Harmonic Ratio in Patients With GLUT1 Deficiency Syndrome

April 27, 2024 updated by: IRCCS National Neurological Institute "C. Mondino" Foundation

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).

Study Overview

Status

Active, not recruiting

Conditions

Intervention / Treatment

Detailed Description

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).

Study Type

Observational

Enrollment (Actual)

32

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Italy
      • Pavia, Italy, 27100
        • Headache Science & Neurorehabilitation Center
      • Pavia, Italy, 27100
        • Child and Adolescent Epileptology Center

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Child
  • Adult

Accepts Healthy Volunteers

Yes

Sampling Method

Non-Probability Sample

Study Population

Patients affected by GLUT1 deficiency syndromes will be enrolled by attending our clinic at the IRCCS Mondino Foundation.

Healthy controls will be age and sex matched people among relatives and caregivers of the patients attending our clinic.

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

Cohorts and Interventions

Group / Cohort
Intervention / Treatment
Healthy controls
Age and sex matched healthy controls
Diagnostic test: Inertial gait analysis
All groups will be evaluated with inertial gait analysis
GLUT1DS
Patients affected by GLUT1 deficiency syndrome
Diagnostic test: Inertial gait analysis
All groups will be evaluated with inertial gait analysis

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Comparison of Harmonic Ratio between patients and healthy controls at baseline
Time Frame: Single evaluation at baseline (V1)
The primary outcome will be the difference in Harmonic Ratio (HR - continuous variable, without unit of measurement) between patients and healthy controls at baseline
Single evaluation at baseline (V1)
Comparison of largest Lyapunov exponent between patients and healthy controls at baseline
Time Frame: Single evaluation at baseline (V1)
A co-primary outcome will be the difference in largest Lyapunov exponent (LLE - continuous variable, without unit of measurement) between patients and healthy controls at baseline
Single evaluation at baseline (V1)

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Comparison of Harmonic Ratio in patients between subsequent visits
Time Frame: Change from baseline (V1) to 6 months after (V2) to 12 months after (V3) to 18 months after (V4) to 24 months after (V5)
A secondary outcome will be the difference in Harmonic Ratio in patients between the baseline and subsequent visits
Change from baseline (V1) to 6 months after (V2) to 12 months after (V3) to 18 months after (V4) to 24 months after (V5)
Comparison of coefficient of variation in patients between subsequent visits
Time Frame: Change from baseline (V1) to 6 months after (V2) to 12 months after (V3) to 18 months after (V4) to 24 months after (V5)
A secondary outcome will be the difference in coefficient of variation in patients between the baseline and subsequent visits
Change from baseline (V1) to 6 months after (V2) to 12 months after (V3) to 18 months after (V4) to 24 months after (V5)
Comparison of largest Lyapunov exponent in patients between subsequent visits
Time Frame: Change from baseline (V1) to 6 months after (V2) to 12 months after (V3) to 18 months after (V4) to 24 months after (V5)
A secondary outcome will be the difference in largest Lyapunov exponent in patients between the baseline and subsequent visits
Change from baseline (V1) to 6 months after (V2) to 12 months after (V3) to 18 months after (V4) to 24 months after (V5)
Comparison of recurrence quantification analysis in patients between subsequent visits
Time Frame: Change from baseline (V1) to 6 months after (V2) to 12 months after (V3) to 18 months after (V4) to 24 months after (V5)
A secondary outcome will be the difference in recurrence quantification analysis in patients between the baseline and subsequent visits
Change from baseline (V1) to 6 months after (V2) to 12 months after (V3) to 18 months after (V4) to 24 months after (V5)
Comparison of Multiscale entropy in patients between subsequent visits
Time Frame: Change from baseline (V1) to 6 months after (V2) to 12 months after (V3) to 18 months after (V4) to 24 months after (V5)
A secondary outcome will be the difference in Multiscale entropy in patients between the baseline and subsequent visits
Change from baseline (V1) to 6 months after (V2) to 12 months after (V3) to 18 months after (V4) to 24 months after (V5)
Comparison of normalized jerk score in patients between subsequent visits
Time Frame: Change from baseline (V1) to 6 months after (V2) to 12 months after (V3) to 18 months after (V4) to 24 months after (V5)
A secondary outcome will be the difference in log dimensionless jerk score in patients between the baseline and subsequent visits
Change from baseline (V1) to 6 months after (V2) to 12 months after (V3) to 18 months after (V4) to 24 months after (V5)
Comparison of coefficient of variation between patients and healthy controls at baseline
Time Frame: Single evaluation at baseline (V1)
A secondary outcome will be the difference in coefficient of variation (CV - continuous variable, without unit of measurement) between patients and healthy controls at baseline
Single evaluation at baseline (V1)
Comparison of normalized jerk score between patients and healthy controls at baseline
Time Frame: Single evaluation at baseline (V1)
A secondary outcome will be the difference in log dimensionless jerk score (LDLJ - continuous variable, without unit of measurement) between patients and healthy controls at baseline
Single evaluation at baseline (V1)
Comparison of recurrence quantification analysis between patients and healthy controls at baseline
Time Frame: Single evaluation at baseline (V1)
A secondary outcome will be the difference in recurrence quantification analysis (RQA - continuous variable, without unit of measurement) between patients and healthy controls at baseline
Single evaluation at baseline (V1)
Comparison of Multiscale entropy between patients and healthy controls at baseline
Time Frame: Single evaluation at baseline (V1)
A secondary outcome will be the difference in Multiscale entropy (MSE - continuous variable, without unit of measurement) between patients and healthy controls at baseline
Single evaluation at baseline (V1)

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

IRCCS National Neurological Institute "C. Mondino" Foundation

Collaborators

University of Roma La Sapienza

Investigators

  • Principal Investigator: Roberto De Icco, IRCCS, Mondino Foundation
  • Principal Investigator: Valentina De Giorgis, IRCCS, Mondino Foundation

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

January 1, 2023

Primary Completion (Estimated)

December 31, 2024

Study Completion (Estimated)

December 31, 2026

Study Registration Dates

First Submitted

May 24, 2023

First Submitted That Met QC Criteria

May 24, 2023

First Posted (Actual)

June 5, 2023

Study Record Updates

Last Update Posted (Actual)

April 30, 2024

Last Update Submitted That Met QC Criteria

April 27, 2024

Last Verified

April 1, 2024

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • Gait analysis in GLUT1DS

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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