Targeted PMP22 TATA-box editing by CRISPR/Cas9 reduces demyelinating neuropathy of Charcot-Marie-Tooth disease type 1A in mice.

Charcot-Marie-Tooth 1A (CMT1A) is the most common inherited neuropathy without a known therapy, which is caused by a 1.4 Mb duplication on human chromosome 17, which includes the gene encoding the peripheral myelin protein of 22 kDa (PMP22). Overexpressed PMP22 protein from its gene duplication is thought to cause demyelination and subsequently axonal degeneration in the peripheral nervous system (PNS). Here, we targeted TATA-box of human PMP22 promoter to normalize overexpressed PMP22 level in C22 mice, a mouse model of CMT1A harboring multiple copies of human PMP22. Direct local intraneural delivery of CRISPR/Cas9 designed to target TATA-box of PMP22 before the onset of disease, downregulates gene expression of PMP22 and preserves both myelin and axons. Notably, the same approach was effective in partial rescue of demyelination even after the onset of disease. Collectively, our data present a proof-of-concept that CRISPR/Cas9-mediated targeting of TATA-box can be utilized to treat CMT1A.

Successful Treatment of Recurrent Primitive Myxoid Mesenchymal Tumor of Infancy With BCOR Internal Tandem Duplication.

Primitive myxoid mesenchymal tumor of infancy (PMMTI) is a rare tumor with <20 cases reported to date. Recently PMMTI tumors have been found to harbor BCOR internal tandem duplication (ITD), the same genetic alteration detected in clear cell sarcoma of the kidney (CCSK). Complete surgical resection of PMMTI is often curative, but no standard of care has been established for unresectable tumors. We describe a female patient who presented at 13 months of age with a paraspinal mass and spinal cord compression. Histology was consistent with PMMTI, and the tumor was found to harbor BCOR ITD. The patient experienced disease recurrences after multiple surgical resections. After failing to respond to vincristine and actinomycin therapy, the patient demonstrated a nearly complete response to a doxorubicin-containing chemotherapy regimen. The patient's therapy was consolidated with proton beam radiotherapy, and she has remained in remission for >12 months after the conclusion of therapy. This case confirms BCOR ITD as a key finding in PMMTI. The therapeutic approach described here is similar to that used for CCSK and provides a model for the treatment of PMMTI not amenable to complete surgical resection.

MR findings of synovial disease in children and young adults: Part 2.

Synovium is the thin membranous lining of a joint. It produces synovial fluid, which lubricates and nourishes the cartilage and bone in the joint capsule. Synovial diseases in children can be classified as normal structures as potential sources of pathology (synovial folds: plicae, infrapatellar fat pad clefts), noninfectious synovial proliferation (juvenile idiopathic arthritis, hemophilic arthropathy, lipoma arborescens, synovial osteochondromatosis, pigmented villonodular synovitis, reactive synovitis), infectious synovial proliferation (pyogenic arthritis, tuberculous arthritis), deposition disease (gouty arthropathy), vascular malformation, malignancy (metastasis) and intra-/periarticular cysts and cyst-like structures. Other intra-articular neoplasms, such as intra-articular synovial sarcoma, can mimic synovial disease in children.