disease: discussing postural instability and ataxia.

Gait and balance difficulties pose significant clinical challenges in Parkinson's disease (PD). The impairment of physiological mechanisms responsible for maintaining natural orthostatism plays a central role in the pathophysiology of postural instability observed in PD. In addition to the well-known rigidity and abnormalities in muscles and joints, various brain regions involved in the regulation of posture, balance, and gait, such as the basal ganglia, cerebellum, and brainstem regions like the pontine peduncle nucleus, are affected in individuals with PD. The recognition of the cerebellum's role in PD has been increasingly acknowledged. Cortical areas and their connections are associated with freezing of gait, a type of frontal lobe ataxia commonly observed in PD. Furthermore, impairments in the peripheral nervous system, including those caused by levodopatherapy, can contribute to gait impairment and imbalance in PD patients. Consequently, individuals with PD may exhibit frontal ataxia, sensory ataxia, and even cerebellar ataxia as underlying causes of gait disturbances and imbalance, starting from the early stages of the disease. The complex interplay between dysfunctional brain regions, impaired cortical connections, and peripheral nervous system abnormalities contributes to the multifaceted nature of gait and balance difficulties in PD. Understanding the intricate mechanisms is crucial for the development of effective therapeutic approaches targeting these specific deficits in PD.

RNF170 mutation causes autosomal dominant sensory ataxia with variable pyramidal involvement.

BACKGROUND: Although hereditary ataxias are a group of clinically and genetically heterogeneous disorders, specific clinical clues can sometimes incriminate certain genes. This can trigger genetic testing in sporadic patients or prompt dissecting certain genes more thoroughly when initial genetic testing is negative. Also for the assembly of gene panels and interpretation of the results, genotype-phenotype correlations remain important to establish. METHODS: We clinically evaluated a Belgian family with autosomal dominant inherited sensory ataxia and variable pyramidal involvement and performed targeted clinical exome sequencing. Secondly, we retrospectively screened sequencing data of an in-house cohort of 404 patients with neuromuscular disorders for variants in the identified gene RNF170. RESULTS: All affected family members showed sensory ataxia on examination. Pyramidal involvement, and sometimes slow-pursuit abnormalities and/or a sensory neuropathy, were more variable findings. We identified the heterozygous variant p.Arg199Cys in RNF170 in all three affected siblings of our family. We did not find additional pathogenic variants in RNF170 in our in-house neuromuscular cohort. CONCLUSIONS: We confirm the heterozygous variant p.Arg199Cys in RNF170 in a Belgian family with autosomal dominant sensory ataxia and variable pyramidal involvement. This constitutes a rare but clinically recognizable phenotype that warrants testing of RNF170. Unlike the distinctive bi-allelic loss of function variants in RNF170 associated with hereditary spastic paraplegia (HSP), the p.Arg199Cys variant is the only one reported in sensory ataxia. It is important for neurologists to be aware of this characteristic phenotype and to include this gene in gene panels for ataxia and HSP.

Sensory neuronopathy is a specific and disabling neurological manifestation of autoimmune hepatitis.

BACKGROUND AND PURPOSE: Neurological manifestations have been identified in the context of autoimmune hepatitis (AIH). Previous case reports highlighted the association between AIH and sensory neuronopathy (SN). Despite that, little is known about the frequency of AIH-related SN and its clinical/neurophysiological profile. Moreover, it is not clear whether SN is an AIH-specific manifestation or related to chronic liver damage. METHODS: Seventy consecutive AIH patients were enrolled and their characteristics were compared with 52 consecutive patients with chronic active hepatitis B. All subjects underwent clinical and neurophysiological evaluation. Further comparisons were performed between AIH SN and AIH non-SN patients. RESULTS: Mean ages and male:female proportions in the AIH and chronic active hepatitis B groups were 42.2 ± 16.3/51.7 ± 13.6 years and 14:56/29:23, respectively. The frequencies of carpal tunnel syndrome, radiculopathy and polyneuropathy were similar between groups. In contrast, SN was identified only in AIH patients (5/70 vs. 0/52, P = 0.04); the overall prevalence of AIH-related SN was 7% with an average profile of a woman in her 40s with asymmetric onset of sensory deficits that chronically evolved to disabling proprioceptive ataxia associated with marked dysautonomia. Neurological disability and hepatocellular damage did not follow in parallel. Anti-fibroblast growth factor receptor type 3 antibodies were found in 3/5 (60%) of the patients with AIH-related SN. Clinical or demographic predictors of SN in the context of AIH could not be identified. CONCLUSION: Sensory neuronopathy, but not other peripheral nervous system diseases, is a specific AIH neurological manifestation. It is often disabling and, in contrast to hepatocellular injury, does not respond to immunosuppression.

Sensory ataxia rating scale: Development and validation of a functional scale for patients with sensory neuronopathies.

Sensory neuronopathies (SN) result from dorsal root ganglia damage and manifest with a combination of sensory deficits and proprioceptive ataxia. Characterization of the natural history and development of therapeutic trials are hampered by the lack of clinical scales that capture the whole spectrum of SN-related manifestations. We propose and validate a rating instrument for SN. Three experienced neuromuscular specialists developed items to rate SN. The resultant instrument was later validated by the assessment of the intra-class correlation coefficient, for inter-rater validity in 48 SN patients, and later in a smaller subset of 16 patients to assess its intra-rater validity. Standardized Crombach's alpha and Oblimin rotation analysis were performed to verify internal consistency and items' relationship, respectively. Evaluation of Sensory Ataxia Rating Scale (SEARS)'s external validity was performed by comparison to: scale for the assessment and rating of ataxia (SARA), Beck balance scale (BBS), and INCAT sensory sum score (ISS). A 10-item scale with an intra-class correlation coefficient >0.95 for intra- and inter-rating measurements with a good internal consistency (standardized Cronbach's alpha of 0.83) were observed. There was a normal distribution of the scores without a floor or ceiling effect. A moderate to good correlation between SEARS and SARA, BBS, and ISS was observed. SEARS is a reliable, easy-to-perform and consistent instrument to rate SN. Larger cohorts and multicenter studies are needed to validate its usefulness towards possible treatment trials.

A "matched" sensory reference can guide goal-directed movements of the affected hand in central post-stroke sensory ataxia.

Patients with central post-stroke sensory ataxia (CPSA) suffer from not only somatosensory dysfunction but also the ataxic movement disorder of the affected limb. These sensory and motor impairments possibly interfere each other, but such interference is still unclear. We evaluated smoothness of grasp movements in CPSA patients using a kinematic analysis, and verified the effect of somatosensory reference from the intact hand on grasp movements. Eight CPSA patients were enrolled. We recorded their reach-and-pinch movements of both affected and intact hands toward the tip of the 3-cm-diameter vertical bar, using a three-dimensional measurement system. When executing these movements of one hand, the patients simultaneously pinched the same diameter bar as the goal tip (matched-reference condition: Matched-Ref) or the 5-cm-diameter thicker bar (mismatched-reference condition: Mismatched-Ref) by the other hand. The normalized jerk index (i.e., movement smoothness) of the affected hand was disturbed compared with the intact hand. The kinematic data of the finger opening and closing phases were also disturbed. These disturbances were partially improved with Matched-Ref but not Mismatched-Ref of the intact hand. We successfully evaluated the features of CPSA, indicating that the somatosensory reference method could be useful for rehabilitation in sensory ataxia.

[Sensory neuronopathy. Its recognition and early treatment]. / Neuronopatía sensitiva. Su reconocimiento y tratamiento temprano.

Sensory neuronopathies or ganglionopathies, or dorsal root ganglion disorders, represent a subgroup of peripheral nervous system diseases, frequently associated with dysinmune or neoplastic disorders and with toxic agents. A degeneration of both central and peripheral sensory proyections is present. Patients typically show early ataxia, loss of deep tendon reflexes and positive sensory symptoms present both in proximal and distal sites of the body. We retrospectively studied 10 cases with a final diagnosis of sensory neuronopathy. Sensory neuropathy was the presenting symptom and the course was subacute in all cases. Paresthesias in upper limbs were a predominant manifestation (100%). Other manifestations included: hypoesthesia (10/10), gait ataxia (8/10), autonomic symptoms (3/10) and perioral paresthesias (3/10). Electrophysiology showed sensory axonal neuronal pattern, with normal motor responses. Final diagnosis was acquired sensory neuronopathy in all patients, associated with Sjögren's syndrome in 2, with lupus erythematosus in 1, with rheumatoid arthritis in 1, with a cancer in 2 (paraneoplastic) and idiopathic in 4. In paraneoplastic cases, the tumor was small cell lung cancer in 1 (with positive anti-Hu antibodies), and epidermoid lung cancer in the other. Eight patients were treated with immunotherapy, high dose intravenous methylprednisolone and/or intravenous immunoglobulin; with poor response in 4 cases, neurologic improvement in 5, and without any change in 1 patient. The present work shows the typical clinical and electrophysiological pattern of subacute sensory neuronopathy, and the relevance of early treatment.

Balance exercise in patients with chronic sensory ataxic neuropathy: a pilot study.

Although exercise therapy is considered part of the treatment of neuropathic patients, and somatosensory input is essential for motor learning, performance and neural plasticity, rehabilitation of patients with sensory ataxia has received little attention so far. The aim of this prospective pilot study was to explore the short- and medium-term efficacy of a 3-week intensive balance and treadmill exercise program in chronic ataxic neuropathy patients; 20 consecutive patients with leg overall disability sum score (ODSS-leg) ≥2, absent/mild motor signs, clinical and therapeutic stability ≥4 months were enrolled. Evaluations were done at baseline, at the end of treatment and at 3- and 6-month follow-up. Outcome measurements included: ODSS-leg, Berg balance scale, 6-min walk distance, and the functional independence measure (FIM) scale. The short-form-36 health status scale (SF-36) was used to measure health-related quality of life (HRQoL). ODSS-leg improved significantly compared with baseline, 3 weeks, 3 months (primary outcome), and 6 months follow-up. A significant improvement in all functional secondary outcome measurements and in some SF-36 subscales was also observed. This pilot study suggests that balance exercise is safe and well tolerated and might be effective in ameliorating disability and HRQoL in patients with chronic peripheral sensory ataxia.

Romberg's test revisited: Changes in classical and advanced sway metrics in patients with pure sensory neuropathy.

OBJECTIVES: The Romberg test, undoubtedly a classical and well-established method in physical neurological assessment of patients with sensory ataxia, has long been suspected to be prone to several limitations. Here, we quantified upright stance before and after visual deprivation in a selected cohort of patients with pure sensory neuropathy. METHODS: Static balance was assessed in sensory neuropathy patients during quiet stance on a force platform under different visual and proprioceptive feedback conditions. Sural nerve neurography was employed to evaluate the severity of peripheral neuropathy. Conventional and advanced postural sway metrics were investigated to draw a quantitative analogy to the clinical Romberg test. RESULTS: Posturographic analyses showed that patients displayed Romberg and vestibular Romberg quotient values around 2, indicating an approximately twofold increase in body sway in the absence of vision. However, the diagnostic discrimination ability between patients and controls was only modest. Even less impactful were the diagnostic contributions of frequency domain and non-linear sway analyses. This was primarily attributed to the heightened body sway exhibited by patients with sensory neuropathy under 'eyes open' conditions, diminishing the contrast with the 'eyes closed' condition as assessed in the classical Romberg test. CONCLUSION: We conclude that the Romberg test, even in its quantitative form with the aid of an apparatus, had an unsatisfactory classification value in terms of distinguishing patients from healthy controls. Instead, it should be interpreted within the comprehensive context of the broader neurological examination and the electrodiagnosis of peripheral nerve function.

Guillain-Barré syndrome post-SARS-CoV-2 vaccine: a systematic review and data analysis on its clinical, laboratory, electrophysiological, and radiological features.

Introduction: Guillain-Barré syndrome (GBS) is a rare disease that affects almost 0.8-1.9 cases per 100,000 people worldwide every year. This is the most prevalent cause of subacute flaccid paralyzing illness today. It is a subacute inflammatory demyelinating polyradiculoneuropathy; the typical scenario involves ascending symmetrical flaccid paralysis, but in some circumstances, sensory, autonomic, and cranial neuropathy may also be involved. Several vaccines have been found to have complications since the previous century. Numerous case reports of GBS in the literature have been reported following COVID-19 vaccines in recent times. Objective: This study aimed to conduct a comprehensive examination of GBS cases that have been reported after COVID-19 vaccines; to analyze the descriptive statistical analysis of data gathered regarding clinical, laboratory, electrophysiological, and radiological characteristics; to discuss, based on the available evidence, whether the disease has a preference for a particular vaccine type; and to speculate on the potential pathogenesis. Methodology: This review has been carried out by recommendations of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Result: Reviewing 60 case reports illustrated that most of them are from the USA (18.1%) and the majority of affected individuals were males (60%). The results favored the association between vector-based SARS-CoV-2 vaccine, particularly AstraZeneca vaccine, and the GBS. The mean of symptoms onset is 11.4 days. The results of diagnostic tests such as LP are consistent mostly with albumin-cytological dissociation (81.81%), where brain and spine MRI was unremarkable in 59.52%. Regarding electrodiagnostic tests, AIDP is the most common variant (61.81%). The management was not consistent among the case reports. However, IVIG is the most frequent way of treating these patients (68.33%). The functional outcome was documented in 47 patients; 65% improved with medical management. Conclusion: This study aimed to conduct a systematic review of reported cases of GBS following COVID-19 vaccines and descriptive statistical analysis of collected data on clinical, laboratory, electrophysiological, and radiological features, to discuss, based on available results, whether the disease has a predilection to a specific vaccine type and to speculate the potential pathogenesis.

[Chronic inflammatory sensory polyradiculopathy]. / Polirradiculopatía inflamatoria crónica sensitiva.

Chronic inflammatory sensory polyradiculopathy is a defined entity, frequently underdiagnosed, and potentially treatable. It must be suspected in patients with sensory ataxia, normal nerve conduction studies, and MRI with thickened lumbosacral nerve roots and gadolinium enhancement. We present the case of a 57-year-old man with marked sensory ataxia on his left leg. Examination showed normal strength, decreased knee and ankle jerks. Light touch and pinprick sensations were reduced below the knees. Vibration and joint position sense were absent at the feet. Nerve conduction studies were normal. Tibial sensory evoked potentials disclosed absent responses bilaterally. CSF was acellular with elevated protein. Lumbosacral magnetic resonance showed thickening of roots, with gadolinium enhancement. The patient was treated with IV-Ig, 2 g/kg, for 5 days with improvement of symptoms. The clinical course, elevated CSF protein, the evidence of root enhancement on the MRI, good response to immunotherapy, and the exclusion of other causes of sensory ataxia, were compatible with the diagnosis of chronic inflammatory sensory polyradiculopathy. To diagnose this disease the identification of isolated involvement of the sensory roots is required.

[Non-cerebellar ataxias: posterior column-like ataxia and cerebellar-like ataxia].

Ataxia is not only due to cerebellar lesions, but also due to non-cerebellar lesions such as those in the brain, spinal cord, dorsal root (DR), peripheral nerve. In this article, optic ataxia is excluded and 'vestibular ataxia' is briefly referred. Non-cerebellar ataxias are generically called sensory ataxia or posterior column ataxia. However, since non-cerebellar lesions, e.g. frontal lobe lesions, may develop "cerebellar-like ataxia" (Hirayama, 2010). At the same time, non-posterior column lesions, e.g. parietal lobe lesion, can show "posterior column-like ataxia". From these viewpoints, I here describe various non-cerebellar ataxia in some disorders such as tabes dorsalis and sensory neuropathies and emphasize a role of a peripheral sensory input to the cerebellum via the DR ganglia and spinocerebellar tract for sensory ataxia because there is the International Consensus (2016) that the ataxia in Miller Fisher syndrome is suggested cerebellar-like clinicophysiologically.

Gait analysis in chemotherapy-induced peripheral neurotoxicity rodent models.

Gait analysis could be used in animal models as an indicator of sensory ataxia due to chemotherapy-induced peripheral neurotoxicity (CIPN). Over the years, gait analysis in in vivo studies has evolved from simple observations carried out by a trained operator to computerised systems with machine learning that allow the quantification of any variable of interest and the establishment of algorithms for behavioural classification. However, there is not a consensus on gait analysis use in CIPN animal models; therefore, we carried out a systematic review. Of 987 potentially relevant studies, 14 were included, in which different methods were analysed (observation, footprint and CatWalk™). We presented the state-of-the-art of possible approaches to analyse sensory ataxia in rodent models, addressing advantages and disadvantages of different methods available. Semi-automated methods may be of interest when preventive or therapeutic strategies are evaluated, also considering their methodological simplicity and automaticity; up to now, only CatWalk™ analysis has been tested. Future studies should expect that CIPN-affected animals tend to reduce hind paw support due to pain, allodynia or loss of sensation, and an increase in swing phase could or should be observed. Few available studies documented these impairments at the last time point, and only appeared later on respect to other earlier signs of CIPN (such as altered neurophysiological findings). For that reason, gait impairment could be interpreted as late repercussions of loss of sensory.

Sensory Ataxic Guillain-Barré Syndrome with Dysgeusia after mRNA COVID-19 Vaccination.

Guillain-Barré syndrome (GBS) has occasionally occurred in people who have received coronavirus disease 2019 (COVID-19) vaccines. Dysgeusia is rare symptom of GBS. We herein report a rare case of sensory ataxic GBS with dysgeusia just after the second dose of the Pfizer-BioNTech COVID-19 vaccine. Although autoantibodies against glycolipids were not detected, immunotherapy with intravenous immunoglobulin and methylprednisolone pulse therapy effectively ameliorated the symptoms. Our report suggests that the COVID-19 vaccine may induce various clinical subtypes of GBS, including a rare variant with sensory ataxia and dysgeusia.

Case report: Autoimmune nodopathy with concurrent serum and CSF IgG4 anti-neurofascin 155 antibodies.

Objective: To report a case of autoimmune nodopathy (AN) with concurrent serum and CSF immunoglobulin (Ig)G4 anti-neurofascin 155 (NF155) and anti-GD1b antibodies. Methods: A 20-year-old male presented distal weakness of the 4 limbs, hypoesthesia, absent tendon reflexes and sensory ataxia. Nerve conduction studies (NCS), MRI, and autoantibody tests were performed. Results: NCS revealed a diffuse demyelinating neuropathy in the peripheral nerve with motor and sensory involvement. MRI of the cervical and lumbar plexus showed diffuse enlargement. IgG4 anti-NF155 antibodies in both serum and CSF and IgG anti-GD1b antibodies in serum were positive. After treatment with IVIg, rituximab, and plasma exchange, the titer of the patient's anti-NF155 antibodies decreased, but symptoms did not significantly improve. Discussion: This patient presented a typical clinical feature of AN with serum and CSF anti-NF155 antibodies and serum anti-GD1b antibodies coexistent but poor response to IVIg, rituximab and plasma exchange. Early detection of antibodies may be helpful in both diagnosis and therapy of the disease. And prospective studies are necessary to demonstrate the potential role of anti-NF155 antibodies in CSF and help further understand this complex and heterogeneous disease.

Clinical Recognition of Sensory Ataxia and Cerebellar Ataxia.

Ataxia is a kind of external characteristics when the human body has poor coordination and balance disorder, it often indicates diseases in certain parts of the body. Many internal factors may causing ataxia; currently, observed external characteristics, combined with Doctor's personal clinical experience play main roles in diagnosing ataxia. In this situation, different kinds of diseases may be confused, leading to the delay in treatment and recovery. Modern high precision medical instruments would provide better accuracy but the economic cost is a non-negligible factor. In this paper, novel non-contact sensing technique is used to detect and distinguish sensory ataxia and cerebellar ataxia. Firstly, Romberg's test and gait analysis data are collected by the microwave sensing platform; then, after some preprocessing, some machine learning approaches have been applied to train the models. For Romberg's test, time domain features are considered, the accuracy of all the three algorithms are higher than 96%; for gait detection, Principal Component Analysis (PCA) is used for dimensionality reduction, and the accuracies of Back Propagation (BP) neural Network, Support Vector Machine (SVM), and Random Forest (RF) are 97.8, 98.9, and 91.1%, respectively.