TBR1 is a human gene encoding a brain-specific transcription factor, principally expressed in the excitatory neurons of the neocortex. It regulates development of axonal projection and expression of numerous genes involved in autism spectrum disorders (ASD) and intellectual disability (ID). Recent progress in detection and analysis of rare variants allowed to identify group of genes with strong statistical evidence for association with ASD risk, of which TBR1. Numerous studies on mice showed that TBR1 heterozygous mice display autistic traits as deficiencies in social interaction, in cognitive flexibility, and in associative memory. Functional analyses on human cell lines have demonstrated that de novo truncating variants in TBR1 identified in patients with sporadic ASD disrupt transcriptional repression activity, localization, homodimerization of TBR1 product.

In 2019, only 12 single nucleotide variants (SNVs) and few copy number variations (CNVs) involving TBR1 have been reported in the literature and clinical descriptions were poor. To provide details on the phenotype linked to TBR1 mutations, we and others gathered 25 new individuals with de novo TBR1 SNV and CNV, complemented by a review of individuals previously reported in the literature. On 38 individuals, all presented developmental delay (DD)/ID, ranging from mild to severe, and 76% of them presented autistic traits. Additional behaviour disorders were observed in 85% of individuals, mainly attention deficit and aggressive behaviour. However, the natural history of patients with TBR1 variations is not well known.

Development of RNA-Seq allowed a better understanding of its transcription factor role and revealed that Tbr1 promotes expression of layer 6 markers as Wnt7b. In heterozygous and homozygous TBR1 mutant mice, Fazel Darbandi et al (1), observed that Wnt7b expression is reduced in cortical layer 6 and that neurons have reduced excitatory and inhibitory synaptic density. They showed that lithium chloride and lithium carbonate, WNT-signalling agonists, rescue the dendritic spines, the synaptic and the axonal defects in Tbr1layer5, Tbr1layer6 and Tbr1 constitutive (Tbr1+/-) mutant mice. They also observed an improvement of social interactions in mice after treatment by lithium. These results suggest an important and novel biological mechanism underlying ASD that may have implications for the treatment of patients with TBR1 variants.

Moreover, lithium treatment has already been evaluated in patients with neurocognitive disorders not linked to TBR1 showing an improvement in the adaptative behaviour and cognition function.

As of today, only symptomatic treatments are available. As lithium increase neuronal activity in mice, and may thus improve the symptoms of this disorder, we propose a clinical trial to study the security and efficacy of lithium carbonate targeting the patients with TBR1-related disorders, with specific and adapted endpoints. Lithium carbonate treatment will be administered after an observation period of 6 to 12 months, allowing to ascertain the stability of neurocognitive abnormalities.

Inclusion Criteria:

• Written informed consent from the patient, parent or legal representative
• ≥6 years old at the time of consent
• Proven pathogenic or probably pathogenic TBR1 variant (SNV confirmed by Sanger sequencing or CNV including only TBR1)
• If applicable: Stable concomitant psychoactive medication regimen (dose and schedule) ≥2 months prior to lithium initiation
• Affected individuals able to take tablet /capsules orally
• Highly effective method of contraception in affected female individuals of childbearing age (Combined hormonal contraception, progestogen-only hormonal contraception, intrauterine device, intrauterine hormone-releasing system or abstinence) during treatment and for at least 3 months after the final dose of lithium
• Highly effective method of contraception in affected men individuals of childbearing age (condom or abstinence) during the treatment and for at least 5 days after the final dose of lithium
• 1 available parent/guardian able to attend all visits having acceptable reading skills

Exclusion Criteria:

Criteria related to associated pathologies leading to particular risks:

• Renal/liver insufficiency (disturbed liver function, abnormal creatinine clearance)
• Unbalanced thyroid or diabetic pathology
• Long QT/Brugada syndrome or familial antecedent of Brugada syndrome, cardiac insufficiency
• Addison disease, dehydration, sodium restriction
• Non-stabilized epileptic disease.

Criteria related to contra-indication to treatment:

• Patient with concomitant diseases for which the experimental treatment by lithium could alter the tolerance
• Hypersensitivity to lactose, lithium or one of its excipients
• Patient with a wheat allergy (other than celiac disease)
• Pregnant or breastfeeding woman

Criteria related to treatments/procedures:

• Parent/guardian incapable of expressing consent
• Person not affiliated to a national health insurance scheme
• Person subject to a court order
• Cognitivo-behavioural therapy focused on ASD in 6 weeks previous to inclusion
• Other genetic pathogenic variant associated to neurocognitive disorders
• Any introduction of psychotropic molecules within 2 months prior to the trial, including neuroleptics, monoamine oxidase inhibitors, stimulants, antidepressants.
• Concomitant use of Angiotensin-Converting Enzyme (ACE) inhibitor, angiotensin II receptor antagonists, Nonsteroidal anti-inflammatory drugs, diuretics.
• Current lithium treatment
• Severe behavioural disorder or refusal to take drug treatment not allowing for compliance with medication;
• Impossibility to perform blood tests to check the lithiaemia when the patient is included.
• Participation in another therapeutic trial