Long‐term observation of a Japanese mucolipidosis IV patient with a novel homozygous p.F313del variant of MCOLN1

Mucolipidosis type IV (MLIV) is an autosomal recessively inherited lysosomal storage disorder characterized by progressive psychomotor delay and retinal degeneration that is associated with biallelic variants in the MCOLN1 gene. The gene, which is expressed in late endosomes and lysosomes of various tissue cells, encodes the transient receptor potential channel mucolipin 1 consisting of six transmembrane domains. Here, we described 14‐year follow‐up observation of a 4‐year‐old Japanese male MLIV patient with a novel homozygous in‐frame deletion variant p.(F313del), which was identified by whole‐exome sequencing analysis. Neurological examination revealed progressive psychomotor delay, and atrophy of the corpus callosum and cerebellum was observed on brain magnetic resonance images. Ophthalmologically, corneal clouding has remained unchanged during the follow‐up period, whereas optic nerve pallor and retinal degenerative changes exhibited progressive disease courses. Light‐adapted electroretinography was non‐recordable. Transmission electron microscopy of granulocytes revealed characteristic concentric multiple lamellar structures and an electron‐dense inclusion in lysosomes. The in‐frame deletion variant was located within the second transmembrane domain, which is of putative functional importance for channel properties.     

Potent and specific antitumor effect of CEA‐targeted photoimmunotherapy

Conventional photodynamic therapy (PDT) for cancer is limited by the insufficient efficacy and specificity of photosensitizers. We herein describe a highly effective and selective tumor‐targeted PDT using a near‐infrared (NIR) photosensitizer, IRDye700DX, conjugated to a human monoclonal antibody (Ab) specific for carcinoembryonic antigen (CEA). The antitumor effects of this Ab‐assisted PDT, called photoimmunotherapy (PIT), were investigated in vitro and in vivo. The Ab‐IRDye conjugate induced potent cytotoxicity against CEA‐positive tumor cells after NIR‐irradiation, whereas CEA‐negative cells were not affected at all, even in the presence of excess photoimmunoconjugate. We found an equivalent phototoxicity and a predominant plasma membrane localization of Ab‐IRDye after both one and six hours of incubation. Either no or little caspase activation and membrane peroxidation were observed in PIT‐treated cells and a panel of scavengers for reactive oxygen species showed only partial inhibition of the phototoxic effect. Strikingly, Ab‐IRDye retained significant phototoxicity even under hypoxia. We established a xenograft model, which allowed us to sensitively investigate the therapeutic efficacy of PIT by non‐invasive bioluminescence imaging. Luciferase‐expressing MKN‐45‐luc human gastric carcinoma cells were subcutaneously implanted into both flanks of nude mice. NIR‐irradiation was performed for only the tumor on one side. In vivo imaging and measurement of the tumor size revealed that a single PIT treatment, with intraperitoneal administration of Ab‐IRDye and subsequent NIR‐irradiation, caused rapid cell death and significant inhibition of tumor growth, but only on the irradiated side. Together, these data suggest that Ab‐IRDye‐mediated PIT has great potential as an anticancer therapeutics targeting CEA‐positive tumors.     

Congenital disorders of glycosylation type IIb with MOGS mutations cause early infantile epileptic encephalopathy,dysmorphic features,and hepatic dysfunction

AimMOGS mutations cause congenital disorders of glycosylation type IIb (CDG-IIb or GCS1-CDG). The specific manifestations caused by the mutations in this gene remain unknown. We aimed to describe the clinical features of CDG- IIb and the effectiveness of urinary oligosaccharide analysis in the diagnosis of CDG- IIb.MethodsPatient 1 was analyzed with whole-exome sequencing (WES) to identify the causative gene of intractable epilepsy and severe developmental delay. After detecting MOGS mutation in patient 1, we analyzed patients 2 and 3 who were siblings and had clinical features similar to those in patient 1. Urinary oligosaccharide analysis was performed to confirm CDG- IIb diagnosis in patient 1. The clinical features of these patients were analyzed and compared with those in eight published cases.ResultsOur three patients presented with early infantile epileptic encephalopathy, generalized hypotonia, hepatic dysfunction and dysmorphic features. In two cases, compound heterozygous mutations in MOGS were identified by WES. Isolation and characterization of the urinary oligosaccharide was performed in one of these cases to confirm the diagnosis of CDG-IIb. Although the isoelectric focusing of transferrin (IEF-T) of serum in this patient was normal, urinary excretion of Hex₄ corresponding to Glc₃Man was observed by mass spectrometry.ConclusionThis report provides clinical manifestations of CDG-IIb with MOGS mutation. CDG-IIb shows a normal IEF profile of serum transferrin and cannot be detected by structural analysis of the patient’s glycoproteins. Characterization of urinary oligosaccharides should be considered to detect this disorder.     

Evaluation of four commercial severe acute respiratory coronavirus 2 antibody tests

IntroductionNumerous severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) serological tests exists commercially; however, their performance using clinical samples is limited. Although insufficient to detect SARS-CoV-2 in the early phase of infection, antibody assays can be of great use for surveillance studies or for some coronavirus disease 2019 (COVID-19) patients presenting late to the hospital.MethodsThis study evaluated the sensitivity and specificity of four commercial SARS-CoV-2 lateral flow antibody tests using 213 serum specimens from 90 PCR-positive confirmed COVID-19 patients. Of 59 negative control sera, 50 were obtained from patients with other respiratory infectious diseases before COVID-19 pandemic began while nine were from patients infected with other respiratory viruses, including two seasonal coronaviruses.ResultsThe varied sensitivities for the four commercial kits were 70.9%, 65.3%, 45.1%, and 65.7% for BioMedomics, Autobio Diagnostics, Genbody, and KURABO, respectively, between sick days 1 and 155 in COVID-19 patients. The sensitivities of the four tests gradually increased over time after infection before sick day 5 (15.0%, 12.5%, 15.0%, and 20.0%); from sick day 11–15 (95.7%, 87.2%, 53.2%, and 89.4%); and after sick day 20 (100%, 100%, 68.6%, and 96.1%), respectively. For severe illness, the sensitivities were quite high in the late phase after sick day 15. The specificities were over 96% for all four tests. No cross-reaction due to other pathogens, including seasonal coronaviruses, was observed.ConclusionsOur results demonstrated the large differences in the antibody test performances. This ought to be considered when performing surveillance analysis.     

The isolation and molecular characterization of Leishmania spp. from patients with American tegumentary leishmaniasis in northwest Argentina

American tegumentary leishmaniasis (ATL) is a group of zoonotic diseases caused by kinetoplastid flagellates of the genus Leishmania. A total of 66 patients diagnosed as positive ATL cases from northwest Argentina were included in this study. Leishmania stocks were isolated in vitro and analyzed over promastigote cultures sown on FTA through nested PCR and sequence of cytochrome b (cyt b). The molecular analysis resulted in the incrimination of L. (Viannia) braziliensis as the predominant species in the studied area, identifying two genotypes of L. (V.) braziliensis, 24 cases of Ab-1 cyt b and 41 cases of Ab-2 cyt b. One L. (V.) guyanensis strain was obtained from a traveler from the Brazilian Amazon. The prevalence of different genotypes was in agreement with previous studies, suggesting the necessity for new systems to study the genetic diversity in more detail. Most of the cases typified in this study were registered in the area of Zenta Valley (Orán, Hipólito Yrigoyen, and Pichanal cities), pointing a link between genotype and geographical origin of the sample. Sex and age distribution of the patients indicate that the transmission was predominantly associated with rural areas or rural activities, although the results might not exclude the possibility of peri-urban transmission. This work represents, so far, the largest isolation and molecular characterization of ATL cases in Argentina.     

Possible involvement of angiotensin-converting enzyme 2 and Mas activation in inhibitory effects of angiotensin II Type 1 receptor blockade on vascular remodeling

We explored the roles of angiotensin-converting enzyme 2 (ACE2), angiotensin-(1-7), and Mas activation in angiotensin II type 1 receptor blockade-mediated attenuation of vascular remodeling. Vascular injury was induced by polyethylene-cuff placement around the mouse femoral artery. After cuff placement, the mRNA level of both ACE2 and Mas was markedly decreased in wild-type mice, whereas ACE mRNA was not changed. Immunostaining of ACE2 and Mas was observed mainly in the media and was reduced in the injured artery. Administration of angiotensin-(1-7) decreased neointimal formation after cuff placement, whereas administration of [D-Ala(7)] angiotensin-(1-7), a Mas antagonist, increased it. Consistent with these results, we also demonstrated that neointimal formation induced by cuff placement was further increased in ACE2 knockout mice. In angiotensin II type 1a receptor knockout mice, mRNA expression and immunostaining of ACE2 and Mas in the injured artery were greater, with less neointimal formation than in wild-type mice. Increased ACE2 expression in the injured artery was also observed by treatment of wild-type mice with an angiotensin II type 1 receptor blocker, olmesartan. These results suggested that activation of the ACE2-angiotensin-(1-7)-Mas axis is at least partly involved in the beneficial effects of angiotensin II type 1 receptor blockade on vascular remodeling.     

A peritoneal marker for optimal timing of ventriculo-peritoneal shunt revision in early childhood

Abstract

The ventriculo-peritoneal shunt placed in a neonate or infant needs revision to lengthen the peritoneal tube at certain times during childhood. The critical time for this revision is not exactly the same between individuals. Furthermore, the level of peritoneal insertion of the shunt tube is often unclear on x-ray films. To plan for and determine the optimal timing of revision, we applied a titanium clip on the peritoneal suture line in three infants as a marker of peritoneal insertion level. During the 31- to 37-month follow-up period, abdominal x-ray clearly demonstrated the peritoneal insertion level in all three patients, allowing accurate determination of the length of the intraperitoneal portion OP) of the shunt tube. The rate of shortening of the length of IP was 20 to 27% of the increase in body height (BH). This technique allows accurate determination of the length of IP and also optimal timing for revision. [Neural Res 1998; 20: 526-528]     

Chromosomal losses and gains in meningiomas: Comparative genomic hybridization (CGH) study of the whole genome

Abstract

We investigated chromosomal aberrations in meningiomas using newly developed comparative genomic hybridization (CGH) technique and compared the results with the proliferating potential of the tumors. This technique permits the entire genome to be surveyed in one session of experiments. Our results revealed chromosomal aberrations in 5 out of 10 (50%) of the tumor samples studied. Losses of the distal parts of chromosome 1p (5 out of 10) and 22q (3 out of 10) were the two most frequent chromosomal aberrations. Losses and/or gains in other regions were only sporadic. The MIB-1 staining indices (MIB-511 %) were 1.9 ± 0.9% (mean ± SD) in benign (n = 8)1 4.5% in atypical (n = 1)1 and 11.7% in anaplastic (n = 1) meningiomas. The comparison of MIB-51 between the tumors with (2.3 ± 0.6%) and without (7.6 ± 0.3%) chromosomal aberrations demonstrated a trend towards an increased MIB-51 in meningiomas with chromosomal aberrations (p < 0.07) by unpaired 5tudent1s t-test. This study suggests that alterations in chromosomes 1p and 22q could be a primary focus of further detailed assessment of tumorigenesis and in understanding the biological behavior of meningiomas. [Neural Res 1998; 20: 612-616]     

Different patterns of cerebellar abnormality and hypomyelination between POLR3A and POLR3B mutations

Background

Mutations of POLR3A and POLR3B have been reported to cause several allelic hypomyelinating disorders, including hypomyelination with hypogonadotropic hypogonadism and hypodontia (4H syndrome). Patients and methods: To clarify the difference in MRI between the two genotypes, we reviewed MRI in three patients with POLR3B mutations, and three with POLR3A mutations. Results: Though small cerebellar hemispheres and vermis are common MRI findings with both types of mutations, MRI in patients with POLR3B mutations revealed smaller cerebellar structures, especially vermis, than those in POLR3A mutations. MRI also showed milder hypomyelination in patients with POLR3B mutations than those with POLR3A mutations, which might explain milder clinical manifestations. Conclusions: MRI findings are distinct between patients with POLR3A and 3B mutations, and can provide important clues for the diagnosis, as these patients sometimes have no clinical symptoms suggesting 4H syndrome.