Use of N-Acetylcysteine in the Treatment of Repetitive and Self-Injurious Behaviors in Cornelia de Lange Syndrome

Use of N-Acetylcysteine (NAC) in the Treatment of Repetitive Behaviors (RB) and Self-Injurious Behaviors (SIB) in Cornelia de Lange Syndrome: A Randomized Double-Blind Placebo-Controlled Pilot Study

This research project is a randomized cross-over pilot trial which aims to test the efficacy of N-acetylcysteine (NAC) for the treatment of Repetitive Behaviors (RB) and self-injurious behavior (SIB) in patients with Cornelia de Lange Syndrome (CdLs).

NAC is a known anti-oxidative stress and neuroprotective agent, which has been shown to decrease the occurrence of SIB such as skin picking. NAC has also shown partial response in trials for compulsive behaviors in Obsessive Compulsive Disorder (OCD) and related disorders in autism.

Cornelia de Lange syndrome (CdLS) is a genetic disorder with autistic features, including RBs and SIB. In this randomized clinical trial, participants with CdLS will be blindly assigned one of two possible treatment arms: 1) placebo (8 weeks) and NAC (8 weeks); or 2) NAC (8 weeks) and placebo (8 weeks), with an intermediate 2-week washout period.

Cornelia de Lange syndrome (CdLS) is a genetic condition caused by mutations in cohesin-related genes, mostly notably NIPBL. The CdLS phenotype includes physical features such as typical facies, limb abnormalities, short stature, and hirsutism as well developmental and behavioral manifestations such as intellectual disability, communication deficits, autistic traits and repetitive/self-injurious behaviors (RBs/SIB).

Behavioral challenges such as RBs/SIB pose a significant obstacle to quality of life to individuals with CdLS and families. In CdLS, disruption of developmental systems can impact neuronal and brain development, and impact GABAergic inhibitory interneuron formation, leading to RBs/SIB. Given the potential for dysregulated excitatory glutamatergic output in CdLS, neuronal oxidative stress may play a role in these maladaptive behaviors. NAC replenishes Central Nervous System (CNS) glutathione, a potent antioxidant and may ameliorate RBs/SIB. NAC has been shown to decrease maladaptive behaviors in autism and grooming disorders such as excoriation disorder (skin picking).

An 18-week cross-over trial is proposed to decrease RBs/SIB comprising two 8-week double-blinded active or placebo treatment with a 2-week wash out period in between. A cross-over design will afford for higher efficiency in sample size for similar power. Dosage will be titrated weekly starting at 600 mg daily and then increased by 600 mg every week to a target dose of 1800 mg per day. Participants will be recruited through CdLS Foundation.

Based on a mechanism for regulation glutamate transmission homeostasis in the central nervous system, the use of NAC may be particularly pertinent to individuals with CdLS. It is known that in CdLS genetic networks that impact on limb formation overlap significantly with developmental systems that impact neuronal and brain development, in particular GABAergic inhibitory interneuron formation. Given a dysregulated excitatory glutamatergic mechanism due to interneuron deficits, which can then lead to neuronal oxidative stress and programmed cell death, NAC may act as a key homeostatic regulator to prevent glutamate overactivity and neuronal damage in CdLS.

Inclusion Criteria:

• Ages 13 to 35 years
• A diagnosis of CdLS as determined by a physician during routine care meeting the major and minor criteria from CdLS guidelines
• Threshold criteria for the presence of RB/SIB as reported on initial screening Children's Yale-Brown Obsessive Compulsive Scale Modified for Pervasive Developmental Disorders (CYBOCS-PDD) > 6 OR Aberrant Behavior Checklist (ABC) stereotypy subscale > 7)
• Being able to attend 4 visits over the course of 18 weeks at the Johns Hopkins Hospital
• No acute safety concerns or need for hospitalization due to psychotic, manic or depressive episode
• Not currently pregnant or lactating/breastfeeding. Whether a participant is pregnant or not will be determined by the participant/caregiver report based on date last menses. If there is any suspicion of pregnancy, the PI will confer with the family to obtain testing through the primary care provider.

Exclusion Criteria:

• Allergy to NAC
• Allergy to Quinine
• Contraindication to NAC (organ transplant; untreated or symptomatic gastric condition)
• Need for another medication with which NAC is contraindicated (antibiotics)