The study, “Severe brain involvement in 5q spinal muscular atrophy type 0,” was published in the Annals of Neurology.
SMA comprises a group of neurodegenerative disorders characterized by the gradual loss of motor neurons — the nerve cells responsible for controlling voluntary muscles — in the spinal cord, leading to muscle weakness and wasting. It is normally caused by mutations in the SMN1 gene, which provides instructions for making the SMN protein that is essential for motor neuron survival.
It is divided into several subtypes (ranging from type 0 to type 4), depending on the age at disease onset and symptom severity. Patients with type 0, a highly severe form whose symptoms become apparent during fetal development (little fetal movement), usually have heart defects, and joint and muscle malformations. These babies rarely survive beyond their first weeks of life.
“Involvement of the central nervous system [composed by the brain, brainstem and cerebellum] is poorly documented in patients with SMA. Despite cognition appearing to be preserved in children with SMA, some cognitive impairment has been suggested in SMA type 1,” the researchers wrote.
In this case study, researchers with the Faculdade de Medicina da Universidade de São Paulo (FMUSP) in Brazil and colleagues described three children with SMA type 0 who survived beyond their first year of life relying on artificial ventilation, but with severe and progressive brain abnormalities. Such brain damage is unusual among SMA patients.
The children — two boys ages 1 and 2 and a 3-year-old girl — had a confirmed genetic diagnosis of SMA type 0, and underwent magnetic resonance imaging (MRI) brain scans before their second month of life and again at or near their current ages.
The 2-year-old boy had an episode of severe bradychardia (slow heart rate) at 3 months old that required five minutes of cardiopulmonary resuscitation. No episodes of cardiorespiratory arrest were reported in the other two children. Head size was normal in all three and none had experienced seizures.
Brain MRI scans showed that all three children had progressive atrophy (shrinkage) in certain regions of the brain, including the cortex and the hippocampus, as well as a severe reduction of white matter. (The cortex is the outer brain layer responsible for cognitive processing, and the hippocampus is a region responsible for short-term memory. White matter refers to brain areas made up of myelinated nerve segments — axons — responsible for the transmission of nerve signals between different regions of the brain.)
The cerebellum, a brain region responsible for body balance and movement control, was spared damage in all cases.
“The likelihood that all or some of the patient conditions resulted from concomitant involvement of other genes related to brain malformations was evaluated. Results of a wide spectrum of genes analyzed by NGS [next-generation sequencing] showed no variants that could be considered disease-causing variants in our patients,” the investigators write.
“We postulate that severe reduction in SMN protein levels might lead to a progressive [brain] dysfunction and degeneration, apparently sparing the cerebellum,” they added.
Because two approved therapies for SMA now exist, “these observations raise the question of whether early intervention in this category of patients, either with SMN2-splicing modulators [Spinraza (nusinersen)] or gene transfer of SMN1 [Zolgensma (AVXS-101)], might interfere with or modify the progression of severe brain [abnormalities],” the researchers said.
Evidence is lacking in SMA type 0 as to “whether these interventions could rescue an already established severe symptomatic state,” they concluded.