Collagen VI-Related Myopathies: Genetic and Clinical Findings

Introduction: Collagen VI-related disorders are a group of heterogeneous muscular diseases due to mutations within the COL6A1, COL6A2, and COL6A3 genes, encoding collagen VI as an essential component of the extracellular matrix. Here, we reported four patients affected by collagen VI-related disorders with genetic variants in COL6A genes. Case Presentation: After a comprehensive clinical examination, four unrelated patients with muscular dystrophy were referred for genetic counseling. Whole-exome sequencing followed by Insilco analysis was done for one affected individual from each family. The analysis of genomic data revealed four different mutations within the COL6A1, COL6A2, and COL6A3 genes in the affected individuals. Conclusions: According to the previous reports, limb-girdle muscular dystrophy is inherited as autosomal dominant, and congenital myosclerosis phenotype is inherited in an autosomal recessive manner. Carrier testing and prenatal testing are possible if pathogenic variants are recognized in an affected family member.

Caregivers’ Grief in Acquired Non-death Interpersonal Loss (NoDIL): A Process Based Model With Implications for Theory, Research, and Intervention

The number of family members caring and caregiving for a loved one undergoing physical and mental changes continues to increase dramatically. For many, this ongoing experience not only involves the “burden of caregiving” but also the “burden of grief” as their loved-one’s newfound medical condition can result in the loss of the person they previously knew. Dramatic cognitive, behavioral, and personality changes, often leave caregivers bereft of the significant relationship they shared with the affected person prior to the illness or injury. This results in what we term conditions of acquired “non-death interpersonal loss” (NoDIL). Current approaches to these losses use an amalgam of models drawn from both death and non-death loss. Despite their utility, these frameworks have not adequately addressed the unique processes occurring in the interpersonal sphere where the grieving caregiver needs to reach some modus vivendi regarding the triad of “who the person was,” “who they are now,” and “who they will yet become.” In this paper we propose a process-based model which addresses cognitive-emotional-behavioral challenges caregivers meet in the face of their new reality. These require a revision of the interpersonal schemas and the relationships that takes into account the ongoing interactions with the affected family member. The model and its utility to identify adaptive and maladaptive responses to NoDIL is elaborated upon with clinical material obtained from caregivers of people diagnosed with major neuro-cognitive disorder and pediatric traumatic brain injury. The article concludes with implications for theory, research and clinical intervention.

Autoimmune and Inflammatory Mechanisms in Cervical Dystonia

There are many causes for cervical dystonia (CD), although most cases are idiopathic and a cause cannot be identified. The observation that 10-15% of cases have an affected family member has pointed to genetic causes, but known genes account for only a small fraction of all cases. The current manuscript describes a series of studies focusing on potential autoimmune or inflammatory mechanisms in CD. First, a case-control survey for 32 autoimmune diseases in 271 subjects with CD confirmed prior anecdotal observations that CD is associated with thyroid disease, which often results from autoimmune mechanisms. Second, unbiased proteomic methods involving a total of 20 subjects with CD, with or without associated thyroid disease, pointed towards a series of overlapping mechanisms relating to the immune system. Third, a multiplex immunoassay focusing on 37 markers associated with neuroinflammation applied to a total of 20 subjects with CD with or without thyroid disease and 20 controls pointed to abnormalities in several specific measures of the immune system. Finally, a broad screening test for neuronal antibodies in a total of 58 subjects with CD did not disclose any specific antibodies. Altogether, the association of CD with thyroid disease and blood-based immune measures point to abnormalities in cell-mediated immunity that may play a pathogenic role for a subgroup of subjects with CD.

Family history of associated disorders in patients with postural tachycardia syndrome

Introduction:Postural tachycardia syndrome is more frequently being recognised in adolescents and adults. However, its pathophysiology remains undefined. We evaluated our database for patterns in family history of clinical symptoms and associated disorders in these patients.Materials and methods:Patients with postural tachycardia syndrome diagnosed in our clinic between 2014 and 2018 and who were less than 19 years at diagnosis were included. The history was reviewed for family members with postural tachycardia syndrome, dizziness and/or syncope, joint hypermobility with or without hypermobile Ehlers–Danlos syndrome, and autoimmune disorders. Statistical analysis assessed the entire cohort plus differences in gender, presence or absence of joint hypermobility, and presence or absence of familial autoimmune disease.Results:A total of 579 patients met inclusion criteria. We found that 14.2% of patients had a family member with postural tachycardia syndrome, with male patients more likely to have an affected family member (20% versus 12.7%, p = 0.04). If the patient also had joint hypermobility, male patients were more likely to have a family member with postural tachycardia syndrome (25% versus 12.6%, p = 0.017), more than one affected family member (7.1% versus 0.74%, p = 0.001), and a family member with joint hypermobility (37.5% versus 23.7%, p = 0.032). Autoimmune disease was seen in 45.1% of family members, but more likely in female patients with concurrent hypermobility (21.1% versus 8.9%, p = 0.035).Discussion:This in-depth analysis of associated familial disorders in patients with postural tachycardia syndrome offers further insight into the pathophysiology of the disorder, and informs further screening of family members in these patients.

Association between Secondary and Primary Sjögren’s Syndrome in a Large Collection of Lupus Families

Objective. Systemic lupus erythematosus (SLE) and Sjögren’s syndrome (SS) share clinical and immunogenetic features and may occur together. We undertook this study to determine the risk of primary SS among SLE-unaffected relatives of SLE patients and whether or not primary and secondary SS tended to occur in the same families.Methods. We collected clinical and serological data on 2694 SLE patients, 7390 SLE-unaffected relatives of the SLE patients, and 1470 matched controls.Results. Of the 2694 subjects with SLE, 548 had secondary SS, while 71 of their 7390 SLE-unaffected relatives had primary SS. None of the 1470 controls had SS as defined herein (p=5×10-5compared to SLE-unaffected relatives). Of the 71 SLE-unaffected relatives with primary SS, 18 (25.3%) had an SLE-affected family member with secondary SS, while only 530 of the 7319 (7.2%) SLE-unaffected relatives without SS did so (p=1×10-8).Conclusion. Among families identified for the presence of SLE, primary and secondary SS tend to occur within the same families. These results highlight the commonalities between these two forms of SS, which in fact correspond to the same disease.

Primary appendiceal mucinous adenocarcinoma in two first-degree relatives: Case report and retrospective chart review.

397 Background: Carcinomas of the appendix are exceedingly rare tumors and have an annual age-adjusted incidence of around 0.4 cases per 100,000. Appendiceal adenocarcinoma accounts for <0.5% of all gastrointestinal neoplasms and, of these, mucinous adenocarcinomas account for the majority. Published accounts of familial instances of primary appendiceal tumors are strikingly rare. Methods: We report two siblings who both developed primary mucinous adenocarcinomas. A genetics evaluation was conducted to determine if there was a recognizable underlying single gene disorder: no DNA mismatch repair defect was evident and no other diagnosis was apparent. A review of appendiceal cancers seen at Mayo Clinic from l997 to the present was conducted to search for additional familial cases. Results: Among 316 cases of primary appendiceal cancer of any histologic type, this sib pair was the only family reporting a second affected family member. Conclusions: The occurrence of appendiceal cancer in siblings may represent a random occurrence. Adenocarcinomas of the most common type of appendiceal cancer and occur at older ages than other histologic subtypes. A strikingly rare predisposition syndrome cannot be ruled out. [Table: see text] No significant financial relationships to disclose.

Abstract 2922: KCNQ1 Gain-of-function Mutation Associated With Familial Atrial Fibrillation

Background : Family history is a risk factor for atrial fibrillation (AF). We report here a 3-generation Caucasian family with familial AF and a highly dysfunctional mutation in KCNQ1 . Methods and Results: In the proband, there was a 9-bp duplication resulting in insertion of the amino acids IAP (IAP54 –56) in the N-terminus of the protein. The kindred included 4 other family members with AF or palpitations. Each affected family member presented with early onset paroxysmal lone AF and no QT prolongation. This variant has previously been reported in presumed healthy African-American individuals (minor allele frequency 1.3%), but has not been studied in vitro . In transfected CHO cells, coexpression of IAP54 –56 with KCNE1 generated currents that were much larger and activated much earlier that wild-type I Ks ( Figure ); e.g. at +20 mV, peak current was 75±8 [IAP54 –56] vs 25±5 [wt] pA/pF after 5-sec pulses (n=7 each, P<0.001). Computational simulations of human atrial action potential (AP) that incorporated Markov models of wt or IAP54 –56-I Ks were performed. At a cycle length of 400ms, accelerated activation of IAP54 –56-I Ks resulted in open state accumulation and increased maximum I Ks amplitude ~40-fold (351 vs 9 pA/pF), resulting in ~6-fold AP duration shortening (44 vs 259 ms). Conclusions: We have identified a KCNQ1 indel in a moderate sized Caucasian kindred with familial AF and normal QT intervals. This variant results in an I Ks gain-of-function and the resulting shortening of atrial action potentials may predispose to AF. This variant has been reported in 1.3% of African-Americans, suggesting it may be a common risk allele in some populations.