Case report: Approaches to treatment-refractory and super-refractory glutamic acid decarboxylase antibody-spectrum disorders.

Background: Glutamic acid decarboxylase antibody-spectrum disorders (GAD-SDs) include a group of autoimmune neurological diseases associated with neuronal excitability, most noticeably stiff person syndrome. Immune modulators are the mainstay of treatment, but a significant number of patients remain refractory. Methods: We present our single-center experience of eight cases of GAD-SD, two of which were refractory to immune modulatory treatments. Results: Of the two cases that were refractory to immunomodulation, one showed significant improvement with bilateral globus pallidus interna deep brain stimulation (GPi DBS) placement, and the other showed significant improvement with autologous hematopoietic stem cell transplant (aHSCT). Discussion: To our knowledge, this is the first instance of GPi DBS placement being noted to improve GAD-SD movements.

Polymerase Chain Reaction (PCR)-Negative Herpes Simplex Virus (HSV) Encephalitis in a 62-Year-Old Woman With p-ANCA Vasculitis.

We present the case of a 62-year-old woman with a past medical history significant for p-ANCA vasculitis (on immunosuppression) who was found to have polymerase chain reaction (PCR)-negative herpes simplex virus (HSV) encephalitis. We also present a review of all identifiable reports of PCR-negative HSV encephalitis in the past 20 years. To our knowledge, this is the first case of PCR-negative HSV encephalitis in a patient with p-ANCA vasculitis and the thirteenth overall in this timeframe. The patient presented with new-onset fever, encephalopathy, and a first-in-lifetime focal motor seizure progressing to status epilepticus. Cerebrospinal fluid (CSF) PCR was negative for HSV on three separate instances between the first and thirteenth days since symptom onset, and the CSF profile was not typical for HSV encephalitis. The patient underwent a brain biopsy, which confirmed the presence of HSV. She continued to worsen despite aggressive seizure control and six days of empiric acyclovir. Unfortunately, she expired despite the reinitiation of acyclovir. When faced with the classical features of encephalitis in the immunocompromised, the suspicion of HSV should remain high despite negative PCR results. The completion of a full course of acyclovir in the absence of clinical improvement should be considered.

Symptomatic Vertebral Hemangioma in a Young Child.

Vertebral hemangiomas (VHs) are the most common benign vertebral neoplasm and typically are asymptomatic, only to be discovered incidentally on imaging from the fourth to fifth decade of life. Seldom do they enlarge to a point of compression, causing pain and focal neurologic deficits. We present the rare case of an 8-year-old female who presented with paraparesis after a fall. Imaging revealed a pathological fracture of the T8 vertebra with retropulsion and spinal cord compression from both fracture and epidural tumor tissue. The patient underwent an anterior and posterior removal of the tumor, decompression, and fusion. Pathological report of specimen biopsy confirmed a benign hemangioma. To the best of our knowledge, this is the same age as the youngest previously reported case of symptomatic VH and it is the longest to be recurrence-free at follow-up. The hemangioma was successfully treated with tumor removal, decompression, and fusion. No adjuvant treatment was required, and she remained asymptomatic without recurrence at her 4-year follow-up.

Cell proliferation in the absence of E2F1-3.

E2F transcription factors regulate the progression of the cell cycle by repression or transactivation of genes that encode cyclins, cyclin dependent kinases, checkpoint regulators, and replication proteins. Although some E2F functions are independent of the Retinoblastoma tumor suppressor (Rb) and related family members, p107 and p130, much of E2F-mediated repression of S phase entry is dependent upon Rb. We previously showed in cultured mouse embryonic fibroblasts that concomitant loss of three E2F activators with overlapping functions (E2F1, E2F2, and E2F3) triggered the p53-p21(Cip1) response and caused cell cycle arrest. Here we report on a dramatic difference in the requirement for E2F during development and in cultured cells by showing that cell cycle entry occurs normally in E2f1-3 triply-deficient epithelial stem cells and progenitors of the developing lens. Sixteen days after birth, however, massive apoptosis in differentiating epithelium leads to a collapse of the entire eye. Prior to this collapse, we find that expression of cell cycle-regulated genes in E2F-deficient lenses is aberrantly high. In a second set of experiments, we demonstrate that E2F3 ablation alone does not cause abnormalities in lens development but rescues phenotypic defects caused by loss of Rb, a binding partner of E2F known to recruit histone deacetylases, SWI/SNF and CtBP-polycomb complexes, methyltransferases, and other co-repressors to gene promoters. Together, these data implicate E2F1-3 in mediating transcriptional repression by Rb during cell cycle exit and point to a critical role for their repressive functions in cell survival.

Allele-specific tumor spectrum in pten knockin mice.

Germline mutations in the tumor suppressor gene PTEN (phosphatase and tensin homology deleted on chromosome 10) cause Cowden and Bannayan-Riley-Ruvalcaba (BRR) syndromes, two dominantly inherited disorders characterized by mental retardation, multiple hamartomas, and variable cancer risk. Here, we modeled three sentinel mutant alleles of PTEN identified in patients with Cowden syndrome and show that the nonsense Pten(4-5) and missense Pten(C124R) and Pten(G129E) alleles lacking lipid phosphatase activity cause similar developmental abnormalities but distinct tumor spectra with varying severity and age of onset. Allele-specific differences may be accounted for by loss of function for Pten(4-5), hypomorphic function for Pten(C124R), and gain of function for Pten(G129E). These data demonstrate that the variable tumor phenotypes observed in patients with Cowden and BRR syndromes can be attributed to specific mutations in PTEN that alter protein function through distinct mechanisms.