Multisystemic RFC1-Related Disorder: Expanding the Phenotype Beyond Cerebellar Ataxia, Neuropathy, and Vestibular Areflexia Syndrome.

Background and Objectives: The RFC1 spectrum has become considerably expanded as multisystemic features beyond the triad of cerebellar ataxia, neuropathy, and vestibular areflexia syndrome (CANVAS) have started to be unveiled, although many still require clinical replication. Here, we aimed to clinically characterize a cohort of RFC1-positive patients by addressing both classic and multisystemic features. In a second part of this study, we prospectively assessed small nerve fibers (SNF) and autonomic function in a subset of these RFC1-related patients. Methods: We retrospectively enrolled 67 RFC1-positive patients from multiple neurologic centers in Portugal. All patients underwent full neurologic and vestibular evaluation, as well as neuroimaging and neurophysiologic studies. For SNF and autonomic testing (n = 15), we performed skin biopsies, quantitative sensory testing, sudoscan, sympathetic skin response, heart rate deep breathing, and tilt test. Results: Multisystemic features beyond CANVAS were present in 82% of the patients, mainly chronic cough (66%) and dysautonomia (43%). Other features included motor neuron (MN) affection and motor neuropathy (18%), hyperkinetic movement disorders (16%), sleep apnea (6%), REM and non-REM sleep disorders (5%), and cranial neuropathy (5%). Ten patients reported an inverse association between cough and ataxia severity. A very severe epidermal denervation was found in skin biopsies of all patients. Autonomic dysfunction comprised cardiovascular (67%), cardiovagal (54%), and/or sudomotor (50%) systems. Discussion: The presence of MN involvement, motor neuropathy, small fiber neuropathy, or extrapyramidal signs should not preclude RFC1 testing in cases of sensory neuronopathy. Indeed, the RFC1 spectrum can overlap not only with multiple system atrophy but also with hereditary motor and sensory neuropathy, hereditary sensory and autonomic neuropathy, and feeding dystonia phenotypes. Some clinical-paraclinical dissociations can pose diagnostic challenges, namely large and small fiber neuropathy and sudomotor dysfunction which are usually subclinical.

Corrigendum: Clinical 3-D gait assessment of patients with polyneuropathy associated with hereditary transthyretin amyloidosis.

[This corrects the article DOI: 10.3389/fneur.2020.605282.].

Gait Characterization and Analysis of Hereditary Amyloidosis Associated with Transthyretin Patients: A Case Series.

Hereditary amyloidosis associated with transthyretin (ATTRv), is a rare autosomal dominant disease characterized by length-dependent symmetric polyneuropathy that has gait impairment as one of its consequences. The gait pattern of V30M ATTRv amyloidosis patients has been described as similar to that of diabetic neuropathy, associated with steppage, but has never been quantitatively characterized. In this study we aim to characterize the gait pattern of patients with V30M ATTRv amyloidosis, thus providing information for a better understanding and potential for supporting diagnosis and disease progression evaluation. We present a case series in which we conducted two gait analyses, 18 months apart, of five V30M ATTRv amyloidosis patients using a 12-camera, marker based, optical system as well as six force platforms. Linear kinematics, ground reaction forces, and angular kinematics results are analyzed for all patients. All patients, except one, showed a delayed toe-off in the second assessment, as well as excessive pelvic rotation, hip extension and external transverse rotation and knee flexion (in stance and swing phases), along with reduced vertical and mediolateral ground reaction forces. The described gait anomalies are not clinically quantified; thus, gait analysis may contribute to the assessment of possible disease progression along with the clinical evaluation.

Supporting the Assessment of Hereditary Transthyretin Amyloidosis Patients Based On 3-D Gait Analysis and Machine Learning.

Hereditary Transthyretin Amyloidosis (vATTR-V30M) is a rare and highly incapacitating sensorimotor neuropathy caused by an inherited mutation (Val30Met), which typically affects gait, among other symptoms. In this context, we investigated the possibility of using machine learning (ML) techniques to build a model(s) that can be used to support the detection of the Val30Met mutation (possibility of developing the disease), as well as symptom onset detection for the disease, given the gait characteristics of a person. These characteristics correspond to 24 gait parameters computed from 3-D body data, provided by a Kinect v2 camera, acquired from a person while walking towards the camera. To build the model(s), different ML algorithms were explored: k-nearest neighbors, decision tree, random forest, support vector machines (SVM), and multilayer perceptron. For a dataset corresponding to 66 subjects (25 healthy controls, 14 asymptomatic mutation carriers, and 27 patients) and several gait cycles per subject, we were able to obtain a model that distinguishes between controls and vATTR-V30M mutation carriers (with or without symptoms) with a mean accuracy of 92% (SVM). We also obtained a model that distinguishes between asymptomatic and symptomatic carriers with a mean accuracy of 98% (SVM). These results are very relevant, since this is the first study that proposes a ML approach to support vATTR-V30M patient assessment based on gait, being a promising foundation for the development of a computer-aided diagnosis tool to help clinicians in the identification and follow-up of this disease. Furthermore, the proposed method may also be used for other neuropathies.

Clinical 3-D Gait Assessment of Patients With Polyneuropathy Associated With Hereditary Transthyretin Amyloidosis.

Hereditary amyloidosis associated with transthyretin V30M (ATTRv V30M) is a rare and inherited multisystemic disease, with a variable presentation and a challenging diagnosis, follow-up and treatment. This condition entails a definitive and progressive motor impairment that compromises walking ability from near onset. The detection of the latter is key for the disease's diagnosis. The aim of this work is to perform quantitative 3-D gait analysis in ATTRv V30M patients, at different disease stages, and explore the potential of the obtained gait information for supporting early diagnosis and/or stage distinction during follow-up. Sixty-six subjects (25 healthy controls, 14 asymptomatic ATTRv V30M carriers, and 27 symptomatic patients) were included in this case-control study. All subjects were asked to walk back and forth for 2 min, in front of a Kinect v2 camera prepared for body motion tracking. We then used our own software to extract gait-related parameters from the camera's 3-D body data. For each parameter, the main subject groups and symptomatic patient subgroups were statistically compared. Most of the explored gait parameters can potentially be used to distinguish between the considered group pairs. Despite of statistically significant differences being found, most of them were undetected to the naked eye. Our Kinect camera-based system is easy to use in clinical settings and provides quantitative gait information that can be useful for supporting clinical assessment during ATTRv V30M onset detection and follow-up, as well as developing more objective and fine-grained rating scales to further support the clinical decisions.

Validation of a Single RGB-D Camera for Gait Assessment of Polyneuropathy Patients.

Motion analysis systems based on a single markerless RGB-D camera are more suitable for clinical practice than multi-camera marker-based reference systems. Nevertheless, the validity of RGB-D cameras for motor function assessment in some diseases affecting gait, such as Transthyretin Familial Amyloid Polyneuropathy (TTR-FAP), is yet to be investigated. In this study, the agreement between the Kinect v2 and a reference system for obtaining spatiotemporal and kinematic gait parameters was evaluated in the context of TTR-FAP. 3-D body joint data provided by both systems were acquired from ten TTR-FAP symptomatic patients, while performing ten gait trials. For each gait cycle, we computed several spatiotemporal and kinematic gait parameters. We then determined, for each parameter, the Bland Altman's bias and 95% limits of agreement, as well as the Pearson's and concordance correlation coefficients, between systems. The obtained results show that an affordable, portable and non-invasive system based on an RGB-D camera can accurately obtain most of the studied gait parameters (excellent or good agreement for eleven spatiotemporal and one kinematic). This system can bring more objectivity to motor function assessment of polyneuropathy patients, potentially contributing to an improvement of TTR-FAP treatment and understanding, with great benefits to the patients' quality of life.

Prevalencia de toxoplasmose, leishmaniose, doenca de Chagas e enteroparasitoses em voluntarios da populacao de Cajati, estado de Sao Paulo, 1998 / Prevalence of toxoplasmosis, leishmaniosis, Chagas disease and intestinal parasitosis in volunteers from Cajati's population, state of Sao Paulo, 1998

Avaliamos a prevalencia de algumas doencas parasitarias no municipio de Cajati-SP (Vale do Ribeira), atraves da Bandeira Cientifica-1998, do Departamento Cientifico do Centro Academico Oswaldo Cruz, da Faculdade de Medicina da Universidade de Sao Paulo. Durante uma semana de intervencao, foram colhidas amostras em pacientes que buscaram ativamente um dos 3 postos de saude locais, englobando...