Infantile Pain Episodes Associated with Novel Nav1.9 Mutations in Familial Episodic Pain Syndrome in Japanese Families

Painful peripheral neuropathy has been correlated with various voltage-gated sodium channel mutations in sensory neurons. Recently Nav1.9, a voltage-gated sodium channel subtype, has been established as a genetic influence for certain peripheral pain syndromes. In this study, we performed a genetic study in six unrelated multigenerational Japanese families with episodic pain syndrome. Affected participants (n = 23) were characterized by infantile recurrent pain episodes with spontaneous mitigation around adolescence. This unique phenotype was inherited in an autosomal-dominant mode. Linkage analysis was performed for two families with 12 affected and nine unaffected members, and a single locus was identified on 3p22 (LOD score 4.32). Exome analysis (n = 14) was performed for affected and unaffected members in these two families and an additional family. Two missense variants were identified: R222H and R222S in SCN11A. Next, we generated a knock-in mouse model harboring one of the mutations (R222S). Behavioral tests (Hargreaves test and cold plate test) using R222S and wild-type C57BL/6 (WT) mice, young (8-9 weeks old; n = 10-12 for each group) and mature (36-38 weeks old; n = 5-6 for each group), showed that R222S mice were significantly (p < 0.05) more hypersensitive to hot and cold stimuli than WT mice. Electrophysiological studies using dorsal root ganglion neurons from 8-9-week-old mice showed no significant difference in resting membrane potential, but input impedance and firing frequency of evoked action potentials were significantly increased in R222S mice compared with WT mice. However, there was no significant difference among Nav1.9 (WT, R222S, and R222H)-overexpressing ND7/23 cell lines. These results suggest that our novel mutation is a gain-of-function mutation that causes infantile familial episodic pain. The mouse model developed here will be useful for drug screening for familial episodic pain syndrome associated with SCN11A mutations

THE INHIBITORY ACTION OF LEAD ON MECHANICAL RESPONSES OF THE PROVENTRICULAR SMOOTH MUSCLE IN THE CHICK

The purpose of the present experiments was to examine the mechanism of the proventricular dilatation caused by lead in the isolated vagus nerveproventricular smooth muscle preparation of the chick. Lead caused dose- and time-dependent inhibition of contractions induced by vagal stimulation, transmural stimulation and externally applied acetylcholine (ACh). Vagally evoked contraction was much more sensitive to the inhibitory action of lead than the contractile response to ACh. The lower the frequency of transmural stimulation, or the lower the concentration of ACh was applied, the greater the inhibitory action of lead on the evoked smooth muscle contraction. The results suggest that proventricular impaction occurring in lead poisoning results from the pre- and postsynaptic inhibition of the vagus nerve-smooth muscle transmission

Astroblastoma: Immunohistochemical and ultrastructural study of distinctive epithelial and probable tanycytic differentiation

We report the clinicopathological findings of astroblastoma found in an 8-year-old girl who was subsequently treated for 11 years. The primary superficially circumscribed tumor was located in the frontoparietal lobe, while the recurrent and the second recurrent tumor were restricted to the same region 11 years later. The tumors obtained on these three occasions showed fundamentally the same histological, immunohistochemical and fine structural features. They exhibited astrocytic as well as ependymal tanycytic features with apparent epithelial cell lineage. The tumor cells showed typical features of astroblastoma comprising prominent perivascular pseudorosettes with remarkable vascular sclerosis. The immunohistochemical study revealed intensive positivity of GFAP, vimentin, epithelial membrane antigen (EMA), cytokeratin, connexin 26 and 32, desmocollin 1 and neuronal cadherin. The fine structure revealed divergent types of junctional complexes, some of which were connected with tonofilament bundles. Numerous microvilli protruded and basal lamina abutted on the tumor cell surface. We report these unique histological features, and stress that astroblastoma should be categorized as a specific type of neuroepithelial tumor

Coincident choroid plexus carcinoma and adrenocortical tumor in an infant

We report a case of a 20-month-old girl with a large choroid plexus carcinoma arising in the left lateral ventricle and an adrenocortical tumor. Following brain tumor resection, the patient was treated with radiation and chemotherapy. The adrenocortical tumor was found with the manifestation of precocious puberty. TP53 gene mutation (exons 4–10) was not detected in either specimen. The patient had leptomeningeal dissemination and died 26 months later