March has kicked off with new SMA publications largely focused on understanding the disease at the cellular and molecular levels. New reviews on progress in SMA treatments have also been released, as has new patient-focused information including new data on carrier frequency.

Understanding SMA

The clinical spectrum of BICD2 mutations.1

This paper describes an investigation into the clinical manifestations of mutations in the bicaudal D cargo adaptor 2 (BICD2) gene that causes autosomal dominant lower extremity predominant spinal muscular atrophy 2A (SMALED2A). Based on clinical data from 11 patients across 5 families with these mutations, the researchers found new patterns of muscle involvement that implicate the pelvic and foot muscles in SMALED2A. Their results also point to the possibility that the sensory system is compromised in this disease. 

Read more here. 

Synaptotagmin 13 is neuroprotective across motor neuron diseases.2

In this article, researchers describe their study into the mechanisms by which certain motor neuron subtypes are spared in diseases like SMA and amyotrophic lateral sclerosis (ALS). The scientists found that oculomotor neurons, which are spared in these diseases, express synaptotagmin 13 (SYT13) at higher levels than do spinal motor neurons, which are compromised. They also found that overexpressing SYT13 in motor neurons from patients with SMA and ALS increased the axon lengths of the cells and enhanced their survival. The authors point to the ability of gene therapy with SYT13 to enhance survival in mouse models of these diseases as well as the ability of SYT13 to reduce endoplasmic reticulum stress and motor neuron apoptosis. The authors conclude that SYT13 represents a resilience factor that is protective of motor neurons and that it could be a therapeutic target in these diseases.

Read more here. 

miR-206 reduces the severity of motor neuron degeneration in the facial nuclei of the brainstem in a mouse model of SMA.4

The molecule miR-206 has been observed to play a role in the regeneration of neuromuscular junctions in motor neuron diseases. In this paper, researchers describe their study showing that miR-206 is upregulated in the brainstem in a mouse model of SMA early on in disease progression and downregulated at late stages. When researchers injected miR-206 intracerebroventricularly, SMA severity was reduced, the disease progressed slower, mice survived longer, and their behavioral performance improved. The authors conclude that miR-206 appears to provide neuroprotection that they hypothesize could occur through the influence of miR-206 on NCX2 expression.

Read more here.

Scoliosis surgery significantly impacts motor abilities in higher-functioning individuals with spinal muscular atrophy 1.5

This paper describes an investigation into the effect of scoliosis surgery on motor function in patients with SMA type 2 and SMA type 3 and is based on an analysis of 17 patients. The results showed that immediate effects on motor function could be observed following scoliosis surgery. The researchers note that compensatory maneuvers were limited when patients were subjected to instrumentation that involved fixation to the pelvis and suggest that clinicians should consider this information when conducting surgeries and counseling families.

Read more here.

Is prophylactic formal fusion with implant revision necessary in non-ambulatory children with spinal muscular atrophy and growing rods who are no longer lengthened?6

In this article, the researchers detail their investigation into the utility of routine posterior spinal fusion in growing rod graduates with SMA. According to the authors, though most non-ambulatory children with SMA and early-onset scoliosis are managed with posterior growing rods followed by fusion, there has been little information on the best clinical approach once children graduate from their growing rods. Though their analysis included only 12 patients, the data suggest that the fusion may not be necessary.

Read more here.

Recent Reviews:

  • Functional roles of non-coding RNAs in motor neuron development and disease.7

Long non-coding RNAs (lncRNAs) are highly expressed in the brain, but as their specific role in spinal motor neurons has not been extensively explored, this review covers what is known about lncRNAs in motor neuron development and motor neuron disease. The authors also discuss the potential of lncRNAs to contribute to motor neuron disease therapies.

Read more here.

  • The genotypic and phenotypic spectrum of BICD2 variants in spinal muscular atrophy.8

In this review, the authors describe an investigation into the relationship between genotype and phenotype for the BICD2 gene. They analyzed data from 14 publications and identified the features of BICD2 variants that appear to cause diseases like SMALED2. 

Read more here. 

Treating SMA

Recent Review:

  • Gene-specific treatment approaches in muscle diseases.9

In this review, the authors discuss antisense oligonucleotide technologies and gene therapies that are currently used as disease-modifying treatments for SMA and Duchenne muscular dystrophy. The authors focus on latest developments and future directions.

Read more here.

  • New treatments for spinal muscular atrophy.10

This review discusses disease-modifying drugs for SMA, including the most impactful studies on these drugs and the challenges associated with them. Nusinersen and gene replacement therapies are widely covered, and the article highlights the potential use of these therapies in 5-q-associated SMA.

Read more here. 

Patient Focus and Policy Implications

Spinal muscular atrophy diagnosis and carrier screening from genome sequencing data.11

In this paper, researchers describe their newly developed method for accurately identifying SMN1 and SMN2 copy number. Because their sequences are nearly identical, analyzing SMN1 and SMN2 has traditionally been challenging. The authors that with this new technique, which leverages genome sequencing data, both affected patients and carriers can be readily identified. The authors therefore conclude that this technique could provide a basis for neonatal tests and carrier screening.

Read more here.

SMN gene copy number analysis by exome-seq: assisting SMA diagnosis and carrier screening.12

This article describes a workflow that the authors established to analyze SMN gene copy number that incorporates exome-seq data analysis. The authors applied the workflow retrospectively to a NICU cohort and validated the approach with multiple ligation-dependent probe amplification. Their results showed that this workflow could provide accurate SMN1 and SMN2 copy number analysis and thus assist in diagnosis and screening.

Read more here.

Carrier frequency of spinal muscular atrophy in a large-scale Korean population.3

The authors of this study argue that given the rise of new gene therapies for SMA, it is important that we understand SMA carrier frequency in different populations to improve our ability to screen for the disease. As such, they studied nearly 1,600 DNA samples from a Korean umbilical cord bank and used multiplex ligation-dependent probe amplification to test the samples for SMN1 and SMN2 gene copies. Their results suggest that the carrier frequency in the Korean population is approximately 1 in 55

Read more here.

References

1. Frasquet M, Camacho A, Vilchez R, et al. The clinical spectrum of BICD2 mutations. Eur J Neurol. February 2020. doi:10.1111/ene.14173

2. Nizzardo M, Taiana M, Rizzo F, et al. Synaptotagmin 13 is neuroprotective across motor neuron diseases. Acta Neuropathol. February 2020. doi:10.1007/s00401-020-02133-x

3. Park JE, Yun SA, Roh EY, Yoon JH, Shin S, Ki CS. Carrier Frequency of Spinal Muscular Atrophy in a Large-scale Korean Population. Ann Lab Med. 2020;40(4):326-330. doi:10.3343/alm.2020.40.4.326

4. Valsecchi V, Anzilotti S, Serani A, et al. miR-206 Reduces the Severity of Motor Neuron Degeneration in the Facial Nuclei of the Brainstem in a Mouse Model of SMA. Mol Ther. January 2020. doi:10.1016/j.ymthe.2020.01.013

5. Young SD, Montes J, Salazar R, et al. Scoliosis Surgery Significantly Impacts Motor Abilities in Higher-functioning Individuals with Spinal Muscular Atrophy1. J Neuromuscul Dis. February 2020. doi:10.3233/JND-190462

6. Hanna R, Sharafinski M, Patterson K, et al. Is prophylactic formal fusion with implant revision necessary in non-ambulatory children with spinal muscular atrophy and growing rods who are no longer lengthened? Spine Deform. February 2020. doi:10.1007/s43390-020-00077-6

7. Chen K-W, Chen J-A. Functional Roles of Long Non-coding RNAs in Motor Neuron Development and Disease. J Biomed Sci. 2020;27(1):38. doi:10.1186/s12929-020-00628-z

8. Koboldt DC, Waldrop MA, Wilson RK, Flanigan KM. The genotypic and phenotypic spectrum of BICD2 variants in spinal muscular atrophy. Ann Neurol. February 2020. doi:10.1002/ana.25704

9. Lehmann Urban D, Schneider I. [Gene-specific treatment approaches in muscle diseases]. Nervenarzt. February 2020. doi:10.1007/s00115-020-00870-8

10. Wurster CD, Gunther R. [New treatments for spinal muscular atrophy]. Nervenarzt. February 2020. doi:10.1007/s00115-020-00871-7

11. Chen X, Sanchis-Juan A, French CE, et al. Spinal muscular atrophy diagnosis and carrier screening from genome sequencing data. Genet Med. February 2020. doi:10.1038/s41436-020-0754-0

12. Liu B, Lu Y, Wu B, et al. SMN gene copy number analysis by exome-seq: assisting SMA diagnosis and carrier screening. J Mol Diagn. February 2020. doi:10.1016/j.jmoldx.2020.01.015