scholarly journals Clinical features and genetics in non-5q spinal muscular atrophy caused by acid ceramidase deficiency

2021 ◽  
Vol 14 (3) ◽  
pp. 424-428
Author(s):  
Mihaela Axente ◽  
◽  
◽  
Elena-Silvia Shelby ◽  
Andrada Mirea ◽  
...  
Keyword(s):  
Spinal Muscular Atrophy ◽  
Motor Neurons ◽  
Muscular Atrophy ◽  
Smn1 Gene ◽  
Progressive Degeneration ◽  
Whole Exome ◽  
Uncertain Significance ◽  
Progressive Myoclonic Epilepsy ◽  
Ceramidase Deficiency ◽  
Next Generation Sequencing Ngs

Spinal muscular atrophy (SMA) is a spectrum of genetically and clinically heterogeneous diseases leading to the progressive degeneration of peripheric motor neurons with subsequent muscle weakness and atrophy. More than 95% of the cases of SMA are represented by homozygous mutations of the SMN1 gene (5q-SMA). Because this disease represents the leading cause of death due to a genetic cause and due to the availability of genetic therapies which can now save the life of the patient and stop the progress of the disease, early diagnosis is crucial. This report presents the case of a 13-year-old patient admitted to our hospital in 2018 who presented a phenotype typical to 5q-SMA. Next-generation sequencing (NGS) and Sanger sequencing of the SMN1 gene were performed, and a negative result was obtained. Consequently, we continued testing using whole-exome sequencing and discovered three mutations in the ASAH1 gene (one pathogenic and two variants of uncertain significance). Pathogenic mutations in the ASAH1 gene are responsible for spinal muscular atrophy with progressive myoclonic epilepsy (SMA-PME) and Farber disease, which overlapped with our patient’s phenotype. Currently, there are 45 SMA cases caused by mutations in the ASAH1 gene reported worldwide; however, the present case is the first reported in Romania.

scholarly journals AN AYURVEDIC MANAGEMENT OF SPINAL MUSCULAR ATROPHY (SMA) – A CASE STUDY

2021 ◽  
Vol 9 (11) ◽  
pp. 2897-2902
Author(s):  
Raheena B ◽  
Shaila Borannavar ◽  
Ananta S Desai
Keyword(s):  
Spinal Muscular Atrophy ◽  
Motor Neurons ◽  
Autosomal Recessive ◽  
Muscular Atrophy ◽  
Genetic Disorder ◽  
The Body ◽  
Erect Posture ◽  
Smn1 Gene ◽  
Autosomal Recessive Pattern

Spinal Muscular Atrophy (SMA) is the second leading genetic disorder inherited in the autosomal recessive pattern due to the absence of the SMN1 gene characterized by loss of motor neurons and progressive muscle wasting, often leading to dependent life and decreased life span. In Ayurveda, this condition can be considered as Kulaja Vyadhi wherein the patient’s Mamsa and Snayu is affected by Vata. This can be regarded as Mamsa-Snayugata Sarvanga Vata. It is said that Prakruta Vata dosha is the life, it is the strength, it is the sustainer of the body, it holds the body and life together. If it is Vikruta it produces Sankocha, Khanja, Kubjatva, Pangutva, Khalli and Soshana of Anga. So, in this disease aggravated Vata does the vitiation of Mamsa and Snayu thus leading to Soshana of both, resulting in Stambha, Nischalikarana of Avayava. A 21years female patient was admitted to our I.P.D with c/o of reduced strength in all four limbs leading to the inability to walk and to maintain erect posture during standing and sitting positions. Based on Ayurvedic principles the patient was initially subjected to Avaranahara Chikitsa followed by Brimhana line of management. Keywords: Mamsagata vata, Snayugata vata, Sarvanga vata, Spinal muscular atrophy (SMA)

scholarly journals SAM68 is a physiological regulator of SMN2 splicing in spinal muscular atrophy

2015 ◽  
Vol 211 (1) ◽  
pp. 77-90 ◽  
Author(s):  
Vittoria Pagliarini ◽  
Laura Pelosi ◽  
Maria Blaire Bustamante ◽  
Annalisa Nobili ◽  
Maria Grazia Berardinelli ◽  
...  
Keyword(s):  
Spinal Muscular Atrophy ◽  
Motor Neurons ◽  
Messenger Rna ◽  
Muscular Atrophy ◽  
Splicing Factors ◽  
Hnrnp A1 ◽  
Smn1 Gene ◽  
Smn2 Gene ◽  
Physiological Regulator

Spinal muscular atrophy (SMA) is a neurodegenerative disease caused by loss of motor neurons in patients with null mutations in the SMN1 gene. The almost identical SMN2 gene is unable to compensate for this deficiency because of the skipping of exon 7 during pre–messenger RNA (mRNA) processing. Although several splicing factors can modulate SMN2 splicing in vitro, the physiological regulators of this disease-causing event are unknown. We found that knockout of the splicing factor SAM68 partially rescued body weight and viability of SMAΔ7 mice. Ablation of SAM68 function promoted SMN2 splicing and expression in SMAΔ7 mice, correlating with amelioration of SMA-related defects in motor neurons and skeletal muscles. Mechanistically, SAM68 binds to SMN2 pre-mRNA, favoring recruitment of the splicing repressor hnRNP A1 and interfering with that of U2AF65 at the 3′ splice site of exon 7. These findings identify SAM68 as the first physiological regulator of SMN2 splicing in an SMA mouse model.

Acid ceramidase deficiency associated with spinal muscular atrophy with progressive myoclonic epilepsy

2015 ◽  
Vol 25 (12) ◽  
pp. 959-963 ◽  
Author(s):  
Joanna J. Gan ◽  
Virginie Garcia ◽  
Jane Tian ◽  
Michele Tagliati ◽  
Joseph E. Parisi ◽  
...  
Keyword(s):  
Spinal Muscular Atrophy ◽  
Muscular Atrophy ◽  
Myoclonic Epilepsy ◽  
Acid Ceramidase ◽  
Progressive Myoclonic Epilepsy ◽  
Ceramidase Deficiency

scholarly journals Case Study on Ayurvedic Management of Spinal Muscular Atrophy (SMA)

2018 ◽  
Vol 9 (3) ◽  
pp. 225-230
Author(s):  
Krishna Santoshi M ◽  
Krishnaiah N
Keyword(s):  
Spinal Muscular Atrophy ◽  
Motor Neurons ◽  
Muscular Atrophy ◽  
Genetic Disorder ◽  
The Body ◽  
Treatment Modalities ◽  
Smn1 Gene ◽  
Hands And Feet ◽  
Autosomal Recessive Pattern

Spinal Muscular Atrophy (SMA) is the second leading genetic disorder inherited in autosomal recessive pattern due to absence of SMN1 gene characterized by loss of motor neurons and progressive muscle wasting, often leading to dependent life and decreased life span. In Ayurveda, SMA can be considered as a type of janma jaata Vata vikara as it has been mentioned that: “Tatra va gati gandhanayoriti vata” that means all the movements of the body are controlled by vata. In Vata vyadhi Lakshanas, few symptoms like Anganam sosha (Atrophy or emaciation of limbs), Sankocha (Contraction), Kanja, Pangulya, Kubjatva (Lameness of hands and feet, hunch-back and shortness), are considered, few of which are also observed in the Spinal Muscular Atrophy. A 2yrs female patient was admitted in our I.P.D who was a known case of SMA II presented with complaints of inability in sitting for longer time without support, unable to stand and walk even with support. Through Ayurvedic principles we have treated adopting various vata hara treatment modalities & also with few palliative treatments as per the need in view of enhancing the quality living.  

scholarly journals Genomic Variability in the Survival Motor Neuron Genes (SMN1 and SMN2): Implications for Spinal Muscular Atrophy Phenotype and Therapeutics Development

2021 ◽  
Vol 22 (15) ◽  
pp. 7896
Author(s):  
Matthew E. R. Butchbach
Keyword(s):  
Spinal Muscular Atrophy ◽  
Motor Neuron ◽  
Motor Neurons ◽  
Muscular Atrophy ◽  
Survival Motor Neuron ◽  
Smn1 Gene ◽  
Spinal Motor Neurons ◽  
Copy Numbers ◽  
Smn Protein ◽  
High Degree

Spinal muscular atrophy (SMA) is a leading genetic cause of infant death worldwide that is characterized by loss of spinal motor neurons leading to muscle weakness and atrophy. SMA results from the loss of survival motor neuron 1 (SMN1) gene but retention of its paralog SMN2. The copy numbers of SMN1 and SMN2 are variable within the human population with SMN2 copy number inversely correlating with SMA severity. Current therapeutic options for SMA focus on increasing SMN2 expression and alternative splicing so as to increase the amount of SMN protein. Recent work has demonstrated that not all SMN2, or SMN1, genes are equivalent and there is a high degree of genomic heterogeneity with respect to the SMN genes. Because SMA is now an actionable disease with SMN2 being the primary target, it is imperative to have a comprehensive understanding of this genomic heterogeneity with respect to hybrid SMN1–SMN2 genes generated by gene conversion events as well as partial deletions of the SMN genes. This review will describe this genetic heterogeneity in SMA and its impact on disease phenotype as well as therapeutic efficacy.

scholarly journals Homozygous TRPV4 mutation causes congenital distal spinal muscular atrophy and arthrogryposis

2018 ◽  
Author(s):  
Jose Velilla ◽  
Michael Mario Marchetti ◽  
Agnes Toth-Petroczy ◽  
Claire Grosgogeat ◽  
Alexis H Bennett ◽  
...  
Keyword(s):  
Spinal Muscular Atrophy ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
In Silico ◽  
Muscular Atrophy ◽  
Structural Modeling ◽  
Recessive Mutation ◽  
Homozygous Mutation ◽  
Functional Studies ◽  
Whole Exome

AbstractObjectiveThe objective of this study is to identify the genetic cause of disease in a congenital form of congenital spinal muscular atrophy and arthrogryposis (CSMAA).MethodsA 2-year-old boy was diagnosed with arthrogryposis multiplex congenita, severe skeletal abnormalities, torticollis, vocal cord paralysis and diminished lower limb movement. Whole exome sequencing was performed on the proband and family members. In silico modeling of protein structure and heterologous protein expression and cytotoxicity assays were performed to validate pathogenicity of the identified variant.ResultsWhole exome sequencing revealed a homozygous mutation in the TRPV4 gene (c.281C>T; p.S94L). The identification of a recessive mutation in TRPV4 extends the spectrum of mutations in recessive forms of the TRPV4-associated disease. p.S94L and other previously identified TRPV4 variants in different protein domains were compared in structural modeling and functional studies. In silico structural modeling suggests that the p.S94L mutation is in the disordered N-terminal region proximal to important regulatory binding sites for phosphoinositides and for PACSIN3, which could lead to alterations in trafficking and/or channel sensitivity. Functional studies by western blot and immunohistochemical analysis show that p.S94L reduces TRPV4 protein stability because of increased cytotoxicity and therefore involves a gain-of-function mechanism.ConclusionThis study identifies a novel homozygous mutation in TRPV4 as a cause of the recessive form of congenital spinal muscular atrophy and arthrogryposis.

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