The Importance of Digging into the Genetics of SMN Genes in the Therapeutic Scenario of Spinal Muscular Atrophy

Costa-Roger, Mar; Blasco-Pérez, Laura; Cuscò, Ivon; Tizzano, Eduardo F.

doi:10.3390/ijms22169029

Cited by 21 publications

(21 citation statements)

References 85 publications

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“…This is crucial in order to evaluate the effects of the approved therapies to unmask long-term benefits in treated patients. Given that not all discordant cases can be explained by this positive variant, it is necessary to further analyze the SMN2 region by NGS to detect other reported candidate variants [ 24 ] and the presence of hybrid SMN1-SMN2 structures [ 20 ], as well as to unravel novel phenotypic modifier variants. In the current therapeutic context, genetic studies in patients confirmed with biallelic SMN1 absence or pathogenic variants should consider not only testing for SMN2 copies but also investigating SMN2 variants and structures as part of the integral characterization of patients receiving expensive and sometimes lifelong therapies.…”

Section: Discussionmentioning

confidence: 99%

“…Concretely, an inverse correlation between the number of SMN2 copies and the severity of the phenotype has been widely reported, given that the higher the number of SMN2 copies producing SMN functional protein, the milder the SMA phenotype [ 19 , 20 , 21 ]. Nevertheless, this correlation is not absolute, since discordant patients have been described in the literature, further classified as better-than-expected or worse-than-expected phenotypes according to their SMN2 copy number [ 19 , 21 ].…”

Section: Introductionmentioning

confidence: 99%

“…Indeed, all differences between SMN1 and SMN2 can be revealed by specific NGS studies [ 12 ]. It is also possible that these findings may relate to phenotype variability or to SMN2 -specific treatment response [ 20 ].…”

Section: Introductionmentioning

confidence: 99%

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Deep Molecular Characterization of Milder Spinal Muscular Atrophy Patients Carrying the c.859G>C Variant in SMN2

Blasco-Pérez

Costa-Roger

Leno-Colorado

et al. 2022

IJMS

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Spinal muscular atrophy (SMA) is a severe neuromuscular disorder caused by biallelic loss or pathogenic variants in the SMN1 gene. Copy number and modifier intragenic variants in SMN2, an almost identical paralog gene of SMN1, are known to influence the amount of complete SMN proteins. Therefore, SMN2 is considered the main phenotypic modifier of SMA, although genotype–phenotype correlation is not absolute. We present eleven unrelated SMA patients with milder phenotypes carrying the c.859G>C-positive modifier variant in SMN2. All were studied by a specific NGS method to allow a deep characterization of the entire SMN region. Analysis of two homozygous cases for the variant allowed us to identify a specific haplotype, Smn2-859C.1, in association with c.859G>C. Two other cases with the c.859G>C variant in their two SMN2 copies showed a second haplotype, Smn2-859C.2, in cis with Smn2-859C.1, assembling a more complex allele. We also identified a previously unreported variant in intron 2a exclusively linked to the Smn2-859C.1 haplotype (c.154-1141G>A), further suggesting that this region has been ancestrally conserved. The deep molecular characterization of SMN2 in our cohort highlights the importance of testing c.859G>C, as well as accurately assessing the SMN2 region in SMA patients to gain insight into the complex genotype–phenotype correlations and improve prognostic outcomes.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Deep Molecular Characterization of Milder Spinal Muscular Atrophy Patients Carrying the c.859G>C Variant in SMN2

Blasco-Pérez

Costa-Roger

Leno-Colorado

et al. 2022

IJMS

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“…Verminderte NAIP-Kopienzahlen bzw. dessen Deletion scheinen mit einem früheren Erkrankungsalter und einem schweren Verlauf assoziiert zu sein 18 , 19 . Es wurden aber auch modifizierende Genveränderungen außerhalb des SMN-Lokus postuliert.…”

Section: Diskussionunclassified

Intrafamiliäre Variabilität des Phänotyps der 5q-assoziierten spinalen Muskelatrophie am Beispiel von 2 Geschwistern

Becker¹,

Cordts²,

Deschauer³

2022

Nervenheilkunde

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ZUSAMMENFASSUNGDie 5q-assoziierte spinale Muskelatrophie (SMA) ist eine autosomal-rezessiv vererbte Erkrankung, die durch biallelische Defekte im SMN1-Gen (survival of motor neuron 1) auf Chromosom 5q verursacht wird. Der Gendefekt bewirkt einen fortschreitenden Untergang motorischer Vorderhornzellen im Rückenmark, was zu progredienten atrophen Paresen führt. Manifestationsalter und Schweregrad können sehr unterschiedlich sein. Die Anzahl der SMN2-Genkopien ist der entscheidende Modifier, es werden jedoch auch andere Faktoren vermutet. Anhand zweier Brüder mit 5q-assoziierter SMA soll gezeigt werden, dass trotz gleicher SMN2-Genkopienzahl erhebliche Unterschiede im Manifestationsalter und klinischen Phänotyp vorliegen können. Dies hat Implikationen für die genetische Beratung von gesunden Geschwistern von SMA-Patienten, da es zeigt, dass auch ältere Geschwister von Betroffenen ein Erkrankungsrisiko haben. Eine genetische Testung von Geschwistern kann nicht nur die Frage der Anlageträgerschaft beantworten, sondern hat auch einen prädiktiven Charakter. Dies ist aufgrund der seit einigen Jahren verfügbaren Therapieoptionen der SMA, deren Wirksamkeit bei frühem Therapiebeginn besonders hoch ist, von besonderer Bedeutung.

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“…In most cases, SMN2 copy number is inversely related to the clinical severity of SMA [1,4,6]. However, this correlation is not absolute [7], and some discordant genotype-phenotype correlations are observed [8].…”

Section: Introductionmentioning

confidence: 99%

Onasemnogene Abeparvovec: A Review in Spinal Muscular Atrophy

Blair

2022

CNS Drugs

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Onasemnogene abeparvovec (Zolgensma ® ) is a gene therapy approved for the treatment of spinal muscular atrophy (SMA). Administered as a one-time intravenous infusion, onasemnogene abeparvovec uses the adeno-associated virus vector to deliver a functional copy of the human survival motor neuron (SMN) gene to motor neuron cells. SMN1 encodes survival motor neuron protein, which is responsible for the maintenance and function of motor neurons. In clinical trials, onasemnogene abeparvovec improved event-free survival, motor function and motor milestone outcomes in patients with SMA, with these improvements maintained over the longer term (up to a median of ≈ 5 years). Onasemnogene abeparvovec was also associated with rapid age-appropriate achievement of motor milestones and improvements in motor function in children with pre-symptomatic SMA, indicating the benefit of early treatment. Onasemnogene abeparvovec was generally well tolerated. Hepatotoxicity is a known risk that can generally be mitigated with prophylactic prednisolone. In conclusion, onasemnogene abeparvovec represents an important treatment option for patients with SMA, particularly when initiated early in the course of the disease. Plain Language SummarySpinal muscular atrophy (SMA) is a rare genetic condition that causes muscle weakness and wasting. Infants with SMA type 1, the most common form of the disease, are unable to sit without support and usually die before the age of 2 years if untreated. SMA is caused by a defect in the survival motor neuron 1 (SMN1) gene. This gene provides instructions for making survival motor neuron protein, which is essential for the health and normal function of the nerves that control muscles. Onasemnogene abeparvovec (Zolgensma ® ) is a gene therapy that replaces the missing SMN1 gene and is given as a one-time infusion into a vein. In patients with SMA, onasemnogene abeparvovec improved event-free survival (alive without breathing support), motor function and achievement of motor milestones. Patients maintained these improvements for up to ≈ 5 years after treatment. Onasemnogene abeparvovec also helped pre-symptomatic children reach motor milestones at ages similar to healthy children. Onasemnogene abeparvovec is generally well tolerated and is an important treatment option for patients with SMA, including those who are yet to develop symptoms.

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The Importance of Digging into the Genetics of SMN Genes in the Therapeutic Scenario of Spinal Muscular Atrophy

Cited by 21 publications

References 85 publications

Deep Molecular Characterization of Milder Spinal Muscular Atrophy Patients Carrying the c.859G>C Variant in SMN2

Deep Molecular Characterization of Milder Spinal Muscular Atrophy Patients Carrying the c.859G>C Variant in SMN2

Intrafamiliäre Variabilität des Phänotyps der 5q-assoziierten spinalen Muskelatrophie am Beispiel von 2 Geschwistern

Onasemnogene Abeparvovec: A Review in Spinal Muscular Atrophy

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