SMN2 gene is one of the important modification genes that affect the progression of SMA disease. Most SMA type 1 patients have 2 copies of SMN2, type 2 patients have 3 copies of SMN2, and type 3 patients have 3-4 copies of SMN2[8]. SMN2 gene copy number is negatively correlated with the severity of SMA, But SMN2 gene copy number does not completely correspond to the clinical phenotype, because not all SMN2 copies are functionally identical. Intragenic SMN2 mutations, partial SMN2 deletions or duplications, and different degrees of SMN2 promoter methylation may further modify the functionality of the SMN2 gene[9,10]. Some studies conducted sequencing analysis of SMN2 gene and found that c. 859G > C mutations are associated with milder cases. Because the SMN2 genes that contain this rare variant would produce a higher number of full-length transcripts and thus of functional protein. Therefore, there are few copies of SMN2 but clinical manifestations. However, SMN2 c.859C>G variant is present in a few patients with chronic SMA, but not in type 1 [11]. Recent studies have revealed the existence of new modified SMA genes. Neuronal Apoptosis Inhibitory Protein gene (NAIP) and Small EDRK-rich factor 1A (SERF1A) are located in the 5q13.2 region. SERF1A gene can regulate the aggregation of SMN proteins. The function of NAIP gene is related to negative regulatory factors of motor neuron apoptosis. About half of patients with severe SMA lack the NAIP and SERF1A genes[12]. According to previous studies, the NAIP gene is deleted in more than 50% of patients with type 1, but the frequency of this gene deletion is much lower in patients with type 2 and 3[13]. Medrano S, et al. found in their study of SMA phenotypes in children that nearly 73% of children with type 1 lacked NAIP gene and 35% of children with type I lacked the SERF1A gene[14].
Both patients we reported had copy number of 3 copies of the SMN2 gene but were clinically typed as type 1. Detection of the patient's genes SMN1 and SMN2 by multiplex-linked probe amplification (MLPA) did not reveal other SMA-modified genes. SMA patients are less likely to have genetic alterations leading to phenotypic inconsistencies. However, further genetic testing is required for the presence of alterations such as mutations, partial deletions, or duplications within the SMN2 gene in 2 patients.
Although the clinical phenotype and natural history of SMA1 are well known in motor, breathing and swallowing, but cognitive development of children and adolescents with this chronic disease has not received much attention. Communication has important effects on neurodevelopment, especially socialization, learning and education. Respiratory muscles and medulla oblongata muscles are the engines of speech function, and the respiratory muscles of SMA type 1 patients are seriously affected[15]. Speech development is often absent or very limited in SMA type 1 patients, which strongly limits social interaction in children with SMA type1. There are few studies on cognitive dysfunction in 5q-SMA patients. These studies evaluated the cognitive function of all patients diagnosed with SMA, and did not report or analyze the patients with cognitive impairment. The severely impaired motor and speech abilities of SMA children hinder the accurate assessment of cognitive function, which may lead to underestimation of their cognitive function[16]. This is the first report of cognitive impairment in 5q-SMA patients in which two SMA type 1 patients developed cognitive impairment at an early stage.
The loss of motor ability may lead to the selective development of learning skills and speech function of SMA patients, so SMA patients look smarter than healthy people. However, SMA patients (mainly type 1 and type 2) are related to severe weakness, which will affect hand coordination and speech acquisition, and the limited interaction between speech and sensory motor will lead to cognitive impairment[6]. Two patients with SMA had significant cognitive impairment in our study, with severe motor limitations and lack of speech at an early stage. Children with SMA type 1 have difficulty communicating because most of them cannot speak and all have poor motor control, and severe motor paralysis in children with SMA type 1 may be related to cognitive delays[17,18]. The cognitive ability of SMA patients is related to motor dysfunction, and SMA patients with greater motor difficulty have poorer performance in attention[19]. The study of cognitive function and disease severity of SMA found that, in men with higher disease severity, lower attention, and working memory ability, and better verbal and verbal fluency test performance[20]. The motor dysfunction of SMA patients may have no obvious correlation with visual-spatial cognitive ability. A study on the cognitive ability of motor and visual space of children with SMA type 2 found that children with SMA type 2 had no difficulty in complex spatial relations, and motor disorder was not the key risk factor for the significant slowdown in the development of spatial search skills[21].
The cognitive function of SMA patients may be related to the age of onset. The influence of cognitive factors may not be related to the early disease itself, the degree and duration of physical disability, but to the onset of movement disorders in early life. SMA with early onset in children can compensate for their physical disability through cognition, and show higher scores in different cognitive abilities[22]. When SMA patients reach adolescence, they "compensate" for their physical deficits by acquiring cognitive skills and knowledge, and the environment mediates higher levels of intelligence[4]. The two patients in this paper were all SMA type 2 with cognitive impairment in infancy, which may be due to early movement disorders leading to less social communication and no formal education, and the patients had obvious cognitive dysfunction. Family background, social aspects, and access to the most suitable education are most likely to play an important role in improving SMA cognitive function. Without strong support and encouragement from these aspects, SMA children may not be able to develop a compensation mechanism, resulting in cognitive impairment[22].
Some studies show that the physical activity of healthy teenagers has a positive impact on cognition, but physical disability in early life may also have a positive impact on cognitive function in other ways[23,24]. The serious physical injury of SMA patients in childhood and adolescence makes them pay more attention to education, so their cognitive function, which is mainly based on knowledge and depends on education, has been improved compensatory. Severe dyskinesia can lead to educational disadvantage, but early educational support seems to stimulate compensatory development.[22].
Our two patients are SMA type 1, who had early onset, obvious cognitive impairment in infancy, and had not received formal education after birth. The gradual lack of stimulation and limited social experience of older children with SMA type 1 may lead to the gap between cognitive ability and language understanding. A study on the task matching of SMA type 1 patients found that SMA type 1 patients had worse task completion. Although SMA type 1 children attend school regularly and receive formal education, they may have difficulties in remembering, processing, or expressing cognitive information. In addition, children with SMA type 1 may start school later, they have more comorbidities and absences from school, which can affect learning and develop cognitive impairments[7]. SMA affects patients' motor function and usually has little effect on cognitive function. A few studies have shown that SMA can affect patients' cognitive function, but usually without severe cognitive impairment. Cognitive dysfunction may be a co-morbidity of the 2 SMA patients, and the cause of their severe cognitive dysfunction needs to be further explored.
There is little evidence in studies about cognitive performance in children with SMA, but children with SMA type 1 are more likely to be affected. Even in children with cognitive ability at birth, lack of cognitive stimulation may lead to cognitive delay[7]. Current research suggests that the cognitive results may be related to the copy number of the SMN2 gene. The lack of SMN protein not only affects spinal motor neurons, but also may affect other cellular compartments of the central nervous system. Severe reduction of SMN protein levels may lead to progressive brain dysfunction and degeneration. A few SMA cases without SMN2 (SMA type 0) will have atrophy of white matter and hippocampus, and these patients also show high signals in the thalamus and basal ganglia on magnetic resonance imaging[25]. Wishart et al. showed that the changes of brain development process were related to low SMN protein level in severe SMA mouse models[26]. The study of brain structure changes in SMA adults and healthy controls found that cerebellum atrophy and gray matter density in the motor cortex increased. Cortical hypertrophy of motor areas was interpreted as cortical reorganization following lower motor neuron degeneration[27]. It is not known whether a deficiency of SMN2 in the central nervous system is the main cause of the reduced intelligence quotient (IQ). Or whether patients are unable to explore their surroundings due to muscle weakness, and therefore their IQ is not fully developed[28]. The abnormal cranial MRI findings of patient 2 in this study suggest that abnormal brain development in SMA patients may be associated with cognitive dysfunction.
In conclusion, Cognitive dysfunction may exist in SMA patients, but there are few relevant studies. Cognitive dysfunction in SMA patients may be related to motor impairment, age of onset and education, and may not be related to the underlying gene mutation. The pathogenesis may be related to brain developmental disorders and SMN protein deficiency. SMA patients present with predominantly mild changes in cognitive function, and this study reported two SMA type 1 patients with severe cognitive dysfunction, whose severe cognitive dysfunction may be a co-morbidity of SMA. Clinical cognitive dysfunction in patients with muscle weakness and atrophy suggests that clinicians should not underdiagnose SMA or misdiagnose it as other diseases. Patients with SMA should undergo early cognitive intervention to prevent progressive development of cognitive impairment. There are few studies on the relationship between cognitive dysfunction and SMA, and there is no evidence of a causal relationship between cognitive characteristics and nusinersen treatment. Further research and exploration are needed in these areas in the future.