Study highlight’s role of ultra-LRS in treating the condition clinically
Two young patients with spinal muscular atrophy (SMA) were found to have rare mutations in their SMN1 gene, according to a study that employed ultra-long read sequencing (ultra-LRS) to analyze extensive DNA segments. The research, published in Neuromuscular Disorders, emphasizes the significance of ultra-LRS in the clinical context of SMA.
The majority of SMA cases, approximately 95%, are caused by the total absence of exon 7 in both copies of the SMN1 gene, inherited from each parent. Exons, which contain the necessary information for protein synthesis, are interspersed with introns in a gene’s structure. Introns are subsequently removed prior to protein production.
When both copies of exon 7 are missing, there is a deficiency of the SMN protein, which is vital for the proper functioning of nerves connected to muscles. This shortage of SMN protein leads to symptoms such as muscle weakness and degeneration. The severity of the disease largely depends on the quantity of the “backup” SMN2 gene, which can also produce some SMN protein.
In this study, researchers from China reported the cases of two individuals diagnosed with SMA who possessed atypical SMN1 mutations. The use of ultra-LRS in their investigation highlights its value in detecting these rare genetic variations.
Two patients with unusual SMN1 gene mutations
Two patients with unique SMN1 gene mutations were studied, with one displaying symptoms of spinal muscular atrophy (SMA) at 11 months and diagnosed with SMA type 2 at age 3. He was treated with Spinraza, an approved SMA therapy, which improved his motor function. Genetic testing did not reveal a clear cause, leading researchers to use ultra-long read sequencing (ultra-LRS) on samples from the patient and his parents.
Ultra-LRS found a deletion in the mother’s SMN1 gene, including exon 1 and part of intron 1. The father had a hybrid gene composed of exons 1 through 7 of the SMN2 gene and exon 8 of SMN1. This is the first reported case of SMA with a partial SMN1 deletion combined with a hybrid SMN gene.
The patient had lower SMN1 gene activity and reduced SMN protein levels compared to an unaffected control, but higher than an SMA type 1 patient. This may be due to the patient having no SMN1 copies, two SMN2 copies, and one hybrid SMN gene copy, which could be equivalent to three SMN2 copies, explaining the less severe SMA type 2 diagnosis.
The second patient, suspected of SMA, died at 2 months from severe pneumonia, lung failure, and muscle weakness. Genetic testing found a deletion in one of the SMN1 copies. Ultra-LRS performed on the father revealed a similar but larger mutation in the SMN1 gene. The mother likely had a complete SMN1 gene deletion, which her son inherited, resulting in an SMA type 1 diagnosis.
Ultra-LRS was used to find the precise deletion locations within the SMN1 gene for both patients. Breakpoint ends were identified within Alu-repetitive elements, which are transposable elements making up 11% of the human genome. Researchers suggested that Alu-mediated rearrangements may be a mechanism for the evolution of these deletions and could be more common in SMA than previously thought.
The study demonstrates the potential of ultra-LRS in identifying structural variations in SMA patients and highlights the importance of understanding Alu-mediated structural variations in clinical practice.
SMN1 Gene Mutation Symptoms
The Survival Motor Neuron 1 (SMN1) gene is necessary for the SMN protein to be produced, which is essential for the healthy operation of motor neurons. This gene causes spinal muscle atrophy, a condition characterized by muscle collapse and wasting.
Hypothetical Case 1: In contrast to the typical proximal-to-distal trend seen in SMA, a 28-year-old lady develops growing muscular weakness in her lower limbs. She can still ambulate, but walking is tough for her, and ascending stairs is difficult for her. She also has sleep apnea and some respiratory issues, none of which are normal for an adult with SMA at her age. An SMN1 gene mutation is confirmed through genetic testing.
Case 2: Usually, SMA affects the lower limbs more severely, but in this hypothetical case, a 10-year-old kid has muscular weakness mostly in his upper limbs, which is atypical for SMA. He also experiences modest swallowing difficulty and speech-related problems, which are not often connected to SMA. Genetic testing reveals an SMN1 gene mutation despite these unusual symptoms.
Both fictitious individuals have peculiar symptoms for SMA. However, because to the wide variation in how SMA manifests, it is essential to speak with a genetic counselor or a professional who specializes in neuromuscular disorders to guarantee an accurate diagnosis and create the best treatment strategy.