ASD, NCOR Gene Mutations, Spironolactone
Conditions
Brief summary
MECP2, a key transcriptional regulator, has been shown to interact with the NCOR1/2 complex to modulate gene expression. Specifically, MECP2 recruits the NCOR complex to specific genomic loci, facilitating histone deacetylation and chromatin remodeling, which are essential for the proper regulation of genes involved in synaptic function and neuronal maturation. Disruptions in the MECP2-NCOR interaction have been implicated in neurodevelopmental disorders, including Rett syndrome and autism spectrum disorder (ASD), highlighting the collaborative role of MECP2 and the NCOR1/2 complex in maintaining neuronal homeostasis. Building on this, NCOR1/2 constitutes the NCOR complex,interacts with many different nuclear receptors to produce special physiological effects. The receptors further recruit epigenome-modifying enzymes that are involved in the transcription of multiple genes involved in neurotransmission and synaptic plasticity. Studies of mice with gene knockout and autistic with NCOR mutations have found that both exhibit clinical symptoms characteristic of ASD, such as deficits in social interaction, spatial learning, and impaired recognition memory. Further study revealed that the cause was the hyperexcitability of GABAergic neurons in the lateral hypothalamus (LH) due to the NCOR1/2 defect, which impaired synaptic plasticity in the hippocampal CA3 region through the single synaptic LHGABA-CA3 neural projection, and thus exhibited learning/memory impairment. Therefore, drugs that affect the NCOR receptor can improve learning/memory impairment by affecting GABA neurons. Spironolactone is a widely used diuretic with good safety. Spironolactone is widely used in the treatment of hypertension, edema, and anti-androgen therapy in children. Spironolactone is currently under investigation as a potential treatment for children with NCOR gene mutations. Preclinical studies have demonstrated that spironolactone can ameliorate ASD-related symptoms in NCOR mutant mice, including reduced sensorimotor capacity, learning disability, and impaired working memory. Furthermore, the efficacy of related diuretics in the treatment of ASD has been demonstrated clinically. Therefore, spironolactone may represent a novel therapeutic target for patients with NCOR-related gene mutations in the future.
Interventions
DRUG.spironolactone
In the first week, the starting dose is 2mg/Kg per body weight once a day, taken with food at lunch every day, and subsequently adjusted according to the situation. If the patient's serum potassium is ≤5.0 mEq/L and the patient's serum creatinine is ≤2.5 mg/dL, treatment should be initiated with 25 mg spironolactone once daily. Increased to 100mg after remission. If the results are not obvious in the first month, increase the drug dose to 3mg/Kg.
Sponsors
Qilu Hospital of Shandong University
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
3 Years to 10 Years
Healthy volunteers
No
Inclusion criteria
1. ADOS-2 diagnostic criteria for autistic children 2. Patients with NCOR related gene mutation detected by whole exon test; 3. Age: 3-10 years old; 4. The subject and (or) guardian sign the informed consent, agreeing that the researcher will cooperate with the clinical trial process and collect clinical data and peripheral blood and urine samples;
Exclusion criteria
1. have other pathogenic mutations (confidence higher than the NCOR related mutation); 2. Boys over 10 years old; 3. Allergic to spironolactone, used spironolactone one month before enrollment; 4. Hyperkalemia, serum potassium concentration \> 5.5mmol/L; 5. Renal insufficiency; 6. Used related drugs one month before enrollment: potassium supplement, angiotensin-converting enzyme inhibitor, angiotensin receptor blocker, digoxin, coletenamine, acetylsalicylic acid, abiraterone; 7. Fever (body temperature above 37.3°); 8. Clinically significant metabolic, hematological, liver, immune, urological, endocrine, neurological, pulmonary, psychiatric, skin, allergic, renal, or other major conditions in the determination of ASD that may affect the interpretation of study findings or patient safety.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Wechsler Intelligence Scale for Children, Fourth Edition (WISC-IV) | 1. Baseline 2. At the end of Cycle 1 (each cycle is 45 days) | Scores range from 40 to 130, with higher scores representing higher intelligence |
| Autism Diagnostic Observation Scale-2 | 1. Baseline ;2. At the end of Cycle 1 (each cycle is 45 days) | The score ranges from 0 to 9, with higher scores indicating more severe autism |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Blood pressure | 1. Baseline 2. At the end of Cycle 1 (each cycle is 60 days) 3.At the end of Cycle 2 (each cycle is 60 days) | Including systolic and diastolic blood pressure |
| The Score of Autism Behavior Checklist (ABC) | 1. Baseline 2. At the end of Cycle 1 (each cycle is 45 days) | The Autism Behavior Checklist (ABC)63 was administered to screen for autism spectrum traits. Parents rated 57 items across five domains: Sensory, Relating, Body and Object Use, Language, and Social/Self-Help Skills. Total scores were classified to indicate the severity of autistic features. |
| The Score of Childhood Autism Rating Scale (CARS) | 1. Baseline ;2. At the end of Cycle 1 (each cycle is 45 days) | The Childhood Autism Rating Scale (CARS)62 provides a clinician-completed global evaluation of autism severity; total scores categorize individuals as non-autistic (\<30), mildly-to-moderately autistic (30-36.5), or severely autistic (≥37). |
| the score of Vineland Adaptive Behavior Scales, Third Edition (Vineland-3) | 1. Baseline ;2. At the end of Cycle 1 (each cycle is 45 days) | Adaptive functioning was evaluated using the Vineland Adaptive Behavior Scales, Third Edition (Vineland-3) 64, which assesses Motor Skills (MOT), Communication (COM), Daily Living Skills (DLS), and Socialization (SOC). Parent-reported scores were stratified into Very Superior (130-140), Superior (115-129), Average (86-114), Low (71-85), or Very Low (≤70) |
| the score of Chinese Communicative Development Inventory (CDI) | 1. Baseline 2. At the end of Cycle 1 (each cycle is 45 days) | Language development was analyzed using the Chinese Communicative Development Inventory (CDI)65, a parent-reported questionnaire that quantifies expressive/receptive vocabulary, syntactic complexity, and gestural communication across multiple subdomains (e.g., verbs, spatial terms, phrases). |
| the score of Conners Parent Symptom Questionnaire (CPRS) | 1. Baseline 2. At the end of Cycle 1 (each cycle is 45 days) | Behavioral challenges were assessed using the Conners Parent Symptom Questionnaire (CPRS)66, which evaluates impulsivity-hyperactivity, conduct problems, learning difficulties, psychosomatic symptoms, and anxiety. Total scores were categorized as Normal, Borderline, or Abnormal. |
| The score of School-Age Children's Behavioral Rating Scale of Executive Function | 1. Baseline 2. At the end of Cycle 1 (each cycle is 45 days) | The School-Age Children's Behavioral Rating Scale of Executive Function evaluated multiple cognitive control processes, including Initiation (ability to begin tasks independently), Working Memory (capacity to hold and manipulate information), Inhibition (control over impulsive responses), and Organization (skills in structuring tasks and materials). Higher scores on this scale indicate better executive function performance in daily activities. |
Countries
China
Contacts
CONTACTCao Aihua Qilu Hospital of Shandong University
Outcome results
None listed