Prevalence, incidence and carrier frequency of 5q–linked spinal muscular atrophy – a literature review

Verhaart, Ingrid E.C.; Robertson, Agata; Wilson, I. J.; Aartsma‐Rus, Annemieke; Cameron, Shona; Jones, Cynthia C.; Cook, Suzanne F.; Lochmüller, Hanns

doi:10.1186/s13023-017-0671-8

Cited by 419 publications

(371 citation statements)

References 110 publications

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“…Spinal muscular atrophy (SMA) is a rare neuromuscular disorder characterized by degeneration of the anterior horn cells in the spinal cord, resulting in progressive muscle weakness and atrophy . SMA is the most common genetic cause of early infant death, with an incidence of approximately 1 in 11 000 live births . SMA is an autosomal recessive disorder caused by a mutation in the survival motor neuron 1 gene ( SMN1 ), located on chromosome 5q13.2.…”

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confidence: 99%

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Nusinersen treatment of spinal muscular atrophy: current knowledge and existing gaps

Gidaro

Servais

2018

Develop Med Child Neuro

115

106

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Spinal muscular atrophy (SMA) is a recessive disorder caused by a mutation in the survival motor neuron 1 gene (SMN1); it affects 1 in 11 000 newborn infants. The most severe and most common form, type 1 SMA, is associated with early mortality in most cases and severe disability in survivors. Nusinersen, an antisense oligonucleotide, promotes production of full-length protein from the pseudogene SMN2. Nusinersen treatment prolongs survival of patients with type 1 SMA and allows motor milestone acquisition. Patients with type 2 SMA also show progress on different motor scales after nusinersen treatment. Nusinersen was recently approved by the European Medicines Agency and the US Food and Drug Administration; it is now reimbursed in several European countries and in the USA. In Australia, the transition from expanded access programme to commercial availability is coming soon. In New Zealand, an expanded access programme is opened, and in Canada price negotiation for the treatment is in progress. In this review we exemplify the clinical benefit of nusinersen in subgroups of patients with SMA. Nusinersen represents the first efficacious marked approved drug in type 1 and type 2 SMA. Different knowledge gaps, such as results in older patients, in patients with permanent ventilation, in patients with neonatal forms, or in patients after spinal fusion, still need to be addressed. WHAT THIS PAPER ADDS: Identifies gaps in knowledge about the efficacy of nusinersen in broader populations of patients with spinal muscular atrophy. Identifies open questions in populations of patients where proof of efficacy is available.

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“…1 SMA is the most common genetic cause of early infant death, with an incidence of approximately 1 in 11 000 live births. 2 SMA is an autosomal recessive disorder caused by a mutation in the survival motor neuron 1 gene (SMN1), located on chromosome 5q13.2. The most common mutation is homozygous deletion of exon 7, resulting in SMN protein deficiency.…”

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confidence: 99%

Nusinersen treatment of spinal muscular atrophy: current knowledge and existing gaps

Gidaro

Servais

2018

Develop Med Child Neuro

115

106

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“…In 1997, the first description of a genetic cause was published, reporting the disease as hereditable in an autosomal recessive way (Lefebvre et al, 1997). The majority of the patients (92%) have homozygous deletions in the survival motor neuron 1 (SMN1) gene located on the telomeric region of chromosome 5q13.2 (Verhaart et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

“…Only few available studies mention incidence and prevalence of the disease. The incidence of all types of SMA is cited as 1 in 10-12.000 live births (Lunn and Wang 2008;Verhaart et al, 2017). The prevalence of the disease, which is the number of living diseased individuals, is observed as 1-5 per 100.000 individuals, even though a broad variability is reported among different geographic regions and a possible sample bias has to be considered because a small error in the number of cases has a large impact on the estimated prevalence (Lunn and Wang 2008).…”

Section: Introductionmentioning

confidence: 99%

The impact of paralog genes: detection of copy number variation in spinal muscle atrophy patients

Laurito¹,

Cueto²,

Perez³

et al. 2018

Biocell

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Spinal muscular atrophy (SMA) is caused by dysfunction of the alpha motor neurons of the spinal cord.It is an autosomal recessive disease associated to the SMN1 gene, located in the subtelomeric region of 5q13. A paralog SMN2 gene is located at the centromeric region of the same chromosome, which apparently originated by an ancestral inverted duplication occurring only in humans. The exon sequence differs in two nucleotides in exon 7 and exon 8, which leads to an SMN2 transcript that lacks exon 7 and results in a truncated protein. Part (10%) of the SMN2 transcripts avoids the splicing of exon 7 but most of the copies are dysfunctional. In a disease scenario, the more SMN2 copies the higher possibility to restore at least partly the effects of SMN1 deficiency. Some therapeutic approaches are being developed to increase the expression of SMN2. To determine the number of SMN1 and SMN2 copies, the methodology must distinguish accurately between both genes. In this work, we present the results obtained using multiplex ligation-dependent probe amplification (MLPA) in 60 SMA suspected patients/carriers derived from different regions of Argentina. In 32 of these DNA samples we found alterations in SMN1. Among these, 16 presented a heterozygous deletion (carrier status) and 14 an homozygous deletion (patient status) in exon 7 and 8 of SMN1. In one case, exon 7 was found homozygously deleted but exon 8 presented a single copy, and in another case, exon 7 was found heterozygously deleted while exon 8 was normal. Almost half of the patients (7/15) presented a normal diploid number of SMN2 while the other half (8/15) presented an increased number. In this work we showed how a probe-based methodology such as MLPA was able to distinguish between the paralog genes and determine the amount of copies in DNA samples from suspected patients/carriers of SMA. BIOCELL

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“…The disease is caused by insufficient levels of survival of motor neuron (SMN) protein due to the homozygous deletion of the SMN1 gene in 95-98% of patients 1 . The estimated prevalence is about 1-2/100,000 persons with an incidence of 1/10,000 live births 2 . In humans, the telomeric SMN1 has an almost-identical centromeric gene called SMN2.…”

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confidence: 99%

Observations from a nationwide vigilance program in medical care for spinal muscular atrophy patients in Chile

Suárez

Palomino

Hervias

et al. 2019

Arq. Neuro-Psiquiatr.

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Spinal muscular atrophy (SMA) has gained much attention in the last few years because of the approval of the first intrathecal treatment for this neurodegenerative disease. Latin America needs to develop the demographics of SMA, timely access to diagnosis, and appropriate following of the standards of care recommendations for patients. These are essential steps to guide health policies. Methods: This was a descriptive study of a cohort of SMA patients from all over Chile. We analyzed the clinical, motor functional, and social data, as well as the care status of nutritional, respiratory and skeletal conditions. We also measured the SMN2 copy number in this population. Results: We recruited 92 patients: 50 male; 23 SMA type-1, 36 SMA type-2 and 33 SMA type-3. The median age at genetic diagnosis was 5, 24 and 132 months. We evaluated the SMN2 copy number in 57 patients. The SMA type-1 patients were tracheostomized and fed by gastrostomy in a 69.6 % of cases, 65% of SMA type-2 patients received nocturnal noninvasive ventilation, and 37% of the whole cohort underwent scoliosis surgery. Conclusion: Ventilatory care for SMA type-1 is still based mainly on tracheostomy. This Chilean cohort of SMA patients had timely access to genetic diagnosis, ventilatory assistance, nutritional support, and scoliosis surgery. In this series, SMA type-1 is underrepresented, probably due to restrictions in access to early diagnosis and the high and early mortality rate. RESUMÉNLa Atrofia Muscular Espinal (AME) ha concitado mucha atención en los últimos 2 años debido a la aprobación del primer tratamiento intratecal para esta enfermedad neurodegenerativa. América Latina necesita desarrollar la demografía de AME, un acceso oportuno al diagnóstico y un seguimiento apropiado de los pacientes que incorporen los estándares de atención recomendados por expertos. Estos son pasos esenciales para orientar las futuras políticas de salud en esta enfermedad. Métodos: Este es un estudio descriptivo de una cohorte de pacientes con AME de todo el país. Se analizaron los datos clínicos, motores, funcionales, sociales y el estado nutricional, respiratorio y esquelético de los pacientes. También medimos el número de copias del gen SMN2 en esta población. Resultados: se reclutaron 92 pacientes, 50 varones; 23 AME tipo 1, 36 AME tipo 2 y 33 AME tipo 3. La edad media al diagnóstico genético fue de 5, 24 y 132 meses respectivamente. Evaluamos el número de copias de SMN2 en 57 pacientes. Un 69,6% de los pacientes con AME tipo 1 estaban traqueostomízados y gastrostomizados , un 65% de los pacientes con AME tipo 2 usaban ventilación nocturna no invasiva y el 37% de toda la cohorte presentaba una cirugía de escoliosis. Conclusión: Esta cohorte chilena de pacientes con AME tuvo acceso oportuno al diagnóstico genético, asistencia ventilatoria, apoyo nutricional y cirugía de escoliosis, sin embargo, la atención ventilatoria para AME tipo 1 continúa aun basándose principalmente en la traqueostomía. En esta serie, AME tipo 1 está subrepresentada, probablemente debido a...

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Prevalence, incidence and carrier frequency of 5q–linked spinal muscular atrophy – a literature review

Cited by 419 publications

References 110 publications

Nusinersen treatment of spinal muscular atrophy: current knowledge and existing gaps

Nusinersen treatment of spinal muscular atrophy: current knowledge and existing gaps

The impact of paralog genes: detection of copy number variation in spinal muscle atrophy patients

Observations from a nationwide vigilance program in medical care for spinal muscular atrophy patients in Chile

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