Variants in genes related to glycogen rare in LOPD patients: Study
More research needed to find 'genetic signature' in Pompe
People with late-onset Pompe disease (LOPD) rarely have genetic variations in genes that are important for making glycogen in muscle cells, a new study suggests.
“We did not find a single variant that strongly affected the phenotype,” or observable characteristics in patients that result from the expression of a gene, the researchers wrote.
Still, the team called for “more extensive work on a set of genes relevant for general cellular function” in LOPD as related to glycogen production.
“It is of utmost importance to enrich the details of the clinical problems in these patients as well as to find a score [measure] that correctly expresses the disease progression or disease pattern,” they wrote.
The study, “Distribution of Exonic Variants in Glycogen Synthesis and Catabolism Genes in Late Onset Pompe Disease (LOPD),” was published in the journal Current Issues in Molecular Biology.
Researchers seek new data on gene variants in LOPD
Glycogen is a branching molecule that’s made of many connected molecules of glucose — the simple sugar that cells burn to get energy. Normally, glycogen is created as a way to store glucose, then when energy is needed, glycogen gets broken down into individual glucose molecules to power the cell. Most glycogen is stored in skeletal muscles, which enable a wide range of movements and functions.
Pompe disease is caused by mutations in the gene GAA, which provides instructions for making an enzyme that is normally required to disassemble glycogen into glucose. Without a functional version of this enzyme, cells cannot properly break down glycogen, so it builds up to toxic levels in cells, ultimately resulting in symptoms of Pompe disease.
Late-onset Pompe, known as LOPD, is defined by symptoms that manifest any time after the first year of life. There can be substantial variability from person to person, however, in terms of the timing of symptoms and how quickly they progress.
Although hundreds of different mutations in the GAA gene have been reported, to date there is no clear connection between the specific type of disease-causing mutation and the clinical manifestations seen in Pompe.
Indeed, sometimes people who have the exact same GAA mutations have dramatically different symptoms. This variability implies there must be other factors that influence the development of LOPD, besides the type of GAA mutation. For example, it’s possible that LOPD may tend to be more or less severe in people with variations in other genes.
Now, researchers in Italy sequenced the protein-coding regions of several genes that are important for putting together glucose to form glycogen, as well as a few genes that like GAA play a role in breaking apart glycogen. The team reasoned that these glycogen-related genes “may represent excellent candidates” as potential modifiers of LOPD.
The study included 30 people with LOPD. The researchers noted that, in line with other studies, there was no clear association between clinical severity and the type of GAA mutation. They also highlighted that, at present, there isn’t a well-established objective way to measure LOPD progression, which makes it harder to draw comparisons among patients.
Variations in glycogen-related genes were found in several participants, but there were no clear associations between any particular variation and clinical differences, according to the team.
We believe that, after more extensive work … it will be possible to identify a ‘genetic signature’ that is relevant to explain, at least in part, the genetic variability, including the course of the disease and response to ERT [enzyme replacement therapy].
Noting that the study was small, the scientists said their findings “highlight the need to collect detailed clinical data for a larger series of patients sharing the same genotype [mutations], as these comparisons may contribute useful data to better understand the natural history of the disease in well-defined subgroups of patients.” Natural history of a disease means what would be expected over time in the absence of treatment.
“We believe that, after more extensive work … it will be possible to identify a ‘genetic signature’ that is relevant to explain, at least in part, the genetic variability, including the course of the disease and response to ERT [enzyme replacement therapy],” the researchers wrote.
The team noted that variations that affect glycogen production were largely present in genes active in the liver, with a lesser presence in genes implicated in the early steps of glycogen synthesis in muscle tissue. The team speculated that a potential explanation for this finding could be that LOPD is more likely in people without other glycogen-related genetic variants, though they stressed that further research is needed.
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