harmonic ratio in patients with glut1 deficiency syndrome

Conditions: GLUT1DS1; Dystonia; Gait Disorders, Neurologic; Gait Ataxia

Summary: glucose transporter deficiency syndrome type 1 (glut1ds) is a rare, genetically determined, neurometabolic disorder . it is estimated that about 90% of affected patients present various pathological gait patterns. ataxic, spastic, ataxo-spastic, or dystonic walking are the main manifestations described to date. the kinematic gait analysis with inertial sensors represents a method that is easily applicable in clinical practice, with possible application in numerous neurological syndromes of the pediatric and adult age. through the kinematic gait analysis, it will be possible to obtain an accurate characterization of the gait of patients with glut1ds. this will allow, in the first place, a better knowledge of locomotor parameters in this rare cohort of patients. given that kinematic analysis through a wearable sensor is a method that can be easily integrated into daily clinical practice, the data obtained could become prognostic biomarkers and significant outcome measures of the disease (also in relation to possible improvements deriving from treatment with a ketogenic diet or in the context of future pharmacological trials).

glucose transporter deficiency syndrome type 1 (glut1ds) is a rare, genetically determined, neurometabolic disorder. the recently estimated incidence is around 1.65-2.22/100,000. glut1 deficiency syndrome is caused by the presence of pathogenic mutations in the slc2a1 gene, whose haploinsufficiency leads to a reduced availability of glucose in the brain with repercussions on brain function. ketogenic dietary therapies (kdt) - diets with a high fat content, reduced carbohydrate content and adequate protein content - represent the current standard of treatment for the syndrome: ketone bodies cross the blood-brain barrier and are an alternative energy source for brain metabolism. it is estimated that about 90% of affected patients present various pathological gait patterns. ataxic, spastic, ataxo-spastic, or dystonic walking are the main manifestations described to date. the kinematic gait analysis with inertial sensors represents a method that is easily applicable in clinical practice, with possible application in numerous neurological syndromes of the pediatric and adult age. a single device worn at the lumbar level can accurately measure spatio-temporal parameters of gait. moreover, with this tool it is possible to assess several trunk inertial indexes. in particular, the harmonic ratio (hr), is a representative index of the fluidity and rhythmicity of gait cycle. along with the largest lyapunov exponent (lle), which is a validated method to quantify gait stability in young and old adults, these are reliable parameter to evaluate any gait alterations in the neurological patient. through the kinematic gait analysis, it will be possible to obtain an accurate characterization of the gait of patients with glut1ds. this will allow, in the first place, a better knowledge of locomotor parameters in this rare cohort of patients. given that kinematic analysis through a wearable sensor is a method that can be easily integrated into daily clinical practice, the data obtained could become prognostic biomarkers and significant outcome measures of the disease (also in relation to possible improvements deriving from treatment with a ketogenic diet or in the context of future pharmacological trials). finally, the identification of a characteristic gait pattern could facilitate the setting up of ad hoc neuromotor rehabilitation activities that are as personalized as possible. the study therefore has the innovative objective of providing an accurate analysis of the spatio-temporal and kinematic parameters of gait in patients with glut1ds, also providing trunk inertial indexes, and to correlate these characteristics with other clinical manifestations of the syndrome, its natural progression, and response to treatment. - the study is divided into 2 work-packages (wp): wp1, which represents the core of the present project, is an observational case-control study. wp2, which represents a pilot sub-study, is a prospective cohort study. within wp1, subjects will participate in a single session (v1). within wp2, subjects will be followed up with 4 further visits (v2, v3, v4 and v5, respectively), spaced 6 months apart. subjects who meet the inclusion criteria will be enrolled and will participate in the study sessions. evaluation scheme foreseen: patients will undergo four different visits, at four different times: * first visit (v1): signing of informed consent, collection of clinical-demographic data, anthropometric measurements, compilation of abc-movement 2, instrumental gait analysis. * second visit (v2): six months after the previous one, clinical re-evaluation, collection of anthropometric measurements, compilation of abc-movement 2, instrumental gait analysis. * third visit (v3): six months after the previous one, clinical re-evaluation, collection of anthropometric measurements, compilation of abc-movement 2, instrumental gait analysis. * fourth visit (v4): six months after the previous one, clinical re-evaluation, collection of anthropometric measurements, compilation of abc-movement 2, instrumental gait analysis. * fifth visit (v5): six months after the previous one, clinical re-evaluation, collection of anthropometric measurements, compilation of abc-movement 2, instrumental gait analysis. gait analysis procedure: to acquire walking data, an inertial sensor (bts g-walk, bts, milan, italy) will be placed at the level of the fifth lumbar vertebra (l5) using an ergonomic belt. the inertial sensor communicates with a laptop via bluetooth connection for data logging and offline analysis. the sensor incorporates a triaxial accelerometer (16 bits/axis), triaxial magnetometer (13 bits), and triaxial gyroscope (16 bits/axis). the sampling frequency is 100 hz, linear and angular trunk accelerations in the anteroposterior (ap), mediolateral (ml) and vertical (v) directions will be recorded. the "walk+" protocol of the g-studio software (g-studio, bts, milan, italy) will be used to detect trunk acceleration, left and right gait cycle phases, and spatiotemporal parameters of pelvic kinematics. the harmonic ratio will be calculated as trunk acceleration data along three directions (vertical, medio-lateral and anteroposterior), decomposing the components of the signal into its harmonics, as the ratio between the sum of the first 10 even and the first 10 odd harmonic multiples of the fundamental frequencies. the other trunk inertial indexes calculated will be the largest lyapunov exponent (lle), coefficient of variation (cv), log dimensionless jerk score (ldlj), the recurrence quantification analysis (rqa), as described in a previous work by castiglia et al. we will also assess the multiscale entropy (mse), as described by bisi et al. before the experimental session, participants will receive a thorough explanation of study procedures. instructions will be given to walk at a speed consistent with the usual walk, along a corridor approximately 3 m wide and 30 m long, in the absence of external factors that may interfere with the cadence and rhythm of the gait cycle. five consecutive tests will be carried out. the trials will be interrupted if the patient should report intolerance to the procedure, asthenia or pain. - statistical plan: referring to the work castiglia et al 2021, which carries out a kinematic analysis on a cohort of patients with parkinson's disease vs controls, the investigators hypothesize to obtain a similar effect size of 0.74. considering a one-tailed t test for the comparison between the two groups (patients and controls), with alpha significance 0.05 power 0.8 and effect size 0.74, the investigators obtain a minimum number of 24 subjects per group. a preliminary normality analysis will be performed to decide whether to use parametric or non-parametric methods, through graphical representation and shapiro wilk test. numerical variables will be described as mean and standard deviation (or median and quartiles if appropriate), categorical variables as raw number and percentage. the two groups will be compared by t test or mann whitney for independent samples. correlation with age will be verified by pearson (or spearman if appropriate) correlation coefficient, both intra-group and globally. the correlation with the quantitative parameters will be verified by pearson's (or spearman's if appropriate) correlation coefficient, both intra-group and globally. correlations with qualitative parameters will be evaluated by t test or anova (mann whitney or kruskal wallis if not normal). the comparison of hr between v1, v2, v3, v4 and v5 will be performed by repeated measures anova (between group factor, whithin factor at time point).

Eligibility criteria:
patients eligibility criteria inclusion criteria: * pediatric and adult patients (range 3-60 years) diagnosed with glut1 deficiency syndrome according to the recommendations of the international study group (klepper et al., 2020) * ability to walk independently the necessary route * compliance with study procedures exclusion criteria: * presence of other neurological or orthopedic comorbidities that may influence gait assessment * poor compliance with study procedures healthy controls eligibility criteria: inclusion criteria: * typically developing healthy volunteers * age range 3-60 years exclusion criteria: * presence of neurological or orthopedic comorbidities that may influence gait assessment