CTLA-4 Haploinsufficiency Presenting as Extensive Enteropathy in a Patient With Very Early Onset Inflammatory Bowel Disease.

Patients with very early onset inflammatory bowel disease (VEO-IBD) have a higher incidence of monogenic disease compared to older age groups. Age, alone, is a strong predictor for monogenic disease. We discuss a case of VEO-IBD in which the patient presented with severe and refractory enteropathy, leading to diagnosis of CTLA-4 haploinsufficiency. Genetic workup showed de novo heterozygous deletions of the CTLA-4 and ICOS genes. This case was unique, as the patient did not have the other manifestations commonly present with the disease. We advocate for early and routine genetic workup of VEO-IBD, as patients with monogenic IBD have high morbidity and mortality, if inadequately treated. Our patient did not respond to conventional treatment modalities and required targeted treatment with Abatacept, a CTLA-4 agonist.

A guide to generating and using hiPSC derived NPCs for the study of neurological diseases.

Post-mortem studies of neurological diseases are not ideal for identifying the underlying causes of disease initiation, as many diseases include a long period of disease progression prior to the onset of symptoms. Because fibroblasts from patients and healthy controls can be efficiently reprogrammed into human induced pluripotent stem cells (hiPSCs), and subsequently differentiated into neural progenitor cells (NPCs) and neurons for the study of these diseases, it is now possible to recapitulate the developmental events that occurred prior to symptom onset in patients. We present a method by which to efficiently differentiate hiPSCs into NPCs, which in addition to being capable of further differentiation into functional neurons, can also be robustly passaged, freeze-thawed or transitioned to grow as neurospheres, enabling rapid genetic screening to identify the molecular factors that impact cellular phenotypes including replication, migration, oxidative stress and/or apoptosis. Patient derived hiPSC NPCs are a unique platform, ideally suited for the empirical testing of the cellular or molecular consequences of manipulating gene expression.

Modeling schizophrenia using induced pluripotent stem cell-derived and fibroblast-induced neurons.

Although schizophrenia affects a number of brain regions and produces a range of clinical symptoms, we believe its origins lie at the level of single neurons and simple networks. Owing to this, as well as to its high degree of heritability, we hypothesize that schizophrenia is amenable to cell-based studies in vitro. Using induced pluripotent stem cell-derived neurons and/or fibroblast-induced neurons, a limitless quantity of live human neurons can now be generated from patient skin biopsies. We predict that cell-based studies will ultimately contribute to our understanding of the molecular and cellular underpinnings of this debilitating disorder.