Reference. Exploring a Mechanism-Based Therapeutic Approach for ZC4H2 Haploinsufficiency
This report explores a therapeutic hypothesis for addressing the potential effects of a loss-of-function variant in the ZC4H2 gene. We describe a pediatric female (born 2020) with developmental delay associated with an early truncation variant in ZC4H2. This genetic alteration is suspected to reduce levels of the functional ZC4H2 protein (encoded by the ZC4H2 gene). Variants in ZC4H2 are associated with Wieacker–Wolff and Miles–Carpenter syndrome, which are characterized by intellectual disability, developmental delay, congenital contractures, and seizures. The patient presents with multiple developmental manifestations, including developmental delay, intellectual disability, joint contractures and dislocations, coronal craniosynostosis, truncal hypotonia, laryngomalacia, rocker bottom feet, and intermittent esotropia. We hypothesize that targeting the downstream effects of ZC4H2 haploinsufficiency, such as synaptic dysfunction and impaired dendritic spine stability, may help mitigate the patient’s symptoms by restoring synaptic homeostasis. This report outlines the rationale for this therapeutic hypothesis, which is informed by genetic findings, prior literature, and recent mechanistic insights. Further studies are needed to validate underlying disease mechanisms and to evaluate the candidate therapy for safety and efficacy.
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The precision medicine process for treating rare disease using the artificial intelligence tool mediKanren foksinska-2022-the
There are over 6,000 different rare diseases estimated to impact 300 million people worldwide. As genetic testing becomes more common practice in the clinical setting, the number of rare disease diagnoses will continue to increase, resulting in the need for novel treatment options. Identifying treatments for these disorders is challenging due to a limited understanding of disease mechanisms, small cohort sizes, interindividual symptom variability, and little commercial incentive to develop new treatments. A promising avenue for treatment is drug repurposing, where FDA-approved drugs are repositioned as novel treatments. However, linking disease mechanisms to drug action can be extraordinarily difficult and requires a depth of knowledge across multiple fields, which is complicated by the rapid pace of biomedical knowledge discovery. To address these challenges, The Hugh Kaul Precision Medicine Institute developed an artificial intelligence tool, mediKanren, that leverages the mechanistic insight of genetic disorders to identify therapeutic options. Using knowledge graphs, mediKanren enables an efficient way to link all relevant literature and databases. This tool has allowed for a scalable process that has been used to help over 500 rare disease families. Here, we provide a description of our process, the advantages of mediKanren, and its impact on rare disease patients.
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- Deleterious de novo variants of X-linked ZC4H2 in females cause a variable phenotype with neurogenic arthrogryposis multiplex congenita (2019)
- S-ketamine reverses hippocampal dendritic spine deficits in flinders sensitive line rats within 1 h of administration (2019)
- Donepezil reverses dendritic spine morphology adaptations and Fmr1 epigenetic modifications in hippocampus of adult rats after adolescent alcohol exposure (2018)
- Risperidone and aripiprazole alleviate prenatal valproic acid-induced abnormalities in behaviors and dendritic spine density in mice (2017)
- ZC4H2, an XLID gene, is required for the generation of a specific subset of CNS interneurons (2015)
- Chronic stimulation of alpha-2A-adrenoceptors with guanfacine protects rodent prefrontal cortex dendritic spines and cognition from the effects of chronic stress (2015)
- Clinical utility of guanfacine extended release in the treatment of ADHD in children and adolescents (2015)
- Structural and functional organization of the postsynaptic density (2014)
- ZC4H2 mutations are associated with arthrogryposis multiplex congenita and intellectual disability through impairment of central and peripheral synaptic plasticity (2013)
- Antihypertensive drug Valsartan promotes dendritic spine density by altering AMPA receptor trafficking (2013)
- Stimulation of α(2A)-adrenoceptors promotes the maturation of dendritic spines in cultured neurons of the medial prefrontal cortex (2012)
- The therapeutic effect of memantine through the stimulation of synapse formation and dendritic spine maturation in autism and fragile X syndrome (2012)
- Pre- and postsynaptic beta-adrenergic activation enhances excitatory synaptic transmission in layer V/VI pyramidal neurons of the medial prefrontal cortex of rats (2008)