Siblings with optic neuropathy and RTN4IP1 mutation.

Inherited optic neuropathies (IONs) are neurodegenerative disorders affecting the optic nerve and the nervous system. Dominant and recessive IONs are known. Many of the dominant IONs are caused by mutations of OPA1. Autosomal-recessive IONs are rare. OPA10 is an autosomal-recessive ION due to mutations in RTN4IP1. Patients with RTN4IP1 mutations show extraocular manifestations. We report brothers with optic neuropathy who had novel mutations in the RTN4IP1 gene. This is the first report of Japanese patients with OPA10. They showed extraocular manifestations resembling mitochondrial encephalopathy.

Early manifestations of BPAN in a pediatric patient.

Neurodegeneration with brain iron accumulation (NBIA) comprises a clinically and genetically heterogeneous group of progressive brain disorders with several distinguishable subtypes. Recently, WDR45 mutations were reported in patients with ß-propeller protein-associated neurodegeneration (BPAN), characterized by early intellectual disability followed by delayed progressive motor and cognitive deterioration with onset in the second to third decade. BPAN has a distinct brain magnetic resonance imaging (MRI) pattern showing iron deposition in the globus pallidus and substantia nigra. To date, many of the BPAN patients have been diagnosed in adulthood. Here, we report on 6-year-old girl with BPAN diagnosed by whole exome sequencing. She showed Rett syndrome-like manifestations, a peculiar facial appearance and mildly elevated serum enzymes. Brain iron accumulation was detected by T2*-weighted MRI and T2-star weighted angiography (SWAN). This unique combination of clinical and neuroimaging features may be helpful for early diagnosis of BPAN.

The spectrum of ZEB2 mutations causing the Mowat-Wilson syndrome in Japanese populations.

Mowat-Wilson syndrome (MWS) is a multiple congenital anomaly syndrome characterized by moderate or severe intellectual disability, a characteristic facial appearance, microcephaly, epilepsy, agenesis or hypoplasia of the corpus callosum, congenital heart defects, Hirschsprung disease, and urogenital/renal anomalies. It is caused by de novo heterozygous loss of function mutations including nonsense mutations, frameshift mutations, and deletions in ZEB2 at 2q22. ZEB2 encodes the zinc finger E-box binding homeobox 2 protein consisting of 1,214 amino acids. Herein, we report 13 nonsense and 27 frameshift mutations from 40 newly identified MWS patients in Japan. Although the clinical findings of all the Japanese MWS patients with nonsense and frameshift mutations were quite similar to the previous review reports of MWS caused by nonsense mutations, frameshift mutations and deletions of ZEB2, the frequencies of microcephaly, Hirschsprung disease, and urogenital/renal anomalies were small. Patients harbored mutations spanning the region between the amino acids 55 and 1,204 in wild-type ZEB2. There was no obvious genotype-phenotype correlation among the patients. A transfection study demonstrated that the cellular level of the longest form of the mutant ZEB2 protein harboring the p.D1204Rfs*29 mutation was remarkably low. The results showed that the 3'-end frameshift mutation of ZEB2 causes MWS due to ZEB2 instability.

Clinical and radiological features of Japanese patients with a severe phenotype due to CASK mutations.

Heterozygous loss of function mutations of CASK at Xp11.4 in females cause severe intellectual disability (ID) and microcephaly with pontine and cerebellar hypoplasia (MICPCH). However, the longitudinal clinical and radiological course of affected patients, including patterns of postnatal growth, has not been described. Neurodevelopmental and imaging information was retrospectively accrued for 16 Japanese (15 female and 1 male) patients with ID and MICPCH associated with CASK mutations. All records were analyzed; patient age ranged from 2 to 16 years at the time of the most recent examinations. The growth pattern, neurological development, neurological signs/symptoms, and facial features were similar in the 15 female patients. Their head circumference at birth was within the normal range in about half, and their height and weight were frequently normal. This was followed by early development of severe microcephaly and postnatal growth retardation. The patients acquired head control almost normally between 3 and 6 months, followed by motor delay. More than half of the female patients had epilepsy. Their MRIs showed microcephaly, brainstem, and cerebellar hypoplasia in early infancy, and a normal or large appearing corpus callosum. The male patient showed a more severe clinical phenotype. These uniform clinical and radiological features should facilitate an early diagnosis and be useful for medical care of females with ID and MICPCH associated with CASK mutations.

Spectra analysis and live-neuron imaging of cyclic AMP binding domain fusing circularly permutated GFP: Data for violet light excitable cyclic AMP indicator.

Cyclic adenosine monophosphate (cyclic AMP) is a second messenger, which is involved in the regulation of various cellular processes, including neuronal firing rate, synaptic plasticity, axon formation and axon elongation in brain. Although the main molecules in the cAMP-mediated signaling pathway are well studied, the spatio-temporal dynamics of the cAMP remain to be elucidated. Live imaging is an informative tool to investigate the cell signaling dynamics. It allows continuous monitoring of a specific cell over a period of time. Thus, optical probes for cAMP are important tools for studying the dynamics of cAMP signaling. Multiple genetically encoded cAMP probes are available [1], [2], including Förster resonance energy transfer (FRET) based or circular permutated fluorescent protein (cpFP) based probes. cpFP-based probes have an advantage of easier handling than FRET-based probes caused by monomeric detection and smaller molecular size. However, there is no cAMP probe compatible with violet light excitation. Therefore, we fused violet light excitable cpGFP to cyclic nucleotide binding domain (CBD) in E. coli cAMP receptor protein. This construct successfully responded to cAMP concentration changes. We show here the spectra data and live-cell imaging data of the violet light excitable cAMP probe which can be used for multi-signal fluorescence imaging.

Hemodynamic Force as a Potential Regulator of Inflammation-Mediated Focal Growth of Saccular Aneurysms in a Rat Model.

Past studies have elucidated the crucial role of macrophage-mediated inflammation in the growth of intracranial aneurysms (IAs), but the contributions of hemodynamics are unclear. Considering the size of the arteries, we induced de novo aneurysms at the bifurcations created by end-to-side anastomoses with the bilateral common carotid arteries in rats. Sequential morphological data of induced aneurysms were acquired by magnetic resonance angiography. Computational fluid dynamics analyses and macrophage imaging by ferumoxytol were performed. Using this model, we found that de novo saccular aneurysms with a median size of 3.2 mm were induced in 20/45 (44%) of animals. These aneurysms mimicked human IAs both in morphology and pathology. We detected the focal growth of induced aneurysms between the 10th and 17th day after the anastomosis. The regional maps of hemodynamic parameters demonstrated the area exposed to low wall shear stress (WSS) and high oscillatory shear index (OSI) colocalized with the regions of growth. WSS values were significantly lower in the growing regions than in ones without growth. Macrophage imaging showed colocalization of macrophage infiltration with the growing regions. This experimental model demonstrates the potential contribution of low WSS and high OSI to the macrophage-mediated growth of saccular aneurysms.

ALDH18A1-related cutis laxa syndrome with cyclic vomiting.

Cutis laxa (CL) syndromes are connective tissue disorders characterized by redundant, sagging, inelastic and wrinkled skin, with organ involvement. Here, we describe a patient with ALDH18A1-related CL who developed cyclic vomiting. The patient was a 12-year-old boy who presented with poor postnatal growth, hypotonia, short stature, joint hyperlaxity, microcephaly, strabismus, bilateral cataracts, facial dysmorphism and severe mental retardation. Bone radiographs showed osteopenia and osteoporosis, and magnetic resonance angiography showed marked kinking and tortuosity of the brain vessels. These findings were clinically compatible with ALDH18A1-related CL. Molecular analysis revealed a de novo heterozygous mutation (p.R138Q) in ALDH18A1. No mutations were found in PYCR1 gene. The patient developed cyclic vomiting with decreased blood levels of ornithine, citrulline, arginine and proline without hyperammonemia and other hypoaminoacidemias were also found. ALDH18A1 encodes Δ(1)-pyrroline-5-carboxylate synthase, which is related to the biosynthesis of ornithine, citrulline, arginine, and proline. Cyclic vomiting has never been reported in other ALDH18A1-related CL patients. This is the first case report of ALDH18A1-related CL with cyclic vomiting associated with amino acid abnormalities.