Natural history in spinal muscular atrophy Type I in Taiwanese population: A longitudinal study.

INTRODUCTION: Spinal muscular atrophy (SMA) is caused by a defect in the survival motor neuron 1 (SMN1) gene. The Cooperative Study of the natural history of SMA Type I in Taiwan is a retrospective, longitudinal, observational study that helps in further understanding SMA disease progression in patients who have not received disease-modifying therapeutic interventions. METHODS: Case report forms were used to collect demographics; genetic confirmation; SMN2 copy number; treatment patterns; and clinical outcomes including ventilator use, endotracheal tube intubation, tracheostomy, gastrostomy, complications, and survival. RESULTS: A total of 111 patients with SMA Type I were identified over the study period (1979-2015). Mean (median) age of onset and age at confirmed diagnosis were 1.3 (0.8) and 4.9 (4.4) months, respectively. SMN1 deletion/mutation was documented in 70 patients and SMN2 copy number in 32 (2 copies, n = 20; 3 copies, n = 12). At 240 months, survival probability for patients born during 1995-2015 versus 1979-1994 was significantly longer (p = 0.0057). Patients with 3 SMN2 copies showed substantially longer 240-month survival versus patients with 2 SMN2 copies. Over the 36-year period, mean (median) age at death was 31.9 (8.8) months. As of December 2015, 95 patients had died, 13 were alive, and 3 were lost to follow-up. The use of supportive measures (tracheostomy and gastrostomy) was associated with improved survival. CONCLUSIONS: These data describe the short survival of patients with SMA Type I in Taiwan in the pretreatment era, emphasizing the positive impact of supportive measures on survival.

The Cure SMA Membership Surveys: Highlights of Key Demographic and Clinical Characteristics of Individuals with Spinal Muscular Atrophy.

BACKGROUND: Cure SMA maintains the largest patient-reported database for people affected with spinal muscular atrophy (SMA). In 2017, Cure SMA initiated annual surveys with their membership to collect demographic and disease characteristics, healthcare, and burden of disease information from patients and caregivers. OBJECTIVE: To summarize results from two large-scale Cure SMA surveys in 2017 and 2018. METHODS: Cure SMA database members were invited to complete surveys; these were completed by caregivers for living or deceased individuals with SMA and/or affected adults. RESULTS: In 2017, 726 surveys were completed for 695 individuals with SMA; in 2018, 796 surveys were completed for 760 individuals with SMA. Data from both survey years are available for 313 affected individuals. Age at symptom onset, distribution of SMN2 gene copy number, and representation of each SMA type in the surveys were consistent with that expected in the SMA population. In the 2018 survey, the average age at diagnosis was 5.2 months for SMA type I and the reported mean age at death for this subgroup was 27.8 months. Between survey years, there was consistency in responses for factors that should not change within individuals over time (e.g., reported age at diagnosis). CONCLUSIONS: Results from the Cure SMA surveys advance the understanding of SMA and facilitate advocacy efforts and healthcare services planning. Longitudinal surveys are important for evaluating the impact of effective treatments on changing phenotypes, and burden of disease and care in individuals with SMA.

Real-World Safety and Effectiveness of Dimethyl Fumarate in Hispanic or Latino Patients with Multiple Sclerosis: 3-Year Results from ESTEEM.

INTRODUCTION: Compared with the non-Hispanic/non-Latino population, Hispanic/Latino patients with multiple sclerosis (MS) are reported to exhibit greater disease severity. Geographical location and genetics play a role in differences observed across Hispanic/Latino subpopulations. We evaluated real-world safety and effectiveness of dimethyl fumarate (DMF) on MS disease activity in Hispanic/Latino patients. METHODS: ESTEEM is an ongoing, 5-year, multinational, prospective study evaluating long-term safety and effectiveness of DMF in patients with MS. This interim analysis included patients newly prescribed DMF in routine practice at 394 sites globally. RESULTS: Overall, 4986 non-Hispanic/non-Latino and 98 Hispanic/Latino patients were analyzed; median (range) follow-up was 18 (2-37) months. Unadjusted annualized relapse rates (ARRs) for 12 months before DMF initiation versus 36 months post DMF initiation, respectively, were: non-Hispanic/non-Latino patients, 0.82 (95% CI 0.80-0.84) versus 0.10 (95% CI 0.09-0.10), 88% lower ARR (P < 0.0001); Hispanic/Latino patients, 0.80 (95% CI 0.65-1.00) versus 0.09 (95% CI 0.06-0.14), 89% lower ARR (P < 0.0001). In total, 28 (29%) Hispanic/Latino patients reported adverse events leading to treatment discontinuation; gastrointestinal (GI) disorders (n = 10, 10%) were the most common, consistent with the non-Hispanic/non-Latino population (8%). Median lymphocyte counts decreased by approximately 24% in the first year (vs 36% decrease in non-Hispanic/non-Latino patients) then remained stable and above the lower limit of normal in most patients. CONCLUSIONS: Relapse rates remained low in Hispanic/Latino patients, consistent with non-Hispanic/non-Latino patients. The safety profile of DMF in Hispanic/Latino patients was consistent with safety findings from the non-Hispanic/non-Latino ESTEEM population, demonstrating the real-world treatment benefit of DMF in the Hispanic/Latino patient cohort.

Real-World Safety and Effectiveness of Dimethyl Fumarate in Black or African American Patients with Multiple Sclerosis: 3-Year Results from ESTEEM.

INTRODUCTION: Black or African American (black/AA) patients with multiple sclerosis (MS) are reported to exhibit greater disease severity compared with non-black or non-AA patients. Whether differences exist in response to MS disease-modifying therapies remains uncertain, as MS clinical trials have included low numbers of non-white patients. We evaluated real-world safety and effectiveness of dimethyl fumarate (DMF) on MS disease activity in black/AA patients. METHODS: ESTEEM is an ongoing, 5-year, multinational, prospective study evaluating long-term safety and effectiveness of DMF in patients with MS. This interim analysis included patients newly prescribed DMF in routine practice at 394 sites globally. RESULTS: Overall, 4897 non-black/non-AA and 187 black/AA patients were analyzed; median (range) follow-up 18 (2-37) months. Unadjusted annualized relapse rates (ARRs) for 12 months before DMF initiation versus 36 months post DMF initiation, respectively, were: non-black/non-AA patients, 0.83 (95% CI 0.80-0.85) versus 0.10 (95% CI 0.09-0.10), 88% lower ARR (P < 0.0001); black/AA patients, 0.68 (95% CI 0.58-0.80) versus 0.07 (95% CI 0.05-0.10), 90% lower ARR (P < 0.0001). In total, 35 (19%) black/AA patients reported adverse events leading to treatment discontinuation; gastrointestinal disorders were most common (7%), consistent with non-black/non-AA patients (8%). Median lymphocyte counts decreased by 22% in the first year (vs 36% in non-black/non-AA patients), then remained stable and above lower limit of normal in most patients. CONCLUSIONS: Relapse rates remained low in black/AA patients, consistent with non-black/non-AA patients. The safety profile of DMF in black/AA patients was consistent with that in the non-black/non-AA ESTEEM population, although lymphocyte decrease was less pronounced in black/AA patients.

Spinal Muscular Atrophy (SMA) Subtype Concordance in Siblings: Findings From the Cure SMA Cohort.

BACKGROUND: Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder caused by homozygous survival of motor neuron 1 (SMN1) gene disruption. Despite a genetic etiology, little is known about subtype concordance among siblings. OBJECTIVE: To investigate subtype concordance among siblings with SMA. METHODS: Cure SMA maintains a database of newly diagnosed patients with SMA, which was utilized for this research. RESULTS: Among 303 sibships identified between 1996 and 2016, 84.8% were subtype concordant. Of concordant sibships, subtype distribution was as follows: Type I, 54.5%; Type II, 31.9%; Type III, 13.2%; Type IV, 0.4%. Subtype and concordance/discordance association was significant (Fisher's exact test; p < 0.0001). Among discordant sibships (chi-square test, p < 0.0001), Types II/III (52.2%) and Types I/II (28.3%) were the most common pairs. No association was found between sibling sex and concordance. Our findings show that most siblings with SMA shared the same subtype concordance (most commonly Type I). CONCLUSIONS: These data are valuable for understanding familial occurrence of SMA subtypes, enabling better individual treatment and management planning in view of new treatment options and newborn screening initiatives.

An overview of the Cure SMA membership database: Highlights of key demographic and clinical characteristics of SMA members.

BACKGROUND: The Cure SMA database is one of the largest patient reported databases for people affected with SMA. OBJECTIVE: The purpose of this study was to examine a subset of affected SMA persons with types I, II, and III from a patient reported database. METHODS: Individuals with SMA were selected from the database using a date of first contact to Cure SMA between 2010 and 2016. Data analyzed included age at diagnosis, number of weeks from SMA diagnosis to contacting Cure SMA, and geographic distribution of individuals. RESULTS: A total of 1,966 individuals with SMA were included in the analysis. Of these individuals, 51.9% had type I, 32.3% had type II, and 15.8% had type III. The average age of diagnosis for type I patients was 5.2 months, 22.1 months for type II, and 97.8 months for type III. From published incidence, about 59.0% of affected individuals in the US are registered in the Cure SMA database. CONCLUSIONS: The Cure SMA database is a unique and robust source of patient reported data that informs on the burden of illness and supports the development of new therapeutic modalities.

Prevalence, incidence and carrier frequency of 5q-linked spinal muscular atrophy - a literature review.

Spinal muscular atrophy linked to chromosome 5q (SMA) is a recessive, progressive, neuromuscular disorder caused by bi-allelic mutations in the SMN1 gene, resulting in motor neuron degeneration and variable presentation in relation to onset and severity. A prevalence of approximately 1-2 per 100,000 persons and incidence around 1 in 10,000 live births have been estimated with SMA type I accounting for around 60% of all cases. Since SMA is a relatively rare condition, studies of its prevalence and incidence are challenging. Most published studies are outdated and therefore rely on clinical rather than genetic diagnosis. Furthermore they are performed in small cohorts in small geographical regions and only study European populations. In addition, the heterogeneity of the condition can lead to delays and difficulties in diagnosing the condition, especially outside of specialist clinics, and contributes to the challenges in understanding the epidemiology of the disease. The frequency of unaffected, heterozygous carriers of the SMN1 mutations appears to be higher among Caucasian and Asian populations compared to the Black (Sub-Saharan African ancestry) population. However, carrier frequencies cannot directly be translated into incidence and prevalence, as very severe (death in utero) and very mild (symptom free in adults) phenotypes carrying bi-allelic SMN1 mutations exist, and their frequency is unknown. More robust epidemiological data on SMA covering larger populations based on accurate genetic diagnosis or newborn screening would be helpful to support planning of clinical studies, provision of care and therapies and evaluation of outcomes.

A multi-source approach to determine SMA incidence and research ready population.

In spinal muscular atrophy (SMA), degeneration of motor neurons causes progressive muscular weakness, which is caused by homozygous deletion of the SMN1 gene. Available epidemiological data on SMA are scarce, often outdated, and limited to relatively small regions or populations. Combining data from different sources including genetic laboratories and patient registries may provide better insight of the disease epidemiology. To investigate the incidence of genetically confirmed SMA, and the number of patients who are able and approachable to participate in new clinical trials and observational research, we used both genetic laboratories, the TREAT-NMD Global SMA Patient Registry and the Care and Trial Sites Registry (CTSR). In Europe, 4653 patients were genetically diagnosed by the genetic laboratories in the 5-year period 2011 to 2015, with 992 diagnosed in 2015 alone. The data provide an estimated incidence of SMA in Europe of 1 in 3900-16,000 live births. Patient numbers in the national patient registries and CTSR were considerably lower. By far, most patients registered in the national patient registries and the CTSR live in Europe and are reported to have SMA type II. Considerable differences between countries in patient participation in the registries were observed. Our findings indicate that not all patients with SMA are accessed by specialist healthcare services and these patients may not have access to research opportunities and optimal care.

Protected graft copolymer-formulated fibroblast growth factors mitigate the lethality of partial body irradiation injury.

We evaluated the mitigating effects of fibroblast growth factor 4 and 7 (FGF4 and FGF7, respectively) in comparison with long acting protected graft copolymer (PGC)-formulated FGF4 and 7 (PF4 and PF7, respectively) administered to C57BL/6J mice a day after exposure to LD50/30 (15.7 Gy) partial body irradiation (PBI) which targeted the gastrointestinal (GI) system. The PGC that we developed increased the bioavailability of FGF4 and FGF7 by 5- and 250-fold compared to without PGC, respectively, and also sustained a 24 hr presence in the blood after a single subcutaneous administration. The dose levels tested for mitigating effects on radiation injury were 3 mg/kg for the PF4 and PF7 and 1.5 mg each for their combination (PF4/7). Amifostine administered prior to PBI was used as a positive control. The PF4, PF7, or PF4/7 mitigated the radiation lethality in mice. The mitigating effect of PF4 and PF7 was similar to the positive control and PF7 was better than other mitigators tested. The plasma citrulline levels and hematology parameters were early markers of recovery and survival. GI permeability function appeared to be a late or full recovery indicator. The villus length and crypt number correlated with plasma citrulline level, indicating that it can act as a surrogate marker for these histology evaluations. The IL-18 concentrations in jejunum as early as day 4 and TPO levels in colon on day 10 following PBI showed statistically significant changes in irradiated versus non-irradiated mice which makes them potential biomarkers of radiation exposure. Other colon and jejunum cytokine levels are potentially useful but require larger numbers of samples than in the present study before their full utility can be realized.

Protected graft copolymer excipient leads to a higher acute maximum tolerated dose and extends residence time of vasoactive intestinal Peptide significantly better than sterically stabilized micelles.

PURPOSE: To determine and compare pharmacokinetics and toxicity of two nanoformulations of Vasoactive Intestinal Peptide (VIP). METHODS: VIP was formulated using a micellar (Sterically Stabilized Micelles, SSM) and a polymer-based (Protected Graft Copolymer, PGC) nanocarrier at various loading percentages. VIP binding to the nanocarriers, pharmacokinetics, blood pressure, blood chemistry, and acute maximum tolerated dose (MTD) of the formulations after injection into BALB/c mice were determined. RESULTS: Both formulations significantly extend in vivo residence time compared to unformulated VIP. Formulation toxicity is dependent on loading percentage, showing major differences between the two carrier types. Both formulations increase in vivo potency of unformulated VIP and show acute MTDs at least 140 times lower than unformulated VIP, but still at least 100 times higher than the anticipated highest human dose, 1-5 µg/kg. These nanocarriers prevented a significant drop in arterial blood pressure compared to unformulated VIP. CONCLUSIONS: While both carriers enhance in vivo residence time compared to unformulated VIP and reduce the drop in blood pressure immediately after injection, PGC is the excipient of choice to extend residence time and improve the safety of potent therapeutic peptides such as VIP.

Single-antigen serological testing for bovine tuberculosis.

Antibody responses are useful indicators of Mycobacterium bovis infection of cattle. Tests for such responses often use multiple M. bovis antigens as detection probes. This is recommended because responses to single antigens may be too variable for consistent diagnosis. However, the use of multiple antigens increases costs and the risk of false-positive results. As an alternative, the SeraLyte-Mbv system detects responses to a single M. bovis antigen, MPB83, by using a chemiluminescent testing platform with a high degree of analytical sensitivity. Testing with the SeraLyte-Mbv system was conducted in a blinded fashion with sera from experimentally infected and control cattle. To assess the species specificity of the single-antigen test, the sample included sera from animals infected with M. bovis (n = 27), M. kansasii (n = 4), M. avium subsp. paratuberculosis (n = 11), M. avium subsp. avium (n = 12), and uninfected animals (n = 15). Upon unblinding of the results, the sensitivity of the SeraLyte-Mbv system relative to the results for animals with known M. bovis infection was 89%. Consistent with the conservation of MPB83 sequences within the genus Mycobacterium, all 4 M. kansasii-infected animals tested positive with the SeraLyte-Mbv system and all 23 M. avium-infected animals tested negative. Blinded analysis of 30 serum samples collected from nine animals at various time points postinfection indicated 100% sensitivity after > or = 3 months postinfection. All 15 uninfected samples in the blinded sample set tested negative with the SeraLyte-Mbv system. Unblinded analysis of sera from an additional 895 animals in 10 accredited bovine tuberculosis-free states revealed 98% specificity overall. The results support the feasibility of single-antigen testing for bovine tuberculosis with the SeraLyte-Mbv system.