Friedreich's Ataxia: Clinical Presentation of a Compound Heterozygote Child with a Rare Nonsense Mutation and Comparison with Previously Published Cases.

Friedreich's ataxia is a neurodegenerative disorder associated with a GAA trinucleotide repeat expansion in intron 1 of the frataxin (FXN) gene. It is the most common autosomal recessive cerebellar ataxia, with a mean age of onset at 16 years. Nearly 95-98% of patients are homozygous for a 90-1300 GAA repeat expansion with only 2-5% demonstrating compound heterozygosity. Compound heterozygous individuals have a repeat expansion in one allele and a point mutation/deletion/insertion in the other. Compound heterozygosity and point mutations are very rare causes of Friedreich's ataxia and nonsense mutations are a further rarity among point mutations. We report a rare compound heterozygous Friedrich's ataxia patient who was found to have one expanded GAA FXN allele and a nonsense point mutation in the other. We summarize the four previously published cases of nonsense mutations and compare the phenotype to that of our patient. We compared clinical information from our patient with other nonsense FXN mutations reported in the literature. This nonsense mutation, to our knowledge, has only been described once previously; interestingly the individual was also of Cuban ancestry. A comparison with previously published cases of nonsense mutations demonstrates some common clinical characteristics.

A Next-Generation TRK Kinase Inhibitor Overcomes Acquired Resistance to Prior TRK Kinase Inhibition in Patients with TRK Fusion-Positive Solid Tumors.

Larotrectinib, a selective TRK tyrosine kinase inhibitor (TKI), has demonstrated histology-agnostic efficacy in patients with TRK fusion-positive cancers. Although responses to TRK inhibition can be dramatic and durable, duration of response may eventually be limited by acquired resistance. LOXO-195 is a selective TRK TKI designed to overcome acquired resistance mediated by recurrent kinase domain (solvent front and xDFG) mutations identified in multiple patients who have developed resistance to TRK TKIs. Activity against these acquired mutations was confirmed in enzyme and cell-based assays and in vivo tumor models. As clinical proof of concept, the first 2 patients with TRK fusion-positive cancers who developed acquired resistance mutations on larotrectinib were treated with LOXO-195 on a first-in-human basis, utilizing rapid dose titration guided by pharmacokinetic assessments. This approach led to rapid tumor responses and extended the overall duration of disease control achieved with TRK inhibition in both patients.Significance: LOXO-195 abrogated resistance in TRK fusion-positive cancers that acquired kinase domain mutations, a shared liability with all existing TRK TKIs. This establishes a role for sequential treatment by demonstrating continued TRK dependence and validates a paradigm for the accelerated development of next-generation inhibitors against validated oncogenic targets. Cancer Discov; 7(9); 963-72. ©2017 AACR.See related commentary by Parikh and Corcoran, p. 934This article is highlighted in the In This Issue feature, p. 920.

Occipital Bony Abnormality and Multiple Strokes in a Pediatric Patient: Case Report and Review of the Current Literature.

This study presents a case of a 15-year-old boy who had a right vertebral artery dissection with distal embolization from repeated trauma from an occipital bony spicule. The authors hypothesize that this bony spicule was contacting the left vertebral artery during head rotation, resulting in trauma to the vessel and formation of emboli which then showered distally, causing strokes in the posterior circulation of the brain. This specific phenomenon has previously been reported three times, only one of which was in pediatric literature. It is important for individuals to be aware of this rare anatomic cause of vertebral artery dissection in patients presenting with an odd constellation of symptoms related to strokes from vertebro-basilar system. Treatment options including early intervention with intravascular coil embolization are also discussed.

Kinetic approach to pathway attenuation using XOMA 052, a regulatory therapeutic antibody that modulates interleukin-1beta activity.

Many therapeutic antibodies act as antagonists to competitively block cellular signaling pathways. We describe here an approach for the therapeutic use of monoclonal antibodies based on context-dependent attenuation to reduce pathologically high activity while allowing homeostatic signaling in biologically important pathways. Such attenuation is achieved by modulating the kinetics of a ligand binding to its various receptors and regulatory proteins rather than by complete blockade of signaling pathways. The anti-interleukin-1beta (IL-1beta) antibody XOMA 052 is a potent inhibitor of IL-1beta activity that reduces the affinity of IL-1beta for its signaling receptor and co-receptor but not for its decoy and soluble inhibitory receptors. This mechanism shifts the effective dose response of the cytokine so that the potency of IL-1beta bound by XOMA 052 is 20-100-fold lower than that of IL-1beta in the absence of antibody in a variety of in vitro cell-based assays. We propose that by decreasing potency of IL-1beta while allowing binding to its clearance and inhibitory receptors, XOMA 052 treatment will attenuate IL-1beta activity in concert with endogenous regulatory mechanisms. Furthermore, the ability to bind the decoy receptor may reduce the potential for accumulation of antibody.target complexes. Regulatory antibodies like XOMA 052, which selectively modulate signaling pathways, may represent a new mechanistic class of therapeutic antibodies.

Development of XPA067.06, a potent high affinity human anti-gastrin monoclonal antibody.

The peptide hormone gastrin is a key factor in regulation of gastric acid secretion. It has also been implicated in the development or maintenance of various types of cancer, such as pancreatic and stomach carcinoma. Inhibition of gastrin activity has potential for therapeutic use as a suppressor of acid secretion as well as an inhibitor of gastrin-responsive tumors. XPA067.06 is an affinity matured, 30 pM fully human anti-gastrin monoclonal antibody that was generated. The antibody was tested in a mouse gastric pH model to determine its effect on acid secretion. In this model, animals were treated with human gastrin, XPA067.06, and H2R or M1 receptor antagonists. Gastric fluid was collected and acid output was measured as a function of pH. XPA067.06 was shown to significantly inhibit gastrin-17-stimulated acid output for at least 48h. These results demonstrate that XPA067.06 effectively binds and neutralizes human gastrin-17 in vivo with rapid onset and prolonged duration of efficacy.

Congenital lymphocytic choriomeningitis virus infection: spectrum of disease.

OBJECTIVE: Lymphocytic choriomeningitis virus (LCMV) is a human pathogen and an emerging neuroteratogen. When the infection occurs during pregnancy, the virus can target and damage the fetal brain and retina. We examined the spectrum of clinical presentations, neuroimaging findings, and clinical outcomes of children with congenital LCMV infection. METHODS: Twenty children with serologically confirmed congenital LCMV infection were identified. The children underwent neuroimaging studies and were followed prospectively for up to 11 years. RESULTS: All children with congenital LCMV infection had chorioretinitis and structural brain anomalies. However, the presenting clinical signs, severity of vision disturbance, nature and location of neuropathology, and character and severity of brain dysfunction varied substantially among cases. Neuroimaging abnormalities included microencephaly, periventricular calcifications, ventriculomegaly, pachygyria, cerebellar hypoplasia, porencephalic cysts, periventricular cysts, and hydrocephalus. The combination of microencephaly and periventricular calcifications was the most common neuroimaging abnormality, and all children with this combination had profound mental retardation, epilepsy, and cerebral palsy. However, others had less severe neuroimaging abnormalities and better outcomes. Some children had isolated cerebellar hypoplasia, with jitteriness as their presenting sign and ataxia as their principal long-term neurological dysfunction. INTERPRETATION: Congenital LCMV infection can have diverse presenting signs, neuroimaging abnormalities, and clinical outcomes. In the companion article to this study, we utilize an animal model to show that the clinical and pathological diversity in congenital LCMV infection is likely due to differences in the gestational timing of infection.

IL-converting enzyme/caspase-1 inhibitor VX-765 blocks the hypersensitive response to an inflammatory stimulus in monocytes from familial cold autoinflammatory syndrome patients.

Familial cold autoinflammatory syndrome (FCAS) and the related autoinflammatory disorders, Muckle-Wells syndrome and neonatal onset multisystem inflammatory disease, are characterized by mutations in the CIAS1 gene that encodes cryopyrin, an adaptor protein involved in activation of IL-converting enzyme/caspase-1. Mutations in cryopyrin are hypothesized to result in abnormal secretion of caspase-1-dependent proinflammatory cytokines, IL-1beta and IL-18. In this study, we examined cytokine secretion in PBMCs from FCAS patients and found a marked hyperresponsiveness of both IL-1beta and IL-18 secretion to LPS stimulation, but no evidence of increased basal secretion of these cytokines, or alterations in basal or stimulated pro-IL-1beta levels. VX-765, an orally active IL-converting enzyme/caspase-1 inhibitor, blocked IL-1beta secretion with equal potency in LPS-stimulated cells from FCAS and control subjects. These results further link mutations in cryopyrin with abnormal caspase-1 activation, and support the clinical testing of caspase-1 inhibitors such as VX-765 in autoinflammatory disorders.

Acute disseminated encephalomyelitis following pleural empyema owing to Boerhaave's syndrome.

Acute disseminated encephalomyelitis is reported in a 14-year-old male patient associated with a pleural empyema caused by an esophageal perforation. During the hospital course, the patient experienced an episode of cardiac arrest, raising the question of hypoxic-ischemic cerebral injury, but the magnetic resonance imaging (MRI) findings and clinical course were most consistent with acute disseminated encephalomyelitis. After a course of methylprednisolone, broad-spectrum antibiotics, and bilateral chest tube placement, the patient recovered with only mild residual deficits, along with resolution of his MRI findings.