Homozygous Deletion Of SMN1 Gene Research Articles

Registry of Patients with Spinal Muscular Atrophy in a Tertiary Care Unit in Egypt

Background Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disease characterized by degeneration of alpha motor neurons in the spinal cord, resulting in progressive proximal muscle weakness and paralysis. Objectives To register patients with SMA who are diagnosed clinically and genetically (typical and atypical forms) in a tertiary care unit in Egypt. Patient and methods 80 Patients with SMA who are diagnosed clinically and genetically at Neuromuscular Unit of Ain Shams University Hospital were registered. Demographical data and genetics of the patients were collected and analyzed. The patients were assessed for skeletal deformities, cardiac evaluation by echo and pulmonary evaluation by PFTs (for patients above 5 years old) and functional assessment by motor scales according to age and type of each patient was done. Results SMA was more common in males with predominance of type II and median age of 4.5 years old, a considerable number of cases had positive history of consanguinity and similar cases in family, 98.8% of cases had the typical form of SMA with homozygous deletion of SMN1 gene with variable SMN2 copy number according to type. 32.5% of cases had skeletal deformities in the form of scoliosis with or without kyphosis, extremities contractures and chest cave deformities. 4 cases had restrictive pattern due to scoliosis cardiac abnormalities were detected in 3 cases of type I. 31 cases were assessed by CHOP INTEND and 49 cases were assessed by HFMSE giving a good tool for assessing disease progress and role of physiotherapy. Severe chest infection and respiratory failure was the cause of death of 3 cases of type I during the period of study. Conclusion registry of SMA patients will lead to a better understanding of the natural history of SMA and the influence of drug treatment. This is crucial to improve the care of SMA patients.

P.084 5q spinal muscular atrophy Canadian Paediatric Surveillance Program – 2020-2021 results

Background: Spinal muscular atrophy (SMA) is the leading genetic cause of infant death and the second most common autosomal recessive disorder; most cases are due to homozygous deletion of SMN1 gene. Methods: This study uses the Canadian Paediatric Surveillance Program to determine the minimum annual incidence of 5q-SMA from birth to 18 years of age in Canada. The protocol can be accessed at www.cpsp.cps.ca/surveillance. Results: Eighteen cases were reported in 2020-2021. Ten (55%) cases were reported from Ontario and the remaining cases were reported from Atlantic Canada and Western Canada. Their median age was 11 months (IQR 4–21); 61% were male. The most common presenting symptoms were hypotonia and delayed motor milestones in 12 (86%) and 10 (71%) cases respectively. On average, the diagnosis was delayed after onset of symptoms by three months for SMA Type 1, by eight months for Type 2, and by 18 months for Type 3. Twelve (86%) cases received nusinersen as their first disease-modifying treatment. Conclusions: Early recognition and newborn screening are essential to reduce diagnostic delay and enable timely treatment of SMA. Other data sources including the Canadian Neuromuscular Disease Registry and molecular genetic laboratories will be used to estimate the annual incidence of pediatric SMA in Canada.

P.112 5q Spinal Muscular Atrophy Canadian Paediatric Surveillance Program - 2020 Results

Background: Spinal muscular atrophy (SMA) is the leading genetic cause of infant death and the second most common autosomal recessive disorder; the majority of cases are due to homozygous deletion of SMN1 gene. Methods: This study uses the Canadian Paediatric Surveillance Program to determine the minimum annual incidence of 5q-SMA from birth to 18 years of age in Canada. The complete protocol can be accessed at www.cpsp.cps.ca/surveillance. Results: Eleven cases were reported in 2020. Five (45%) cases were reported from Ontario and the remaining cases were reported from Atlantic Canada and Western Canada. Their median age was 12 months (IQR 6–21); 64% were male. The most common presenting symptoms were delayed motor milestone and hypotonia in 7 (64%) cases. On average, the diagnosis was delayed after the onset of symptoms by three months for SMA Type 1, by eight months for Type 2, and by 18 months for Type 3. Eight (73%) cases received nusinersen as their first disease-modifying treatment. Conclusions: Early recognition and newborn screening are essential to reduce diagnostic delay and enable timely treatment of SMA. Other data sources including the Canadian Neuromuscular Disease Registry and molecular genetic laboratories will be used to estimate the annual incidence of pediatric SMA in Canada.

Constraints of carrier screening in spinal muscular atrophy: Co-existence of deletion and duplication in SMN1 gene and false negative MLPA result

Spinal Muscular Atrophy (SMA) is the second most common autosomal recessive genetic disorder. Deletion/duplication changes in SMN1 gene are common features in SMA patients. MLPA (Multiplex Ligation-dependent Probe Amplification) is a robust method for investigation of copy number changes because it not only deals with investigating the SMN1 gene but also adjacent genes such as NAIPE, GTFH2 and SMN2. This study was carried out by MLPA and STR markers to SMA carrier screening on people were referred to Dr. Zeinali's Medical Genetics laboratory. Analysis of 150 unrelated families with at least one affected child suspected of having SMA identified causative mutations in 106 families. Among the nighty-nine patients with a homozygous deletion of SMN1 gene (93.3%), there were ten patients with only one parent showing this deletion as heterozygote, and the other parent had two copies of the gene with normal MLPA result. The results were unexpected findings in an autosomal recessive disorder. Paternity and maternity were tested and confirmed.Further analysis of the grandparents showed that the parents inherited both deletion and duplication from one of their parents. So they have two copies of SMN1 genes in a chromosome and no copy on the other one.Due to high carrier frequency of SMA in highly consanguineous population as Iran, co-existence of deletion and duplication must be highly considered. It seems that performing genetic testing only in patients and parents is not sufficient and investigation of the grandparents or autozygosity mapping is also necessary to have reliable results especially for next pregnancies.

SMN1 gene deletion analysis using mid-trimester amniotic fluid cells by real-time PCR

Objectives To investigate the prenatal diagnosis method of spinal muscular atrophy with amniotic fluid sample. Methods Totally 1 064 amniotic fluid samples from mid-trimester pregnant women were enrolled during January 2015 and January 2016 in 4 hospitals. Genetic analysis was performed for detecting potential contamination of maternal tissue by a genetic technique based on short tandem repeat (STR) markers. Deletion of SMN1 gene was detected in 1 062 uncontaminated amniotic fluid samples by real-time PCR and multiplex ligation-dependent probe amplification (MLPA) respectively. Results Two contaminated amniotic fluid samples were detected within 1 064 mid-trimester pregnant women by STR genotyping. The other 1 062 uncontaminated amniotic fluid samples were tested by real-time PCR. There were 37 samples with heterozygous deletion of Exon 7 of SMN1 gene (3.67%), 34 samples with heterozygous deletion of Exon 8 of SMN1 gene (3.2%) and two samples with homozygous deletion of Exon7 and Exon8 of SMN1 gene (0.19%) respectively, while other samples observed with no deletion of Exon7 and Exon8 in SMN1 gene. Totally 41 samples with heterozygous or homozygous deletion of SMN1 gene and 55 samples with undetected deletion of SMN1 gene were confirmed by MLPA and the results showed 100% consistence with that of real-time PCR. Conclusions Both real-time PCR and MLPA are suitable for detecting the deletion of SMN1 gene with amniotic fluid sample. Real-time PCR exhibits less sample requirement and time compared with MLPA.(Chin J Lab Med, 2016, 39: 418-422) Key words: Muscular atrophy, spinal; Amniotic fluid; Survival of motor neuron 1 protein; Gene deletion; Real-time polymerase chain reaction; Multiplex polymerase chain reaction

Carrier screening for spinal muscular atrophy in 4719 pregnant women in Shanghai region

Spinal muscular atrophy (SMA) is a common and fatal autosomal recessive disorder. Approximately 94% of SMA patients are caused by homozygous deletion of SMN1 gene. SMA carrier screening is recommended considering the high carrier frequency (1 in 35-50) as well as severity of the disease. A prospective population-based cohort study was carried out on 4719 pregnant women from Shanghai region. Copy numbers of SMN1 and SMN2 genes were effectively determined with denaturing high performance liquid chromatography (DHPLC) technique. The method has detected 94% of SMA cases with deletion or conversion of the SMN1 genes. Ninety SMA carriers with only one copy of the SMN1 gene were identified among the 4719 pregnant woman. The carrier rate was 1.9%. Respectively, 1.2% and 0.6% of the carriers were caused by SMN1 gene deletion and SMN1 gene conversion. Through this study, we have determined the frequency of SMA mutation carriers in a population of pregnant women. The result may provide a basis for genetic counseling in order to reduce the rate of SMA affected births.

Genotypic and clinical features of spinal muscular atrophy type 3

To explore the genotypic and clinical features and laboratory examinations of spinal muscular atrophy type 3 (SMA III). Results of genetic testing and laboratory exams of 18 SMA III patients were collected and analyzed. The average age of onset of patients was 6.1 years, with the course of disease lasting from 13 months to 28 years. All patients became symptomatic with lower extremity muscle weakness. The symptoms gradually aggregated, with proximal lower limb muscle becoming atrophic and proximal upper limb muscle becoming weak. Genetic testing indicated that all subjects possessed homozygous deletions of SMN1 gene. Electromyography (EMG) of 15 subjects indicated neurogenic damage. Whilst younger patients had normal level of creatine kinase (CK), elder patients had higher level of CK, though no linear correlation was found. Full understanding of Clinical, especially the growth features of SMA III, in combination with genetic testing, can facilitate diagnosis and early intervention of the disease.

Prenatal diagnosis of spinal muscular atrophy: Indian scenario

To study the psychosocial issues associated with prenatal diagnosis of SMA in India and the use of SMN1 copy number analysis for carrier detection prior to offering prenatal diagnosis. Homozygous deletion of SMN1 gene was done by PCR-RFLP. Copy number analysis of SMN1 gene was performed by quantitative PCR. We report our experience of eight cases of prenatal diagnosis for SMA and the use of carrier detection prior to offering prenatal diagnosis. Quantitative PCR results show that SMN1 copy number analysis is useful to identify couples at risk. Case analyses depict unique psychosocial issues associated with prenatal diagnosis of SMA from India.