Brain fluid biomarkers may help distinguish SMA types, study finds

Marisa Wexler MS avatar

by Marisa Wexler MS |

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Blood is shown in vials and in a pipette.

Levels of certain molecules in cerebrospinal fluid (CSF) — the liquid that surrounds the brain and spinal cord — may help researchers distinguish between different types of spinal muscular atrophy (SMA), a study suggests.

The study, “Metabolomics of cerebrospinal fluid reveals candidate diagnostic biomarkers to distinguish between spinal muscular atrophy type II and type III,” was published in CNS Neuroscience and Therapeutics.

SMA is a genetic disorder characterized by symptoms including muscle weakness and wasting. The main types of SMA are caused by mutations in the SMN1 gene, which provides instructions for making the SMN protein. These mutations cause little to no SMN protein being produced.

A gene called SMN2 also provides instructions for making SMN protein. However, due to a slight genetic difference, the SMN2 gene produces only about 10% as much functional SMN protein as the SMN1 gene. Usually, a higher number of copies of the SMN2 gene is associated with lower disease severity.

SMA is divided into five main types, numbered 0 through 4, based on when and how symptoms manifest in the absence of treatment.

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Identifying new biomarkers ‘imperative’

‘It is widely acknowledged that SMN2 copy number can predict clinical classification,” the researchers wrote. “However, when SMN2 copy number is 2 or 3, it does not provide any indication as to whether SMA is type II or type III. Therefore, it is imperative to identify new biomarkers to facilitate the prediction of clinical classifications.”

This study specifically focused on SMA types 2 and 3. People with SMA type 2 first start experiencing symptoms between the ages of 6 months and 18 months. They develop the ability to sit independently but never the ability to walk. People with SMA type 3 start experiencing symptoms after 18 months, and they do develop the ability to walk, but often lose this ability fairly early on as the disease progresses.

The team of scientists in China measured levels of various molecules in CSF from 40 children with SMA, 27 with type 2 and 13 with type 3. None of the children had previously been treated with any disease-modifying therapy. Statistical models identified a total of 135 molecules that were present at significantly different levels in children with different types of SMA.

“This study identified metabolite markers in the CSF of children with SMA types II and III,” the researchers wrote.

In further tests, the researchers zeroed in on a handful of biomarkers that were especially promising for distinguishing between type 2 and type 3 SMA, noting plausible biological explanations for some of the associations. Patients with type 2 SMA, for example, tended to have higher levels of cinobufagin, a compound that’s associated with cell death. Higher levels of this molecule may reflect more extensive nerve cell death in patients with type 2 disease, which is by definition more severe than type 3.

The scientists also found seven CSF markers that showed significant associations with scores on the Hammersmith Functional Motor Scale, a standardized measure of motor function. Patients with higher motor function scores tended to have higher levels of a CSF marker called dihydromaleimide beta-D-glucoside.

The researchers noted that these analyses were limited to a small number of patients, so further studies will be needed to verify the results. Still, they said that “these metabolic markers in the CSF are promising candidate prognostic factors for SMA.”

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