Spinal muscular atrophy is a devastating motor neuron disease characterized by severe cases of fatal muscle weakness.It is one of the most common genetic causes of mortality among infants aged less than 2 years.Biomar...Spinal muscular atrophy is a devastating motor neuron disease characterized by severe cases of fatal muscle weakness.It is one of the most common genetic causes of mortality among infants aged less than 2 years.Biomarker research is currently receiving more attention,and new candidate biomarkers are constantly being discovered.This review initially discusses the evaluation methods commonly used in clinical practice while briefly outlining their respective pros and cons.We also describe recent advancements in research and the clinical significance of molecular biomarkers for spinal muscular atrophy,which are classified as either specific or non-specific biomarkers.This review provides new insights into the pathogenesis of spinal muscular atrophy,the mechanism of biomarkers in response to drug-modified therapies,the selection of biomarker candidates,and would promote the development of future research.Furthermore,the successful utilization of biomarkers may facilitate the implementation of gene-targeting treatments for patients with spinal muscular atrophy.展开更多
Spinal and bulbar muscular atrophy is a neurodegenerative disease caused by extended CAG trinucleotide repeats in the androgen receptor gene,which encodes a ligand-dependent transcription facto r.The mutant androgen r...Spinal and bulbar muscular atrophy is a neurodegenerative disease caused by extended CAG trinucleotide repeats in the androgen receptor gene,which encodes a ligand-dependent transcription facto r.The mutant androgen receptor protein,characterized by polyglutamine expansion,is prone to misfolding and forms aggregates in both the nucleus and cytoplasm in the brain in spinal and bulbar muscular atrophy patients.These aggregates alter protein-protein interactions and compromise transcriptional activity.In this study,we reported that in both cultured N2a cells and mouse brain,mutant androgen receptor with polyglutamine expansion causes reduced expression of mesencephalic astrocyte-de rived neurotrophic factor.Overexpressio n of mesencephalic astrocyte-derived neurotrophic factor amelio rated the neurotoxicity of mutant androgen receptor through the inhibition of mutant androgen receptor aggregation.Conversely.knocking down endogenous mesencephalic astrocyte-derived neurotrophic factor in the mouse brain exacerbated neuronal damage and mutant androgen receptor aggregation.Our findings suggest that inhibition of mesencephalic astrocyte-derived neurotrophic factor expression by mutant androgen receptor is a potential mechanism underlying neurodegeneration in spinal and bulbar muscular atrophy.展开更多
Introduction: Infantile spinal muscular atrophy (ISA) is an autosomal recessive disease caused by primary degeneration of cells in the anterior horn of the spinal cord, leading to muscle weakness and hypotonia. Its in...Introduction: Infantile spinal muscular atrophy (ISA) is an autosomal recessive disease caused by primary degeneration of cells in the anterior horn of the spinal cord, leading to muscle weakness and hypotonia. Its incidence is estimated at 1 in 6000 births worldwide. In Africa, particularly in Senegal, there are few studies interested on this pathology. We therefore deemed this study necessary, which set itself the objective of describing the diagnostic, therapeutic and progressive aspects of infantile spinal muscular atrophy at the Albert Royer National Children’s Hospital Center in Dakar (CHNEAR). Methodology: We conducted a retrospective descriptive study over a period of two (2) years from December 2020 to December 2022. Included were all hospitalized patients in whom the diagnosis of spinal muscular atrophy was made with or without genetic confirmation. The data were collected on a pre-established form then entered and analyzed with the following software: Excel 2013 and R version 4.1.3. Results: During our study period, 2100 children were hospitalized, the annual incidence was 0.76%. The average age of our patients was 9 ± 9 months with a range of 3 months to 32 months and the median was 6.5 months. The sex ratio was 7. The notion of family consanguinity was found in 62.5% of cases and the notion of ISA in the family in 25% of cases. Hypotonia and respiratory distress were found at the forefront in equal proportions (50% of cases). Electromyogram (EMG) was performed in 3 patients (37.5%). Symptomatic medical treatment was administered in 100% of patients, 04 patients had benefited from respiratory physiotherapy, i.e. 50% of cases, and genetic counseling was carried out in one patient (12.5%). The evolution was immediately favorable in 2 patients or 25% of cases, unfavorable in 75% of cases with a death rate of 50% and the average age of death was 5.5 months ± 1 with extremes ranging from 3 to 7 months. Conclusion: The number of Infantile spinal muscular atrophy cases remains low in hospitals in Dakar. Diagnostic means are still difficult to access. The course is difficult to predict and is often marked in the long term by respiratory difficulties which can be fatal.展开更多
In this case report, we describe the anesthetic management for a 36-year-old G2P0010 at 36 weeks gestation with Spinal Muscular Atrophy Type III who underwent an emergent caesarean section due to fetal footling breech...In this case report, we describe the anesthetic management for a 36-year-old G2P0010 at 36 weeks gestation with Spinal Muscular Atrophy Type III who underwent an emergent caesarean section due to fetal footling breech position. The patient is a wheelchair-bound quadriplegic with kyphoscoliosis and a lack of cough reflex who required nasal continuous noninvasive ventilatory support (CNVS) for chronic hypercapnic respiratory failure. Surgery was done under general anesthesia due to its emergent nature, and the patient was successfully extubated and transitioned to nasal CNVS in the operating room at the end of the case. Postoperative care was provided in the medical intensive care unit for three days without complication and the patient was discharged home uneventfully.展开更多
Spinal muscular atrophy(SMA)is a genetic disorder that primarily affects infants and leads to muscle weakness,atrophy,and paralysis.The main cause is the homozygous mutation or deletion of the SMN1 gene,resulting in i...Spinal muscular atrophy(SMA)is a genetic disorder that primarily affects infants and leads to muscle weakness,atrophy,and paralysis.The main cause is the homozygous mutation or deletion of the SMN1 gene,resulting in inadequate levels of the survival motor neuron(SMN)protein.Approved treatments focus on restoring SMN levels through various approaches,but there is a need for“SMN-independent”therapies that target other pathological processes.Skeletal muscle is closely involved in SMA pathology,with impaired muscle function observed before motor neuron degeneration.Studies have revealed that SMN loss leads to skeletal muscle mitochondrial structural abnormalities,impaired respiration,and accumulation of reactive oxygen species.展开更多
Objective To understand the deletion in the survival motor neuron gene (SMN) of childhood onset spinal muscular atrophy (SMA) in Chinese, and the value of diagnosis of SMA using polymerase chain reaction restric...Objective To understand the deletion in the survival motor neuron gene (SMN) of childhood onset spinal muscular atrophy (SMA) in Chinese, and the value of diagnosis of SMA using polymerase chain reaction restriction fragment length polymorphism (PCR RFLP)method. Methods\ Deletions of SMN gene of exon 7 and 8 in 10 cases of presumed SMA, and 20 normal controls from 6 families and 30 unrelated controls were performed by PCR RFLP analysis. Results\ Deletions of SMN gene detected in 9 of 10 (90%) cases of presumed SMA . No deletions of SMN in the telomere were found in the other members of families and controls.Conclusion\ PCR RFLP is a sensitive, specific and simple method in diagnosis of SMA.\;展开更多
Spinal muscular atrophy（SMA）is a hereditary pediatric motor neuron（MN）disease：survival motor neuron 1（SMN1）gene mutation determines MN degeneration and,consequently,muscle atrophy,breathing and swallowing diffi...Spinal muscular atrophy（SMA）is a hereditary pediatric motor neuron（MN）disease：survival motor neuron 1（SMN1）gene mutation determines MN degeneration and,consequently,muscle atrophy,breathing and swallowing difficulties,and,in the most severe cases,premature death.A second unaffected gene（SMN2）is present,but it can only produce a limited amount of functional protein,modulating the disease severity and progression.展开更多
Infantile-onset spinal muscular atrophy is the quintessential example of a disorder characterized by a predominantly neurodegenerative phenotype that nevertheless stems from perturbations in a housekeeping protein.Res...Infantile-onset spinal muscular atrophy is the quintessential example of a disorder characterized by a predominantly neurodegenerative phenotype that nevertheless stems from perturbations in a housekeeping protein.Resulting from low levels of the Survival of Motor Neuron(SMN)protein,spinal muscular atrophy manifests mainly as a lower motor neuron disease.Why this is so and whether other cell types contribute to the classic spinal muscular atrophy phenotype continue to be the subject of intense investigation and are only now gaining appreciation.Yet,what is emerging is sometimes as puzzling as it is instructive,arguing for a careful re-examination of recent study outcomes,raising questions about established dogma in the field and making the case for a greater focus on milder spinal muscular atrophy models as tools to identify key mechanisms driving selective neuromuscular dysfunction in the disease.This review examines the evidence for novel molecular and cellular mechanisms that have recently been implicated in spinal muscular atrophy,highlights breakthroughs,points out caveats and poses questions that ought to serve as the basis of new investigations to better understand and treat this and other more common neurodegenerative disorders.展开更多
Spinal muscular atrophy （SMA） is an autosomal recessive neuromuscular disorder characterized by degeneration and loss of anterior horn cells in the spinal cord and brain stem nuclei, leading to progressive limb and ...Spinal muscular atrophy （SMA） is an autosomal recessive neuromuscular disorder characterized by degeneration and loss of anterior horn cells in the spinal cord and brain stem nuclei, leading to progressive limb and trunk paralysis and muscular atrophy. Depending on the age of onset and maximum muscular function achieved, SMA is recognized as SMA1, SMA2, SMA3 or SMA4, and most patients have a deletion or truncation of the survival motor neuron 1 （SMN1） gene. In this report, we present a patient with a mild SMA phenotype, SMA3, and define his genetic abnormality. Tetra-primer amplification refractory mutation system PCR combined with restriction fragment length polymorphism analysis and array comparative genomic hybridization were used to determine the genetic variations in this patient. A 500 kb deletion in chromosome 5q13.2, including homozygous deletion of neuronal apoptosis inhibitory protein, and heterozygous deletion of occludin and B-double prime 1 was identified. This SMA region deletion did not involve SMN, indicating that SMN was likely to function normally. The phenotype was dependent of the large deletion and neuronal apoptosis inhibitory protein, occludin and B-double prime 1 may be candidate genes for SMA3.展开更多
BACKGROUND： Spinal muscular atrophy （SMA） is a kind of degenerative disease of nervous system. There are 4 types in clinic, especially types Ⅰ, Ⅱ and Ⅲ are common, and the researches on those 3 types are relativ...BACKGROUND： Spinal muscular atrophy （SMA） is a kind of degenerative disease of nervous system. There are 4 types in clinic, especially types Ⅰ, Ⅱ and Ⅲ are common, and the researches on those 3 types are relative mature. Type IV is a kind of adult spinal muscular atrophy （ASMA）, which has low incidence rate and is often misdiagnosed as amyotrophic lateral sclerosis, muscular dystrophy, cervical syndrome, or others.OBJEETIVE： To observe the clinical features of 46 ASMA patients and analyze the relationship between course and activity of daily living. DESIGN ： Case analysis.SETTING： Departments of Neurology of the 81 Hospital of Chinese PLA, the Second Affiliated Hospital of Nanjing Medical College and General Hospital of Nanjing Military Area Command of Chinese PLA.PARTICIPANTS ： A total of 46 ASMA patients were selected from the Departments of Neurology of the 81 Hospital of Chinese PLA, the Second Affiliated Hospital of Nanjing Medical College and General Hospital of Nanjing Military Area Command of Chinese PLA between April 1998 and January 2002. All patients were consentient. Among 46 cases, there were 37 males and 9 females with the mean age of 42 years. The patients＇ courses in all ranged from 6 months to 23 years, concretely, courses of 37 cases were less than or equal to 5 years, and those of 9 cases were more than or equal to 6 years.METHODS： ① All the 46 ASMA patients were asked to check blood sedimentation, anti O, serum creatinine, creatine, blood creatine phosphokinase （CPK） and muscular biopsy as early as possible. ②X-ray was used to measure plain film of cervical vertebra borderline film of cranium and neck at proximal end of upper limb of 25 cases and plain film of abdominal vertebra at proximal end of lower limb of 17 cases. ③ Cerebrospinal fluid of lumbar puncture was checked on 42 cases, for routine examination, biochemical examination, and immunoglobulin examination. Electromyogram （EMG） was also examined to 42 cases. ④ Barthel index was used to evaluate activities of daily living （ADL） of patients with various courses. The index ranged from 1 to 100. The more the index of a ASMA was, the stronger his independence was. ⑤ The Barthel indexes of patients with courses ≤ 5 years and those ≥ 6 years were compared with univariate analysis of variance. MAIN OUTCOME MEASURES： ① Incidences of all patients at the first time; ② values of relative blood and blood biochemistry; ③results of muscular biopsy; ④ results of EMG and relative X-ray plain film of 42 cases; ⑤ results of cerebrospinal fluid of 42 cases; ⑥ comparisons of Barthel index of patients with various courses.RESULTS： A total of 46 ASMA patients were involved in the final analysis. ① Incidence on the first time： 25 patients had the disease at the proximal end of upper limb, 17 at the proximal end of lower limb, and 4 at the four limbs. ② Value of serum-blood CPK of one fourth patients was increased slightly （3.034-9.735 μkat/L; normal value： 0.400-3.001 μkat/L）, and other values of blood and blood biochemical indicator were normal. ③Results of muscle biopsy of all patients showed that a small group of muscular atrophy could be observed mostly, and muscle group in the same type and compensatory hypertrophy of muscle fibres were also observed with ATP enzyme staining. ④ Results of EMG of 42 cases suggested that 37 patients had mild and moderate nerve-derived injury and 3 had mild muscle-derived injury. Results of all the X-ray plain films in this study were normal. ⑤ Results of routine, biochemical and immunoglobulin examination in cerebrospinal fluid of lumbar puncture in 42 cases were all normal. ⑥The difference between Barthel indexes of patients with courses ≤ 5 years and those ≥ 6 years was not significant [（64.73±20.38） vs （68.89±21.76） points, P〉 0.05]. CONCLUSION ： ① Amyasthenia is mainly occurred at the proximal end of the four limbs of ASMA patients. A small group of muscular atrophy is its mostly pathological change, and the progression of the disease is slow. ② Most patients have mild and moderate nerve-derived injury under EMG examination.③ The duration of a patient suffered from the disease has no obvious effect on his ADL ability.展开更多
BACKGROUND In Behçet’s disease(BD),very few cases of muscular involvement have been reported previously.The natural history and therapeutic protocol for muscular involvement in BD are obscure due to the low inci...BACKGROUND In Behçet’s disease(BD),very few cases of muscular involvement have been reported previously.The natural history and therapeutic protocol for muscular involvement in BD are obscure due to the low incidence of peripheral neuropathy or myopathy in BD.The purpose of our study was to report a rare case of BD with chronic,focal forms of neuromyopathy and review the relevant literature.CASE SUMMARY We herein report the case of a 54-year-old man who presented with progressive muscular atrophy and weakness of both thighs 2 years after the presentation of the cardinal symptoms of BD.The past medical history,electrophysiological study,neurological examination,blood tests,magnetic resonance imaging study,and histological exam were performed for the differential diagnosis.Relevant literature on muscular involvement in BD was reviewed.Neurological examination revealed that muscular involvement was predominantly localized in the proximal parts of the lower extremities.Heterogeneous enhancement of several thigh muscles was observed on magnetic resonance imaging,which corresponded with the clinical manifestations.Histological study of one of the enhanced muscles showed denervation atrophy of the muscle with superimposed myopathic changes,while electrophysiological studies only suggested denervation.CONCLUSION To our knowledge,this is the first case of neurogenic muscular atrophy with a specific set of clinical,radiological,electrophysiological,and histological findings reported in BD.展开更多
BACKGROUND: Peroneal muscular atrophy (PMA) is characterized by insidious onset, gradually progressive course of disease, very mild disability degree and easily subjecting to missed diagnosis and misdiagnosis. Nerve c...BACKGROUND: Peroneal muscular atrophy (PMA) is characterized by insidious onset, gradually progressive course of disease, very mild disability degree and easily subjecting to missed diagnosis and misdiagnosis. Nerve conductive velocity is helpful in the diagnosis of atypical cases. OBJECTIVE: To retrospectively analyze the characteristics of clinical manifestation, electromyogram (EMG), motor and sensory nerve conduction velocity of patients with PMA. DESIGN: Retrospective case analysis. SETTING: Department of Neurology, Guangzhou First People's Hospital. PARTICIPANTS: Twenty-four patients with PMA, including 16 males and 8 females, aged 5-68 years old, admitted to Guangzhou First People's Hospital between March 1996 and January 2006 were recruited. Informed consents were obtained from all the patients. METHODS: All the patients subjected to EMG and detection of nerve conduction velocity at distal end of four extremities with a Keypoint evoked potential/ EMG instrument (Denmark). Sensory and motor conduction velocity, EMG changes of upper and lower extremities were observed, and relationship of neuroelectrophysiological characteristics and clinical symptoms was analyzed. MAIN OUTCOME MEASURES: Changes in sensory and motor conduction velocity, EMG and clinical manifestations of 24 patients. RESULTS: ① All the patients suffered from insidious onset and gradually progressive course of PMA. Muscular atrophy of lower extremity was found in 14 patients, and that of upper extremity in 5 patients. ②Routine nerve conduction study showed that sensory and motor conduction velocity were stepped down, especially in 16 patients with typeⅠPMA (demyelinating pattern, nerve conduction velocity below normal level 50%). Motor nerve conduction velocity of median nerve, ulnar nerve, common peroneal nerve and tibial nerve averaged 34.8 m/s, 37.2 m/s, 16.5 m/s and 17.4 m/s, respectively; Sensory nerve conduction velocity of median nerve, ulnar nerve and sural nerve averaged 27.9%, 24.6 m/s and 3.1 m/s, respectively. Slowing conduction velocity and muscular strength involvement were disproportionate, i.e. myasthenia was relatively lessened, sensory and motor conduction velocities were greatly decreased. Nerve conduction velocity in distal end of two lower extremities was not detected in 8 patients, but who could still walk. CONCLUSION: ①PMA of patients is characterized by insidious onset and gradually progressive course of disease. Clinical symptom is the base to diagnose PMA. ②Neuroelectrophysiological study is a simple and easy-to-operate means with good reproducibility in diagnosing PMA. Patients with abnormal myasthenia in lower extremity can be detected in the early stage.展开更多
Spinal muscular atrophy is an autosomal recessive neuromuscular disease with incidence of 1 in 5000 to 10000 live births and is produced by homozygous deletion of exons 7 and 8 in the SMN1 gene.The SMN1 and SMN2 genes...Spinal muscular atrophy is an autosomal recessive neuromuscular disease with incidence of 1 in 5000 to 10000 live births and is produced by homozygous deletion of exons 7 and 8 in the SMN1 gene.The SMN1 and SMN2 genes encode the survival motor neuron protein,a crucial protein for the preservation of motor neurons.Use of the newer drug,Nusinersen,from early infancy has shown improvement in clinical outcomes of spinal muscular atrophy patients.展开更多
Objective To investigate the clinical features and magnetic resonance imaging (MRI) findings of patients with Hirayama disease simply presenting proximal upper extremity muscular atrophy. Methods Three patients with H...Objective To investigate the clinical features and magnetic resonance imaging (MRI) findings of patients with Hirayama disease simply presenting proximal upper extremity muscular atrophy. Methods Three patients with Hirayama disease simply展开更多
Purpose: To compare the accuracy of a commercially available MLPA kit with a laboratory developed RT-PCR assay for the detection of SMN1 and SMN2 copy numbers in clinical samples. Methods: We developed and validated a...Purpose: To compare the accuracy of a commercially available MLPA kit with a laboratory developed RT-PCR assay for the detection of SMN1 and SMN2 copy numbers in clinical samples. Methods: We developed and validated a laboratory developed real time PCR based test capable of detecting SMN1 and SMN2 copy numbers in individuals. We also validated an MLPA kit purchased from MRC Holland for the same purpose. We then analyzed a series of 1027 anonymized samples using both technologies. When discrepant results were obtained, each sample was re-analyzed at least twice using both platforms. Results: Five samples did not yield results in either assay. For SMN1 copy number analysis, 2 RT-PCR assays revealed indeterminant results and all 1020 other samples were concordant for SMN1 copy number. There were 9 discrepancies in SMN2 copy number determination mostly due to a variability in MLPA analysis. Conclusion: Both MLPA and RTPCR assays give a reliable estimate of SMN1 copy number and are therefore appropriate for population based carrier screening for Spinal Muscular Atrophy Type 1. The MLPA kit has a low incidence (<1%) of underestimating the SMN2 copy number by 1 copy, but this inconsistency is of little clinical significance and can be overcome by replicate testing.展开更多
Spinal muscular atrophy (SMA) is devastating genetic disease characterized by progressive loss of motor neuron and skeletal muscle weakness. SMA is the most common lethal genetic disease in infancy. SMA is caused by d...Spinal muscular atrophy (SMA) is devastating genetic disease characterized by progressive loss of motor neuron and skeletal muscle weakness. SMA is the most common lethal genetic disease in infancy. SMA is caused by deletion or mutation of SMN1 gene and subsequent lack of SMN protein. Our purpose in this study was to evaluate the therapeutic potential of rufinamide, an antiepileptic drug. In this study, SMA patient-derived fibroblasts and differentiated spinal motor neurons (MNs) using SMA patient-derived iPSCs were used as in vitro SMA model. SMN mRNA was significantly increased by addition of rufinamide in type III SMA patient-derived fibroblasts. Furthermore, rufinamide stimulated neurite elongation in type III SMA patient derived-iPSCs-MNs. In contrast of the result using type III SMA patient-derived fibroblasts, the expression level of SMN mRNA was not changed after rufinamide treatment in type I SMA patient-derived fibroblasts, and rufinamide did not affect neurite outgrowth in type I SMA patients derived-iPSCs-MNs. These findings indicate that rufinamide may be one of the potential candidate drugs for mild type of SMA.展开更多
To the Editor:5q spinal muscular atrophy(5qSMA)is an autosomal recessive neuromuscular disorder caused by the lack of the survival motor neuron(SMN)protein encoded by the SMN1 gene,located at 5q11.2-q13.3.[1]The incid...To the Editor:5q spinal muscular atrophy(5qSMA)is an autosomal recessive neuromuscular disorder caused by the lack of the survival motor neuron(SMN)protein encoded by the SMN1 gene,located at 5q11.2-q13.3.[1]The incidence is 1/10,000-1/6000 live births,and the mutation carrier rate in China is 1/42.[1]Spinal muscular atrophy(SMA)is mainly divided into four subtypes:SMA type I,II,III,and IV,based on the motor milestones ever achieved.Types I-III occur in children,[1]which often result in progressive muscular atrophy and weakness as well as multi-system dysfunction,including nutritional and metabolic issues.[2]Children with SMA may have hidden nutritional and lipid imbalances,despite normal body appearance and anthropometric measurements,making it difcult to detect early and intervene.展开更多
Background This study investigated the efficacy and safety of nusinersen,an antisense oligonucleotide,in patients with spinal muscular atrophy(SMA)types II(OMIM:253,550)or III(OMIM:253,400),including those with severe...Background This study investigated the efficacy and safety of nusinersen,an antisense oligonucleotide,in patients with spinal muscular atrophy(SMA)types II(OMIM:253,550)or III(OMIM:253,400),including those with severe scoliosis or requiring respiratory support via mechanical ventilation.Methods Data from 40 patients with genetically confirmed SMA who were treated with nusinersen at our institute from March 2019 to April 2022 were retrospectively analyzed.Of these,30 patients with an age of onset<3 years and not on permanent ventilation were selected.Clinical and genetic characteristics were investigated,and motor function was evaluated based on the Hammersmith Functional Motor Scale-Expanded(HFMSE)score.Results The mean age of symptom onset was 1.2 years.Most patients were diagnosed with SMA type II(27/30,90%).Nusinersen was administered via computed tomography-guided or direct intrathecal injection in 87%(26/30)and 13%(4/30)of the patients,respectively.At the 6-,14-,22-,and 26-month follow-ups,72%,71%,88%,and 86%of patients showed motor improvement,respectively,with mean changes in HFMSE scores of 2.10,2.88,4.21,and 5.29,respectively.Multivariable analysis showed that the use of noninvasive ventilation was associated with poorer outcomes of motor function.Conclusions Patients with SMA type II or III who received nusinersen treatment showed significant improvement in motor function.A longer treatment duration led to a higher number of patients with improved motor function.No significant side effects of nusinersen were observed.Patients with SMA,even those with severe scoliosis or on respiratory support,can be safely treated using nusinersen.展开更多
In a new Science publication,Arbab and colleagues observe a substantial improvement in life span and motor functions of adenosine-base edited spinal muscular atrophy(SMA)mice with restored endogenous survival motor ne...In a new Science publication,Arbab and colleagues observe a substantial improvement in life span and motor functions of adenosine-base edited spinal muscular atrophy(SMA)mice with restored endogenous survival motor neuron(SMN)protein expression and regulation.1 This study provides proof-of-principle for the use of adenosine base editing(ABE)as a possible one-time,permanent therapy for SMA.展开更多
Background Infantile proximal spinal muscular atrophy （SMA） is a common autosomal recessive neuromuscular disorder. Approximately 90-95% cases of SMA result from homozygous deletion of survival motor neuron gene 1（...Background Infantile proximal spinal muscular atrophy （SMA） is a common autosomal recessive neuromuscular disorder. Approximately 90-95% cases of SMA result from homozygous deletion of survival motor neuron gene 1（SMN1） and 5% cases are caused by compound heterozygous mutation （a SMN1 deletion on one allele and a subtle mutation on the other allele）.Methods In this research, two unrelated patients were clinically diagnosed according to the criteria of proximal SMA. Genetic diagnosis was performed to detect the homozygous deletion of exon 7 of SMN1 by PCR-restriction fragment length polymorphism （RFLP） and genomic sequencing. Multiplex ligation-dependent probe amplification （MLPA） analysis was carried out to measure copy numbers of SMN1, SMN2 and neuronal apoptosis inhibitor protein （NAIP） in the patients. Further sequencing of SMN1allele-specific PCR （AS-PCR） and SMN1 clones were also performed to analyze the point mutation of SMN1 gene. Additionally,the pedigree analysis of these two families was carried out to identify the transmission of the mutation.Results The inconsistent results using PCR-RFLP and genomic sequencing showed homozygous deletion of exon 7 of SMN1 and heterozygous deletion accompanied with a suspicious mutation in SMN1 gene, respectively. MLPA analysis of these two cases exhibited one SMN1 copy deletion. One identical c.863G〉T （p. Arg288Met） mutation was found in two cases by sequencing the SMN1 clones, which confirmed that both cases were SMA compound heterozygotes. One case showed partial conversion to form hybrid SMN （SMN2 17/SMN1 E8） identified by clones sequencing and another case carrying 3 SMN2 implied complete conversion from SMN1 to SMN2.Conclusion p. Arg288Met is more a disease-causing mutation than a polymorphism variation, and children with this mutation may have more severe phenotypes.展开更多
基金supported by the Collaborative Innovation Center for Clinical and Translational Science by Chinese Ministry of Education&Shanghai,No.CCTS-2022205the“Double World-Class Project”of Shanghai Jiaotong University School of Medicine(both to JZ)。
文摘Spinal muscular atrophy is a devastating motor neuron disease characterized by severe cases of fatal muscle weakness.It is one of the most common genetic causes of mortality among infants aged less than 2 years.Biomarker research is currently receiving more attention,and new candidate biomarkers are constantly being discovered.This review initially discusses the evaluation methods commonly used in clinical practice while briefly outlining their respective pros and cons.We also describe recent advancements in research and the clinical significance of molecular biomarkers for spinal muscular atrophy,which are classified as either specific or non-specific biomarkers.This review provides new insights into the pathogenesis of spinal muscular atrophy,the mechanism of biomarkers in response to drug-modified therapies,the selection of biomarker candidates,and would promote the development of future research.Furthermore,the successful utilization of biomarkers may facilitate the implementation of gene-targeting treatments for patients with spinal muscular atrophy.
基金supported by the National Key R&D Program of China,No.2021YFA0805200(to SY)the National Natural Science Foundation of China,No.31970954(to SY)two grants from the Department of Science and Technology of Guangdong Province,Nos.2021ZT09Y007,2020B121201006(both to XJL)。
文摘Spinal and bulbar muscular atrophy is a neurodegenerative disease caused by extended CAG trinucleotide repeats in the androgen receptor gene,which encodes a ligand-dependent transcription facto r.The mutant androgen receptor protein,characterized by polyglutamine expansion,is prone to misfolding and forms aggregates in both the nucleus and cytoplasm in the brain in spinal and bulbar muscular atrophy patients.These aggregates alter protein-protein interactions and compromise transcriptional activity.In this study,we reported that in both cultured N2a cells and mouse brain,mutant androgen receptor with polyglutamine expansion causes reduced expression of mesencephalic astrocyte-de rived neurotrophic factor.Overexpressio n of mesencephalic astrocyte-derived neurotrophic factor amelio rated the neurotoxicity of mutant androgen receptor through the inhibition of mutant androgen receptor aggregation.Conversely.knocking down endogenous mesencephalic astrocyte-derived neurotrophic factor in the mouse brain exacerbated neuronal damage and mutant androgen receptor aggregation.Our findings suggest that inhibition of mesencephalic astrocyte-derived neurotrophic factor expression by mutant androgen receptor is a potential mechanism underlying neurodegeneration in spinal and bulbar muscular atrophy.
文摘Introduction: Infantile spinal muscular atrophy (ISA) is an autosomal recessive disease caused by primary degeneration of cells in the anterior horn of the spinal cord, leading to muscle weakness and hypotonia. Its incidence is estimated at 1 in 6000 births worldwide. In Africa, particularly in Senegal, there are few studies interested on this pathology. We therefore deemed this study necessary, which set itself the objective of describing the diagnostic, therapeutic and progressive aspects of infantile spinal muscular atrophy at the Albert Royer National Children’s Hospital Center in Dakar (CHNEAR). Methodology: We conducted a retrospective descriptive study over a period of two (2) years from December 2020 to December 2022. Included were all hospitalized patients in whom the diagnosis of spinal muscular atrophy was made with or without genetic confirmation. The data were collected on a pre-established form then entered and analyzed with the following software: Excel 2013 and R version 4.1.3. Results: During our study period, 2100 children were hospitalized, the annual incidence was 0.76%. The average age of our patients was 9 ± 9 months with a range of 3 months to 32 months and the median was 6.5 months. The sex ratio was 7. The notion of family consanguinity was found in 62.5% of cases and the notion of ISA in the family in 25% of cases. Hypotonia and respiratory distress were found at the forefront in equal proportions (50% of cases). Electromyogram (EMG) was performed in 3 patients (37.5%). Symptomatic medical treatment was administered in 100% of patients, 04 patients had benefited from respiratory physiotherapy, i.e. 50% of cases, and genetic counseling was carried out in one patient (12.5%). The evolution was immediately favorable in 2 patients or 25% of cases, unfavorable in 75% of cases with a death rate of 50% and the average age of death was 5.5 months ± 1 with extremes ranging from 3 to 7 months. Conclusion: The number of Infantile spinal muscular atrophy cases remains low in hospitals in Dakar. Diagnostic means are still difficult to access. The course is difficult to predict and is often marked in the long term by respiratory difficulties which can be fatal.
文摘In this case report, we describe the anesthetic management for a 36-year-old G2P0010 at 36 weeks gestation with Spinal Muscular Atrophy Type III who underwent an emergent caesarean section due to fetal footling breech position. The patient is a wheelchair-bound quadriplegic with kyphoscoliosis and a lack of cough reflex who required nasal continuous noninvasive ventilatory support (CNVS) for chronic hypercapnic respiratory failure. Surgery was done under general anesthesia due to its emergent nature, and the patient was successfully extubated and transitioned to nasal CNVS in the operating room at the end of the case. Postoperative care was provided in the medical intensive care unit for three days without complication and the patient was discharged home uneventfully.
基金supported by AFM-Telethon2013/Project 16662(to CB).
文摘Spinal muscular atrophy(SMA)is a genetic disorder that primarily affects infants and leads to muscle weakness,atrophy,and paralysis.The main cause is the homozygous mutation or deletion of the SMN1 gene,resulting in inadequate levels of the survival motor neuron(SMN)protein.Approved treatments focus on restoring SMN levels through various approaches,but there is a need for“SMN-independent”therapies that target other pathological processes.Skeletal muscle is closely involved in SMA pathology,with impaired muscle function observed before motor neuron degeneration.Studies have revealed that SMN loss leads to skeletal muscle mitochondrial structural abnormalities,impaired respiration,and accumulation of reactive oxygen species.
文摘Objective To understand the deletion in the survival motor neuron gene (SMN) of childhood onset spinal muscular atrophy (SMA) in Chinese, and the value of diagnosis of SMA using polymerase chain reaction restriction fragment length polymorphism (PCR RFLP)method. Methods\ Deletions of SMN gene of exon 7 and 8 in 10 cases of presumed SMA, and 20 normal controls from 6 families and 30 unrelated controls were performed by PCR RFLP analysis. Results\ Deletions of SMN gene detected in 9 of 10 (90%) cases of presumed SMA . No deletions of SMN in the telomere were found in the other members of families and controls.Conclusion\ PCR RFLP is a sensitive, specific and simple method in diagnosis of SMA.\;
文摘Spinal muscular atrophy（SMA）is a hereditary pediatric motor neuron（MN）disease：survival motor neuron 1（SMN1）gene mutation determines MN degeneration and,consequently,muscle atrophy,breathing and swallowing difficulties,and,in the most severe cases,premature death.A second unaffected gene（SMN2）is present,but it can only produce a limited amount of functional protein,modulating the disease severity and progression.
基金Research on SMA in the Monani lab is funded by NIH(R21 NS099921,R01 NS104218)Cure SMA and Roche Inc(to URM).
文摘Infantile-onset spinal muscular atrophy is the quintessential example of a disorder characterized by a predominantly neurodegenerative phenotype that nevertheless stems from perturbations in a housekeeping protein.Resulting from low levels of the Survival of Motor Neuron(SMN)protein,spinal muscular atrophy manifests mainly as a lower motor neuron disease.Why this is so and whether other cell types contribute to the classic spinal muscular atrophy phenotype continue to be the subject of intense investigation and are only now gaining appreciation.Yet,what is emerging is sometimes as puzzling as it is instructive,arguing for a careful re-examination of recent study outcomes,raising questions about established dogma in the field and making the case for a greater focus on milder spinal muscular atrophy models as tools to identify key mechanisms driving selective neuromuscular dysfunction in the disease.This review examines the evidence for novel molecular and cellular mechanisms that have recently been implicated in spinal muscular atrophy,highlights breakthroughs,points out caveats and poses questions that ought to serve as the basis of new investigations to better understand and treat this and other more common neurodegenerative disorders.
基金the Foundation of Science and Technology Department of Zhejiang Province,China,No. 2007C33049Fund for Fostering Talents in Basic Science of the National Natural Science Foundation of China,No. J0710043
文摘Spinal muscular atrophy （SMA） is an autosomal recessive neuromuscular disorder characterized by degeneration and loss of anterior horn cells in the spinal cord and brain stem nuclei, leading to progressive limb and trunk paralysis and muscular atrophy. Depending on the age of onset and maximum muscular function achieved, SMA is recognized as SMA1, SMA2, SMA3 or SMA4, and most patients have a deletion or truncation of the survival motor neuron 1 （SMN1） gene. In this report, we present a patient with a mild SMA phenotype, SMA3, and define his genetic abnormality. Tetra-primer amplification refractory mutation system PCR combined with restriction fragment length polymorphism analysis and array comparative genomic hybridization were used to determine the genetic variations in this patient. A 500 kb deletion in chromosome 5q13.2, including homozygous deletion of neuronal apoptosis inhibitory protein, and heterozygous deletion of occludin and B-double prime 1 was identified. This SMA region deletion did not involve SMN, indicating that SMN was likely to function normally. The phenotype was dependent of the large deletion and neuronal apoptosis inhibitory protein, occludin and B-double prime 1 may be candidate genes for SMA3.
文摘BACKGROUND： Spinal muscular atrophy （SMA） is a kind of degenerative disease of nervous system. There are 4 types in clinic, especially types Ⅰ, Ⅱ and Ⅲ are common, and the researches on those 3 types are relative mature. Type IV is a kind of adult spinal muscular atrophy （ASMA）, which has low incidence rate and is often misdiagnosed as amyotrophic lateral sclerosis, muscular dystrophy, cervical syndrome, or others.OBJEETIVE： To observe the clinical features of 46 ASMA patients and analyze the relationship between course and activity of daily living. DESIGN ： Case analysis.SETTING： Departments of Neurology of the 81 Hospital of Chinese PLA, the Second Affiliated Hospital of Nanjing Medical College and General Hospital of Nanjing Military Area Command of Chinese PLA.PARTICIPANTS ： A total of 46 ASMA patients were selected from the Departments of Neurology of the 81 Hospital of Chinese PLA, the Second Affiliated Hospital of Nanjing Medical College and General Hospital of Nanjing Military Area Command of Chinese PLA between April 1998 and January 2002. All patients were consentient. Among 46 cases, there were 37 males and 9 females with the mean age of 42 years. The patients＇ courses in all ranged from 6 months to 23 years, concretely, courses of 37 cases were less than or equal to 5 years, and those of 9 cases were more than or equal to 6 years.METHODS： ① All the 46 ASMA patients were asked to check blood sedimentation, anti O, serum creatinine, creatine, blood creatine phosphokinase （CPK） and muscular biopsy as early as possible. ②X-ray was used to measure plain film of cervical vertebra borderline film of cranium and neck at proximal end of upper limb of 25 cases and plain film of abdominal vertebra at proximal end of lower limb of 17 cases. ③ Cerebrospinal fluid of lumbar puncture was checked on 42 cases, for routine examination, biochemical examination, and immunoglobulin examination. Electromyogram （EMG） was also examined to 42 cases. ④ Barthel index was used to evaluate activities of daily living （ADL） of patients with various courses. The index ranged from 1 to 100. The more the index of a ASMA was, the stronger his independence was. ⑤ The Barthel indexes of patients with courses ≤ 5 years and those ≥ 6 years were compared with univariate analysis of variance. MAIN OUTCOME MEASURES： ① Incidences of all patients at the first time; ② values of relative blood and blood biochemistry; ③results of muscular biopsy; ④ results of EMG and relative X-ray plain film of 42 cases; ⑤ results of cerebrospinal fluid of 42 cases; ⑥ comparisons of Barthel index of patients with various courses.RESULTS： A total of 46 ASMA patients were involved in the final analysis. ① Incidence on the first time： 25 patients had the disease at the proximal end of upper limb, 17 at the proximal end of lower limb, and 4 at the four limbs. ② Value of serum-blood CPK of one fourth patients was increased slightly （3.034-9.735 μkat/L; normal value： 0.400-3.001 μkat/L）, and other values of blood and blood biochemical indicator were normal. ③Results of muscle biopsy of all patients showed that a small group of muscular atrophy could be observed mostly, and muscle group in the same type and compensatory hypertrophy of muscle fibres were also observed with ATP enzyme staining. ④ Results of EMG of 42 cases suggested that 37 patients had mild and moderate nerve-derived injury and 3 had mild muscle-derived injury. Results of all the X-ray plain films in this study were normal. ⑤ Results of routine, biochemical and immunoglobulin examination in cerebrospinal fluid of lumbar puncture in 42 cases were all normal. ⑥The difference between Barthel indexes of patients with courses ≤ 5 years and those ≥ 6 years was not significant [（64.73±20.38） vs （68.89±21.76） points, P〉 0.05]. CONCLUSION ： ① Amyasthenia is mainly occurred at the proximal end of the four limbs of ASMA patients. A small group of muscular atrophy is its mostly pathological change, and the progression of the disease is slow. ② Most patients have mild and moderate nerve-derived injury under EMG examination.③ The duration of a patient suffered from the disease has no obvious effect on his ADL ability.
文摘BACKGROUND In Behçet’s disease(BD),very few cases of muscular involvement have been reported previously.The natural history and therapeutic protocol for muscular involvement in BD are obscure due to the low incidence of peripheral neuropathy or myopathy in BD.The purpose of our study was to report a rare case of BD with chronic,focal forms of neuromyopathy and review the relevant literature.CASE SUMMARY We herein report the case of a 54-year-old man who presented with progressive muscular atrophy and weakness of both thighs 2 years after the presentation of the cardinal symptoms of BD.The past medical history,electrophysiological study,neurological examination,blood tests,magnetic resonance imaging study,and histological exam were performed for the differential diagnosis.Relevant literature on muscular involvement in BD was reviewed.Neurological examination revealed that muscular involvement was predominantly localized in the proximal parts of the lower extremities.Heterogeneous enhancement of several thigh muscles was observed on magnetic resonance imaging,which corresponded with the clinical manifestations.Histological study of one of the enhanced muscles showed denervation atrophy of the muscle with superimposed myopathic changes,while electrophysiological studies only suggested denervation.CONCLUSION To our knowledge,this is the first case of neurogenic muscular atrophy with a specific set of clinical,radiological,electrophysiological,and histological findings reported in BD.
文摘BACKGROUND: Peroneal muscular atrophy (PMA) is characterized by insidious onset, gradually progressive course of disease, very mild disability degree and easily subjecting to missed diagnosis and misdiagnosis. Nerve conductive velocity is helpful in the diagnosis of atypical cases. OBJECTIVE: To retrospectively analyze the characteristics of clinical manifestation, electromyogram (EMG), motor and sensory nerve conduction velocity of patients with PMA. DESIGN: Retrospective case analysis. SETTING: Department of Neurology, Guangzhou First People's Hospital. PARTICIPANTS: Twenty-four patients with PMA, including 16 males and 8 females, aged 5-68 years old, admitted to Guangzhou First People's Hospital between March 1996 and January 2006 were recruited. Informed consents were obtained from all the patients. METHODS: All the patients subjected to EMG and detection of nerve conduction velocity at distal end of four extremities with a Keypoint evoked potential/ EMG instrument (Denmark). Sensory and motor conduction velocity, EMG changes of upper and lower extremities were observed, and relationship of neuroelectrophysiological characteristics and clinical symptoms was analyzed. MAIN OUTCOME MEASURES: Changes in sensory and motor conduction velocity, EMG and clinical manifestations of 24 patients. RESULTS: ① All the patients suffered from insidious onset and gradually progressive course of PMA. Muscular atrophy of lower extremity was found in 14 patients, and that of upper extremity in 5 patients. ②Routine nerve conduction study showed that sensory and motor conduction velocity were stepped down, especially in 16 patients with typeⅠPMA (demyelinating pattern, nerve conduction velocity below normal level 50%). Motor nerve conduction velocity of median nerve, ulnar nerve, common peroneal nerve and tibial nerve averaged 34.8 m/s, 37.2 m/s, 16.5 m/s and 17.4 m/s, respectively; Sensory nerve conduction velocity of median nerve, ulnar nerve and sural nerve averaged 27.9%, 24.6 m/s and 3.1 m/s, respectively. Slowing conduction velocity and muscular strength involvement were disproportionate, i.e. myasthenia was relatively lessened, sensory and motor conduction velocities were greatly decreased. Nerve conduction velocity in distal end of two lower extremities was not detected in 8 patients, but who could still walk. CONCLUSION: ①PMA of patients is characterized by insidious onset and gradually progressive course of disease. Clinical symptom is the base to diagnose PMA. ②Neuroelectrophysiological study is a simple and easy-to-operate means with good reproducibility in diagnosing PMA. Patients with abnormal myasthenia in lower extremity can be detected in the early stage.
文摘Spinal muscular atrophy is an autosomal recessive neuromuscular disease with incidence of 1 in 5000 to 10000 live births and is produced by homozygous deletion of exons 7 and 8 in the SMN1 gene.The SMN1 and SMN2 genes encode the survival motor neuron protein,a crucial protein for the preservation of motor neurons.Use of the newer drug,Nusinersen,from early infancy has shown improvement in clinical outcomes of spinal muscular atrophy patients.
文摘Objective To investigate the clinical features and magnetic resonance imaging (MRI) findings of patients with Hirayama disease simply presenting proximal upper extremity muscular atrophy. Methods Three patients with Hirayama disease simply
文摘Purpose: To compare the accuracy of a commercially available MLPA kit with a laboratory developed RT-PCR assay for the detection of SMN1 and SMN2 copy numbers in clinical samples. Methods: We developed and validated a laboratory developed real time PCR based test capable of detecting SMN1 and SMN2 copy numbers in individuals. We also validated an MLPA kit purchased from MRC Holland for the same purpose. We then analyzed a series of 1027 anonymized samples using both technologies. When discrepant results were obtained, each sample was re-analyzed at least twice using both platforms. Results: Five samples did not yield results in either assay. For SMN1 copy number analysis, 2 RT-PCR assays revealed indeterminant results and all 1020 other samples were concordant for SMN1 copy number. There were 9 discrepancies in SMN2 copy number determination mostly due to a variability in MLPA analysis. Conclusion: Both MLPA and RTPCR assays give a reliable estimate of SMN1 copy number and are therefore appropriate for population based carrier screening for Spinal Muscular Atrophy Type 1. The MLPA kit has a low incidence (<1%) of underestimating the SMN2 copy number by 1 copy, but this inconsistency is of little clinical significance and can be overcome by replicate testing.
文摘Spinal muscular atrophy (SMA) is devastating genetic disease characterized by progressive loss of motor neuron and skeletal muscle weakness. SMA is the most common lethal genetic disease in infancy. SMA is caused by deletion or mutation of SMN1 gene and subsequent lack of SMN protein. Our purpose in this study was to evaluate the therapeutic potential of rufinamide, an antiepileptic drug. In this study, SMA patient-derived fibroblasts and differentiated spinal motor neurons (MNs) using SMA patient-derived iPSCs were used as in vitro SMA model. SMN mRNA was significantly increased by addition of rufinamide in type III SMA patient-derived fibroblasts. Furthermore, rufinamide stimulated neurite elongation in type III SMA patient derived-iPSCs-MNs. In contrast of the result using type III SMA patient-derived fibroblasts, the expression level of SMN mRNA was not changed after rufinamide treatment in type I SMA patient-derived fibroblasts, and rufinamide did not affect neurite outgrowth in type I SMA patients derived-iPSCs-MNs. These findings indicate that rufinamide may be one of the potential candidate drugs for mild type of SMA.
基金Key Technologies Research and Development Program of Zhejiang Province(No.2021C03099)Key R&D Program of Zhejiang Province(No.2022C03167)+2 种基金National Natural Science Foundation(No.82271735)Zhejiang Province Public Welfare Technology Application Research Project(No.LGC21H090001)Scientific Research Fund of Zhejiang University(No.XY2022045)
文摘To the Editor:5q spinal muscular atrophy(5qSMA)is an autosomal recessive neuromuscular disorder caused by the lack of the survival motor neuron(SMN)protein encoded by the SMN1 gene,located at 5q11.2-q13.3.[1]The incidence is 1/10,000-1/6000 live births,and the mutation carrier rate in China is 1/42.[1]Spinal muscular atrophy(SMA)is mainly divided into four subtypes:SMA type I,II,III,and IV,based on the motor milestones ever achieved.Types I-III occur in children,[1]which often result in progressive muscular atrophy and weakness as well as multi-system dysfunction,including nutritional and metabolic issues.[2]Children with SMA may have hidden nutritional and lipid imbalances,despite normal body appearance and anthropometric measurements,making it difcult to detect early and intervene.
文摘Background This study investigated the efficacy and safety of nusinersen,an antisense oligonucleotide,in patients with spinal muscular atrophy(SMA)types II(OMIM:253,550)or III(OMIM:253,400),including those with severe scoliosis or requiring respiratory support via mechanical ventilation.Methods Data from 40 patients with genetically confirmed SMA who were treated with nusinersen at our institute from March 2019 to April 2022 were retrospectively analyzed.Of these,30 patients with an age of onset<3 years and not on permanent ventilation were selected.Clinical and genetic characteristics were investigated,and motor function was evaluated based on the Hammersmith Functional Motor Scale-Expanded(HFMSE)score.Results The mean age of symptom onset was 1.2 years.Most patients were diagnosed with SMA type II(27/30,90%).Nusinersen was administered via computed tomography-guided or direct intrathecal injection in 87%(26/30)and 13%(4/30)of the patients,respectively.At the 6-,14-,22-,and 26-month follow-ups,72%,71%,88%,and 86%of patients showed motor improvement,respectively,with mean changes in HFMSE scores of 2.10,2.88,4.21,and 5.29,respectively.Multivariable analysis showed that the use of noninvasive ventilation was associated with poorer outcomes of motor function.Conclusions Patients with SMA type II or III who received nusinersen treatment showed significant improvement in motor function.A longer treatment duration led to a higher number of patients with improved motor function.No significant side effects of nusinersen were observed.Patients with SMA,even those with severe scoliosis or on respiratory support,can be safely treated using nusinersen.
基金This work was supported by project grants from the German Research Foundation(Deutsche Forschungsgemeinschaft,project numbers CA 893/18-1 and GA 402/25-1)by TU Dresden.
文摘In a new Science publication,Arbab and colleagues observe a substantial improvement in life span and motor functions of adenosine-base edited spinal muscular atrophy(SMA)mice with restored endogenous survival motor neuron(SMN)protein expression and regulation.1 This study provides proof-of-principle for the use of adenosine base editing(ABE)as a possible one-time,permanent therapy for SMA.
基金This study was supported by grants from the National Natural Science Foundation of China （No. 81050034） and from the Foundation of Capital Institute of Pediatrics （No.10-B09）.
文摘Background Infantile proximal spinal muscular atrophy （SMA） is a common autosomal recessive neuromuscular disorder. Approximately 90-95% cases of SMA result from homozygous deletion of survival motor neuron gene 1（SMN1） and 5% cases are caused by compound heterozygous mutation （a SMN1 deletion on one allele and a subtle mutation on the other allele）.Methods In this research, two unrelated patients were clinically diagnosed according to the criteria of proximal SMA. Genetic diagnosis was performed to detect the homozygous deletion of exon 7 of SMN1 by PCR-restriction fragment length polymorphism （RFLP） and genomic sequencing. Multiplex ligation-dependent probe amplification （MLPA） analysis was carried out to measure copy numbers of SMN1, SMN2 and neuronal apoptosis inhibitor protein （NAIP） in the patients. Further sequencing of SMN1allele-specific PCR （AS-PCR） and SMN1 clones were also performed to analyze the point mutation of SMN1 gene. Additionally,the pedigree analysis of these two families was carried out to identify the transmission of the mutation.Results The inconsistent results using PCR-RFLP and genomic sequencing showed homozygous deletion of exon 7 of SMN1 and heterozygous deletion accompanied with a suspicious mutation in SMN1 gene, respectively. MLPA analysis of these two cases exhibited one SMN1 copy deletion. One identical c.863G〉T （p. Arg288Met） mutation was found in two cases by sequencing the SMN1 clones, which confirmed that both cases were SMA compound heterozygotes. One case showed partial conversion to form hybrid SMN （SMN2 17/SMN1 E8） identified by clones sequencing and another case carrying 3 SMN2 implied complete conversion from SMN1 to SMN2.Conclusion p. Arg288Met is more a disease-causing mutation than a polymorphism variation, and children with this mutation may have more severe phenotypes.
