Relevant Outcome Measures for Creatine Transporter Deficiency Patient

Hospices Civils de Lyon197 enrolled

Overview

Creatine transport deficiency (CTD) is a rare genetic disorder related to pathogenic variants in the SLC6A8 gene, located on chromosome Xq28. Clinical diagnosis of CTD is based on clinical presentation, an increased urinary creatine/creatinine ratio and a severe decreased creatine peak on 1H-MRS magnetic resonance spectroscopy. A retrospective study with questionnaires identified that most CTD patients had moderate to severe intellectual disability. Less than one third of patients were able to speak in sentences. Seizures were present in 59% of the patients. 41% had autistic features. Motor dysfunction was mentioned in 58%, and gastrointestinal symptoms were reported in 35% of the patients. Several new therapeutic avenues are currently emerging in this disease for which no treatment has been available until now : cyclocreatine (interesting but unfortunately with very little clinical applicability due to its toxicity; dodecyl creatine ester incorporated into lipid nanocapsules with intranasal administration; pharmaco-chaperoning (for the folding-deficient creatine transporter variants, Ultragenyx pharmaceuticals new prodrug designed to deliver creatine to the brain (UX068). These new pharmacological treatment options may offer future opportunities to improve cognition in CTD patients. A key issue is to determine outcome measures that are accessible to these patients, despite the importance of their cognitive deficit. In a preliminary study (on 31 CTD patients), investigators showed for example, that 75% of patients were unable to perform a Wechsler scale, which is one of the most used neuropsychological test to determine patient IQ (intelligence quotient). Most of the existing cognitive tests were developed to distinguish typically developing persons and ID (intellectual disability) patients, leading to a floor effect in the latter who systematically fail these tests. Therefore, these tests are not adapted to capture the potential effect of a drug in ID patient group. The identification of reliable and sensitive outcome measures for use in clinical trials in ID patients was recognized as a priority in a meeting convened by the NIH. N-of-1 trials (also called Single-Case Experimental Designs or SCEDs) appear of great interest for rare diseases, statistical power coming from the number of repeated measures, which leads to choose outcome measures that can be repeated multiple times. This innovative study will allow to efficiently preparing future therapeutic trials, by specifying the phenotype of the patients, and by determining the most adapted outcome measures taking into account their cognitive deficiency and the type of experimental design to be used in the context of rare diseases.

Study Type

Interventions

Clinical endpointsOTHER

1. Number of epileptic seizures 2. Change in antiepileptic treatment (increase or decrease) 3. Visual analogical scale on a target symptom defined with the parents, 4. CGI, 5. Actimetry data over 24 hours, 6. Podometry data over 24 hours, 7. 6 minutes' walk test, 8. Clinical examination 9. Feasibility of performing an MRI without any anesthesia on a mock scanner

Parental questionnairesOTHER

10- Adaptive assessment with Vineland Adaptive Behavior scale II, 11- Mac Arthur questionnaire regarding language, 12- Pervasive Development Disorder in Mentally Retarded persons Scale (PDD-MRS), 13- Dunn sensory profile, 14- Aberrant Behavior Checklist, 15- Nisonger Child Behavior Rating form, 16- Social Responsiveness Scale 2, 17- Scales assessing the impact on primary caregiver (CBI-M/ Beach Center Family QOL)

Quality of life scaleOTHER

18- Quality of life scale (PedsQL 4.0 for children or San Martin scale if the patient is older than 18)

Cognitive assessmentsOTHER

19- Leiter 3 scale (4 cognitive sub-tests to be able to compute the non-verbal IQ and 2 non-verbal memory sub-tests) or Bayley 4 if Leiter 3 is not possible 20- CPM-BF 21- Simple reasoning task on tablet (match-to-sample task) 22- Implicit rules learning (modified Brixton), 23- 4 sub-tests from the WPPSI-IV ("zoo location" to assess spatial memory, "block design" to assess visuo-constructive abilities, "bug search" , "cancellation"), 24- Attention assessment (4 sub-tests from KITTAP: alert, go/no go, flexibility, divided attention), 25- Elementary visuo-spatial perception (on tablets)

Language assessmentsOTHER

26- EXALANG 3-6 (10 sub-tests testing for expressive and receptive language assessments), 27- PPVT-5 (receptive vocabulary), EVT-3 (expressive vocabulary), 28- Automatic language analysis (during a 10 minutes interaction, play).

Motor assessmentsOTHER

29- Kinematic task (specifically designed), 30- Purdue-Pegboard test, 31- Renzi test

Social assessmentsOTHER

32- Eye-tracking analysis of social visual scenes and social preference index (movies), 33- theory of mind assessment, 34- ADOS scale (Autism Spectrum Disorder), 35- sensitivity to inequality, 36- pro-social behaviors (help of the psychologist)

3T MRIOTHER

37- Structural, metabolic and functional data

Cardiac assessmentsOTHER

38- ECG 39- Ultrasound

Biological collectionOTHER

40- Blood sample 41- Urinary sample 42- Superficial skin biopsy

Eligibility

Sex: ALLMin age: 2 YearsMax age: 60 YearsHealthy volunteers:

Medical Language ↔ Plain English

Inclusion Criteria: Male CTD patients (n=24) * Male CTD patients having a confirmed mutation in the SLC6A8 gene, * Aged \> 5 to \< 35 years * Whose maternal language is French, * Having signed the informed consent and/or for whom parents/legal guardian have signed the informed consent, * Affiliated to national Health Insurance system or parents/legal guardian affiliated to national health insurance system. Female CTD patients (n=15) * Female CTD patients having a confirmed mutation in the SLC6A8 gene, * Aged \> 5 to \< 60 years, * Whose maternal language is French, * Having signed the informed consent and/or for whom parents/legal guardian have signed the informed consent. * Affiliated to national Health Insurance system (sécurité sociale) or parents/legal guardian affiliated to national health insurance system Sex- and chronological age-matched controls (n=24) * Male * Aged \> 5 to \< 35 years * Whose maternal language is French, * Having signed the informed consent and/or for whom parents/legal guardian have signed the informed consent, * Affiliated to national health insurance system or parents/legal guardian affiliated to national health insurance system. Sex- and chronological age-matched female controls (n=15) * female, * Aged \> 5 to \< 60 years, * Whose maternal language is French, * Having signed the informed consent and/or for whom parents/legal guardian have signed the informed consent * Affiliated to national Health Insurance system (sécurité sociale) or parents/legal guardian affiliated to national health insurance system Sex- and mental age-matched controls (n=39) * Male and female * Aged \> 2 to \< 8 years * Whose maternal language is French, * For whom parents/legal guardian have signed the informed consent, * Affiliated to national health insurance system or parents/legal guardian affiliated to national health insurance system. Typically developed children (n=80) * Male and female * Aged \> 2 to \< 8 years * Whose maternal language is French, * For whom parents/legal guardian have signed the informed consent, * Affiliated to national health insurance system or parents/legal guardian affiliated to national health insurance system. Sex- and chronological age-matched controls and Sex- and mental age-matched controls, aged \< 8 years, could also be included in the Typically developed children group, as the data from the Typically developed children are only necessary to complete the developmental trajectory of the new tasks. Non-inclusion Criteria: CTD patients (n=39): * Having a contraindication to the MRI examination (people using a pacemaker or an insulin pump, people wearing a metal prosthesis or an intracerebral clip, and claustrophobic subjects), * Refusal of the subject and/or the subject's parents to be informed of possible abnormalities detected by MRI, * Refusal of the subject and/or the subject's parents/legal guardian to be informed of possible abnormalities detected during the cardiac assessment. Sex- and chronological age-matched controls (n=39) * History of neurological or psychiatric disorder, * Repetition of a grade, * Learning disability requiring rehabilitation (speech therapy, psychomotor or oculomotor therapy), * For participants agreeing on performing the MRI examination, having a contraindication to the MRI examination (use of a pacemaker or an insulin pump, people wearing a metal prosthesis or an intracerebral clip, and claustrophobic subjects) and refusal of the subject and/or the subject's parents/legal guardian to be informed of possible abnormalities detected by MRI. Sex- and mental age-matched controls (n=39) * History of neurological or psychiatric disorder, * Repetition of a grade, * Learning disability requiring rehabilitation (speech therapy, psychomotor or oculomotor therapy). Typically developed children (n=80) * History of neurological or psychiatric disorder, * Repetition of a grade, * Learning disability requiring rehabilitation (speech therapy, psychomotor or oculomotor therapy).

Outcomes

Primary Outcomes

Clinical endpoints : number of epileptic seizures

Number of epileptic seizures

Time frame: Up to 90 Days

Clinical endpoints : antiepileptic treatment

Change in antiepileptic treatment (increase or decrease)

Time frame: For all 24 CTD patients: all examinations at V1 (Day 1/Day2) For 9 out of 24 CTD patients: examinations repeated every two weeks at V2 (Day15), V3 (Day30), V4 (Day45), V5 (Day60), V6 (Day75) and V7 (Day90).

Clinical endpoints : Visual analogical scale

Visual analogical scale on a target symptom defined with the parents,

Time frame: Up to 90 Days

Clinical endpoints : actimetry

Actimetry data over 48 hours

Time frame: Up to 90 Days

Clinical endpoints : podometry

Podometry data over 24 hours

Time frame: Up to 90 Days

Clinical endpoints : walk test

6 minutes' walk test

Time frame: Up to 90 Days

Clinical endpoints : Clinical examination

Clinical examination

Clinical endpoints :Feasibility of performing an MRI

Feasibility of performing an MRI without any anesthesia on a mock scanner

Parental questionnaires : Vineland Adaptive Behavior scale II

Adaptive assessment with Vineland Adaptive Behavior scale II

Time frame: For all 24 CTD patients: V1 (Day1/Day2), For 9 out 24 CTD patients: repeated at V7 (Day90).

Parental questionnaires : Mac Arthur questionnaire

Mac Arthur questionnaire regarding language

Time frame: For all 24 CTD patients: at V1 (Day1/Day2), For 9 out 24 CTD patients: repeated at V3 (Day30) and V7 (Day90).

Parental questionnaires : PDD-MRS

Pervasive Development Disorder in Mentally Retarded persons Scale (PDD-MRS)

Time frame: For all 24 CTD patients: at V1 (Day1/Day2), For 9 out 24 CTD patients: repeated at V7 (Day90).

Parental questionnaires : Dunn sensory profile

Dunn sensory profile

Time frame: For all 24 CTD patients: at V1 (Day1/Day2), For 9 out 24 CTD patients: repeated at V3 (Day30) and V7 (Day90).

Parental questionnaires : Aberrant Behavior Checklist

Aberrant Behavior Checklist

Time frame: For all 24 CTD patients: at V1 (Day1/Day2), For 9 out 24 CTD patients: repeated at V2 (Day15), V3 (Day30), V4 (Day45), V5 (Day60), V6 (Day75) and V7 (Day90).

Parental questionnaires : Nisonger Child Behavior Rating form

Nisonger Child Behavior Rating form

Time frame: For all 24 CTD patients: at V1 (Day1/Day2), For 9 out 24 CTD patients: repeated at V7 (Day90).

Parental questionnaires : Social Responsiveness Scale 2

Social Responsiveness Scale 2

Time frame: For all 24 CTD patients: at V1 (Day1/Day2), For 9 out 24 CTD patients: repeated at V7 (Day90).

Parental questionnaires : impact on primary caregiver

Scales assessing the impact on primary caregiver (CBI-M/ Beach Center Family QOL)

Time frame: For all 24 CTD patients: at V1 (Day1/Day2), For 9 out 24 CTD patients: repeated at V3 (Day30) and V7 (Day90).

Quality of life scale

Quality of life scale (PedsQL 4.0 for children or San Martin scale if the patient is older than 18)

Time frame: For all 24 CTD patients: At V1 (Day1/Day2) For 9 out of 24 CTD patients: Repeated at V3 (Day30) and V7 (Day90).

Cognitive assessments : Leiter 3 scale

Leiter 3 scale (4 cognitive sub-tests to be able to compute the non-verbal IQ and 2 non-verbal memory sub-tests) or Bayley 4 if Leiter 3 is not possible

Time frame: For the 24 CTD patients: at V1 (Day1/Day2), For 9 out of 24 CTD patients: repeated at V7 (Day90). Controls: Cognitive assessment at V1(Day 1)

Cognitive assessments : CPM-BF

CPM-BF : Raven's coloured Progressive Matrices

Time frame: For the 24 CTD patients: at V1 (Day1/Day2), For 9 out of 24 CTD patients: repeated at V7 (Day90). Controls: Cognitive assessment at V1(Day 1)

Cognitive assessments : reasoning task

Simple reasoning task on tablet (match-to-sample task)

Time frame: For the 24 CTD patients: at V1 (Day1/Day2), For 9 out of 24 CTD patients: repeated at V2 (Day15), V3 (Day30), V4 (Day45), V5 (Day60), V6 (Day75) and V7 (Day90). Controls: Cognitive assessment at V1(Day 1)

Cognitive assessments : Implicit rules learning

Implicit rules learning (modified Brixton),

Cognitive assessments : WPPSI-IV

4 sub-tests from the WPPSI-IV ("zoo location" to assess spatial memory, "block design" to assess visuo-constructive abilities, "bug search" , "cancellation"),

Time frame: For the 24 CTD patients: at V1 (Day1/Day2), For 9 out of 24 CTD patients: repeated at V3 (Day30) and V7 (Day90). Controls: Cognitive assessment at V1(Day 1)

Cognitive assessments : Attention assessment

Attention assessment (4 sub-tests from KITTAP: alert, go/no go, flexibility, divided attention),

Time frame: For the 24 CTD patients: at V1 (Day1/Day2), For 9 out of 24 CTD patients: repeated at V3 (Day30) and V7 (Day90). Controls: Cognitive assessment at V1(Day 1)

Cognitive assessments : Elementary visuo-spatial perception

Elementary visuo-spatial perception (on tablets)

Language assessments : EXALANG 3-6

EXALANG 3-6 - Computerized battery for the evaluation of oral and written language : 10 sub-tests testing for expressive and receptive language assessments

Time frame: For all 24 CTD patients: performed at V1 (Day1/Day2). For 9 out of 24 CTD patients: repeated at V3 (Day30), and V7 (Day90). Controls: Language assessment at V1(Day 1)

Language assessments : vocabulary

PPVT-5 : Peabody Picture Vocabulary Test Fifth Edition = receptive vocabulary, EVT-3 : Expressive Vocabulary Test third edition,

Time frame: For all 24 CTD patients: performed at V1 (Day1/Day2). For 9 out of 24 CTD patients: repeated at V3 (Day30), and V7 (Day90). Controls: Language assessment at V1(Day 1)

Language assessments : Automatic language analysis

Automatic language analysis (during a 10 minutes interaction, play).

Time frame: For all 24 CTD patients: performed at V1 (Day1/Day2). For 9 out of 24 CTD patients: repeated at V3 (Day30), and V7 (Day90). Controls: Language assessment at V1(Day 1)

Motor assessments : Kinematic task

Kinematic task (specifically designed)

Time frame: CTD patients : performed at V1 (Day1/Day2). Controls: Motor assessment at V1 (Day 1)

Motor assessments : Purdue-Pegboard test

Purdue-Pegboard test

Time frame: CTD patients : performed at V1 (Day1/Day2), V3(Day30), and V7 (Day90). Controls: Motor assessment at V1 (Day 1)

Motor assessments : Renzi test

Renzi test

Time frame: CTD patients : performed at V1 (Day1/Day2), V3(Day30), and V7 (Day90). Controls: Motor assessment at V1 (Day 1)

Social assessments : Eye-tracking

Eye-tracking analysis of social visual scenes and social preference index (movies)

Time frame: CTD patients : performed at V1 (Day1/Day2), V3 (Day30) and V7 (Day90). Controls : Social assessment at V1(Day1)

Social assessments : Theory of mind assessment

Theory of mind assessment

Time frame: CTD patients : performed at V1 (Day1/Day2). Controls : Social assessment at V1(Day1)

Social assessments : ADOS scale (Autism Diagnostic Observation Scale)

ADOS scale (Autism Spectrum Disorder)

Time frame: CTD patients : performed at V1 (Day1/Day2). Controls : Social assessment at V1(Day1)

Social assessments : Sensitivity to inequality

Sensitivity to inequality

Time frame: CTD patients : performed at V1 (Day1/Day2). Controls : Social assessment at V1(Day1)

Social assessments : Pro-social behaviors (help of the psychologist)

Pro-social behaviors (help of the psychologist)

Time frame: CTD patients : performed at V1 (Day1/Day2). Controls : Social assessment at V1(Day1)

Secondary Outcomes

Neuroimaging (MRI)

The MRI will be performed to describe structural and functional neuroanatomical profile of CTD patient in comparison to chronological age-matched controls and variability in creatine peak assessment using MR spectroscopy

Time frame: V1 (Day1/Day2)

Cardiac assessments : Electrocardiogram

Electrocardiogram (ECG) will be performed to describe CTD patients cardiac profile (especially the risk of increased QTC and/or cardiac echography abnormality)

Time frame: CTD patients: V1 (Day1/Day2)

Cardiac assessments : Ultrasound

Cardiac Ultrasound will be performed to describe CTD patients cardiac profile (especially the risk of increased QTC and/or cardiac echography abnormality)

Time frame: CTD patients: V1 (Day1/Day2)

Biological collection : Blood sample

Blood sample (plasma and peripheral blood mononuclear cells)

Time frame: CTD patients: V1 (Day1/Day2)

Biological collection : Urine sample

Urine sample will be collected to create a collection of biological samples associated with clinical and genomic data from CTD patients. In the future this will be usefull for research labs to investigate new biomarkers (not identified yet) or to test for the efficiency of new therapeutic approaches in vitro (on cultivated fibroblasts or after the development of iPS cells or organoïds) in this rare disease.

Time frame: CTD patients: V1 (Day1/Day2)

Biological collection : Superficial skin biopsy

Superficial skin biopsy will be performed to get cultivated fibroblasts to create a collection of biological samples associated with clinical and genomic data from CTD patients. In the future this will be usefull for research labs to investigate new biomarkers (not identified yet) or to test for the efficiency of new therapeutic approaches in vitro (on cultivated fibroblasts or after the development of iPS cells or organoïds) in this rare disease.

Relevant Outcome Measures for Creatine Transporter Deficiency Patient

Overview

Conditions

Interventions

Eligibility

Locations (1)

Outcomes

Primary Outcomes

Secondary Outcomes

Central Contacts