Prolonged standing behaviour in people with joint hypermobility syndrome

Background Joint Hypermobility Syndrome (JHS) is a rare Heritable Disorder of Connective tissue characterised by generalised joint laxity and chronic widespread pain. Joint Hypermobility Syndrome has a large impact on patients’ day to day activities, and many complain of symptoms when standing for prolonged periods. This study investigates whether people with JHS exhibit the same behaviours to deal with the effects of prolonged standing as people with equal hypermobility and no pain, and people with normal flexibility and no pain. Methods Twenty three people with JHS, 22 people with Generalised Joint Hypermobility (GJH), and 22 people with normal flexibility (NF) were asked to stand for a maximum of 15 min across two force-plates. Fidgets were counted and quantified using a cumulative sum algorithm and sway parameters of the quiet standing periods between fidgets were calculated. Results Average standing time for participants with JHS was 7.35 min and none stood for the full 15 min. All participants with GJH and NF completed 15 min of standing. There were no differences in fidgeting behaviour between any groups. There was a difference in anteroposterior sway (p = .029) during the quiet standing periods. Conclusion There is no evidence to suggest people with JHS exhibit different fidgeting behaviour. Increased anteroposterior-sway may suggest a muscle weakness and strengthening muscles around the ankle may reduce postural sway and potentially improve the ability to stand for prolonged periods.

The Musculoskeletal Manifestations of Marfan Syndrome: Diagnosis, Impact, and Management

Purpose of Review Marfan syndrome (MFS) is an autosomal dominant heritable disorder of fibrillin-1 (FBN1) with predominantly ocular, cardiovascular, and musculoskeletal manifestations that has a population prevalence of approximately 1 in 5–10,000 (Chiu et al. Mayo Clin Proc. 89(1):34–42, 146, Dietz 3, Loeys et al. J Med Genet. 47(7):476–85, 4). Recent Findings The vascular complications of MFS still pose the greatest threat, but effective management options, such as regular cardiac monitoring and elective surgical intervention, have reduced the risk of life-threatening cardiovascular events, such as aortic dissection. Although cardiovascular morbidity and mortality remains high, these improvements in cardiovascular management have extended the life expectancy of those with MFS by perhaps 30–50 years from an estimated mean of 32 years in 1972 (Dietz 3, Gott et al. Eur J Cardio-thoracic Surg. 10(3):149–58, 147, Murdoch et al. N Engl J Med. 286(15):804–8, 148). The musculoskeletal manifestations of MFS, which to date have received less attention, can also have a significant impact on the quality of life and are likely to become more important as the age of the Marfan syndrome population increases (Hasan et al. Int J Clin Pract. 61(8):1308–1320, 127). In addition, musculoskeletal manifestations are often critically important in the diagnosis of MFS. Summary Here, we review the main clinically relevant and diagnostically useful musculoskeletal features of MFS, which together contribute to the “systemic features score” (referred to hereafter as systemic score), part of the revised Ghent nosology for MFS. We discuss current treatment strategies and highlight the need for a multidisciplinary approach to diagnosis and management. Finally, we review new pharmacological approaches that may be disease modifying and could help to improve the outcome for individuals with this syndrome.

Waardenburg syndrome type 2A in a large Iranian family with a novel MITF gene mutation

Background The characteristics of Waardenburg syndrome (WS) as a scarce heritable disorder are sensorineural hearing loss and deficits of pigmentation in the skin, hair, and eye. Here, clinical features and detection of the mutation in the MITF gene of WS2 patients are reported in a sizable Iranian family. Methods A man aged 28-years represented with symptoms of mild unilateral hearing loss (right ear), complete heterochromia iridis, premature graying prior to 30 years of age, and synophrys. In this research, there was a sizable family in Iran comprising three generations with seven WS patients and two healthy members. Whole exome sequencing was applied for proband for the identification of the candidate genetic mutations associated with the disease. The detected mutation in proband and investigated family members was validated by PCR-Sanger sequencing. Results A novel heterozygous mutation, NM_198159.3:c.1026dup p.(Asn343Glufs*27), in exon 9 of the MITF gene co-segregated with WS2 in the affected family members. The variant was forecasted as a disease-causing variant by the Mutation Taster. According to the UniProt database, this variant has been located in basic helix-loop-helix (bHLH) domain of the protein with critical role in DNA binding. Conclusions A frameshift was caused by a nucleotide insertion, c.1026dup, in exon 9 of the MITF gene. This mutation is able to induce an early termination, resulting in forming a truncated protein capable of affecting the normal function of the MITF protein. Helpful information is provided through an exactly described mutations involved in WS to clarify the molecular cause of clinical characteristics of WS and have a contribution to better genetic counseling of WS patients.

Behavioral Variant Frontotemporal Dementia: Diagnosis and Treatment Interventions

Purpose of Review The diagnosis and treatment of behavioral variant frontotemporal dementia is challenging and often delayed because of overlapping symptoms with more common dementia syndromes or primary psychiatric illnesses. The purpose of this paper is to explore the relevant presentation, diagnostic workup, pathophysiology, and both pharmacologic and non-pharmacologic management. Recent Findings Behavioral variant frontotemporal dementia is a highly heritable disorder. The gradual accumulation of diseased protein culminates in the destruction of those brain circuits responsible for much of one’s emotional and social functioning. Summary Behavioral variant frontotemporal dementia is a progressive neurodegenerative disorder with a far-reaching impact on patients and caregivers. Patients often present with emotional blunting, lack of empathy, apathy, and behavioral disinhibition. Non-pharmacologic interventions and caregiver support are the cornerstone of treatment. The use of cholinesterase inhibitors and memantine is not supported by the evidence. While current pharmacologic therapies target only certain symptoms, there are disease modifying agents currently in or nearing the clinical research stage.

The effect of schizophrenia-associated CNVs on other psychiatric disorders

AimsSchizophrenia is a highly heritable disorder, sharing genetic roots with other psychiatric disorders from both common and rare genetic variants. Copy number variants (CNVs) are one of the rare causes which increase the risk of a variety of psychiatric, medical and physical phenotypes. The role of schizophrenia-associated CNVs is becoming of increasingly scientific and clinical importance in the field of psychiatry, with new CNV-phenotype relationships opening perspectives for understanding the aetiology of psychiatric disorders. This paper aims to investigate whether 13 schizophrenia (SZ)-associated CNVs or any SZ-CNV-carrier status increase the risk for 9 psychiatric phenotypes, reduce levels of happiness, change duration of sleep, and increase the index of multiple deprivation.MethodThe study includes 421,268 participants of British or Irish descent (aged 40–69 years), containing 418,036 controls and 3232 schizophrenia-associated CNV carriers. The data are secondary from the UK Biobank, an online resource containing data on array-genotyped participants with their specific phenotypic information. Prior to analysis, CNV selection led to the exclusion of any CNV with less than 5 hits in the UK Biobank population. Incidence of each phenotype was based on self-reported diagnoses, questionnaires or hospital ICD-10 diagnoses, with a minimum of 500 cases. Both binary logistic and linear regression were used to assess the incidence of these phenotypes in relation to the CNVs, adjusted for age, sex, and ethnicity as potential cofounders.ResultOverall, 12/13 CNVs were nominally associated with at least one phenotype, including 114/168 possible associations and 54 undetectable associations as not every CNV carrier displayed one of the chosen phenotypes. 41 associations were statistically significant (p < 0.05) and 13 survived Bonferroni Correction (p < 2.98 × 10-4). All significant associations met the expected change except 15q11.2 deletion and any CNV carrier status which showed a decrease in likelihood of addiction.ConclusionThese findings suggest schizophrenia-associated CNV can affect range of psychiatric phenotypes. By building on existing reports, understanding the widespread effects of CNVs in the aetiology and pathogenicty of psychiatric disorders may overtime aid in strengthening our search for more targetted, effective treatments.Many thanks to Professor George Kirov for supervising and supporting this project.

Metastatic Insulinoma Presenting After Bariatric Surgery in a Patient Subsequently Diagnosed With MEN 1

Background: Hypoglycemia is a recognized complication of bariatric procedures due to changes in the gut hormonal milieu. Possible causes of hypoglycemia include dumping syndrome, nesidioblastosis and rarely insulinoma. MEN1 is a heritable disorder characterized by the occurrence of parathyroid, anterior pituitary and pancreatic islet cell tumors. Clinical Case: A 48 yo female with HTN, depression, PCOS, primary hyperparathyroidism s/p 3.5 gland parathyroidectomy 2008, facial angiofibroma 2011, obesity s/p gastric sleeve 2018, and a history of DMT2 presented with frequent episodes of hypoglycemia. DMT2 was diagnosed in 2003, but all DM drugs were withdrawn shortly after sleeve gastrectomy. One year after surgery, she started to develop primarily fasting hypoglycemia in the 40-50 mg/dl range confirmed on CGM. Symptoms included perioral numbness, diaphoresis and confusion which resolved with glucose tablets. She reported a 7 kg weight regain due to eating every 2 hours to minimize episodes but symptoms progressed. Family history was significant for HTN and DM. A 72 hour fast confirmed hyperinsulinemia with symptomatic hypoglycemia at a serum glucose of 37 mg/dl, a suppressed ß-hydroxybutyrate of 0.6 mmol/L, elevated proinsulin 7.7 ρmol/L and inappropriate normal c-peptide 0.8 ng/mL. The oral hypoglycemic panel was negative. A pancreatic protocol CT revealed a 1.2 cm heterogeneous arterial enhancing lesion in the body of pancreas, a 0.6 cm focus in the tail of pancreas, a 1.6 cm enhancing lesion in the liver and a 1.4 cm abdominal wall mass. Genetic testing was positive for MEN-1 and additional biochemical evaluation including VIP, gastrin and glucagon was negative. A pituitary MRI was unremarkable. She underwent an ex-lap, partial hepatectomy, distal pancreatectomy, splenectomy, and resection of the duodenal mass. The pancreas had multiple NETs, largest was 1.6 cm and stained positive for insulin. The liver mass demonstrated a metastatic well differentiated NET. The 1.7 cm duodenal mass was consistent with a leiomyoma. All surgical margins were negative, but focal lymphovascular and perineural invasion was identified with negative lymph nodes (0/27). She was diagnosed with a metastatic insulinoma with histopathology revealing a well differentiated neuroendocrine tumor G1, &lt;1mitosis/2mm2, Ki-67 less than 3%, stage pT1N0M1. Hypoglycemia resolved post-operatively. Conclusion: Hypoglycemia predominantly in the fasting state, worsening shortly after bariatric surgery, or refractory to dietary or medical management should be further evaluated to exclude insulinoma. Given her medical history, there was concern for MEN-1, thus prompting genetic testing. Unlike with sporadic cases, there is a higher rate of recurrence with MEN-1 associated insulinoma. Highly unusual is also the finding of metastatic disease, occurring only in 4- 14% of all insulinoma cases.

Adaptation of balance reactions following forward perturbations in people with joint hypermobility syndrome

Background Joint Hypermobility Syndrome (JHS) is a Heritable Disorder of Connective tissue characterised by joint laxity and chronic widespread arthralgia. People with JHS exhibit a range of other symptoms including balance problems. To explore balance further, the objective of this study is to compare responses to forward perturbations between three groups; people who are hypermobile with (JHS) and without symptoms and people with normal flexibility. Methods Twenty-one participants with JHS, 23 participants with Generalised Joint Hypermobility (GJH) and 22 participants who have normal flexibility (NF) stood on a platform that performed 6 sequential, sudden forward perturbations (the platform moved to the anterior to the participant). Electromyographic outcomes (EMG) and kinematics for the lower limbs were recorded using a Vicon motion capture system. Within and between group comparisons were made using Kruskal Wallis tests. Results There were no significant differences between groups in muscle onset latency. At the 1st perturbation the group with JHS had significantly longer time-to-peak amplitude than the NF group in tibialis anterior, vastus medialis, rectus femoris, vastus lateralis, and than the GJH group in the gluteus medius. The JHS group showed significantly higher cumulative joint angle (CA) than the NF group in the hip and knee at the 1st and 2nd and 6th perturbation, and in the ankle at the 2nd perturbation. Participants with JHS had significantly higher CA than the GJH group at the in the hip and knee in the 1st and 2nd perturbation. There were no significant differences in TTR. Conclusions The JHS group were able to normalise the timing of their muscular response in relation to control groups. They were less able to normalise joint CA, which may be indicative of impaired balance control and strength, resulting in reduced stability.

Prevention in Autism Spectrum Disorder: A Lifelong Focused Approach

Autism Spectrum Disorder (ASD) is a complex highly heritable disorder, in which multiple environmental factors interact with the genes to increase its risk and lead to variable clinical presentations and outcomes. Furthermore, the inherent fundamental deficits of ASD in social attention and interaction critically diverge children from the typical pathways of learning, “creating” what we perceive as autism syndrome during the first three years of life. Later in life, training and education, the presence and management of comorbidities, as well as social and vocational support throughout the lifespan, will define the quality of life and the adaptation of an individual with ASD. Given the overall burden of ASD, prevention strategies seem like a cost-effective endeavour that we have to explore. In this paper, we take a life course approach to prevention. We will review the possibilities of the management of risk factors from preconception until the perinatal period, that of early intervention in the first three years of life and that of effective training and support from childhood until adulthood.

Intracellular and Extracellular Markers of Lethality in Osteogenesis Imperfecta: A Quantitative Proteomic Approach

Osteogenesis imperfecta (OI) is a heritable disorder that mainly affects the skeleton. The inheritance is mostly autosomal dominant and associated to mutations in one of the two genes, COL1A1 and COL1A2, encoding for the type I collagen α chains. According to more than 1500 described mutation sites and to outcome spanning from very mild cases to perinatal-lethality, OI is characterized by a wide genotype/phenotype heterogeneity. In order to identify common affected molecular-pathways and disease biomarkers in OI probands with different mutations and lethal or surviving phenotypes, primary fibroblasts from dominant OI patients, carrying COL1A1 or COL1A2 defects, were investigated by applying a Tandem Mass Tag labeling-Liquid Chromatography-Tandem Mass Spectrometry (TMT LC-MS/MS) proteomics approach and bioinformatic tools for comparative protein-abundance profiling. While no difference in α1 or α2 abundance was detected among lethal (type II) and not-lethal (type III) OI patients, 17 proteins, with key effects on matrix structure and organization, cell signaling, and cell and tissue development and differentiation, were significantly different between type II and type III OI patients. Among them, some non–collagenous extracellular matrix (ECM) proteins (e.g., decorin and fibrillin-1) and proteins modulating cytoskeleton (e.g., nestin and palladin) directly correlate to the severity of the disease. Their defective presence may define proband-failure in balancing aberrances related to mutant collagen.

Cutaneous elastorrhexis; A Heralding Sign of Gronblad-Strandberg Syndrome: A Case Report

Introduction: Pseudoxanthoma Elasticum (PXE), also called Gronblad-Strandberg syndrome, is an autosomal recessive disorder due to mutation in the ABCC6 allele on chromosome 16p. It is characterized by the progressive fragmentation and calcification of elastin fibers of the dermis, blood vessels, and Bruch’s membrane of the eye. In this article, the authors present a case of PXE with cutaneous elastorrhexis. Case Presentation: A 31-year-old female presented with skin changes in the form of yellowish linearly arranged papules over the lateral side of the neck and anterior abdomen since adolescence. Her retinoscopy and cardiovascular examinations were reported as normal. The molecular analysis could not be done due to financial limitations. Based on these findings, the patient was suspected of PXE according to the revised criteria for the diagnosis of PXE. Conclusions: Skin lesions are generally first to appear in adolescence. Ocular findings develop at later ages, i.e., third or fourth decades. Cardiovascular manifestations develop later in life. Hence, skin changes can aid in the early diagnosis of PXE and help clinicians to screen patients for systemic complications. Being a multisystem heritable disorder with morbidity and mortality, there is a need to formulate the clinical criteria for definitive diagnosis in resource-poor settings where molecular assays cannot be performed. The recognition of typical skin lesions can aid in the accurate diagnosis to facilitate the early detection and management of life-threatening systemic complications.