Research progress on biomarkers for the monitoring of Spinal muscular atrophy / 中华医学遗传学杂志

Spinal muscular atrophy (SMA) is the most common neuromuscular disease in children, which seriously affects children's health. At present, gene and molecular modification therapy for SMA have become hot spots. However, there are many uncertainties about when people with SMA should start treatment, how well the drugs can treat, and the prognosis. Therefore, reliable biomarkers for monitoring and evaluation are urgently needed. This review will summarize the progress made in SMA biomarker research in recent years.

An evaluation of carrier detection for Spinal muscular atrophy using digital PCR assay / 中华医学遗传学杂志

OBJECTIVE@#To assess the effectiveness and feasibility of carrier detection for Spinal muscular atrophy (SMA) by using digital PCR assay.@*METHODS@#Peripheral blood samples were collected from 214 pregnant women who were routinely screened for SMA carriers, of which 204 were randomly selected samples and 10 were samples with known copy numbers of SMN1 exons 7 and 8. Samples with known copy numbers of SMN1 exons 7 and 8 were randomly mixed into the experiment to validate the performance of the digital PCR assay.@*RESULTS@#The copy numbers of SMN1 exons 7 and 8 and SMN2 exons 7 and 8 in peripheral blood samples were detected by digital PCR assay. The results of SMN1 exons 7 and 8 were compared with those of the quantitative PCR method to assess the reliability and clinical performance of the digital PCR assay. Among the 204 random samples, digital PCR has detected five samples with simultaneous heterozygous deletion of SMN1 exons 7 and 8, three samples with heterozygous deletion of SMN1 exon 8 only, and 196 samples with no deletion of SMN1 exons 7 and 8. Ten samples with known SMN1 exons 7 and 8 copy numbers were detected with the expected values. The digital PCR test results were fully consistent with that of the quantitative PCR.@*CONCLUSION@#The results of digital PCR for the detection of copy number variation of SMN1 exons 7 and 8 were consistent with qPCR. Digital PCR assay was able to clearly distinguish the copy number of the target genes, therefore can be used for SMA carrier screening. Moreover, it can also detect copy number of SMN2 exons 7 and 8, which can provide more information for genetic counseling.

El difícil camino al diagnóstico del paciente con atrofia muscular espinal / The difficult path to diagnosis of the patient with spinal muscular atrophy

Introducción. Con las nuevas terapias, el diagnóstico temprano de la atrofia muscular espinal (AME) es esencial. El objetivo de este estudio es analizar los distintos componentes que influyen en el retraso diagnóstico. Población y métodos. Se incluyeron pacientes con un diagnóstico molecular de AME tipo I, II y III. Se estudiaron varios parámetros, como la edad al momento de la aparición del primer signo, qué signo fue y el intervalo entre este y el diagnóstico confirmado. Neurólogos especialistas realizaron entrevistas que se complementaron con la revisión de historias clínicas cuando fue necesario. Resultados. Se entrevistaron 112 pacientes. AME I n = 40, AME II n = 48, AME III n = 24. La mediana de edad en meses al momento del reporte del primer signo fue AME I: 1,5 (R 0-7), AME II: 9 (R 2-20), AME III: 18 (R 8-180). Los primeros signos fueron reconocidos por los padres en el 75 % al 85 % de las veces en todos los subtipos. La mediana del tiempo transcurrido entre el primer signo y la primera consulta médica fue menor a un mes en los tres tipos. La mediana de tiempo transcurrido en meses entre el primer signo y el diagnóstico molecular confirmado fue en AME I: 2 (R 0-11), en AME II: 10 (3-46) y en AME III: 31,5 (R 4-288). Conclusiones. Existe un significativo retraso en el diagnóstico de la AME relacionado fundamentalmente a la falta de sospecha clínica. La demora es menor en AME I y mayor en AME III. Otros factores incluyen deficiencias en el sistema de salud.

Introduction. News treatments, make early diagnosis of spinal muscular atrophy (SMA) critical. The objective of this study is to analyze the different factors that influence delay in diagnosis. Population and methods. Patients with a molecular diagnosis of types I, II, and III SMA were included. Several parameters were studied, such as age at onset of first sign, what sign it was, and the time from recognition of first sign to confirmed diagnosis. Neurologists specialized in SMA conducted interviews, supported by the review of medical records when deemed necessary. Results. A total of 112 patients were interviewed. SMA I n = 40, SMA II n = 48, SMA III n = 24. The median age in months at the time of reporting the first sign was SMA I: 1.5 (R: 0­7), SMA II: 9 (R: 2­20), SMA III: 18 (R: 8­180). In all subtypes, first signs were identified by parents from 75% to 85% of the times. The median time from first sign to first medical consultation was less than a month in all 3 types. The median time in months, from first sign to confirmed molecular diagnosis in SMA I was: 2 (R: 0­11), in SMA II: 10 (R: 3­46), in SMA III: 31.5 (R: 4­288). Conclusions. There is a significant delay in SMA diagnosis mainly related to the absence of clinical suspicion. The delay is shorter in SMA I and longer in SMA III. Other factors include deficiencies in the health care system.

Clinical and genetic characteristics of 9 rare cases with coexistence of dual genetic diagnoses / 中华儿科杂志

Objective: To analyze the clinical and genetic characteristics of pediatric patients with dual genetic diagnoses (DGD). Methods: Clinical and genetic data of pediatric patients with DGD from January 2021 to February 2022 in Peking University First Hospital were collected and analyzed retrospectively. Results: Among the 9 children, 6 were boys and 3 were girls. The age of last visit or follow-up was 5.0 (2.7,6.8) years. The main clinical manifestations included motor retardation, mental retardation, multiple malformations, and skeletal deformity. Cases 1-4 were all all boys, showed myopathic gait, poor running and jumping, and significantly increased level of serum creatine kinase. Disease-causing variations in Duchenne muscular dystrophy (DMD) gene were confirmed by genetic testing. The 4 children were diagnosed with DMD or Becker muscular dystrophy combined with a second genetic disease, including hypertrophic osteoarthropathy, spinal muscular atrophy, fragile X syndrome, and cerebral cavernous malformations type 3, respectively. Cases 5-9 were clinically and genetically diagnosed as COL9A1 gene-related multiple epiphyseal dysplasia type 6 combined with NF1 gene-related neurofibromatosis type 1, COL6A3 gene-related Bethlem myopathy with WNT1 gene-related osteogenesis imperfecta type XV, Turner syndrome (45, X0/46, XX chimera) with TH gene-related Segawa syndrome, Chromosome 22q11.2 microduplication syndrome with DYNC1H1 gene-related autosomal dominant lower extremity-predominant spinal muscular atrophy-1, and ANKRD11 gene-related KBG syndrome combined with IRF2BPL gene-related neurodevelopmental disorder with regression, abnormal movement, language loss and epilepsy. DMD was the most common, and there were 6 autosomal dominant diseases caused by de novo heterozygous pathogenic variations. Conclusions: Pediatric patients with coexistence of double genetic diagnoses show complex phenotypes. When the clinical manifestations and progression are not fully consistent with the diagnosed rare genetic disease, a second rare genetic disease should be considered, and autosomal dominant diseases caused by de novo heterozygous pathogenic variation should be paid attention to. Trio-based whole-exome sequencing combining a variety of molecular genetic tests would be helpful for precise diagnosis.

Efficacy and safety of salbutamol in treatment of children with later-onset spinal muscular atrophy / 浙江大学学报·医学版

OBJECTIVES@#To investigate the clinical efficacy and safety of salbutamol in the treatment of children with later-onset spinal muscular atrophy (SMA).@*METHODS@#This study is a prospective single-arm phase Ⅲ clinical study. Pediatric patients with SMA type Ⅱ and Ⅲ who visited Department of Neurology, Children's Hospital, Zhejiang University School of Medicine from December 2020 to June 2022 were enrolled. All patients were evaluated with motor function scales, pulmonary function test and drug safety before study. Patients were treated with salbutamol tablets orally, with an initial dose of 1 mg (tid). If tolerable, the dose was increased to 1.5 mg (tid) in the second week, then increased to 2 mg (tid) from the third week and maintained for 6 months. Patients were followed up at 1, 3 and 6 months of treatment.@*RESULTS@#Twenty-six patients were enrolled, including 10 boys and 16 girls. There were 16 cases of SMA type Ⅱ and 10 cases of type Ⅲ with age at treatment initiation of 5.67 (3.13, 7.02) years and disease duration of 2.54 (1.31, 4.71) years. The Hammersmith Functional Motor Scale-Expanded (HFMSE) scores were increased from 14.0 (6.5, 43.0) before treatment to 26.0 (15.0, 46.5) after treatment (Z=－4.144, P<0.01) in 25 cases. The Revised Upper Limb Module Scale scores were increased from 33.0 (25.5, 36.0) before treatment to 35.0 (31.0, 36.5) after treatment (Z=－2.214, P<0.05) in 9 cases. In 7 ambulant children with SMA type Ⅲ, the six minutes walking distance was increased by 30 (15, 52) m after a 6-month treatment (Z=－2.366, P<0.05). Compared with the baseline pulmonary functions the patients showed a significant increase in forced vital capacity (FVC), forced expiratory volume in one second (FEV1), and peak expiratory flow (PEF) in 15 cases after treatment (all P<0.05). According to patients and caregivers subjective reporting, there were various degrees of improvement in coughing, sputum production ability and exercise endurance. No serious adverse events were observed during the study.@*CONCLUSIONS@#Short-term oral administration of salbutamol may improve motor and pulmonary functions in later-onset SMA children with good safety.

Analysis of a Chinese pedigree affected with Spinal muscular atrophy due to compound heterozygous variants of SMN gene / 中华医学遗传学杂志

OBJECTIVE@#To analyze variants of SMN gene in a Chinese pedigree affected with Spinal muscular atrophy (SMA).@*METHODS@#A Chinese pedigree diagnosed at the Nanchang First Hospital in January 2020 was selected as the study subject. Peripheral blood samples were collected for the extraction of DNA. All exons of the SMN gene were detected by multiple ligation-dependent probe amplification (MLPA). Potential variants of the SMN gene were also detected by Whole exome sequencing (WES), and the result was verified by Sanger sequencing. cDNA extracted from fresh blood sample was used as a template to verify the location of variant on the SMN genes.@*RESULTS@#The proband was found to harbor a heterozygous deletion of the SMN1 Exon7+Exon8, and a heterozygous c.81G>A variant. The SMN1 Exon7+Exon8 deletion was inherited from her father and grandmother, whilst the c.81G>A variant was inherited from her mother and maternal grandfather. Her aunt was also a carrier of the heterozygous deletion, while her paternal aunt, her husband, and their daughter were not. cDNA amplification and Sanger sequencing confirmed that the c.81G>A variant was located in the SMN1 gene.@*CONCLUSION@#MLPA combined with NGS and Sanger sequencing can identify compound heterozygous variants of the SMN gene in the SMA patients.

Molecular pathological mechanism of liver metabolic disorder in mice with severe spinal muscular atrophy / 南方医科大学学报

OBJECTIVE@#To explore the molecular pathological mechanism of liver metabolic disorder in severe spinal muscular atrophy (SMA).@*METHODS@#The transgenic mice with type Ⅰ SMA (Smn-/- SMN20tg/2tg) and littermate control mice (Smn+/- SMN20tg/2tg) were observed for milk suckling behavior and body weight changes after birth. The mice with type Ⅰ SMA mice were given an intraperitoneal injection of 20% glucose solution or saline (15 μL/12 h), and their survival time was recorded. GO enrichment analysis was performed using the RNA-Seq data of the liver of type Ⅰ SMA and littermate control mice, and the results were verified using quantitative real-time PCR. Bisulfite sequencing was performed to examine CpG island methylation level in Fasn gene promoter region in the liver of the neonatal mice.@*RESULTS@#The neonatal mice with type Ⅰ SMA showed normal milk suckling behavior but had lower body weight than the littermate control mice on the second day after birth. Intraperitoneal injection of glucose solution every 12 h significantly improved the median survival time of type Ⅰ SMA mice from 9±1.3 to 11± 1.5 days (P < 0.05). Analysis of the RNA-Seq data of the liver showed that the expression of the target genes of PPARα related to lipid metabolism and mitochondrial β oxidation were down-regulated in the liver of type Ⅰ SMA mice. Type Ⅰ SMA mice had higher methylation level of the Fasn promoter region in the liver than the littermate control mice (76.44% vs 58.67%). In primary cultures of hepatocytes from type Ⅰ SMA mice, treatment with 5-AzaC significantly up-regulated the expressions of the genes related to lipid metabolism by over 1 fold (P < 0.01).@*CONCLUSION@#Type Ⅰ SMA mice have liver metabolic disorder, and the down-regulation of the target genes of PPARα related to lipid and glucose metabolism due to persistent DNA methylation contributes to the progression of SMA.

Analysis of 4 children with DYNC1H1 gene related spinal muscular atrophy with lower extremity predominant 1 / 中华儿科杂志

Objective: To investigate the clinical features and gene variation characteristics of children with dynein cytoplasmic 1 heavy chain 1 (DYNC1H1) gene associated spinal muscular atrophy with lower extremity predominant (SMALED) 1. Methods: The clinical data of 4 SMALED1 children admitted to Peking University First Hospital from December 2018 to May 2021, who were found to have pathogenic variation of DYNC1H1 gene through genetic testing, except for other genes known to be related to motor retardation, were retrospectively summarized to analyze the phenotype and genotype characteristics. Results: There were 3 males and 1 female. The age of onset was 1 year, 1 day, 1 day and 4 months, respectively. The age of diagnosis was 4 years and 10 months, 9 months, 5 years and 9 months, and 3 years and 1 month, respectively. The clinical manifestations were muscle weakness and muscular atrophy of lower limbs, 2 cases with foot deformity, 1 case with early non progressive joint contracture, 1 case with hip dislocation and 1 case with mental retardation. De novo heterozygous missense variations in DYNC1H1 gene were found in all 4 children. According to the rating of American College of medical genetics and genomics, they were all possible pathogenic and pathogenic variations, with p.R598C, p.P776L, p.Y1109D variations had been reported, and p.I1086R variation had not been reported. Conclusions: For those with unexplained lower limb muscle weakness, muscle atrophy, joint contracture and foot deformity, upper limb motor ability related retention, with or without mental retardation, as well as the motor ability progresses slowly, it is necessary to consider the possibility of SMALED1 and the detection of DYNC1H1 gene when necessary.

Results of carrier screening for Spinal muscular atrophy among 35 145 reproductive-aged individuals from Dongguan region / 中华医学遗传学杂志

OBJECTIVE@#To carry out carrier screening for Spinal muscular atrophy (SMA) in reproductive-aged individuals from Dongguan region and determine the carrier frequency of SMN1 gene mutations.@*METHODS@#Reproductive-aged individuals who underwent SMN1 genetic screening at the Dongguan Maternal and Child Health Care Hospital from March 2020 to August 2022 were selected as the study subjects. Deletions of exon 7 and 8 (E7/E8) of the SMN1 gene were detected by real-time fluorescence quantitative PCR (qPCR), and prenatal diagnosis was provided for carrier couples by multiple ligation-dependent probe amplification (MLPA).@*RESULTS@#Among the 35 145 subjects, 635 were found to be carriers of SMN1 E7 deletion (586 with heterozygous E7/E8 deletion, 2 with heterozygous E7 deletion and homozygous E8 deletion, and 47 with sole heterozygous E7 deletion). The carrier frequency was 1.81% (635/35 145), with 1.59% (29/1 821) in males and 1.82% (606/33 324) in females. There was no significant difference between the two genders (χ² = 0.497, P = 0.481). A 29-year-old woman was found to harbor homozygous deletion of SMN1 E7/E8, and was verified to have a SMN1∶SMN2 ratio of [0∶4], none of her three family members with a [0∶4] genotype had clinical symptoms. Eleven carrier couples had accepted prenatal diagnosis, and one fetus was found to have a [0∶4] genotype, and the pregnancy was terminated.@*CONCLUSION@#This study has determined the SMA carrier frequency in Dongguan region for the first time and provided prenatal diagnosis for carrier couples. The data can provide a reference for genetic counseling and prenatal diagnosis, which has important clinical implications for the prevention and control of birth defects associated with SMA.

Clinical profile of genetically confirmed Spinal Muscular Atrophy (SMA) Among Filipino children less than 18 years old

@#Spinal muscular atrophy (SMA) is the most common inherited lethal disease in children. Confirmatory diagnosis is based on molecular genetic testing of survival motor neuron (SMN) genes. We aimed to describe the phenotypic presentation of Filipino infants and children with SMA based on the copy number analysis of SMN genes. Medical records of 17 Filipino children were reviewed from January 2017 to December 2019. De-identified clinical data fulfilled the diagnostic criteria defined by the International SMA Consortium. Among Filipino children, the predominant SMA type by copy number was type I having two copies of SMN2 gene. The clinical severity based on symptom onset and highest functional motor capacity attained correlated with SMN2 copy number congruent with existing data. A significant time lag between symptom onset to confirmation of genetic diagnosis was noted. Nine out of the 17 (52%) children did not have a family history of the disease, raising the possibility of mutation carriers in these families since the incidence of de novo mutations in literature is about 2%. These data offered the first epidemiological pattern of genetically confirmed SMA among Filipino children; provided additional information for genetic counselling; and an avenue to consider pre-symptomatic newborn screening and carrier testing that would change proactive measures and opportunities for therapy. These measures unavoidably will decrease the incidence and prevalence of disease in the future.

Application of single sperm sequencing for the preimplantation genetic testing of a Chinese family affected with Spinal muscular atrophy / 中华医学遗传学杂志

OBJECTIVE@#To assess the value of single sperm sequencing in preimplantation genetic testing for monogenic disease (PGT-M).@*METHODS@#A Chinese couple with two children whom had died of Spinal muscular atrophy (SMA) and attended the Jiangxi Provincial Maternal and Child Health Care Hospital in June 2020 was selected as the subject. Eleven single sperm samples were isolated by mechanical immobilization and subjected to whole genome amplification. Real-time PCR and Sanger sequencing were used to detect the SMN1 variants in the single sperm samples. Genomic DNA of the wife, her parents and the husband, as well as one single sperm sample harboring the SMN1 variant and two single sperm samples without the variant were used for the linkage analysis. Targeted capture and high-throughput sequencing were carried out to test 100 single nucleotide polymorphisms distributed within 2 Mb up- and downstream the variant site. The haplotypes linked with the SMN1 variants were determined by linkage analysis. Blastocyst embryos were harvested after fertilizing by intracytoplasmic sperm injection. Cells from the trophoblasts of each embryo were biopsied and subjected to whole genome amplification and targeted capture and high-throughput sequencing to determine their carrier status. Chromosomal aneuploidy of wild-type embryos was excluded. An euploid embryo of high quality was transferred. Amniotic fluid sample was taken at 18 weeks of gestation to confirm the status of the fetus.@*RESULTS@#Genetic testing showed that the couple both had deletion of exons 7 ~ 8 of the SMN1 gene. The wife has inherited the deletion from her father, while the husband was de novo. The haplotypes of the husband were successfully constructed by single sperm sequencing. Preimplantation genetic testing has indicated that 5 embryos had harbored the heterozygous variant, 4 embryos were of the wild type, among which 3 were euploid. Prenatal diagnosis during the second trimester of pregnancy has confirmed that the fetus did not carry the deletion.@*CONCLUSION@#By single sperm sequencing and PGT-M, the birth of further affected child has been successfully avoided.

Diagnóstico tardío de atrofia muscular espinal en paciente con síndrome de Down / Late diagnosis of spinal muscular atrophy in a patient with Down syndrome

El síndrome de Down (SD) es la anomalía cromosómica más frecuente entre los recién nacidos vivos. La atrofia muscular espinal (AME), por su parte, es una enfermedad neuromuscular caracterizada por la degeneración progresiva de las motoneuronas del asta anterior de la médula espinal que produce atrofia muscular, debilidad y parálisis. Presentamos el caso de una niña de 6 años con síndrome de Down derivada a nuestro centro para estudio por cuadro de debilidad muscular generalizada de evolución crónica con falta de adquisición de la marcha. Realizamos una revisión bibliográfica enfocándonos en el compromiso neurológico esperable en el síndrome de Down, la evolución de los hitos del desarrollo motor grueso estipulado para este grupo de pacientes y en los hallazgos que deben sugerir la presencia de una enfermedad neuromuscular.

A case of a 6-year-old girl with Down's syndrome is presented. She was referred to our center due to a history of generalized muscle weakness of chronic evolution, associated to her inability to walk. Her mother claimed that the girl's muscle weakness always called her attention as well as the difficulties to the development of motor skills shown by her daughter compared to other children, whether they were healthy or with Down's syndrome. There was information in her medical record and physical exam that strongly suggested the possibility of suffering a neuromuscular disorder. We asked for a molecular study that confirmed the spinal muscular atrophy diagnosis. We carried out a bibliographical revision focusing on the expected neurological impairment in Down's syndrome, the retardation of the gross motor skills development determined for this kind of patients and on the findings that must suggest a neuromuscular disorder.

Caracterización clínica y funcional de pacientes con atrofia muscular espinal en el centro-occidente colombiano / Clinical-functional characterization of patients with spinal muscular atrophy in Central-Western Colombia

Introducción. La atrofia muscular espinal es una enfermedad neurodegenerativa huérfana de origen genético que afecta las neuronas motoras del asta anterior de la médula espinal, y produce atrofia y debilidad muscular. En Colombia, son pocos los estudios publicados sobre la enfermedad y no hay ninguno con análisis funcional. Objetivo. Caracterizar clínica y funcionalmente una serie de casos de atrofia muscular espinal del centro-occidente colombiano. Materiales y métodos. Se hizo un estudio descriptivo transversal, entre el 2007 y el 2020, de pacientes con diagnóstico clínico y molecular de atrofia muscular espinal que consultaron en el centro de atención. La evaluación funcional se realizó con las escalas Hammersmith y Chop Intend. En la sistematización de los datos, se empleó el programa Epi-Info, versión 7.0. Resultados. Se analizaron 14 pacientes: 8 mujeres y 6 hombres. La atrofia muscular espinal más prevalente fue la de tipo II, la cual se presentó en 10 casos. Se encontró variabilidad fenotípica en términos de funcionalidad en algunos pacientes con atrofia muscular espinal de tipo II, cinco de los cuales lograron alcanzar la marcha. La estimación de la supervivencia fue de 28,6 años. Conclusiones. Los hallazgos en el grupo de pacientes analizados evidenciaron que los puntajes de la escala de Hammersmith revisada y expandida, concordaron con la gravedad de la enfermedad.

Introduction: Spinal muscular atrophy is a rare genetic neurodegenerative disorder affecting the motor neurons of the anterior horn of the spinal cord, which results in muscle atrophy and weakness. In Colombia, few studies have been published on the pathology and none with functional analysis. Objective: To characterize clinically and functionally some cases of spinal muscular atrophy patients from Central-Western Colombia. Materials and methods: We conducted a cross-sectional descriptive study between 2007 and 2020 with patients clinically and molecularly diagnosed with spinal muscular atrophy who attended a care center. For the functional assessment we used the Hammersmith and Chop-Intend scales and the data were systematized with the Epi-Info, version 7.0 software. Results: We analyzed 14 patients (42.8 % men). The most prevalent spinal muscular atrophy was type II with 71.4 %. We found phenotypic variability in terms of functionality in some patients with type II spinal muscular atrophy, 37.5 % of whom reached gait. Survival was estimated at 28.6 years. Conclusions: The findings in the group of patients analyzed revealed that the scores of the revised and expanded Hammersmith scales correlated with the severity of SMA.

Farmacoterapia da atrofia muscular espinhal / Pharmacotherapy of spinal muscular atrophy

Realizar uma revisão bibliográfica sobre os medicamentos específicos empregados no tratamento da Atrofia Muscular Espinhal (AME), uma doença genética neurodegenerativa caracterizada por fraqueza nos membros e atrofia muscular. Revisão narrativa de literatura, realizada por meio de um estudo descritivo, com abordagem qualitativa, baseada em estudos por meio de uma seleção classificatória de pesquisas sobre a farmacoterapia da AME. Os fármacos aprovados para o tratamento da AME fazem parte do arsenal da terapia gênica: nusinersena, onasemnogeno abeparvoveque e risdiplam. Com exceção do onasemnogeno abeparvoveque, utilizado em dose única, os demais devem ser utilizados pelo resto da vida. Todos eles, de maneiras distintas, elevam os níveis da proteína SMN (sobrevivência do neurônio motor), cuja deficiência leva à morte dos neurônios motores, causando aos sintomas progressivos da AME. Estes medicamentos apresentam custo elevado e são pouco acessíveis, sendo que apenas o nusinersena é disponibilizado pelo SUS. No momento as alternativas de tratamento farmacológico são escassas e de difícil acesso e a cura, apesar dos esforços da ciência, ainda está distante da realidade. No entanto, a terapia gênica se mostra como um diferencial para o tratamento e controle da AME, representando uma inovação e esperança para os pacientes com esta doença

Recent research on the treatment of spinal muscular atrophy / 中国当代儿科杂志

Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disease characterized by progressive muscular weakness and atrophy. SMA, as an inherited disease, is the leading cause of death in infants and young children. Rapid progress has been made in the research field of SMA in recent years, and some related treatment drugs have been successfully approved for marketing. This article reviews the recent research advances in the treatment of SMA.

Expert consensus on preimplantation genetic testing for spinal muscular atrophy / 中华医学遗传学杂志

Spinal muscular atrophy (SMA) is an autosomal recessive motor neuron degenerative disease, which is the most common fatal neuromuscular disease in pediatrics with a high carrier frequency and can lead to progressive symmetrical muscle weakness and atrophy of the trunk and limbs. Preimplantation genetic testing (PGT) can be used to prevent the birth of children with SMA effectively. To standardize PGT technologies for SMA, experts from the fields of neurology, pediatrics and reproductive genetics have discussed and drafted this consensus for guiding its clinical application.

Adult-onset non-5q proximal spinal muscular atrophy: a comprehensive review / Atrofia muscular espinhal não-5q proximal de início no adulto: uma revisão abrangente

Abstract Background: Adult-onset spinal muscular atrophy (SMA) represents an expanding group of inherited neurodegenerative disorders in clinical practice. Objective: This review aims to synthesize the main clinical, genetic, radiological, biochemical, and neurophysiological aspects related to the classical and recently described forms of proximal SMA. Methods: The authors performed a non-systematic critical review summarizing adult-onset proximal SMA presentations. Results: Previously limited to cases of SMN1-related SMA type 4 (adult form), this group has now more than 15 different clinical conditions that have in common the symmetrical and progressive compromise of lower motor neurons starting in adulthood or elderly stage. New clinical and genetic subtypes of adult-onset proximal SMA have been recognized and are currently target of wide neuroradiological, pathological, and genetic studies. Conclusions: This new complex group of rare disorders typically present with lower motor neuron disease in association with other neurological or systemic signs of impairment, which are relatively specific and typical for each genetic subtype.

RESUMO Antecedentes: Atrofia muscular espinhal (AME) de início no adulto representa um grupo de doenças neurodegenerativas hereditárias em expansão na prática clínica. Objetivo: Este artigo de revisão sintetiza os principais aspectos clínicos, genéticos, radiológicos, bioquímicos e neurofisiológicos relacionados às formas clássicas e recentemente descritas de AME proximal do adulto. Métodos: Os autores realizaram uma revisão crítica não sistemática descrevendo as principais apresentações de AME proximal de início no adulto. Resultados: Previamente restrito às apresentações de AME tipo 4 associada ao gene SMN1, este grupo atualmente envolve mais de 15 diferentes condições clínicas que compartilham entre si a presença de comprometimento progressivo e simétrico do neurônio motor inferior se iniciando no adulto ou no idoso. Novos subtipos clínicos e genéticos de AME proximal de início no adulto foram reconhecidas e são alvos atuais de estudos direcionados a aspectos neurorradiológicos, patológicos e genéticos. Conclusões: Este novo grupo complexo de doenças raras tipicamente se apresenta com doença do neurônio motor inferior em associação com outros sinais de comprometimento neurológico ou sistêmico, os quais apresentam padrões relativamente específicos para cada subtipo genético.

Healthcare resource utilization of spinal muscular atrophy in the Brazilian Unified Health System: a retrospective database study / Utilização de Recursos em Saúde para pacientes de atrofia muscula espinhal (AME 5q) no Sistema de Saúde Público brasileiro: um estudo retrospectivo em base de dados

Objective: To describe the healthcare resource utilization (HCRU) related to patients with spinal muscular atrophy (SMA) treated at the Brazilian Unified Health System (SUS) since 2015 according to age-groups. Methods: This study analyzed outpatient and inpatient data for SMA patients from the Brazilian Unified Health System database (DATASUS) from January 2015 to September 2020. Data were collected from patients with ICD-10 codes G12.0 (Infantile spinal muscular atrophy, type I [Werdnig-Hoffman]) or G12.1 (Other inherited spinal muscular atrophy), plus with at least one claim of nusinersen OR at least one claim of any SMA-related procedure groups codes since 2010. SMA-related procedures were defined based on collaborative work involving authors from medical boarding composed by physicians from SUS. Results: In total, 3,775 patients with SMA fulfilled the eligibility criteria. Physiotherapy changed from 11.34 (2.49 ­ 24.40) procedures PPPY in the 0 - 6-month old group to 3.30 (0.84 ­ 11.76) procedures PPPY in the > 36-month old group. The median of orthosis was 1.64 (0.66 ­ 3.41) procedures PPPY in the 0 ­ 6-month old group and 0.63 (0.34 ­ 1.33) PPPY in the > 36-month-old group. Exams were primarily performed for younger groups (0 ­ 6 months and > 6 ­ 18 months). The percentage of patients that needed some ventilatory care seems greater, and the speech therapy and the use of nusinersen seem lower along with age. Conclusion: This study has demonstrated important HCRU at the SUS setting with SMA patients. In addition, our results highlight the need to implement evidence-based strategies to manage SMA patients and drive cost savings for the health care system.

Objetivo: Descrever a utilização de recursos em saúde de pacientes com atrofia muscular espinhal (AME) no Sistema Público de Saúde Brasileiro (SUS) desde 2015, de acordo com a faixa etária. Métodos: Analisaram-se os dados hospitalares e ambulatoriais de pacientes com AME no DATASUS de janeiro de 2015 a setembro de 2020. Foram incluídos pacientes com código de CID-10 G12.0 (atrofia muscular espinhal infantil tipo I ­ Werdning-Hoffman) ou G12.1 (outras atrofias medulares espinhais hereditárias) com pelo menos um registro utilizando o código de nusinersena ou o código de procedimento relacionado à doença desde 2010. Os procedimentos relacionados à doença foram definidos por meio de trabalho colaborativo entre autores, incluindo três autores médicos que atuam no SUS. Resultados: No total, 3.775 pacientes com AME preencheram os critérios de elegibilidade. Procedimentos de fisioterapia passaram de 11,34 (2,49 ­ 24,40) por paciente por ano (PPPY) no grupo 0 ­ 6 meses para 3,30 (0,84 ­ 11,76) PPPY no grupo > 36 meses. A mediada de procedimentos de órteses foi de 1,64 (0,66 ­ 3,41) PPPY no grupo 0 ­ 6 meses para 0,63 (0,34­ 1,33) PPPY no grupo > 36 meses. Exames foram realizados principalmente por pacientes mais jovens (0 ­ 6 meses e > 6 ­ 18 meses). A porcentagem de pacientes que realizaram procedimentos ventilatórios parece aumentar ao longo da idade, já a fonoterapia e o uso de nusinersena parecem reduzir. Conclusão: Este estudo demonstra uma importante utilização de recursos em saúde no SUS pelos pacientes com AME e destaca a necessidade de implementação de estratégias baseadas em evidência para gerenciar esses pacientes e o uso de recursos no sistema de saúde