Brain Involvement in SMA Type 1 Still Poorly Understood, Review Finds

Children with spinal muscular atrophy (SMA) type 1 may have neurodegeneration in several areas of the brain, with impaired cognitive function and profound speech difficulties, according to a review study.

However, brain involvement in this severe type of SMA is understudied and further research — using objective measures and following patients over time — is needed to clarify this aspect of type 1 disease, the researchers noted.

Such research, and the information it will uncover, will not only help to better understand the broad impact of SMA type 1, but also will aid in identifying appropriate brain-related outcome measures to evaluate the effectiveness of current and future therapies in this patient population, the team said.

The review study, “Brain, cognition, and language development in spinal muscular atrophy type 1: a scoping review,” was published in the journal Developmental Medicine & Child Neurology.

SMA type 1, the second most severe type of the disease, accounts for 60% of all cases and is the most common genetic cause of death in infants, with a life expectancy of less than two years when left untreated.

Type 1 is classified into three subgroups according to the age at symptom onset: within the first 2 weeks of life (type 1a), by 3 months of age (type 1b), and between ages 3 and 6 months (type 1c).

While there is extensive data on the respiratory, bulbar (swallowing), and motor function of these patients, “less attention has been paid to other features of the disease, including brain involvement,” the researchers wrote. Of note, in addition to swallowing, bulbar function refers to other abilities related to the muscles that control breathing, chewing, and speaking.

Importantly, problems in brain functions, such as cognition, speech, and language, have become even more obvious with the increased number of available disease-modifying therapies, as children with SMA type 1 are living longer.

“A better understanding of the characteristics and extent of brain involvement in SMA type 1 is crucial for a deeper comprehension of the clinical features of the disease and for personalized patient management,” the researchers wrote.

Now, researchers in Italy and the U.K. have systematically reviewed published studies up to December 2019 reporting analysis of brain features, cognitive function, and speech/language development in people with SMA type 1.

A total of 19 studies, covering 283 type 1 patients, were included in analysis: 11 focusing on brain features (18 individuals; three studies in mouse models), four on cognition (63 patients), and four on speech/language development (202 people). All but one study included untreated patients.

Results from the limited number of infants and children assessed for brain features showed these patients had signs of neurodegeneration and abnormalities in several brain regions, along with brain shrinkage. Brain involvement seemed to be even more clear in the most severe subtype (type 1a).

While brain abnormalities were not assessed over time in these patients, longitudinal studies in those with SMA type 0, the most severe form of the disease, suggested the presence of progressive brain involvement, the team noted.

In addition, data from mouse models further supported “a possible primary brain involvement in patients with SMA type 1,” the researchers wrote.

The available data on patients’ cognitive function — most involving a typically developing comparison group of people — were contradictory. Older research suggested normal cognitive function, while more recent studies reported performances below normal, particularly in expression, social interaction, and problem-solving.

Less severe forms of the disease, namely type 2 and 3, are reported to have normal speech/language skills relative to their unaffected peers. However, those with type 1 showed poorer performances in several brain functions, such as attention, executive function, and speech/language.

Notably, the data also showed that “functional and intelligible speech is rarely achieved in children untreated for SMA type 1,” the researchers wrote.

Still, language analyses in these patients were limited to parent reports and non-formal assessments.

Overall, the review study highlighted that “a comprehensive understanding of brain involvement in SMA type 1 is still lacking,” the team wrote. This is likely associated with the difficulty of assessing brain functions in severely affected patients, who often were not able to provide verbal or gestural responses due to severe muscle weakness.

“Considering that the limited interaction with the environment owing to poor expressive communication skills has been shown to further impact on cognitive development in several neurodevelopmental disorders, alternative and augmentative ways to communicate are recommended from early in life,” the researchers said.

The team also noted that analyzed studies had, on their own, several limitations, including a small number of patients, and a lack of comparison groups, appropriate statistical analyses, and validated and/or standardized measures.

“Future longitudinal studies focusing on standardized assessments of cognitive and speech/language development in SMA type 1 are required, as well as longitudinal neuroimaging evaluations performed alongside,” the researchers wrote.

These studies will help to better understand the broad clinical features of SMA type 1 — contributing to the growing notion that SMA may be a multi-system disorder. They also will help to “improve … the personalization of rehabilitation programs supporting patients’ autonomies and quality of life,” the team said.

New data also will help define additional outcome measures for evaluating the effectiveness of current and new potential therapies for SMA in lessening brain-related impairments.

Since speech involves both muscular and neurological domains, further studies also are needed to clarify whether bulbar function improvements will allow children to develop normal communication skills, or whether residual brain deficits will challenge such achievement, the team noted.