Problems with Metabolizing Fat Molecules Also Evident, and Worrisome, in SMA Children, Study Says

Although damage to motor neurons characterizes spinal muscular atrophy, problems with lipid (fat) metabolism are an important feature of SMA that should be addressed to minimize the risk of heart and liver disease related to high levels of fatty molecules in people with the disorder, a study found.

Complications due to poor lipid metabolism — the synthesis and breakdown of fatty molecules largely ingested in foods or synthesized by the liver — are coming to the fore as Zolgensma, Spinraza, and other potential treatments address SMA’s root cause, the researchers noted.

Their study, “Abnormal fatty acid metabolism is a core component of spinal muscular atrophy,” published in Annals of Clinical and Translational Neurology, recommended the creation of nutritional guidelines and metabolic screenings for SMA patients.

The gradual loss of motor neurons — the nerve cells responsible for controlling voluntary muscles — that leads to muscle weakness and wasting is caused by mutations in the SMN1 gene, which provides instructions for making the SMN protein essential for motor neuron survival.

“SMA has traditionally been considered a motor neuron disease. However, this view has evolved as defects in multiple non‐neuronal cell types have been identified,” the investigators said, adding that “metabolic defects” like problems in blood sugar and lipid metabolism are known in SMA.

“As such, standard of care statements have highlighted the need for further research in metabolic status in SMA patients to inform future nutritional guidelines, but strong comprehensive studies are currently still lacking,” the investigators wrote.

Researchers at the University of Ottawa in Canada, working with colleagues, set out to explore defects in lipid metabolism in people with different forms of SMA, as well as in several mouse models of disease.

Their study involved a total of 72 children (median age, 3.8 years), including 14 with SMA type 1, 52 with type 2 and six with type 3, recruited at two treatment centers in Italy. To look for defects in metabolism, the team did a full lipid profile, analyzing levels of the main lipids in each child.

They also analyzed liver samples obtained post-mortem from 10 type 1 patients, and performed histology (tissue), lipid and gene expression analyses in several mouse models of SMA. (Gene expression is the process by which information in a gene is synthesized to create a working product, like a protein.)

Results showed the children with SMA were highly prone to dyslipidemia, a general term that refers to the presence of abnormally high levels of cholesterol and/or triglycerides in the blood.

Tissue analysis of liver samples also revealed a tendency toward fatty liver disease, a condition in which the liver becomes inflamed and damaged due to the accumulation of fatty substances.  Specifically, 37.5% of these samples showed evidence of steatosis, while a rate of 0.7% is normal for children ages 2 to 4.

Likewise, mouse models of SMA showed a series of problems related to lipid metabolism. These included evidence of high levels of liver triglycerides, dyslipidemia, the presence of non-alcoholic fatty liver disease (NAFLD), and abnormal activity of metabolic genes in muscle cells.

Importantly, metabolic defects were observed before the animals started losing their nerve supply (denervation), indicating these abnormalities are not caused by denervation.

“Altogether, our clinical studies in SMA … provide strong evidence of defects in [lipid] metabolism. The greater predisposition to develop dyslipidemia and fatty liver in SMA patients as well as the identification of [non-alcoholic fatty liver disease ] in [SMA] mice emphasize that defects in metabolism can lead to added co‐morbidities, especially in the new therapeutic era of SMA, where lifespan is extended,” the researchers wrote.

Comorbidity is the presence of one or more conditions that occur together with a primary disease, like SMA.

“Indeed, this work further highlights the importance of establishing currently lacking nutritional guidelines, performing early screening for metabolic defects in treated SMA patients, as well as developing systemic therapeutic strategies that incorporate non‐neuronal organs to ensure overall optimal management of SMA,” they concluded.