Mexican Pompe patients carry 2 GAA gene mutations: Study
Country’s genetic diversity may explain results, researchers say
People with Pompe disease examined for a study in Mexico carried a combination of GAA gene mutations associated with both infantile and adult-onset types of the disease, a finding the authors said may be related to the genetic diversity of the Mexican population.
“Further population-wide studies are required to better characterize the incidence of this disease in Mexican population,” the researchers wrote in the study, “Mutational spectrum and genotype-phenotype correlation in Mexican patients with infantile-onset and late-onset Pompe disease,” published in Molecular Genetics & Genomic Medicine.
Pompe is caused by inherited mutations in the GAA gene. This gene carries instructions for acid alpha-glucosidase (GAA), an enzyme that breaks down the complex sugar molecule glycogen. Such mutations result in deficient or absent GAA activity and the accumulation of glycogen to toxic levels in cells, mainly in muscles.
The condition can manifest in the first months of life, referred to as infantile-onset Pompe disease (IOPD), or after 12 months, called late-onset Pompe (LOPD).
The researchers described the different types of GAA gene mutations in a group of 29 patients from 21 families from across Mexico. Understanding the relationship between specific GAA mutation and clinical presentation “is crucial for predicting the clinical behavior of the disease,” they wrote.
Patient population, symptoms varied
Of the 29 patients examined, 22 (75.8%) were female. Among them, LOPD patients showed symptoms between the ages of 2 and 43, while those with IOPD had symptom onset between one and 9 months. Six (85.7%) of those with IOPD had died by the time of the study.
A total of 26 patients received a Pompe diagnosis due to low blood levels of the GAA enzyme and the presence of two disease-causing GAA gene mutations.
Seven of the 29 patients displayed homozygous variants, meaning the same mutation in both GAA gene copies (one from each parent), while 22 were compound heterozygous, or two different mutations in each gene.
The most common mutation was called c.-32-13T>G (rs386834236), which occurred in 14 alleles, or versions of GAA, all of which were heterozygous and associated with LOPD. Of the 13 patients with this mutation, 11 (85%) showed weakness in the muscles closest to the body (proximal), 10 (77%) had gait disorders, and four (30%) had hyperlordosis, an abnormal inward curvature of the lower spine.
Four (30%) had a history of sleep apnea — when breathing repeatedly stops and starts during sleep one — one (8%) had a history of pneumonia, and four (30%) with breathing abnormalities. Twelve (92%) had low GAA enzymatic activity, with nine (69%) undergoing enzyme replacement therapy (ERT) at the time of the study.
The variant c.2560C>T (rs121907943) was identified in four alleles, in one homozygous and two compound heterozygous patients. Both LOPD patients also displayed muscle weakness, gait disorders, and hyperlordosis. The one IOPD patient, with onset at 3 months, had heart disease and required mechanical breathing support but died at seven months.
Two unrelated patients carried the c.1445C>T mutation (rs2039212985), comprising three alleles (6%). One patient, diagnosed at age 21, was homozygous with muscle weakness, gait problems, sleep apnea, and slight breathing abnormalities.
In contrast, the other patient was compound heterozygous, carrying this mutation and another called c.1674_1675delTG. Symptoms first appeared at 2 years of age with proximal muscle weakness, and by age 5, the patient had developed heart disease and shortness of breath. Family history revealed an unspecified heart-related death in an older brother.
A c.1979G>A variant, associated with an atypical clinical presentation, was found in two heterozygous patients, with one diagnosed with LOPD and the other with IOPD. The LOPD patient showed symptoms at 10 years, marked by proximal muscle weakness, severe scoliosis (sideways curvature of the spine), and swallowing difficulties. The IOPD patient with this mutation had heart disease but was still living at age 5.
The team also discovered two new GAA mutations, one of which, called c.1615G>A, was classified as likely disease-causing. The patient carrying this mutation, alongside c.1987delC, developed lung failure and died at 10 months after a single dose of ERT.
The second new mutation was called c.1076-20_1076-4delAAGTCGGCGTTGGCCTG and was carried by a patient who presented symptoms, including proximal muscle weakness and progressive hepatomegaly (enlarged liver), at age 3.
LOPD patients had mutations associated with both infantile and adult-onset Pompe, “which may be related to genetic diversity within Mexican population,” the team wrote. “We identified 23 variants in this series, comprising the largest [Pompe disease] series in the Mexican population,” they wrote.
“We believe that prompt clinical and molecular assessment for [Pompe disease] should be conducted in a timely manner, enabling earlier diagnosis and the opportunity for treatment in earlier stages of the disease,” the researchers added.
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