Combination of SMN2 copy number and NAIP deletion predicts disease severity in spinal muscular atrophy

Watihayati, M S; Hayati, Fatemeh; Marini, Marzuki; Baig, Atif Amin; Zahiruddin, Wan Mohd; Sasongko, Teguh Haryo; Tang, Thean‐Hock; Zabidi-Hussin, Z A M H; Nishio, Hisahide; Zilfalil, Bin Alwi

doi:10.1016/j.braindev.2008.08.012

Cited by 50 publications

(34 citation statements)

References 16 publications

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“…Notably, SMN2 defects in isolation do not seem to cause the disease [7–9]. Other modifiers that might play a role are NAIP , H4F5 , GTF2H2 and PLS3 [10–15]. NAIP , H4F5 and GTF2H2 are thought to be a modifiers due to their proximity to the SMN1 gene and NAIP also shows homology to apoptosis inhibitory proteins [12, 14, 16].…”

Section: Introductionmentioning

confidence: 99%

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

Verhaart

Robertson

Wilson

et al. 2017

Orphanet J Rare Dis

500

389

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Spinal muscular atrophy linked to chromosome 5q (SMA) is a recessive, progressive, neuromuscular disorder caused by bi-allelic mutations in the SMN1 gene, resulting in motor neuron degeneration and variable presentation in relation to onset and severity. A prevalence of approximately 1–2 per 100,000 persons and incidence around 1 in 10,000 live births have been estimated with SMA type I accounting for around 60% of all cases. Since SMA is a relatively rare condition, studies of its prevalence and incidence are challenging. Most published studies are outdated and therefore rely on clinical rather than genetic diagnosis. Furthermore they are performed in small cohorts in small geographical regions and only study European populations. In addition, the heterogeneity of the condition can lead to delays and difficulties in diagnosing the condition, especially outside of specialist clinics, and contributes to the challenges in understanding the epidemiology of the disease. The frequency of unaffected, heterozygous carriers of the SMN1 mutations appears to be higher among Caucasian and Asian populations compared to the Black (Sub-Saharan African ancestry) population. However, carrier frequencies cannot directly be translated into incidence and prevalence, as very severe (death in utero) and very mild (symptom free in adults) phenotypes carrying bi-allelic SMN1 mutations exist, and their frequency is unknown.More robust epidemiological data on SMA covering larger populations based on accurate genetic diagnosis or newborn screening would be helpful to support planning of clinical studies, provision of care and therapies and evaluation of outcomes.Electronic supplementary materialThe online version of this article (doi:10.1186/s13023-017-0671-8) contains supplementary material, which is available to authorized users.

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Section: Introductionmentioning

confidence: 99%

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

Verhaart

Robertson

Wilson

et al. 2017

Orphanet J Rare Dis

500

389

View full text Add to dashboard Cite

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“…Future therapeutic strategies are aimed at increasing SMN protein levels, either by replacing SMN1 or by splicing modulation or SMN2 activation 4. Although the relationship has not been fully elucidated, the related NAIP is also known to be associated with SMA disease severity 161718…”

Section: Discussionmentioning

confidence: 99%

“…Several studies have shown that a deletion in NAIP is related to the disease type 161718. Shin et al19 conducted the first study of deletions in SMN and NAIP in Korean SMA patients; however, NAIP deletions were not detected in any of their five patients.…”

Section: Discussionmentioning

confidence: 99%

Genotype-Phenotype Correlation ofSMN1andNAIPDeletions in Korean Patients with Spinal Muscular Atrophy

et al. 2017

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Background and PurposeSpinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disease characterized by progressive muscle weakness and atrophy. Most SMA patients have a homozygous deletion in survival of motor neuron 1 (SMN1) gene, and neuronal apoptosis inhibitory protein (NAIP) gene is considered a phenotype modifier. We investigated the genotype-phenotype correlation of SMN1 and NAIP deletions in Korean SMA patients.MethodsThirty-three patients (12 males and 21 females) treated at the Asan Medical Center between 1999 and 2013 were analyzed retrospectively. The polymerase chain reaction (PCR), restriction-fragment-length polymorphism analysis, and multiplex PCR were used to detect deletions in SMN1 (exons 7 and 8) and NAIP (exons 4 and 5). We reviewed clinical presentations and outcomes and categorized the patients into three clinical types. NAIP deletion-driven differences between the two genotypes were analyzed.ResultsDeletion analysis identified homozygous deletions of SMN1 exons 7 and 8 in 30 patients (90.9%). Among these, compared with patients without an NAIP deletion, those with an NAIP deletion showed a significantly lower age at symptom onset (1.9±1.7 months vs. 18.4±20.4 months, mean±SD; p=0.007), more frequent type 1 phenotype (6/6 vs. 8/24, p=0.005), and worse outcomes, with early death or a requirement for ventilator support (4/4 vs. 2/12, p=0.008).ConclusionsHomozygous deletion in SMN1 and a concurrent NAIP deletion were associated with an early onset, severe hypotonia, and worse outcome in SMA patients. Deletion analysis of NAIP and SMN1 can help to accurately predict prognostic outcomes in SMA.

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“…The number of SMN2 copies often has prognostic value regarding the severity of SMA disease presentation, with a milder presentation being associated with a larger number of SMN2 copies (22, 23, 25, 26). The profile generated by a sample with homozygous SMN1 deletion displays a simple melting peak associated with the presence of only the SMN2 gene and the T:A base pair at position c.840 (Fig.…”

Section: Discussionmentioning

confidence: 99%

Newborn Screening for Spinal Muscular Atrophy by Calibrated Short-Amplicon Melt Profiling

et al. 2012

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BACKGROUND The management options for the autosomal recessive neurodegenerative disorder spinal muscular atrophy (SMA) are evolving; however, their efficacy may require presymptom diagnosis and continuous treatment. To identify presymptomatic SMA patients, we created a DNA-based newborn-screening assay to identify the homozygous deletions of the SMN1 (survival of motor neuron 1, telomeric) gene observed in 95%–98% of affected patients. METHODS We developed primers that amplify a 52-bp PCR product from homologous regions in the SMN1 and SMN2 (survival of motor neuron 2, centromeric) genes that flank a divergent site at site c.840. Post-PCR high-resolution melt profiling assessed the amplification product, and we used a unique means of melt calibration to normalize profiles. Samples that we had previously characterized for the numbers of SMN1 and SMN2 copies established genotypes associated with particular profiles. The system was evaluated with approximately 1000 purified DNA samples, 100 self-created dried blood spots, and >1200 dried blood spots from newborn-screening tests. RESULTS Homozygous deletion of SMN1 exon 7 produced a distinctive melt profile that identified SMA patients. Samples with different numbers of SMN1 and SMN2 copies were resolved by their profiles. All samples with homozygous deletions were unambiguously recognized, and no normal sample was misidentified as a positive. CONCLUSIONS This assay has characteristics suitable for population-based screening. A reliable screening test will facilitate the identification of an SMA-affected cohort to receive early intervention to maximize the benefit from treatment. A prospective screening trial will allow the efficacy of treatment options to be assessed, which may justify the inclusion of SMA as a target for population screening.

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Combination of SMN2 copy number and NAIP deletion predicts disease severity in spinal muscular atrophy

Cited by 50 publications

References 16 publications

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

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

Genotype-Phenotype Correlation ofSMN1andNAIPDeletions in Korean Patients with Spinal Muscular Atrophy

Newborn Screening for Spinal Muscular Atrophy by Calibrated Short-Amplicon Melt Profiling

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