Comparing the Superficial Vasculature of the Central Nervous System in Six Laboratory Animals: A Hypothesis About the Role of the “Circle of Willis”

We provide images of the entire central nervous system vasculature, and compare the anatomical findings in six different laboratory animals. A detailed understanding of the specific anatomy for each is important in the design of experimental modeling and for understanding the specific function of each target organ . Six different types of animals, the Korean wild mouse, C57BL/6J mouse, F344 rat, mongolian gerbil, Syrian hamsters, and guinea pigs, were included. To stain the blood vessels in each of the animals, Alcian blue reagent was used to perfuse each species. The bifurcation and anastomotic patterns of the anterior cerebral arteries differed in each species. The vascular supply to the olfactory nerve was visualized as a single artery supplying both olfactory nerves, and arteries supplying the lateral portion of the olfactory nerves originating from the olfactory bulb area. The posterior communicating arteries of the six animals demonstrated unique morphologies. The shape of the hypophyseal portal system varied by species. Most animals used in this study had a hexagonal Circle of Willis, except for the Korean wild mouse. Using this approach, we successfully mapped the brain vascular system in six different species of animals. This information and the images created can guide other researchers as they design research studies and create experimental models for new surgical procedures and approaches. Anat Rec, 2019. © 2019 Wiley Periodicals, Inc. Anat Rec, 302:2049–2061, 2019. © 2019 American Association for Anatomy     

Cognitive fusion and depressive symptoms in women with chronic pain: A longitudinal growth curve modelling study over 12 months

This study aims to (a) explore individual differences in women with chronic pain (CP) in regard to pain intensity, functional impairment, cognitive fusion, and depressive symptoms and (b) longitudinally test whether cognitive fusion is a significant predictor of depression symptoms, while controlling for pain intensity and functional impairment, over a 12‐month period. This study follows a longitudinal design and was conducted in a sample of 86 women with CP who responded to an online battery of questionnaires in three equally spaced assessment moments. In order to explore the growth trajectory of variables of interest, latent growth curve models were examined. Also, correlation analyses were conducted between demographic and illness‐related variables and depressive symptoms, as well as between all variables in all assessment moments. Cognitive fusion and functional impairment (but not pain intensity) were significantly associated with baseline levels of depressive symptoms. Cognitive fusion significantly predicted the growth trajectory of depressive symptoms, whereas pain intensity and functional impairment did not. No demographic (age, marital status, education, socio‐economic) nor illness‐related variables (number of CP diagnoses, duration of CP, taking medication) were associated with depressive symptoms at any point. These results suggest that the trajectory of depressive symptoms in women with CP is not predicted by the intensity of pain nor pain‐related functional impairment, but rather by the tendency to get entangled with internal experiences (e.g., thoughts, emotions, and physical sensations), which may or may not be related to pain‐specific contents. Clinical implications are discussed.     

CAPN5 genetic inactivation phenotype supports therapeutic inhibition trials

Small molecule pharmacological inhibition of dominant human genetic disease is a feasible treatment that does not rely on the development of individual, patient‐specific gene therapy vectors. However, the consequences of protein inhibition as a clinical therapeutic are not well‐studied. In advance of human therapeutic trials for CAPN5 vitreoretinopathy, genetic inactivation can be used to infer the effect of protein inhibition in vivo. We created a photoreceptor‐specific knockout (KO) mouse for Capn5 and compared the retinal phenotype to both wild‐type and an existing Capn5 KO mouse model. In humans, CAPN5 loss‐of‐function (LOF) gene variants were ascertained in large exome databases from 60,706 unrelated subjects without severe disease phenotypes. Ocular examination of the retina of Capn5 KO mice by histology and electroretinography showed no significant abnormalities. In humans, there were 22 LOF CAPN5 variants located throughout the gene and in all major protein domains. Structural modeling of coding variants showed these LOF variants were nearby known disease‐causing variants within the proteolytic core and in regions of high homology between human CAPN5 and 150 homologs, yet the LOF of CAPN5 was tolerated as opposed to gain‐of‐function disease‐causing variants. These results indicate that localized inhibition of CAPN5 is a viable strategy for hyperactivating disease alleles.     

Extension of the Pompe mutation database by linking disease‐associated variants to clinical severity

Pompe disease is an autosomal recessive lysosomal storage disorder caused by disease‐associated variants in the acid alpha‐glucosidase (GAA) gene. The current Pompe mutation database provides a severity rating of GAA variants based on in silico predictions and expression studies. Here, we extended the database with clinical information of reported phenotypes. We added additional in silico predictions for effects on splicing and protein function and for cross reactive immunologic material (CRIM) status, minor allele frequencies, and molecular analyses. We analyzed 867 patients and 562 GAA variants. Based on their combination with a GAA null allele (i.e., complete deficiency of GAA enzyme activity), 49% of the 422 disease‐associated variants could be linked to classic infantile, childhood, or adult phenotypes. Predictions and immunoblot analyses identified 131 CRIM negative and 216 CRIM positive variants. While disease‐associated missense variants were found throughout the GAA protein, they were enriched up to seven‐fold in the catalytic site. Fifteen percent of disease‐associated missense variants were predicted to affect splicing. This should be confirmed using splicing assays. Inclusion of clinical severity rating in the Pompe mutation database provides an invaluable tool for diagnosis, prognosis of disease progression, treatment regimens, and the future development of personalized medicine for Pompe disease.     

A case report of cutaneous melanocytoma with CRTC1‐TRIM11 fusion: Is CMCT distinct from clear cell sarcoma of soft tissue?

Pathological diagnosis of dermal melanocytic tumors is often problematic owing to histological resemblance. Recently, cutaneous melanocytoma with CRTC1‐TRIM11 (CMCT) was added to this category. However, only six cases have been reported so far. We herein present a case of a 77‐year‐old Japanese man with CMCT. The patient presented a nodule in the right thigh and underwent surgical resection. Histological examination indicated a well‐demarcated 6 × 5 mm‐sized tumor nodule in the dermis and subcutis. The tumor was amelanotic, consisting of uniform nests and fascicles of spindled, or epithelioid cells. The melanocytic nature was evident by immunohistochemistry. The CRTC1‐TRIM11 fusion was detected by TRIM11 immunostaining, chromogenic in situ hybridization, and RT‐PCR/direct sequencing. He has been free from the tumor for 1 year after additional resection. The main differential diagnosis of CMCT includes primary and metastatic dermal malignant melanomas (MM) and dermal/subcutaneous clear cell sarcoma (CCS). Additionally, histological overlap with paraganglioma‐like dermal melanocytic tumor was considered. Although some investigators argue that CMCT is a variant of CCS, we think it should be separated from CCS, and subcutaneous/dermal CCS should be confined to tumors with EWSR1‐ATF1/ CREB1 fusion. However, longer follow‐up and more case studies are needed for revealing the true prognosis of CMCT.     

Maladaptive behaviors in individuals with Angelman syndrome

Maladaptive behaviors are challenging and a source of stress for caregivers of individuals with Angelman Syndrome (AS). There is limited information on how these maladaptive behaviors vary over time among individuals with AS due to different genetic etiologies. In this study, caregivers of 301 individuals with AS were asked questions about their child's behavior and completed the Aberrant Behavior Checklist‐Community version (ABC‐C). Developmental functioning was evaluated with either the Bayley Scales of Infant Development, Third Edition (Bayley‐III) or the Mullen Scales of Early Learning (MSEL). Family functioning was assessed using the parent‐completed Parenting Stress Index (PSI) and the Family Quality of Life questionnaire (FQoL). Approximately 70% of participants had AS due to a deletion on the maternally‐inherited copy of chromosome 15q11q13. Results revealed that at baseline, individuals with AS had low scores in the domains of lethargy (mean: 2.6–4.2 depending on genotype) and stereotypy (mean: 2.3–4.2 depending on genotype). Higher cognitive functioning was associated with increased irritability (r = 0.32, p < .01). Hyperactivity (p < .05) and irritability (p < .05) increased with age across all genotypes and should be ongoing targets for both behavioral and pharmacological treatment. Concerns for short attention span were endorsed by more than 70% of caregivers at baseline. Maladaptive behaviors, particularly hyperactivity, irritability and aggression, adversely affected parental stress, and family quality of life.     

Palatal evaluation and treatment in 22q11.2 deletion syndrome

Palatal involvement occurs commonly in patients with 22q11.2 Deletion Syndrome (22qDS), and includes palatal clefting and velopharyngeal dysfunction in the absence of overt or submucous clefts. The reported incidence and distribution of palatal abnormalities vary in the literature. The aim of this article is to revisit the incidence and presenting features of palatal abnormalities in a large cohort of patients with 22qDS, summarize the surgical treatments performed in this cohort, and provide an overview of surgical treatment protocols and management guidelines for palatal abnormalities in this syndrome. Charts of 1,121 patients seen through the 22q and You Center at the Children's Hospital of Philadelphia were reviewed for palatal status, demographic factors, deletion size, and corrective surgical procedures. Statistical analysis was performed using Pearson's chi‐squared test to identify differences between gender, deletion size, and palatal abnormality. Of the patients with complete evaluations, 67% were found to have a palatal abnormality. The most common finding was velopharyngeal dysfunction in 55.2% of patients, and in 33.3% of patients, this occurred in the absence of palatal clefting. There was no significant difference in the incidence of palatal abnormalities by gender; however, a difference was noted among race (p < 0.01) and deletion sizes (p < 0.01). For example, Caucasian and Asian patients presented with a much higher prevalence of palatal abnormalities, and conversely those with nested deletions presented with a much lower rate of palatal defects. Overall, 26.9% of patients underwent palatal surgery, and the most common indication was velopharyngeal dysfunction. Palatal abnormalities are a hallmark feature of 22q11.2 Deletion Syndrome; understanding the incidence, presenting features, and treatment protocols are essential for practitioners counseling and treating families affected with this disorder.     

Dental and craniofacial characteristics caused by the p.Ser40Leu mutation in IFITM5

Severe forms of osteogenesis imperfecta (OI) are usually caused by mutations in genes that code for collagen Type I and frequently are associated with craniofacial abnormalities. However, the dental and craniofacial characteristics of OI caused by the p.Ser40Leu mutation in the IFITM5 gene have not been reported. We investigated a 15‐year‐old girl with severe OI caused by this mutation. She had marked deformations of extremity long bones. There were no clinical or radiological signs of dentinogenesis imperfecta, but one tooth was missing and several teeth were impacted. Cone beam computed tomography revealed a generalized osteopenic appearance of the craniofacial skeleton, bilateral enlargement of mandibular bodies, and areas of cortical erosions. The cranial base and skull showed a generalized granular bone pattern with a mixture of osteosclerosis and osteolysis. Sphenoid and frontal sinuses were congenitally missing. Cephalometric analysis indicated a Class III growth pattern. In this case, the IFITM5 p.Ser40Leu mutation did not affect tooth structure but was associated with deformities in craniofacial bones that resemble those in the other parts of the skeleton.