Evaluation of the Effects of KCNQ1 Mutation on Insulin Tolerance and Obsessive Compulsive Features in Long QT Romano-Ward Syndrome Patients.
- Conditions
- Romano-Ward SyndromeHealthy IndividualsCompulsive BehaviorLong QT Syndrome
- Interventions
- Behavioral: Cognitive assessment of obsessive-compulsive and impulsive behavioursGenetic: Genomic analysisDiagnostic Test: Glucoregulation assessment
- Registration Number
- NCT04715256
- Lead Sponsor
- Biotrial
- Brief Summary
The objectives of the study are to investigate if KCNQ1 mutation in Romano-Ward long QT patients can be associated with changes in insulin regulation and with psychological features of compulsivity, impulsivity and behavioural rigidity.
- Detailed Description
Romano-Ward Syndrome (RWS) is a rare disorder characterized by prolongation of the QT interval, as well as T-wave abnormalities and possibly polymorphic ventricular fibrillation. RWS is inherited in an autosomal dominant fashion. Mutations in the potassium voltage-gated channel subfamily Q Member 1 (KCNQ1), potassium voltage-gated channel subfamily H member 2 (KCNH2), sodium voltage-gated channel alpha subunit 5 (SCN5A), potassium voltage-gated channel subfamily E regulatory subunit 1 (KCNE1), and potassium voltage-gated channel subfamily E regulatory subunit 2 (KCNE2) genes are known to be causative, and these five genes together are responsible for virtually 100% of cases of RWS.
Dysregulation of insulin signalling has been implicated in multimorbidity across the lifespan, in particular in type 2 diabetes, metabolic syndrome, obesity and RWS. Numerous studies have shown a relationship between RWS and hyperinsulinemia. More recently, altered insulin signalling has also been implicated in neurodegenerative brain disorders, dementias and Alzheimer's disease. Diseases characterized by dysregulation of insulin signalling (i.e. insulinopathies) present a major health, societal, and economic burden. These insulin signalling-associated diseases are mostly chronic, and with limited or absent curative treatments. At the current time, the recognition and clinical management of insulin comorbidity remains poorly established; brain-based comorbidity is generally neglected, and medical efforts are only devoted to the management of the primary, somatic diagnosis.
The present study will be a part of the European Union (EU)-funded PRIME (for Prevention and Remediation of Insulin Multimorbidity in Europe) research program, which primary goal is to identify and specify the molecular mechanisms underlying the insulin multimorbidities through investigation of the diseases that cause the highest burden and costs to patients and society, and to outline new directions for research and clinical care thereof. The primary hypothesis of the PRIME project is that comorbidity observed in these somatic diseases (DM2, metabolic syndrome, obesity, RWS) is a result of dysregulated central and peripheral insulin signalling, downstream of synaptic dysfunction and of learning, memory, and executive functions impairments. This non-competitive EU Horizon2020 project will study the role of KCNQ1, a key molecule in insulin regulation, in the insulinopathies across different levels of organismal organisation.
The study will include 50 KCNQ1-mutated subjects (mainly RWS patients but also subjects carrying the KCNQ1 mutation but without phenotypic manifestation of long QT syndrome, and, because of the strong interest of the PRIME project in genetic analyses, family relatives carrying the same KCNQ1 mutation) and 50 matched healthy subjects. By comparing the test population to healthy subjects, the main objective of the trial is to test the hypothesis of an involvement of KCNQ1 in compulsivity, impulsivity and cognitive rigidity.
The insulin regulation evaluations will be performed by measuring glucose, insulin and glycated haemoglobin (HbA1c) in subjects. Compulsivity, impulsivity and behavioural rigidity will be assessed using 4 neuropsychological questionnaires (OCI-R, ASBQ, UPPS-P, CHIRP) and one objective test, the CPT.
Moreover, DNA extraction will be performed in order to search for associations between mutations, insulin regulation and psychological features in conducting a Genome-Wide Association Study (GWAS) (exploratory objective).
Recruitment & Eligibility
- Status
- UNKNOWN
- Sex
- All
- Target Recruitment
- 100
- In the investigator's opinion, the subject is generally healthy based on their medical records (subjects with KCNQ1 mutation only), medical history, physical examination, vital signs, body weight, ECG (except long QT if applicable), and based on the results of haematology, clinical chemistry, urinalysis, urine drug screen (UDS) and serology;
- Subjects with a KCNQ1 mutation: genotyped as having a mutation on the KCNQ1 gene with or without phenotypic manifestation of long QT syndrome;
- Relatives of subjects with a KCNQ1 mutation: KCNQ1-mutated family relatives (with or without phenotypic expression) of a subject carrying a KCNQ1 mutation (Romano-Ward patients or subjects without phenotypic manifestation of long QT syndrome);
- Relatives of subjects with a KCNQ1 mutation must live in a different household than the subject with the KCNQ1 mutation;
- All subjects: negative UDS by dipstick analysis: opiates, methadone, cocaine, amphetamines (including ecstasy), barbiturates, benzodiazepines, and cannabinoids at admission to the assessment visit;
- All subjects: negative alcohol breath test at admission to the assessment visit.
- All subjects: having taken within 1 year before the assessment visit or currently taking any of the following medications: a. Antidiabetics: metformin, pioglitazone, acarbose, miglitol, sitagliptin, vildagliptin, saxagliptin, exenatide, liraglutide, semaglutide, repaglinide, nateglinide, insulin. b. Medications interfering with the central nervous system (CNS) such as any antipsychotic, antidepressant or regular use of anxiolytic medications > once a week, or any attention deficit/hyperactivity disorder (ADHD) medication (e.g. methylphenidate);
- Healthy subjects and relatives of subjects with a KCNQ1 mutation not phenotypically affected: any of the following on a de novo ECG: a. Heart rate (HR) < 40 bpm or > 100 bpm; b. PR interval <120 msec; c. Abnormal repolarization; d. QT interval corrected for HR using Fridericia's formula (QTcF) > 450 msec for male subjects or > 470 msec for female subjects.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description KCNQ1 mutated subjects Genomic analysis This arm includes : * KCNQ1-mutated subjects with long QT Romano-Ward syndrome * KCNQ1-mutated subjects without phenotypic expression of the Romano-Ward syndrome * family relatives of a KCNQ1-mutated enrolled subject, carrying the KCNQ1 family mutation Healthy subjects Cognitive assessment of obsessive-compulsive and impulsive behaviours Healthy subjects will be matched to KCNQ1 subjects. The matching factors will be age per decade (18-28 years, \> 28-38 years, \> 38-48 years), gender and body mass index (BMI: ≤ 24.9 kg/m2; 25-29.9 kg/m2; \> 30 kg/m2). Healthy subjects Genomic analysis Healthy subjects will be matched to KCNQ1 subjects. The matching factors will be age per decade (18-28 years, \> 28-38 years, \> 38-48 years), gender and body mass index (BMI: ≤ 24.9 kg/m2; 25-29.9 kg/m2; \> 30 kg/m2). Healthy subjects Glucoregulation assessment Healthy subjects will be matched to KCNQ1 subjects. The matching factors will be age per decade (18-28 years, \> 28-38 years, \> 38-48 years), gender and body mass index (BMI: ≤ 24.9 kg/m2; 25-29.9 kg/m2; \> 30 kg/m2). KCNQ1 mutated subjects Cognitive assessment of obsessive-compulsive and impulsive behaviours This arm includes : * KCNQ1-mutated subjects with long QT Romano-Ward syndrome * KCNQ1-mutated subjects without phenotypic expression of the Romano-Ward syndrome * family relatives of a KCNQ1-mutated enrolled subject, carrying the KCNQ1 family mutation KCNQ1 mutated subjects Glucoregulation assessment This arm includes : * KCNQ1-mutated subjects with long QT Romano-Ward syndrome * KCNQ1-mutated subjects without phenotypic expression of the Romano-Ward syndrome * family relatives of a KCNQ1-mutated enrolled subject, carrying the KCNQ1 family mutation
- Primary Outcome Measures
Name Time Method Outcome related to glucoregulation : glycated haemoglobin (HbA1c) 15 minutes Blood HbA1c concentration
Outcome related to glucoregulation : glycemia 2hours following an oral glucose challenge 2 hours Plasma glucose concentration
Outcome related to glucoregulation : fasted glycemia 15 minutes Plasma glucose concentration
Outcome related to glucoregulation : fasted insulin levels 15 minutes Plasma insulin concentration
- Secondary Outcome Measures
Name Time Method Continuous Performance Task (CPT) 1 hour Variables of the CPT : omission errors, commission errors/false alarms, hits, hit rate, hit reaction time, difference between hit rate and false alarms rate (d').
Obsessive Compulsive Inventory-Revised (OCI-R) questionnaire total score and subscale scores 30 minutes Subscales of OCI-R: washing, obsessing, hoarding, ordering, checking, neutralising
Adult Social Behaviour Questionnaire (ASBQ) total score and subscale scores 30 minutes Subscales of ASBQ : reduced contacts, reduced empathy, reduced interpersonal insight, violations of social conventions, insistence of sameness, sensory stimulation and motor stereotypies.
Childhood Retrospective Perfectionism Questionnaire (CHIRP) total score 30 minutes Total score
Urgency, Premeditation, Perseverance, Sensation seeking, and Positive urgency scale (UPPS-P) subscale scores 30 minutes Subscales of UPPS-P: negative urgency, lack of premeditation, lack of perseverance, sensation-seeking, positive urgency
Trial Locations
- Locations (2)
L'Institut du Thorax, Nantes Hospital
🇫🇷Nantes, France
Biotrial Clinical Unit
🇫🇷Rennes, France