Safety and outcomes of eculizumab for acetylcholine receptor-positive generalized myasthenia gravis in clinical practice.

INTRODUCTION/AIMS: Safety and outcomes data on eculizumab for generalized myasthenia gravis (gMG) in clinical practice remain limited. Outcomes and concomitant medication use may differ in practice compared with clinical trials. We analyzed the clinical and safety outcomes of patients who received eculizumab at our institutions. METHODS: Patients with acetylcholine receptor antibody positive (AChR+) gMG, who received ≥1 dose of eculizumab and had ≥1 follow-up before December 10, 2021, were identified. Data were abstracted by chart review. Outcomes included MG Foundation of America Post Intervention Status (MGFA-PIS), Clinical Classification (MGFA-CC), MG-Activities of Daily Living (MG-ADL), concurrent immunomodulatory therapy use, and adverse events. RESULTS: Twelve patients were included. Mean age at eculizumab initiation was 57.4 y (range, 21-77). Eight had refractory MG. Four had history of thymoma and thymectomy. A mean of 3.2 (range, 2-5) immunomodulatory therapies were previously tried. Mean follow-up duration was 18 mo (range, 2-21.6). Clinical improvement occurred rapidly; MGFA-PIS was improved in 80%, and MGFA-CC improved in 83% at 1 mo. Mean MG-ADL decreased from 8.7 to 2.8 at 1 mo, and remained ≤3 .5 over 1.5 y. Mean daily prednisone dose decreased from 22.5 mg to 7.2 mg at 1.5 y. Five of 7 patients discontinued maintenance IVIG or PLEX. No patients had meningococcal infections and adverse events were mild. DISCUSSION: Clinical improvement occurred in most patients after eculizumab initiation, beginning as quickly as 1 mo. Steroids were tapered and maintenance IVIG and PLEX were discontinued in most. Eculizumab had a favorable safety profile even when combined with other immunosuppressants.

The Impact of Fabry Disease on Reproductive Fitness.

Fabry disease (FD) is a pan-ethnic, X-linked, progressive lysosomal storage disorder caused by pathogenic mutations in the GLA gene. Published case reports and abstracts suggest that decreased reproductive fitness may occur in males with FD. In order to understand the impact of FD on reproductive fitness and increase the accuracy of reproductive genetic counseling, this study examines a large, multi-centered population of individuals with FD to determine if males have reduced reproductive fitness. Study data were collected on 376 patients through two, gender-specific surveys distributed across the United States and Canada. The number of biological live-born children among individuals with FD was compared to statistics from the general population. Information was also collected on reduced sperm count, depression, pain, use of assisted reproductive technology, and reproductive choice. On average, females affected by FD had more biological live-born children (1.8) than males affected by FD (1.1). However, males affected by FD had an increased mean number of biological children (1.1) compared to the mean number of biological children fathered by men in the United States (0.9). Sixteen of the 134 males with FD reported oligospermia, which suggests that an infertility work up may be indicated for males having difficulty impregnating their partners. In our large multicenter sample, males and females with FD do not exhibit reduced reproductive fitness; on average they have more biological children than the general population in the United States. This information should assist clinicians in providing accurate reproductive genetic counseling and treatment for individuals with FD.

Understanding the gastrointestinal manifestations of Fabry disease: promoting prompt diagnosis.

Fabry disease is a rare X-linked lysosomal storage disease characterized by the dysfunction of multiple systems, including significant gastrointestinal involvement such as diarrhea, abdominal pain, early satiety and nausea. The gastrointestinal symptoms of Fabry disease are thought to be due to neuropathic and myopathic changes leading to symptoms of dysmotility that are encountered in many other disorders. The gastrointestinal symptoms can often be one of the presenting signs of the disease in childhood, but can be misdiagnosed by gastroenterologists for many years due to their nonspecific presentation. As the chief treatment for Fabry is enzyme-replacement therapy that has been shown to stabilize and possibly reverse disease course, recognition of these symptoms and early diagnosis in an attempt to prevent progression with treatment, is critical.

Determinants of white matter hyperintensity burden in patients with Fabry disease.

OBJECTIVE: Using a semiautomated volumetric MRI assessment method, we aimed to identify determinants of white matter hyperintensity (WMH) burden in patients with Fabry disease (FD). METHODS: Patients with confirmed FD and brain MRI available for this analysis were eligible for this protocol after written consent. Clinical characteristics were abstracted from medical records. T2 fluid-attenuated inversion recovery MRI were transferred in electronic format and analyzed for WMH volume (WMHV) using a validated, computer-assisted method. WMHV was normalized for head size (nWMHV) and natural log-transformed (lnWMHV) for univariate and multivariate linear regression analyses. Level of significance was set at p < 0.05 for all analyses. RESULTS: Of 223 patients with FD and WMHV analyzed, 132 (59%) were female. Mean age at MRI was 39.2 ± 14.9 (range 9.6-72.7) years, and 136 (61%) patients received enzyme replacement therapy prior to enrollment. Median nWMHV was 2.7 cm(3) (interquartile range 1.8-4.0). Age (ß 0.02, p = 0.008) and history of stroke (ß 1.13, p = 0.02) were independently associated with lnWMHV. However, WMH burden-as well as WMHV predictors-varied by decade of life in this cohort of patients with FD (p < 0.0001). CONCLUSIONS: In this largest-to-date cohort of patients with FD who had volumetric analysis of MRI, age and prior stroke independently predicted the burden of WMH. The 4th decade of life appears to be critical in progression of WMH burden, as novel predictors of WMHV emerged in patients aged 31-40 years. Future studies to elucidate the biology of WMH in FD and its role as potential MRI marker of disease progression are needed.

Development and evaluation of a regional, large-scale interprofessional collaborative care summit.

The Northeastern/Central Pennsylvania Interprofessional Education Coalition (NECPA IPEC) is a coalition of faculty from multiple smaller academic institutions with a mission to promote interprofessional education. An interprofessional learning program was organized, which involved 676 learners from 10 different institutions representing 16 unique professions, and took place at seven different institutions simultaneously. The program was a 3-hour long summit which focused on the management of a patient with ischemic stroke. A questionnaire consisting of the Interprofessional Education Perception Scale (IEPS) questionnaire (pre-post summit), Likert-type questions, and open comment questions explored the learners' perceptions of the session and their attitudes toward interprofessional learning. Responses were analyzed using descriptive statistics and statistical tests for difference and qualitative thematic coding. The attitude of learners toward interprofessional education (as measured by the IEPS) was quite high even prior to the summit, so there were no significant changes after the summit. However, a high percentage of learners and facilitators agreed that the summit met its objective and was effective. In addition, the thematic analysis of the open-ended questions confirmed that students learned from the experience with a sense of the core competencies of interprofessional education and practice. A collaborative approach to delivering interprofessional learning is time and work intensive but beneficial to learners.

Cognitive function in adults aging with fabry disease: a case-control feasibility study using telephone-based assessments.

We examined the feasibility of recruiting US adults ≥45 years old with Fabry disease (FD) for telephone assessments of cognitive functioning. A case-control design matched each FD participant on age, sex, race, and education to four participants from a population-based study. Fifty-four participants with FD age 46-72 years were matched to 216 controls. Standardized cognitive assessments, quality of life (QOL), and medical histories were obtained by phone, supplemented by objective indices of comorbidities. Normalized scores on six cognitive tasks were calculated. On the individual tasks, scores on list recall and semantic fluency were significantly lower among FD participants (p-values < 0.05), while scores on the other four tasks did not differ. After averaging each participant's normalized scores to form a cognitive composite, we examined group differences in composite scores, before and after adjusting for multiple covariates using generalized estimating equations. The composite scores of FD cases were marginally lower than controls before covariate adjustments (p = 0.08). QOL and mental health variables substantially attenuated this finding (p = 0.75), highlighting the influence of these factors on cognition in FD. Additional adjustment for cardiovascular comorbidities, kidney function, and stroke had negligible impact, despite higher prevalence in the FD sample. Telephone-based cognitive assessment methods are feasible among adults with FD, affording access to a geographically dispersed sample. Although decrements in discrete cognitive domains were observed, the overall cognitive function of older adults with FD was equivalent to that of well-matched controls before and after accounting for multiple confounding variables.

Fabry disease practice guidelines: recommendations of the National Society of Genetic Counselors.

Identification and comprehensive care of individuals who have Fabry disease (FD) requires a multidisciplinary approach inclusive of genetic testing, test interpretation, genetic counseling, long term disease symptom monitoring, treatment recommendations, and coordination of therapy. The purpose of this document is to provide health care professionals with guidelines for testing, care coordination, identification of psychosocial issues, and to facilitate a better understanding of disease treatment expert recommendations for patients with Fabry disease. These recommendations are the opinions of a multicenter working group of genetic counselors, medical geneticists, and other health professionals with expertise in Fabry disease counseling, as well as representatives/founders of the two United States based Fabry disease patient advocacy groups who are themselves affected by Fabry disease. The recommendations are U.S. Preventive Task Force Class III, and they are based on clinical experience, a review of pertinent English-language articles, and reports of expert committees. This document reviews the genetics of Fabry disease, the indications for genetic testing, interpretation of results, psychosocial considerations, and references to professional and patient resources.

SRY gene expression in the ovotestes of XX true hermaphrodites.

PURPOSE: The pathogenesis of 46 XX true hermaphroditism is uncertain and the role of the SRY gene in ovotestis development has not been thoroughly evaluated. We ascertained the presence of the SRY gene and SRY protein in the ovotestis. MATERIALS AND METHODS: We evaluated 8 ovotestes by cytogenetic analysis of fibroblast cell culture and analysis of gonadal tissue by polymerase chain reaction to detect the SRY gene and by immunohistochemistry with a monoclonal antibody to human recombinant SRY protein. RESULTS: Fibroblast culture of the ovotestes demonstrated a 46XX karyotype. By polymerase chain reaction all 8 ovotestes demonstrated the SRY gene at low levels. By immunohistochemistry SRY protein was detected in all ovotestes, predominantly in Sertoli and germ cells. CONCLUSIONS: The SRY gene has a role in ovotestis genesis. Mosaicism with a Y bearing cell line in the gonad is a possible explanation and further study is warranted.