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.

Three years pilot of spinal muscular atrophy newborn screening turned into official program in Southern Belgium.

Three new therapies for spinal muscular atrophy (SMA) have been approved by the United States Food and Drug Administration and the European Medicines Agency since 2016. Although these new therapies improve the quality of life of patients who are symptomatic at first treatment, administration before the onset of symptoms is significantly more effective. As a consequence, newborn screening programs have been initiated in several countries. In 2018, we launched a 3-year pilot program to screen newborns for SMA in the Belgian region of Liège. This program was rapidly expanding to all of Southern Belgium, a region of approximately 55,000 births annually. During the pilot program, 136,339 neonates were tested for deletion of exon 7 of SMN1, the most common cause of SMA. Nine SMA cases with homozygous deletion were identified through this screen. Another patient was identified after presenting with symptoms and was shown to be heterozygous for the SMN1 exon 7 deletion and a point mutation on the opposite allele. These ten patients were treated. The pilot program has now successfully transitioned into the official neonatal screening program in Southern Belgium. The lessons learned during implementation of this pilot program are reported.

Sometimes they come back: New and old spinal muscular atrophy adults in the era of nusinersen.

BACKGROUND AND PURPOSE: Following the commercial availability of nusinersen, there have been a number of new referrals of adults with spinal muscular atrophy (SMA) not regularly followed in tertiary-care centers or enrolled in any disease registry. METHODS: We compared demographics and disease characteristics, including assessment of motor and respiratory function, in regularly followed patients and newcomers subdivided according to the SMA type. RESULTS: The cohort included 166 adult patients (mean age: 37.09 years): one type I, 65 type II, 99 type III, and one type IV. Of these 166, there were 67 newcomers. There was no significant difference between newcomers and regularly followed patients in relation to age and disease duration. The Hammersmith Functional Motor Scale Expanded and Revised Upper Limb Module scores were higher in the regularly followed patients compared to newcomers in the whole cohort and in both SMA II and II. A difference was also found on ventilatory status (p = 0.013) and Cobb's angle >50° (p = 0.039) between the two subgroups. No difference was found in scoliosis surgery prevalence (p > 0.05). CONCLUSIONS: Our results showed differences between the two subgroups, even if less marked in the type III patients. In the type II patients, there was a higher proportion of newcomers who were in the severe end of the spectrum. Of the newcomers, only approximately a third initiated treatment, as opposed to the 51% in the regularly followed patients. The identification of patients who were not part of the registries will help to redefine the overall prevalence of SMA and the occurrence of different phenotypes.

Impact of a national population-based carrier-screening program on spinal muscular atrophy births.

Spinal muscular atrophy (SMA) is a genetic neurodegenerative disease. Population carrier screening for SMA was introduced in Israel in 2008 through health-care services' insurance plans and expanded to the entire Israeli population in 2013 by a national health program. The aim of the study was to evaluate the impact of carrier screening on reducing the rate of birth of infants with SMA. All cases of prenatal and postnatal diagnosis of SMA in 2008-2017 were identified from databases of relevant government organizations, genetic laboratories in medical centers, and health care systems in Israel. Since 2013, screening was performed in 309,352 individuals, of whom 5741 were found to be carriers (carrier rate 1:54). Given an average of 180,000 live births annually, the predicted rate of SMA diagnosis was 15 cases per year. Prior to 2013, the average rate of prenatally diagnosed SMA was 4.66 cases per year, compared with 7.75 cases per year following population-wide provision of screening. The annual rate of postnatally diagnosed cases remained steady since 2008, with an average of 7- 7.25 cases per year. Screening has been effective in increasing prenatal detection of SMA but has had no effect on the rate of confirmed postnatal diagnoses. We speculate that screening rates may be affected by social, cultural, and religious factors.

Carrier Screening and Prenatal Diagnosis for Spinal Muscular Atrophy in 13,069 Chinese Pregnant Women.

Spinal muscular atrophy (SMA) is a relatively common, life-shortening, autosomal recessive neuromuscular disease. The carrier frequency of SMA ranges from approximately 0.98% to 2.02%, depending on ethnicity. The American College of Medical Genetics has therefore recommended population screening for SMA carrier status, regardless of race or ethnicity. We performed the largest-scale carrier screening for SMA carriers in mainland China. Carrier screening was offered to 36,470 pregnant women between July 2017 and June 2019, of whom 13,069 women accepted the screening program [35.83%; 95% credibility interval (CI), 35.34%-36.33%]. Copy numbers of exons 7 and 8 in the SMN1 gene were detected by real-time quantitative PCR, and the results were confirmed by multiplex ligation-dependent probe amplification. A total of 231 women were identified as carriers (1.77%; 95% CI, 1.56%-2.01%), indicating a carrier prevalence of approximately 1:56 in the population. After detailed genetic counseling, 207 paternal partners were recalled and tested. Both partners were carriers in 10 couples, of whom prenatal diagnosis was implemented in seven, and one fetus was diagnosed with SMA. Carrier screening could provide couples with informed reproductive choices. Our workflow and experience of carrier screening may facilitate the popularization of SMA carrier screening in mainland China.

Incidence and Clinical Features of TRPV4-Linked Axonal Neuropathies in a USA Cohort of Charcot-Marie-Tooth Disease Type 2.

Mutations in TRPV4 are linked to a group of clinically distinct, but also overlapping axonal neuropathies, including Charcot-Marie-Tooth disease type 2C (CMT2C), scapuloperoneal spinal muscular atrophy, and congenital distal spinal muscular atrophy. The incidence of TRPV4-linked cases ranges from 0 to 7% in overall axonal neuropathy cohorts from European countries and Australia. However, the data from other areas remain largely unknown. In this study, we screened for TRPV4 mutations in a well-characterized USA cohort of 62 unrelated CMT2 patients without mutations in MFN2, GARS, NEFL, and GDAP1. All 15 coding exons of TRPV4 were analyzed by Sanger-sequencing. Clinical features of TRPV4-linked patients were compared with those lacking TRPV4 mutations. We identified two TRPV4 mutations in two patients. A TRPV4-R316C was identified in a patient with family history, while a TRPV4-R269C in an apparently sporadic case. Marked clinical variations were observed in the patients with TRPV4 mutations. Our data suggest that TRPV4-linked CMT2C accounts for a sizable fraction in this USA cohort of CMT2; it has a wide phenotypic spectrum, and vocal cord paralysis, scapular weakness and wasting, skeletal dysplasia, and hearing loss are suggestive signs for TRPV4-linked CMT2C.

Perfil demográfico y clínico-funcional de pacientes con atrofia muscular espinal atendidos en el Instituto Teletón Santiago / Demographic and clinical-functional profile of patients with spinal muscular atrophy attending Instituto Teletón Santiago

Introducción: La atrofia muscular espinal (AME) es una enfermedad neuromuscular (ENM) severa caracterizada por la degeneración de las motoneuronas alfa del asta anterior de la médula espinal, generando una debilidad progresiva de la musculatura proximal. La incidencia mundial se estima en 1/6.000-10.000 nacidos vivos. Contamos con escasos datos de las características de los pacientes con AME en la población chilena. Objetivo: Determinar magnitud, características demográficas y clínico funcionales de los pacientes con AME atendidos en el Instituto Teletón Santiago (ITS). Pacientes y Método: Estudio descriptivo transversal, basado en revisión del sistema informático ITS, fichas clínicas y encuesta telefónica. Resultados: Se identificaron 62 pacientes con AME con controles en ITS, 49 (79%), fueron incluidos. 30,6%, 36,7% y 32,7% corresponden a pacientes con AME 1, 2 y 3 respectivamente. Edad promedio 10,6 ± 6,6 años; pérdida de marcha edad mediana de 6,8 años en pacientes AME 3. 67,3% requieren algún tipo de asistencia ventilatoria, 44,9% presentan trastornos de deglución, 75,5% escoliosis, 49,0% subluxación o luxación de cadera, 79,6% retracciones articulares y 65,3% dolor. En participación, el 83% de las actividades de ocio se realizan dentro del hogar, principalmente de tipo tecnológico; 77,5% realiza salidas sociales. Conclusión: Las características clínico funcionales de los pacientes con AME, evidencian un grupo que presenta un alto nivel de dependencia en todos los tipos de la enfermedad, múltiples comorbilidades y alteraciones músculo-esqueléticas secundarias y por ello requiere de un programa de rehabilitación multidisciplinaria tal como lo describe la literatura internacional.

Introduction: Spinal muscular atrophy (SMA) is a severe neuromuscular disease (NMD) characterized by the loss of alpha motor neurons of the anterior horn of the spinal cord, causing progressive weakness of proximal muscles. Global prevalence is estimated to be 1/6,000-10,000 live births. There is limited data on SMA patients in the Chilean population. Objective: To establish the scale, demographics and functional-clinical characteristics of SMA patients attending Instituto Teletón Santiago (ITS). Patients and Method: Cross-sectional, descriptive study based on the review of ITS's data information system, clinical records and telephone surveys. Results: 62 SMA patients were identified attending regular controls at ITS, 49 (79%) were included in the study. 30.6%, 36.7% and 32.7% correspond to SMA 1, 2 or 3, respectively. Average age 10.6 ± 6.6 years; loss of gait at a median age of 6.8 years in SMA 3 patients. 67.3% require some type of breathing assistance, 44.9% have swallowing problems, 75.5% scoliosis, 49% hip dislocation or subluxation, 79.6% contracture of joints and 65.3% pain. In terms of social participation, 83% of recreational activities are carried out indoors, mainly related to the use of technology; and 77.5% go out to take part in social activities. Conclusion: Functional-clinical characteristics of SMA patients show that there is a group with high levels of dependence in all types of the disease, multiple concurrent disorders and secondary musculoskeletal conditions, and therefore, in the necessity to have a multidisciplinary rehabilitation system, as described in international literature.

Population genomic screening of all young adults in a health-care system: a cost-effectiveness analysis.

PURPOSE: To consider the impact and cost-effectiveness of offering preventive population genomic screening to all young adults in a single-payer health-care system. METHODS: We modeled screening of 2,688,192 individuals, all adults aged 18-25 years in Australia, for pathogenic variants in BRCA1/BRCA2/MLH1/MSH2 genes, and carrier screening for cystic fibrosis (CF), spinal muscular atrophy (SMA), and fragile X syndrome (FXS), at 71% testing uptake using per-test costs ranging from AUD$200 to $1200 (~USD$140 to $850). Investment costs included genetic counseling, surveillance, and interventions (reimbursed only) for at-risk individuals/couples. Cost-effectiveness was defined below AUD$50,000/DALY (disability-adjusted life year) prevented, using an incremental cost-effectiveness ratio (ICER), compared with current targeted testing. Outcomes were cancer incidence/mortality, disease cases, and treatment costs reduced. RESULTS: Population screening would reduce variant-attributable cancers by 28.8%, cancer deaths by 31.2%, and CF/SMA/FXS cases by 24.8%, compared with targeted testing. Assuming AUD$400 per test, investment required would be between 4 and 5 times higher than current expenditure. However, screening would lead to substantial savings in medical costs and DALYs prevented, at a highly cost-effective ICER of AUD$4038/DALY. At AUD$200 per test, screening would approach cost-saving for the health system (ICER = AUD$22/DALY). CONCLUSION: Preventive genomic screening in early adulthood would be highly cost-effective in a single-payer health-care system, but ethical issues must be considered.

Surgical management of camptocormia in Parkinson's disease: systematic review and meta-analysis.

OBJECTIVE: Camptocormia is a potentially debilitating condition in the progression of Parkinson's disease (PD). It is described as an abnormal forward flexion while standing that resolves when lying supine. Although the condition is relatively common, the underlying pathophysiology and optimal treatment strategy are unclear. In this study, the authors systematically reviewed the current surgical management strategies for camptocormia. METHODS: PubMed was queried for primary studies involving surgical intervention for camptocormia in PD patients. Studies were excluded if they described nonsurgical interventions, provided only descriptive data, or were case reports. Secondarily, data from studies describing deep brain stimulation (DBS) to the subthalamic nuclei were extracted for potential meta-analysis. Variables showing correlation to improvement in sagittal plane bending angle (i.e., the vertical angle caused by excessive kyphosis) were subjected to formal meta-analysis. RESULTS: The query resulted in 9 studies detailing treatment of camptocormia: 1 study described repetitive trans-spinal magnetic stimulation (rTSMS), 7 studies described DBS, and 1 study described deformity surgery. Five studies were included for meta-analysis. The total number of patients was 66. The percentage of patients with over 50% decrease in sagittal plane imbalance with DBS was 36.4%. A duration of camptocormia of 2 years or less was predictive of better outcomes (OR 4.15). CONCLUSIONS: Surgical options include transient, external spinal stimulation; DBS targeting the subthalamic nuclei; and spinal deformity surgery. Benefit from DBS stimulation was inconsistent. Spine surgery corrected spinal imbalance but was associated with a high complication rate.

Surgical treatment of spinal disorders in Parkinson's disease.

PURPOSE: Most patients suffering from Parkinson's disease (PD) exhibit alterations in the posture, which can in several cases give rise to spine deformities, both in the sagittal and the coronal plane. In addition, degenerative disorders of the spine frequently associated to PD, such as spinal stenosis and sagittal instability, can further impact the quality of life of the patient. In recent years, spine surgery has been increasingly performed, with mixed results. The aim of this narrative review is to analyze the spinal disorders associated to PD, and the current evidence about their surgical treatment. METHODS: Narrative review. RESULTS: Camptocormia, i.e., a pronounced flexible forward bending of the trunk with 7% prevalence, is the most reported sagittal disorder of the spine. Pisa syndrome and scoliosis are both common and frequently associated. Disorders to the spinopelvic alignment were not widely investigated, but a tendency toward a lower ability of PD patients to compensate the sagittal malalignment with respect to non-PD elderly subjects with imbalance seems to emerge. Spine surgery in PD patients showed high rates of complications and re-operations. CONCLUSIONS: Disorders of the posture and spinal alignment, both in the sagittal and in the coronal planes, are common in PD patients, and have a major impact on the quality of life. Outcomes of spine surgery are generally not satisfactory, likely mostly due to muscle dystonia and poor bone quality. Knowledge in this field needs to be consolidated by further clinical and basic science studies. These slides can be retrieved under Electronic Supplementary Material.

Reproductive genetic carrier screening for cystic fibrosis, fragile X syndrome, and spinal muscular atrophy in Australia: outcomes of 12,000 tests.

PurposeTo describe our experience of offering simultaneous genetic carrier screening for cystic fibrosis (CF), fragile X syndrome (FXS), and spinal muscular atrophy (SMA).MethodsCarrier screening is offered through general practice, obstetrics, fertility, and genetics settings before or in early pregnancy. Carriers are offered genetic counseling with prenatal/preimplantation genetic diagnosis available to those at increased risk.ResultsScreening of 12,000 individuals revealed 610 carriers (5.08%; 1 in 20): 342 CF, 35 FXS, 241 SMA (8 carriers of 2 conditions), approximately 88% of whom had no family history. At least 94% of CF and SMA carriers' partners were tested. Fifty couples (0.42%; 1 in 240) were at increased risk of having a child with one of the conditions (14 CF, 35 FXS, and 1 SMA) with 32 pregnant at the time of testing. Of these, 26 opted for prenatal diagnosis revealing 7 pregnancies affected (4 CF, 2 FXS, 1 SMA).ConclusionThe combined affected pregnancy rate is comparable to the population risk for Down syndrome, emphasizing the need to routinely offer carrier screening. The availability of appropriate genetic counseling support and a collaborative approach between laboratory teams, genetics services, health professionals offering screening, and support organizations is essential.

Population screening for spinal muscular atrophy: A mixed methods study of the views of affected families.

Autosomal recessive conditions are a significant health burden with few treatments. Population carrier screening has been suggested as a means to tackle them. Little is known about the views of affected families despite the potential for direct impacts on them. Data are presented on attitudes among families affected by Spinal Muscular Atrophy (SMA) toward two population screening programs, pre-conception, and prenatal. Data were gathered through qualitative interviews (n = 36) and a survey (n = 337). Eighty-two survey participants had SMA and 255 were family members. The majority were in favor of screening (75%). Reasons for supporting pre-conception screening support were a belief that it would reduce SMA-related terminations and raise awareness of SMA in the population. For prenatal screening, reasons for support included a belief in the importance of informed decision-making and the need to reduce suffering. Key reasons for non-support of pre-conception screening included concerns about carrier stigmatization and social engineering. For prenatal screening, concerns focused on the collateral loss of high quality of life lives affected by SMA. This study highlights that those affected by SMA are predominantly in favor of screening, although pre-conception screening is most favored. While family members and adults with SMA had largely consistent views, perceptions varied according to the severity (type) of SMA, with those affected by SMA type II the least likely to support screening. These findings suggest that screening for SMA is a complex issue for affected families, underscoring the need to consider and include their views when planning and implementing screening programs. © 2016 Wiley Periodicals, Inc.

Mapping the differences in care for 5,000 spinal muscular atrophy patients, a survey of 24 national registries in North America, Australasia and Europe.

Spinal muscular atrophy (SMA) is an autosomal recessive genetic disorder characterised by the degeneration of motor neurons and progressive muscle weakness. It is caused by homozygous deletions in the survival motor neuron gene on chromosome 5. SMA shows a wide range of clinical severity, with SMA type I patients often dying before 2 years of age, whereas type III patients experience less severe clinical manifestations and can have a normal life span. Here, we describe the design, setup and utilisation of the TREAT-NMD national SMA patient registries characterised by a small, but fully standardised set of registry items and by genetic confirmation in all patients. We analyse a selection of clinical items from the SMA registries in order to provide a snapshot of the clinical data stratified by SMA subtype, and compare these results with published recommendations on standards of care. Our study included 5,068 SMA patients in 25 countries. A total of 615 patients were ventilated, either invasively (178) or non-invasively (437), 439 received tube feeding and 455 had had scoliosis surgery. Some of these interventions were not available to patients in all countries, but differences were also noted among high-income countries with comparable wealth and health care systems. This study provides the basis for further research, such as quality of life in ventilated SMA patients, and will inform clinical trial planning.

Análisis genético molecular en atrofia muscular espinal / Molecular evaluation in infantile spinal muscular atrophy

Introducción: La atrofia muscular espinal de la infancia (AMEi) es una enfermedad neurodegenerativa, causada principalmente por deleciones del gen SMN 1 en su locus 5q11.1-13.3. La severidad va desde el tipo I, que compromete la vida en edades tempranas, hasta el tipo IV. Objetivos: Se describen hallazgos moleculares en pacientes con AME, nacionalmente remitidos al Instituto de Neurología y Neurocirugía así como se reporta la frecuencia por 100.000 habitantes en cada una de las provincias de la isla. Pacientes y Métodos: 105 pacientes fueron estudiados, remitidos entre 1997 y 2011. Para la detección de las deleciones se utilizó la técnica de reacción en cadena de la polimerasa (PCR) con cebadores correspondientes a los exones 7 y 8 del gen SMN 1, y digestión con enzimas DraI y DdeI respectivamente y analizados en gel de agarosa al 2 por ciento. Resultados y Discusión: Se encontró un 59 por ciento diagnosticados como AME I, 28,6 por ciento AME II, 12,4 por ciento AME III. Del total de casos 36,2 por ciento resultaron tener deleción de los exones 7 y 8, 35,2 por ciento deleción del exón 7 solamente y 28,2 por ciento no presentaron deleción de los exones correspondientes. Se discuten dichos resultados de acuerdo a la literatura internacional. Se presentan los resultados de frecuencias por 100.000 habitantes en cada provincia del país y discuten dichas frecuencias de acuerdo a la diversidad ancestral de la población cubana. Se concluye lo novedoso del estudio que constituye el primer reporte en una población caribeña.

Introduction: Infantile Spinal Muscular Atrophy (infantile SMA) is a neurodegenerative disease caused primarily by the deletion of the SMN1 gene at 5q11.1 - 13.3. Its severity ranges from type I, in early childhood, to type IV. Objectives: To describe molecular findings in patients with SMA, who were nationally referred to the Institute of Neurology and Neurosurgery and to describe the frequency per 100,000 people in each province of the island. Patients and Methods: 105 patients, referred between 1997 and 2011, were studied. The polymerase chain reaction (PCR) technique was used to detect the deletions of exons 7 and 8 of the SMN1 gene, and DraI and DdeI enzymes, in 2 percent agarose gel, were used for digestion. Results: 59 percent of the patients were diagnosed with SMA I, 28.6 percent with SMA II and 12.4 percent with SMA III. 36.2 percent of total patients presented deletions of exons 7, 8, 35.2 percent only deletion of exon 7 and 28.2 percentdid not present deletion of exons. Conclusion: These results are discussed according to the international literature. The frequency per 100,000 inhabitants in each province is presented and discussed according to ancestral diversity of the Cuban population. Also, the originality of the study is mentioned as it is the first report of this type in a Caribbean population.

Smoking is not a risk factor for sporadic amyotrophic lateral sclerosis in an Australian population.

BACKGROUND: Controversy persists as to whether smoking is a risk factor for sporadic amyotrophic lateral sclerosis (SALS), the most common form of sporadic motor neuron disease (SMND). We therefore undertook a large case-control study of smoking and SALS in Australia. METHODS: Cases and controls were recruited Australia-wide over a 10-year period. SALS and the other subgroups of SMND were categorised on the basis of neurologists' reports. Controls were partners or friends of SMND patients or community volunteers. Individuals filled in a questionnaire regarding smoking habits. A total of 809 patients with SMND (631 with SALS) and 779 controls were included in the study. SALS males and females were analysed separately. RESULTS: No differences between SALS patients and control groups were found with regard to (1) the odds ratios of ever-smokers, ex-smokers or current smokers compared to never-smokers, (2) the means of numbers of cigarettes per day, years of smoking, pack years or age smoking began or (3) the proportions of their parents who had ever smoked. The proportion of ever-smokers and mean pack years did not differ between the clinical subgroups of SMND or between different sites of SALS onset. Partner smoking did not increase the risk of SMND. CONCLUSION: This Australian case-control study does not support a link between cigarette smoking and any form of SMND.

Pan-ethnic carrier screening and prenatal diagnosis for spinal muscular atrophy: clinical laboratory analysis of >72,400 specimens.

Spinal muscular atrophy (SMA) is a leading inherited cause of infant death with a reported incidence of ~1 in 10,000 live births and is second to cystic fibrosis as a common, life-shortening autosomal recessive disorder. The American College of Medical Genetics has recommended population carrier screening for SMA, regardless of race or ethnicity, to facilitate informed reproductive options, although other organizations have cited the need for additional large-scale studies before widespread implementation. We report our data from carrier testing (n = 72,453) and prenatal diagnosis (n = 121) for this condition. Our analysis of large-scale population carrier screening data (n = 68,471) demonstrates the technical feasibility of high throughput testing and provides mutation carrier and allele frequencies at a level of accuracy afforded by large data sets. In our United States pan-ethnic population, the calculated a priori carrier frequency of SMA is 1/54 with a detection rate of 91.2%, and the pan-ethnic disease incidence is calculated to be 1/11,000. Carrier frequency and detection rates provided for six major ethnic groups in the United States range from 1/47 and 94.8% in the Caucasian population to 1/72 and 70.5% in the African American population, respectively. This collective experience can be utilized to facilitate accurate pre- and post-test counseling in the settings of carrier screening and prenatal diagnosis for SMA.

Spinal muscular atrophy: an update.

Spinal muscular atrophy (SMA) is the most common childhood neurodegenerative disease. We report an infant with SMA type 1 and discuss the recent developments in SMA genetics, pathophysiology, and possible treatment options. Because SMA type 1 remains a fatal illness for which there is not yet a cure, the focus of patient care continues to be symptomatic. Thus, the most appropriate aspects of care at present and future are also discussed.

Large-scale population screening for spinal muscular atrophy: clinical implications.

PURPOSE: To determine the frequency of SMN1 deletion carriers in the Israeli population and to assess the feasibility of population screening for spinal muscular atrophy. METHODS: A total of 6394 individuals without family history of spinal muscular atrophy underwent genetic screening by multiplex ligation-dependent probe amplification, designed to detect SMN1 exon 7 and exon 8 copy number. RESULTS: One hundred fifty-nine individuals carried an SMN1 heterozygous exon 7 deletion, yielding a carrier frequency of 1:40. About 10.8% of individuals were found to carry two or more SMN1 exon 7 copies on the same chromosome (cis configuration). This implies that some deletion carriers may not be detected by multiplex ligation-dependent probe amplification or similar quantitative methods. The acceptance of spinal muscular atrophy screening among women undergoing testing for fragile X syndrome and cystic fibrosis reached 93%. CONCLUSIONS: Currently used molecular techniques cannot detect about 5% of spinal muscular atrophy carriers with a cis configuration or individuals with SMN1 sequence mutations and de novo deletions. Thus, it is estimated that the spinal muscular atrophy carrier detection rate is about 90%. Given the severity of spinal muscular atrophy, the relatively high carrier frequency, and the estimated detection rate, we conclude that population-based screening for spinal muscular atrophy is feasible and acceptable.