Focus on breathing and swallowing to see the new progress in the correction and treatment of spinal muscular atrophy

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Spinal muscular atrophy (SMA) is a neuromuscular disorder
in which functional SMN protein is not produced due to homozygous deletion/mutation of motor neuron survival gene 1 (SMN1).
As a disease originating from the central nervous system, SMA not only involves motor neurons α anterior horn of the spinal cord, resulting in progressive and symmetric muscle weakness and muscle atrophy, but also affects motor neurons of the medulla oblongata, causing swallowing dysfunction, which in turn affects multiple physiological processes
such as respiration and nutrition.
As the disease progresses, SMA can cause multiple systemic abnormalities including bone, respiratory, digestive, and cardiovascular ^{systems [1].}

In recent years, a variety of disease-modifying therapy (DMT) drugs have been shown to be effective in improving the motor function of SMA patients, but there is still a lack of sufficient understanding of the therapeutic management of respiratory and swallowing function.

(1) Be alert to SMA respiratory complications and pay attention to early respiratory management

SMA often affects the respiratory system, and respiratory failure is the most common cause of death in children with SMA

The effect of SMA on the respiratory system depends on the type of SMA and the severity of muscle loss, and most children with SMA type 1 develop complications of worsening respiratory function in the first year of life and require a variety of treatments to support airway clearance and ventilation
.
Natural history studies suggest that 100% of children with SMA type 1 older than 12 months require nutrition, combined nutrition, or ventilatory support
due to respiratory failure.
Sixty-one percent of children with SMA type 1 require one intubation ≥ the first year of life ^[2].

In a retrospective study in Japan, 52 percent and 13 percent of patients with type 2 and type 3 SMA required noninvasive positive pressure ventilation (NPPV), respectively ^[3].

The pathophysiological changes of the respiratory system characteristic of SMA are mainly intercostal muscle weakness, thoracic deformation, and decreased lung volume and ventilation, resulting in a series of respiratory problems such as hypoventilation, weakened cough, sputum blockage, reflux and aspiration, and recurrent respiratory infections ^[4], and eventually death
due to pneumonia, atelectasis and respiratory failure.
Of the multisystem impairments and complications involved in SMA, respiratory problems are the leading cause
of death in children with SMA.

Respiratory management is critical for patients with SMA, and strategies have shifted from reactive to early active therapy ^[4].

Good airway management improves comfort and reduces intubation, intensive care unit admission, and case fatality in
children with SMA.
The Expert Consensus on Respiratory Management of Spinal Muscular Atrophy (2022 Edition) emphasizes that reasonable and effective respiratory management strategies are of great significance
to stabilize the respiratory function of patients with SMA and reduce the incidence of respiratory related complications and disease mortality.

The ultimate goal of respiratory management for patients with SMA is to prolong survival, achieve normal gas exchange, relieve sleep-breathing problems, prolong home care, and improve quality of life
.
Management principles have shifted from reactive treatment in the past to active treatment
with early onset.
However, management strategies for patients with SMA vary by disease type and maximal motor milestone, and the specific management approach should correspond to the results of the assessment of respiratory problems (Table 1).

Table 1.
Principles of respiratory status detection and respiratory management in patients with SMA

Therapeutic drugs for the improvement of respiratory function in patients with SMA

Early intervention and management of respiratory problems in patients with SMA can significantly reduce the morbidity and mortality of respiratory diseases, and etiological treatment remains critical
.
In recent years, the treatment of SMA etiology has progressed rapidly, and the main purpose is to increase the production of full-length functional SMN protein ^[4].

Nocinaxen is an antisense oligonucleotide designed to increase the expression of the SMN2 protein and is the world's first DMT drug
approved for the treatment of all types of SMA in children and adults.
Since 2011, several clinical studies of nocinaxen in the treatment of patients of different ages and types of SMA have been initiated, demonstrating the significant benefits of nocinaxen in improving motor function and increasing event-free survival and overall survival in patients with SMA ^[5].

Nocinaxen also includes respiratory-related clinical endpoints
in its clinical trials.
In the NURTURE study [^6] of children who started nocinaxen prior to SMA symptoms, interim data from 4.
9 years of follow-up (as of February 2021) showed that all children were alive without permanent ventilation or tracheostomy, and that 84% (21/25) of patients did not require respiratory intervention (Figure 1).

A prospective observational study of 28 patients with SMA types 1 to 3 ^[7] evaluated the effect
of nocinaxen on respiratory function in children with SMA in the first year of treatment.
The results of this study showed a decrease in lung function and an improvement in sleep apnea in the first year of treatment with nocinaxen (Figure 2).

Figure 1.
Interim results of the NURTURE study over 4.
9 years

Figure 2.
Sleep apnea-hypopnea index (AHI) in patients with SMA type 1, 2, and 3 at baseline and 1 year

(2) The high incidence of swallowing problems in SMA patients, and it is very important for SMA patients to improve the function of the medulla oblongata

Feeding and swallowing problems can occur in patients of all types and ages with SMA

Autopsy studies of patients with SMA have found that patients with SMA have abnormal brainstem motor nuclei, which is manifested by an impaired
caudal-tocordial gradient of bulbar function (speech and swallowing).
Van der Heul et al.
found that a significant proportion of patients with SMA had bulbar problems ^[8].

A cross-sectional study of 145 patients with SMA types 1 to 4 ^[9] showed that swallowing-related problems
may occur in patients with all types of SMA.
Swallowing and feeding problems are particularly pronounced in young patients with SMA types 1 and 2 SMA, and are often associated with more severe bulbar complications ^[10,11], including occlusion, chewing, and mouth opening problems, dysphagia with tracheal protective dysfunction, and gastroesophageal reflux disease, and an increased
risk of aspiration pneumonia, asphyxia, and failure to thrive.

Older patients with milder severity of SMA also have some swallowing and feeding problems
.
A study of 118 patients with SMA aged 1 to 75 years in the Dutch registry ^[8] showed that patients with type 3 or 4 SMA aged 30 years and older frequently reported bulbar problems, including bite, chewing-related fatigue, choking, and weak
sound.
Therefore, for older patients with mild SMA, swallowing and feeding problems should not be underestimated
.

The occurrence of dysphagia in patients with SMA is not only related to the medulla oblongata, but also has a certain correlation with lower motor neurons

Swallowing is regulated by a series of processes regulated by the swallowing center located in the medulla oblongata, and dysphagia is thought to be associated with bulbar dysfunction ^[12].

In patients with SMA, dysphagia is also affected
by lower motor neuron dysfunction and compensatory head posture.
Lower motor nerve dysfunction affects the strength of the tongue and submental muscles, resulting in poor head position and reduced mouth opening, which are the causes of dysphagia ^[12,13].

In a cross-sectional study of 108 patients with SMA ^[14], motor status, respiratory status, and head posture control were independent risk factors
for swallowing problems in patients with SMA type 2 and 3.
A cross-sectional study of 145 patients with SMA types 1 to 4 [^9] showed that reduced maximum mouth opening was one of
the determinants of dysphagia in patients with SMA1 and 2.

A prospective non-interventional observational study of 151 patients with SMA ^[15] evaluated the expected treatment symptoms of patients by the MYMOP2 scale, and showed that improvement in bulbar function was one of the
main treatment expectations for patients with SMA1 and 2.
It can be seen that improving bulbar function is important
for patients with SMA.

DMT drugs are effective in maintaining and improving bulbar swallowing function in patients with SMA

Data on bulbar function in the NURTURE trial, longitudinal results assessed in the 3.
8-year interim analysis by PASA questionnaire, a comprehensive tool for assessing swallowing capacity, ^showed preservation of swallowing function in presymptomatic children treated with nocinaxen (Figure 3); As of the last PASA assessment, 92% (23/25) of children (23/25) maintained swallowing ability; On average, parental concerns
about their child's ability to swallow were not reported within 2 years.

Figure 3.
FOR MOST PASA PROGRAMS, THE CHILDREN WERE CONSISTENTLY RATED AS NEVER OR RARELY (A) 'GENERAL FEEDING', (B) 'DRINKING LIQUID FOODS', (C) 'EATING SOLID FOODS' DIFFICULTIES, AND (D) PARENTAL ASSESSMENT OF SWALLOWING PROBLEMS, REGARDLESS OF THE SMN2 COPY NUMBER DURING OVER THE 2-YEAR TEST PERIOD

Berti et al.
^[17] recently proposed a new structured assessment tool (OrSAT) specifically designed to record different aspects related to speech, swallowing, and feeding ability in patients with type 1 SMA, to analyze the swallowing ability of 20 children with type 1 SMA who received nocinaxen between the ages of 3 and 15 months, and the study confirmed that nocinaxen has some efficacy on swallowing function, as confirmed
by key studies 。 The degree of impairment of swallowing function at the start of treatment can help predict swallowing progression; OrSAT, a structured assessment tool, can help provide an overview of swallowing capacity and detect changes over time in the clinic, which can help help the clinic develop appropriate intervention plans
.

In addition, several real-world studies ^[18,19] have confirmed that nocinaxate improves bulbar swallowing function, especially in adult patients
.
Further and more in-depth studies
are needed to validate the formation of a new outcome measure of improvement in medulla function and other methods of assessing bulbar function, including sound, language, swallowing, etc.

summary

SMA is a serious progressive motor neuron disease, which affects not only the anterior horn motor neurons of the spinal cord, but also the brainstem motor neurons, which can cause systemic multisystem abnormalities
such as bone, respiratory, and digestive.
As the world's first approved disease-modifying therapeutic drug, the emergence of nocinaxen has brought the clinical treatment of SMA into a new historical stage
.
Several pivotal studies and real-world studies have confirmed that nocinaxen can sustainably improve and stabilize important functions such as movement, breathing, and swallowing in patients with various types of SMA, and alter the natural course of
the disease.
In terms of improvement in swallowing and respiratory function in patients with SMA, nocinaxen is currently the treatment with the most authoritative evidence
.
In the future, it is necessary to accumulate more experience and evidence in respiratory and swallowing management in disease research and clinical practice, so as to better serve and optimize SMA treatment management strategies and comprehensively improve the quality of life of
SMA patients.

References

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A severe mouse model of spinal muscular atrophy develops early systemic inflammation.
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Bulbar Problems Self-Reported by Children and Adults with Spinal Muscular Atrophy.
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[9] Wadman RI, van Bruggen HW, Witkamp TD, et al.
Bulbar muscle MRI changes in patients with SMA with reduced mouth opening and dysphagia.
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Feeding difficulties in children and adolescents with spinal muscular atrophy type 2.
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Dysphagia in spinal muscular atrophy type II: more than a bulbar problem.
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e1.

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[18] Veerapandiyan A, Eichinger K, Guntrum D, et al.
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