Study findings highlight challenges of diagnosing Pompe disease
Few people screened for Pompe found to carry disease-causing mutations
Among almost 3,000 people with symptoms consistent with Pompe disease, fewer than 40 were found to carry genetic mutations known to cause the rare condition and receive a confirmed diagnosis, according to the findings of a new study that researchers say highlights the challenges of diagnosing Pompe.
Importantly, the researchers also say the results underline how crucial it is for anyone suspected of having Pompe to undergo enzyme testing and genetic counseling, so as to avoid a misdiagnosis.
“The diagnosis of [Pompe] poses challenges due to its diverse clinical presentations among patients, the rarity of the condition, and the complexities involved in recognizing its symptoms,” the researchers wrote, adding that, “consequently, [the disease] often remains underdiagnosed.”
The study, “Mutation Spectrum of GAA Gene in Pompe Disease: Current Knowledge and Results of an Italian Study,” was published in the International Journal of Molecular Sciences.
Common symptoms contribute to difficulties in diagnosing Pompe
Due to its rarity, Pompe can be challenging for clinicians to properly identify and diagnose. Further, diagnosing Pompe is made all the more difficult because many of its symptoms — such as fatigue, muscle weakness and pain, breathing problems, and heart disease — resemble those of other conditions. Moreover, symptoms can emerge at any age, vary widely from person to person, and progress at different rates and severity.
Pompe disease is caused by mutations in the GAA gene, which disrupt the function of the GAA enzyme. Without this enzyme, glycogen, a complex sugar molecule used for energy storage, builds up to toxic levels inside cells. Muscle cells are particularly affected because they use glycogen as the main energy source to power muscle movements.
Thus, to reach a confirmed diagnosis, tests for mutations in the GAA gene and/or the activity of the GAA enzyme in biofluids are conducted.
In this report, a team of researchers in Italy detailed their experience screening 2,934 individuals — 1,670 males and 1,264 females — with signs and symptoms of Pompe disease. Infantile-onset Pompe was suspected in 165 children younger than 1 year of age, while late-onset disease was considered in the remaining 2,769.
The first step taken by the researchers was to examine GAA activity in dried blood spots collected from different hospital departments. About half of the samples came from neurology, with the others collected from pediatrics, internal medicine, rheumatology, and metabolic diseases.
Of the individuals screened, 2,489 had normal GAA enzyme activity rates, defined as at least 6 nanomoles/mL per hour (nmol/mL/h). No or reduced activity, or 3 nmol/mL/h or less, was found in 105 samples, and 340 had activity between 3 and 6 nmol/mL/h.
Next, 445 individuals with less than 6 nmol/mL/h of GAA enzyme activity underwent genetic screening to identify GAA gene mutations.
Among 105 with no or severely reduced enzyme activity (3 nmol/mL/h or less), the team identified 39 people with Pompe-associated mutations in both copies of the GAA gene; one copy is inherited from each biological parent. The remaining 51 samples were considered false positives, with low enzyme activity but no associated GAA mutations, and 15 carried a causative mutation in one gene copy.
The researchers suggested the reduced enzyme activity found in the blood samples from some individuals may be due to a condition related to low white blood cell counts and/or improper storage/transport of the samples.
39 of nearly 3,000 people ultimately diagnosed with Pompe in study
Most GAA mutations detected in this study had been reported in Pompe variant databases. One common mutation, called IVS1 (c.-32-13 T>G), was found in 25 of the 39 individuals screened. Five additional mutations had not been previously described.
The team noted that the Italian patients in this study showed a genetic profile similar to that of the broader European population, with IVS1 being the most common.
In most cases, mutations showed compound heterozygous patterns, meaning different mutations in each of the two GAA copies. A separate analysis detected four individuals with deleted DNA segments in one copy of their GAA gene alongside a causative mutation in the other.
In an assessment of the patients’ family members, compound heterozygote mutations were found on parental chromosomes in 31 cases, which “confirmed the diagnosis of [Pompe] from a genetic point of view,” the researchers wrote.
This report presents a work on Pompe disease, highlighting the importance of genetic counseling and enzyme testing to avoid misdiagnosis. … Diagnostic delay or misdiagnosis in a patient with [Pompe] signs and symptoms are the most critical points in determining the evolution of the patient’s clinical and therapeutic history.
Among those with GAA activity between 3 and 6 nmol/mL/h, 22 had variants of uncertain significance in one GAA copy, indicating that the functional significance of these mutations “are still relatively unknown.”
“We can conclude that our results allow us to set the cutoff for enzyme activity at [less than] 3 nmol/mL/h for the identified cases of [Pompe],” the team wrote.
Overall, according to the researchers, these findings show some of the difficulties of diagnosing Pompe, even among people showing signs of the disease.
“This report presents a work on Pompe disease, highlighting the importance of genetic counseling and enzyme testing to avoid misdiagnosis,” the researchers concluded. “Diagnostic delay or misdiagnosis in a patient with [Pompe] signs and symptoms are the most critical points in determining the evolution of the patient’s clinical and therapeutic history.”
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