Communicating the diagnosis of spinal muscular atrophy in endogamous vs. non-endogamous regions.

INTRODUCTION: The high prevalence of endogamy, or inbreeding, in northeastern Brazil, is due to historical and cultural factors, with large families living in cities far from the coast and subject to low socioeconomic and infrastructure levels. This breeding practice results in low genetic variability with an increased prevalence of rare autosomal recessive and neurodegenerative diseases, such as spinal muscular atrophy (SMA). OBJECTIVE: Understanding the impact of communicating the diagnosis of SMA on the mental health of patients and their families and the differences between the Northeast (endogamous region) and the other regions of Brazil (non-endogamous ones). METHODS: Cross-sectional study obtained through a structured questionnaire about the moment of receiving the SMA diagnosis, containing the Impact of Event Scale-Revised. RESULTS AND DISCUSSION: The sample consisted of 100 volunteers from all regions of Brazil, 47 patients diagnosed with SMA and 53 family members present at the time of the diagnosis. There was a predominance of females (83%) and homogeneity between the groups for the variables gender, age, color, education, religion, and SMA subtype (1, 2, 3, and 4). The Northeast region, representing 43% of the sample, despite being less economically favored, showed greater satisfaction with medical care and inclusion in health services, with less self-reported psychological trauma and fewer signs of post-traumatic stress disorder (PTSD) related to the moment of receiving the diagnosis. The non-endogamous regions, in turn, reported the presence of strong waves of emotion, sleep problems, feelings of irritability, anger, and the presence of bad thoughts related to this situation. CONCLUSION: The feeling of inclusion in health services and satisfaction with medical care in the endogamous region had a positive impact on the mental health of those involved, reducing psychological trauma and signs of PTSD arising from the communication of the SMA diagnosis.

Newborn Screening and Birth Prevalence for Spinal Muscular Atrophy in the US.

This cross-sectional study describes the collection and use of state-provided data on newborn screening for spinal muscular atrophy.

Metabolic syndrome is common in adults with 5q-spinal muscular atrophy and impacts quality of life and fatigue.

INTRODUCTION/AIMS: Spinal muscular atrophy (SMA) is a multisystem disorder. We assessed metabolic syndrome (MetS) prevalence in adults with SMA and its association with motor function, quality of life (QoL), fatigue, and depression. METHODS: MetS was diagnosed using 2009 consensus criteria. Hammersmith Functional Motor Scale Expanded (HFMSE), Revised Upper Limb Module (RULM), Fatigue Severity Scale (FSS), Beck Depression Inventory (BDI), and 36-Item Short Form Health Survey (SF-36) were recorded and correlations between muscle function, depression, fatigue, QoL, and MetS were analyzed. RESULTS: We included 36 individuals (18 males; mean age: 38.7 ± 14.6 years). MetS was present in 25.0%. The most common component of MetS was central obesity (69.7%). Nearly half of the SMA individuals exhibited at least one abnormal lipid level result. Individuals with MetS more frequently were SMA type 3 (77.8% vs. 37.0%, p = .02) and had higher levels of fatigue (48.4 ± 6.7 vs. 39.5 ± 11.6, p = .03) than those without MetS. No associations of the presence of MetS with ambulatory status or HFMSE/RULM scores were observed. SMA individuals with MetS scored significantly lower in mental and social domains of QoL and total SF-36 score (p = .04). We observed weak to moderate correlations between the presence of MetS and SMA type, presence of comorbidities, QoL, and fatigue. DISCUSSION: The frequency of MetS was modestly higher among adults with SMA than in the general population, particularly in SMA type 3. MetS was associated with reduced QoL and increased fatigue. Larger studies are needed to fully understand the significance of MetS in adults with SMA.

Controles de salud durante la pandemia e impacto clínico del COVID-19 en niños con enfermedad neuromuscular / Health checkups during the pandemic and clinical impact of COVID-19 in children with neuromuscular disease

Introducción. Los niños con enfermedad neuromuscular (ENM) requieren cuidados crónicos de salud (CCS) y podrían presentar COVID-19 grave. Objetivos. Describir CCS para niños con ENM durante la pandemia y evolución del COVID-19 en este grupo. Población y métodos. Cohorte prospectiva unicéntrica. Se incluyeron pacientes de 2-18 años, con ≥ 1 año de seguimiento previo a la pandemia. Se recolectaron variables demográficas, relativas a los CCS y al COVID-19 mediante historias clínicas y encuestas telefónicas. Resultados. Se incluyeron 226 pacientes; el 71 % varones, mediana de edad 11,3 años. Presentaban distrofias musculares (55,7 %) y atrofia muscular espinal (23 %). Comparando el primer año de pandemia con el previo, el 30 % no realizó controles médicos y el 25 % no realizó kinesioterapia. Otros disminuyeron la frecuencia. Hubo 52 casos de COVID-19. Fueron sintomáticos el 82 %: el 88,4 % leves/moderados y el 11,6 % graves. No hubo fallecidos. Conclusiones. La pandemia impactó negativamente en los CCS y los casos de COVID-19 fueron mayormente leves.

Introduction. Children with neuromuscular disease (NMD) require chronic health care (CHC) and may develop severe COVID-19. Objectives. To describe CHC for children with NMD during the pandemic and the course of COVID-19 in this group. Population and methods. Prospective, single-center cohort. Patients aged 2 to 18 years with ≥ 1 year of follow-up prior to the pandemic were included. Demographic variables in relation to CHC and COVID-19 were collected from medical records and via telephone surveys. Results. A total of 226 patients with a median age of 11.3 years were included; 71% were males. They had muscular dystrophy (55.7%) and spinal muscular atrophy (23%). When comparing the first year of the pandemic with the previous year, 30% did not have a health checkup and 25% did not receive kinesiotherapy. Others did, but with a lower frequency. A total of 52 COVID-19 cases were reported; 82% were symptomatic: 88.4% were mild/moderate and 11.6%, severe. No patient died. Conclusions. The pandemic had a negative impact on CHC, and COVID-19 cases were mostly mild.

Epidemiology of Spinal Muscular Atrophy Based on the Results of a Large-Scale Pilot Project on 202,908 Newborns.

BACKGROUND: This study presents the findings of a newborn screening (NBS) pilot project for 5q-spinal muscular atrophy (5q-SMA) in multiple regions across Russia for during the year 2022. The aim was to assess the feasibility and reproducibility of NBS for SMA5q in diverse populations and estimate the real prevalence of 5q-SMA in Russia as well as the distribution of patients with different number of SMN2 copies. METHODS: The pilot project of NBS here was based on data, involving the analysis of 202,908 newborns. SMA screening assay was performed using a commercially available real-time polymerase chain reaction kit, the Eonis SCID-SMA. RESULTS: In one year, 202,908 newborns were screened, identifying 26 infants with homozygous deletion of SMN1 exon 7, yielding an estimated 5q-SMA incidence of 1:7804 newborns. It was found that 38.46% had two SMN2 copies, 42.31% had three copies, 15.38% had four copies, and 3.85% had five copies of SMN2. Immediate treatment was proposed for patients with two or three SMN2 copies. Infants with four or more SMN2 copies warranted further investigation on management and treatment. Short-term monitoring after gene therapy showed motor function improvements. Delays in treatment initiation were observed, including the testing for adeno-associated virus 9 antibodies and nonmedical factors. CONCLUSIONS: The study emphasizes the need for a standardized algorithm for early diagnosis and management through NBS to benefit affected families. Overall, the NBS program for 5q-SMA in Russia demonstrated the potential to improve outcomes and transform SMA from a devastating disease to a chronic condition with evolving medical requirements.

No significant sex differences in incidence or phenotype for the SMNΔ7 mouse model of spinal muscular atrophy.

Spinal muscular atrophy (SMA) is an autosomal recessive disease that affects 1 out of every 6,000-10,000 individuals at birth, making it the leading genetic cause of infant mortality. In recent years, reports of sex differences in SMA patients have become noticeable. The SMNΔ7 mouse model is commonly used to investigate pathologies and treatments in SMA. However, studies on sex as a contributing biological variable are few and dated. Here, we rigorously investigated the effect of sex on a series of characteristics in SMA mice of the SMNΔ7 model. Incidence and lifespan of 23 mouse litters were tracked and phenotypic assessments were performed at 2-day intervals starting at postnatal day 6 for every pup until the death of the SMA pup(s) in each litter. Brain weights were also collected post-mortem. We found that male and female SMA incidence does not differ significantly, survival periods are the same across sexes, and there was no phenotypic difference between male and female SMA pups, other than for females exhibiting lesser body weights at early ages. Overall, this study ensures that sex is not a biological variable that contributes to the incidence ratio or disease severity in the SMNΔ7 mouse model.

The socioeconomic burden of spinal muscular atrophy in Saudi Arabia: a cross-sectional pilot study.

Background: Spinal muscular atrophy (SMA) is a rare debilitating condition with a significant burden for patients and society. However, little is known about how it affects Saudi Arabia's population. The socioeconomic and medical characteristics of affected SMA patients and their caregivers are lacking. Purpose: This study aimed to describe the socioeconomic and medical characteristics of SMA patients and caregivers in Saudi Arabia. Patients and methods: A cross-sectional questionnaire-based study was conducted using snowball sampling. Assessment tools including EuroQol (EQ-5D-5L) and visual analog scale (EQ-VAS), Generalized Anxiety Disorder 7-item (GAD-7), Patient Health Questionnaire (PHQ-9), and Costs for Patients Questionnaire (CoPaQ) were used to assess the quality of life (QoL), anxiety, depression, and out-of-pocket expenditures. Results: Sixty-four caregivers of SMA patients participated. Type I patients had higher sibling concordance, ICU hospitalization, and mechanical support needs. Type III patients had better QoL. Type I patients' caregivers had higher depression scores. Type III patients' caregivers had higher out-of-pocket expenditures. Forty-eight percent received supportive care, while others received SMA approved therapies. Conclusion: SMA imposes a significant socioeconomic burden on patients and caregivers, requiring more attention from the healthcare system. Access to innovative therapies varied across SMA types. Pre-marital screening and early detection are crucial to reduce disease incidence and ensure timely treatment.

Carrier screening for spinal muscular atrophy in 22913 Chinese reproductive age women.

BACKGROUND: To determine the carrier frequency of, and evaluate a carrier screening program for, spinal muscular atrophy (SMA) in reproductive age women in Shenzhen area. METHODS: A staged screening procedure was used to perform carrier screening for SMA in 22,913 Chinese reproductive age women between 2019 and 2022 in Shenzhen area of China. First, the copy number of exon 7 in the SMN1 gene were detected in women of reproductive age using real-time quantitative polymerase chain reaction. If SMA carriers were detected, their spouses were then recommended to test. Prenatal diagnosis was carried out in couples who were both carriers. RESULTS: A total of 389 women were found to be SMA carriers (1.70%, 95% CI: 1.53%-1.87%), indicating the carrier prevalence was approximately 1:59. Despite the proportion of nonpregnant women increased from 37.96% in 2019 to 58.18% in 2022 (p < 0.05) among the 22,913 reproductive age women, the recall rate of spouses was still not high (62.21%, 95% CI: 57.39%-67.03%). Eight partners were found to be SMA carriers and two fetuses were determined to have SMA with no copies of the SMN1 gene. CONCLUSION: Although the acceptability and awareness of SMA carrier screening in Chinese population has increased in recent years, it still fails to reach the ideal expectation. Our experience may provide a basis for and facilitate the popularization of SMA carrier screening in Shenzhen area.

Familial motor neuron disease: co-occurrence of PLS and ALS (-FTD).

OBJECTIVE: To report the frequency and characteristics of patients diagnosed with primary lateral sclerosis (PLS) with a positive family history for motor neuron diseases (MND) in the Netherlands and to compare our findings to the literature. METHODS: Patients were identified through our ongoing, prospective population-based study on MND in The Netherlands, which also includes a standardized collection of patient characteristics, genetic testing, and family history. Only patients meeting the latest consensus criteria for definite PLS were included. The family history was considered positive for MND if any family members had been diagnosed with PLS, amyotrophic lateral sclerosis (ALS)(-FTD), or progressive muscular atrophy (PMA). Additionally, the literature was reviewed on PLS cases in which MND co-occurred within the same family. RESULTS: We identified 392 definite PLS cases, resulting in 9 families with a PLS patient and a positive family history for MND (2.3%). In only one of these pedigrees, a pathogenic variant (C9orf72 repeat expansion) was found. Our literature review revealed 23 families with a co-occurrence of PLS and MND, with 12 of them having a potentially pathogenic genetic variant. CONCLUSIONS: The consistent observation of PLS patients with a positive family history for MND, evident in both our study and the literature, implies the presence of shared underlying genetic factors between PLS and ALS. However, these factors are yet to be elucidated.

Health checkups during the pandemic and clinical impact of COVID-19 in children with neuromuscular disease. / Controles de salud durante la pandemia e impacto clínico del COVID-19 en niños con enfermedad neuromuscular.

Introduction. Children with neuromuscular disease (NMD) require chronic health care (CHC) and may develop severe COVID-19. Objectives. To describe CHC for children with NMD during the pandemic and the course of COVID-19 in this group. Population and methods. Prospective, single-center cohort. Patients aged 2 to 18 years with ≥ 1 year of follow-up prior to the pandemic were included. Demographic variables in relation to CHC and COVID-19 were collected from medical records and via telephone surveys. Results. A total of 226 patients with a median age of 11.3 years were included; 71% were males. They had muscular dystrophy (55.7%) and spinal muscular atrophy (23%). When comparing the first year of the pandemic with the previous year, 30% did not have a health checkup and 25% did not receive kinesiotherapy. Others did, but with a lower frequency. A total of 52 COVID-19 cases were reported; 82% were symptomatic: 88.4% were mild/moderate and 11.6%, severe. No patient died. Conclusions. The pandemic had a negative impact on CHC, and COVID-19 cases were mostly mild.

Introducción. Los niños con enfermedad neuromuscular (ENM) requieren cuidados crónicos de salud (CCS) y podrían presentar COVID-19 grave. Objetivos. Describir CCS para niños con ENM durante la pandemia y evolución del COVID-19 en este grupo. Población y métodos. Cohorte prospectiva unicéntrica. Se incluyeron pacientes de 2-18 años, con ≥ 1 año de seguimiento previo a la pandemia. Se recolectaron variables demográficas, relativas a los CCS y al COVID-19 mediante historias clínicas y encuestas telefónicas. Resultados. Se incluyeron 226 pacientes; el 71 % varones, mediana de edad 11,3 años. Presentaban distrofias musculares (55,7 %) y atrofia muscular espinal (23 %). Comparando el primer año de pandemia con el previo, el 30 % no realizó controles médicos y el 25 % no realizó kinesioterapia. Otros disminuyeron la frecuencia. Hubo 52 casos de COVID-19. Fueron sintomáticos el 82 %: el 88,4 % leves/moderados y el 11,6 % graves. No hubo fallecidos. Conclusiones. La pandemia impactó negativamente en los CCS y los casos de COVID-19 fueron mayormente leves.

Preconception or prenatal acceptance of SMN1 gene carrier screening and carrier rate of spinal muscular atrophy: a retrospective study in 18,818 reproductive age women in Wuhan area of China.

OBJECTIVE: Spinal muscular atrophy (SMA) is an autosomal recessive disorder mainly affecting the neuromuscular system, which seriously threatens the life and health of patients. But few studies have reported the acceptance rate of SMA gene screening and SMA carrier rate in China. The present study aimed to clarify the two issues in China through a retrospective analysis of 18,818 reproductive age women in Wuhan area of China. METHODS: The copy number (CN) of exons 7 and 8 in survival motor neuron 1 (SMN1) gene was detected by real-time quantitative PCR, and the results were verified by multiplex ligation-dependent probe amplification. RESULTS: Carrier screening was offered to 44,953 women of childbearing age in our medical center from March, 2018, to February, 2022, of whom 18,818 were enrolled in the program. A total of 336 women were identified as carriers (1.73%; 326/18,808; without fertility history of the children with SMA). Among 18,818 reproductive age women, 286 spouses (85.12%; 286/336) were successfully recalled for screening. The results showed 17 couples at high risk of having children with SMA, of whom prenatal diagnosis was implemented in 11, and 6 fetuses were identified with SMA. All the 5 pregnant women bearing the 6 SMA fetuses chose to terminate the pregnancy by artificial abortion. CONCLUSION: Reproductive age women and their spouses in Wuhan area showed a positive attitude toward general screening for SMA carriers. Given the high early mortality of children with SMA, screening for SMA carriers in women of reproductive age is necessary and feasible.

Newborn Screening for Spinal Muscular Atrophy: A 2.5-Year Experience in Hyogo Prefecture, Japan.

Newborn screening (NBS) for spinal muscular atrophy (SMA) is necessary, as favorable outcomes can be achieved by treatment with disease-modifying drugs in early infancy. Although SMA-NBS has been initiated in Japan, its clinical results have not been fully reported. We report the findings of the initial 2.5 years of a pilot SMA-NBS of approximately 16,000 infants conducted from February 2021 in Hyogo Prefecture, Japan. Clinical data of 17 infants who tested positive were retrospectively obtained from the NBS follow-up centers participating in this multicenter cohort observational study. Genetic testing revealed 14 false positives, and three infants were diagnosed with SMA. Case 1 had two copies of survival motor neuron (SMN) 2 and showed SMA-related symptoms at diagnosis. Case 2 was asymptomatic, with two copies of SMN2. Asymptomatic case 3 had four copies of SMN2 exon 7, including the SMN1/2 hybrid gene. Cases 1 and 2 were treated within 1 month and case 3 at 8 months. All the patients showed improved motor function scores and did not require respiratory support. The identification of infants with SMA via NBS and early treatment improved their motor and respiratory outcomes. Thus, implementation of SMA-NBS at a nationwide scale should be considered.

Prevalence of morbidities across the lifespan for adults with spinal muscular atrophy: a retrospective cohort study.

BACKGROUND: Recently approved treatments for spinal muscular atrophy (SMA) may shift clinical care priorities to secondary complications associated with SMA-related aging. To date, there is little knowledge about the natural history of morbidities across the adult lifespan for SMA. The objective of this study was to identify the prevalence and odds ratio (OR) of various morbidities among adults with vs. without SMA prior to SMA-related treatment. METHODS: This was a retrospective cohort study that accessed Medicare fee-for-service and commercial claims data from 01/01/2008-12/22/2016. Data from adults ≥ 18 years old with SMA and without SMA matched (1:200 case:control) on demographics, region, and study entry year were included. The prevalence of 30 morbidities across physiologic systems (e.g., cardiovascular, metabolic, musculoskeletal, urinary) and mental health disorders was examined. Age- and sex-adjusted OR was estimated using logistic regression for each morbidity and effect modification by age and sex was tested. RESULTS: There were 2,427 adults with SMA (mean [SD] age, 59.7 [17.4] years; 49.0% female) and 484,528 matched adults without SMA. Adults with vs. without SMA had a higher prevalence and adjusted OR of all 30 morbidities, ranging from OR = 1.61 (95% CI = 1.45-1.80) for hypothyroidism to OR = 7.80 (95% CI = 7.10-8.57) for fluid/electrolyte disorders. There was effect modification by age for 24 morbidities. The OR was highest for the youngest age group (18-40 years; OR range, 2.38 to 117.7; all P < 0.05) and declined with older age groups, but still remained significantly elevated in the oldest age group (≥ 75 years; OR range, 1.30 to 5.96; all P < 0.05). CONCLUSIONS: The limitations of this study are that evidence of morbidities were limited to diagnostic claims and information on SMA type and symptoms or onset were not available. In conclusion, adults with SMA had a higher and earlier prevalence of a variety of morbidities across physiological systems and mental health disorders.

How do orphan disease patients live during the pandemic of Omicron variant? A nationwide survey of spinal muscular atrophy patients in China.

OBJECTIVES: To investigate the challenges of patients with spinal muscular atrophy (SMA) during the Omicron variant COVID-19 pandemic. DESIGN: A cross-sectional survey was conducted in China from January 02, 2023, to January 12, 2023, using a questionnaire that covered three aspects: (1) Demographic information; (2) SMA-related information; and (3) COVID-19-related information. We recruited patients with SMA from 33 provinces. The prevalence, course, and clinical manifestations of COVID-19 were calculated. The relationships between independent and outcome variables were investigated. RESULTS: In total, 677 patients (male: 349; female: 328) were included in this study (average age = 11.40 years); 534 (78.88%) suffered from COVID-19. The most common symptoms were fever (95.51%), cough (57.87%), and sputum (49.44%). Of the infected patients, 91.57% recovered with at-home care, and 8.43% were hospitalized; 1.31% were admitted to the intensive care unit (ICU). A positive correlation was observed between the SMA severity and hospitalization rate. The ICU stay rate in patients with SMA type I was significantly higher than that in other SMA types. CONCLUSION: This is the first large sample survey to timely reveal the living situation of patients with SMA during the COVID-19 pandemic's Omicron variant. Patients with SMA type I should be paid more attention in terms of hospitalization and ICU stay.

Association between spinal muscular atrophy type and delayed diagnosis and the risk of spinal deformity in Indonesian patients.

BACKGROUND: Spinal muscular atrophy (SMA) is a genetic disease that causes muscle weakness and atrophy. Delayed diagnosis can lead to loss of motoric functions, which may then progress to deformities such as thoracolumbar scoliosis, pelvic obliquity, and hip subluxation/dislocation. The lack of information or limited experience among healthcare providers and costly genetic tests can cause delayed diagnosis. The current study aimed to assess the characteristics of patients with SMA. Moreover, the association between SMA type and delayed diagnosis and the risk of spinal deformity in the Indonesian SMA Community was evaluated. METHODS: This was a cross-sectional study performed on 53 patients diagnosed with SMA. Data about patients' characteristics were obtained from the Indonesian SMA Community using a questionnaire in August 2019. The information included age, sex, SMA type, age at suspicion and definite diagnosis of SMA, and presence of spinal deformities. Then, descriptive analysis and logistic regression analysis were performed, and the Kruskal-Wallis test and the Chi-square test were utilized. RESULTS: The median age of patients suspected of SMA was 24 months. A definitive diagnosis of SMA was obtained at 36 months. Further, 43% of patients presented with SMA type 2 and 58% with spinal deformities. Results showed a positive correlation between time interval between suspicion and definite diagnosis of SMA and the risk of spinal deformities (B = 0,07; p > 0.05). Delayed diagnosis was more common in SMA type 3 than in SMA types 1 and 2, and SMA type 2 was correlated with a twofold risk of spinal deformities (p = 0.03; prevalence ratio = 2.09). CONCLUSIONS: SMA type 2 is associated with a twofold risk of spinal deformities. Delayed diagnosis is more common in SMA type 3 than in SMA types 1 and 2. Moreover, there was an association between the time interval between suspicion and definite diagnosis of SMA and the risk of spinal deformities in patients with SMA.

Prevalence of Spinal Muscular Atrophy in the Era of Disease-Modifying Therapies: An Italian Nationwide Survey.

OBJECTIVE: Spinal muscular atrophy (SMA) is a neurodegenerative disorder caused by mutations in the SMN1 gene. The aim of this study was to assess the prevalence of SMA and treatment prescription in Italy. METHODS: An online survey was distributed to 36 centers identified by the Italian government as referral centers for SMA. Data on the number of patients with SMA subdivided according to age, type, SMN2 copy number, and treatment were collected. RESULTS: One thousand two hundred fifty-five patients with SMA are currently followed in the Italian centers with an estimated prevalence of 2.12/100,000. Of the 1,255, 284 were type I, 470 type II, 467 type III, and 15 type IV with estimated prevalence of 0.48, 0.79, 0.79 and 0.02/100,000, respectively. Three patients with SMA 0 and 16 presymptomatic patients were also included. Approximately 85% were receiving one of the available treatments. The percentage of treated patients decreased with decreasing severity (SMA I: 95.77%, SMA II: 85.11%, SMA III: 79.01%). DISCUSSION: The results provide for the first time an estimate of the prevalence of SMA at the national level and the current distribution of patients treated with the available therapeutical options. These data provide a baseline to assess future changes in relation to the evolving therapeutical scenario.

Newbornscreening SMA - From Pilot Project to Nationwide Screening in Germany.

Now that targeted therapies for spinal muscular atrophy are available, attempts are being made worldwide to include screening for spinal muscular atrophy in general newborn screening. In Germany, after pilot projects from 2018-2021, it was included in the general newborn screening from October 2021. To ensure a smooth transition, criteria for follow-up were developed together with key stakeholders. At the beginning of the transition to nationwide screening, false positive findings were reported in 3 patients. After optimization of the screening method in the laboratories concerned, all findings have been subsequently confirmed. On average, the first presentation to a neuromuscular center occurred on day 12 of life, and in patients with 2 or 3 SMN2 copies, therapy started on day 26 of life. Compared with the pilot project, there was no significant delay in timing.