Diagnostic criteria for spinal muscular atrophy 5q

Background. The variety of phenotypic manifestations of spinal muscular atrophy 5q (5qCMA) is the reason for the difficulty in diagnosing and delaying the diagnosis, which is of particular importance today due to the emergence of new etiopathogenetic therapeutic possibilities.Objective: determination of the main clinical features and symptoms of 5qCMA with onset at different age periods, and the development of an algorithm that can help in making decisions regarding the need for testing the SMN1 gene by primary care and hospital doctors.Materials and methods. A retrospective analysis of the case histories of patients observed at the Research Center of Medical Genetics with a confirmed diagnosis of 5qCMA was carried out.Results. The study included data from 315 patients, including: 173 with type I, 95 and 47 with types II and III 5qCMA. In all cases, the presence and diagnostic significance of 27 signs and symptoms were analyzed, depending on the age of disease manifestation. An attempt was made to isolate the main symptoms, which are the basis for the mandatory exclusion of 5qCMA by molecular genetic methods in patients with the onset of the disease before and after 18 months of life.

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

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)

Onasemnogene Abeparvovec (Zolgensma)

CADTH reimbursement reviews are comprehensive assessments of the clinical effectiveness and cost-effectiveness, as well as patient and clinician perspectives, of a drug or drug class. The assessments inform non-binding recommendations that help guide the reimbursement decisions of Canada's federal, provincial, and territorial governments, with the exception of Quebec. This review assesses onasemnogene abeparvovec (Zolgensma), given as a single-dose IV infusion of 1.1 × 1014 vector genomes/kg Indication: For the treatment of pediatric patients with 5q SMA with biallelic mutations in the survival motor neuron 1 (SMN1) gene and: 3 or fewer copies of the SMN2 gene or infantile-onset SMA

Copy Number Assessment of SMN1 Based on Real-Time PCR With High-Resolution Melting: Fast and Highly Reliable Testing

Background: Spinal muscular atrophy (SMA) is a common neuromuscular disorder, caused by absence of both copies of the survival motor neuron 1 (SMN1) gene. Population-wide SMA screening to quantify copy number of SMN1 is recommended by multiple regions. SMN1 diagnostic assay with simplified procedure, high sensitivity and throughput is still needed.Methods: Real-Time PCR with High-Resolution Melting for the quantification of the SMN1 gene exon 7 copies and SMN1 gene exon 8 copies was established and confirmed by multiplex ligation-dependent probe amplification (MLPA). The diagnosis of 2563 individuals including SMA patients, suspected cases and the general population were analyzed by the real-time PCR. The results were compared with the gold standard test MPLA. Results: In this study, the homozygous deletions, heterozygous deletions were identified by Real-Time PCR with High-Resolution Melting method with an incidence of 10.18% and 2.42%, respectively. In addition, the R value distribution (P>0.05) among the 8 replicates and the coefficient of variation (CV<0.003) suggested that the qPCR screening test had high reproducibility. High concordance was obtained between Real-Time PCR with High-Resolution Melting and MPLA. Conclusions: The qPCR based on High-Resolution Melting provides a sensitive and high-throughput approach to large-scale SMA carrier screening with low cost and labor.

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

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.

O Processo de Incorporação do Nusinersena ao Sistema Único de Saúde para Tratamento da Atrofia Muscular Espinhal

A Atrofia Muscular Espinhal (AME) é uma doença neurodegenerativa, na qual o gene SMN1 não é expresso, caracterizada por fraqueza muscular, paralisia e dificuldades respiratórias. Trata-se de uma doença crônica que não possui prognóstico de cura, porém existe um fármaco chamado nusinersena em processo de incorporação junto ao Sistema Único de Saúde (SUS), que traz avanços ao seu tratamento. Este trabalho tem como objetivo compreender a necessidade e o processo de incorporação do nusinersena ao SUS, através de revisão bibliográfica feita em bancos de dados científicos eletrônicos. A AME apresentava tratamento paliativo de difícil acesso, contudo o nusinersena promove melhorias no quadro clínico dos pacientes. Anteriormente à padronização deste no SUS, os pacientes tinham que entrar com ação judicial para conseguir o acesso ao medicamento, o que era um processo demorado em função de questões burocráticas, porém através da portaria nº 24, de 24 de abril de 2019 houve a incorporação deste ao SUS. A análise deste processo mostra que o fármaco é de alto custo e visto o impacto que este pode gerar no orçamento do SUS, permitiu-se o uso do fármaco para pacientes com diagnóstico genético obrigatório, que não estejam fazendo uso de ventilação mecânica e somente em centros de referência durante três anos, sendo o processo reavaliado após o prazo. Palavras-chave: Atrofia Muscular Espinhal. Sistema Único de Saúde. Judicialização da Saúde. Farmacoeconomia. Abstract Spinal Muscular Atrophy (AME) is a neurodegenerative disease - SMN1 gene is not expressed - which causes muscle weakness, paralysis and breathing difficulties. It is a chronic disease that has no prognosis for cure, but there is a recent drug called nusinersen in the incorporation process with SUS that brings advances in its treatment. This work aims to understand the need and the process of incorporating nusinersen to SUS, through a bibliographic review made in electronic scientific databases. EBF presented palliative treatment that is difficult to access, however nusinersen promotes improvements in the patients’ clinical conditions . Prior to its standardization in SUS, patients had to take legal action to obtain access to the medication, which was a lengthy process due to bureaucratic issues, however, through Ordinance No. 24, dated from April 24th, 2019, this was incorporated into SUS. The analysis of this process shows that the drug is of high cost and given the impact it can have on the SUS budget, the use of the drug was allowed for patients with mandatory genetic diagnosis, who are not using mechanical ventilation and only in referral centers for three years, the process being reassessed after the deadline. Keywords: Spinal Muscular Atrophy. Unified Health System. Health Judicialization. Economics, Pharmaceutical.

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

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.

Onasemnogene Abeparvovec-xioi: Gene Therapy for Spinal Muscular Atrophy

Objective: To review the efficacy and safety of onasemnogene abeparvovec-xioi (Zolgensma) in the treatment of spinal muscular atrophy (SMA). Data Sources: An English-language literature search of PubMed, MEDLINE, and Ovid (1946 to December 2019) was completed using the terms onasemnogene, AVXS-101, and spinal muscular atrophy. Manufacturer prescribing information, article bibliographies, and data from ClinicalTrials.gov were incorporated in the reviewed data. Study Selection/Data Extraction: All studies registered on ClinicalTrials.gov were incorporated in the reviewed data. Data Synthesis: Onasemnogene is the first agent for SMA utilizing gene therapy to directly provide survival motor neuron 1 ( SMN1) gene to produce SMN protein. Four publications of 1 clinical trial, 1 comparison study of treatment effects, and 1 combination therapy case series have been published. Relevance to Patient Care and Clinical Practice: Onasemnogene is a one time dose approved by the Food and Drug Administration for SMA patients <2 years old who possess mutations in both copies of the SMN1 gene. Conclusion: Onasemnogene appears to be an efficacious therapy for younger pediatric patients with SMA type 1. Concerns include drug cost and potential liver toxicity. Long-term benefits and risks have not been determined.