New GAA mutations linked to infantile-onset disease
Three new mutations in the GAA gene were linked with heart disease and severe breathing problems in infants with infantile-onset Pompe disease (IOPD) in Malaysia, a study reports.
“The novel mutations identified in this study expands the mutation spectrum for IOPD,” the researchers wrote.
Also, among the 17 IOPD patients evaluated, survival rate was low despite enzyme replacement therapy (ERT), underscoring “the importance of early diagnosis and treatment in achieving better treatment outcomes,” the researchers added.
The study, “Genotype, phenotype and treatment outcomes of 17 Malaysian patients with infantile-onset Pompe disease and the identification of 3 novel GAA variants,” was published in the Orphanet Journal of Rare Diseases.
Pompe disease occurs due to mutations in both copies of the GAA gene, which codes for alpha-glucosidase, an enzyme that breaks down a complex sugar molecule called glycogen. The mutations result in deficient enzyme levels or production of a faulty enzyme.
As a result, glycogen builds up to toxic levels inside cells in the body, particularly in the muscles, leading to symptoms of Pompe.
Mutations that cause the alpha-glucosidase enzyme to be completely absent or non-working usually cause infantile-onset Pompe, which usually manifests in the first year of life and is generally the most severe type of the disease.
ERT approved for Pompe aims to provide patients with a working alpha-glucosidase enzyme. In IOPD patients, it has been shown to prolong survival, particularly when begun very soon after birth.
Still, “response to ERT is variable, with suboptimal outcomes in some patients even when treatment is started early,” the researchers wrote.
Study design included long-term outcomes
Now, a team of researchers in Malaysia described the clinical and genetic features, as well as ERT-associated long-term outcomes, of 17 infants (11 girls, six boys) who were diagnosed with IOPD sometime between 2000 and 2020. These infants included two pairs of siblings.
Their median age at symptom presentation was 3 months and they were diagnosed a median of three months later. Most infants (88.2%) had classic IOPD, while two, who were 10 and 12 months at presentation, had non-classic IOPD, a less-severe form that generally manifests later in infancy.
All had hypertrophic cardiomyopathy, a typical symptom of IOPD in which the heart walls thicken and stiffen, making it harder for the heart to pump blood to the rest of the body.
Most (94%) had respiratory insufficiency, which results in inadequate oxygen supply to the cells in the body. Other common symptoms were low muscle tone (88%), failure to thrive (82%), trouble feeding (76%), and an enlarged liver (76%).
Genetic testing, performed in 15 infants, revealed a total of 14 different mutations located across the length of the GAA gene. “The mutations are well distributed across the GAA gene,” the researchers wrote.
The most common mutation was c.1935C>A (D645E), which is relatively frequent in Asian populations, occurring in eight of all tested infants. Two of these infants carried the mutation in both GAA gene copies.
The three new GAA mutations
Three new mutations — c.1552-14_1552-1del, deletion of exons 2-3, and deletion of exons 6-10 — were identified in three infants — one in each infant. An exon is a protein-coding region within a gene.
Each of the infants carried an already known mutation in the other copy of the GAA gene.
All three infants (two Chinese and one Indian in ethnicity) experienced hypertrophic cardiomyopathy and respiratory insufficiency as initial symptoms. Low muscle tone, feeding difficulties, and liver enlargement each were reported in two patients.
Two infants showed a failure to thrive, and all three experienced heart failure, which occurs when the heart is no longer able to pump blood.
The effects of the two exon deletion mutations were analyzed using a computer simulation of the enzyme’s structure.
Deletion of exons 2-3 results in the loss of some parts of alpha-glucosidase, including its signal peptide. A signal peptide is a short stretch of amino acids (protein’s building blocks) at the beginning of a protein that guides it to its appropriate location within a cell. Without a signal peptide, the enzyme’s activity could be reduced.
Deletion of exons 6-10 results in the loss of part of the enzyme’s catalytic domain, the region where the enzyme interacts with glycogen. As such, this mutation likely impairs glycogen binding and its breakdown.
All but one infant received the ERT Myozyme (alglucosidase alfa), sold as Lumizyme in the U.S., at a median age of 7 months.
At the time of writing, researchers reported five patients (three with classic IOPD and two with atypical IOPD) were still alive, with ages between about 3.5 years and 20 years. All five became able to walk independently between the ages of 2 and 5 years, and all showed normalization of heart walls thickness after ERT initiation.
Examining survival rates
Overall survival rate was 29%, with a mean age of death of 17.5 months (range, 6 months to 3.5 years). Nine of the deceased patients had started ERT at the age of 6 months or older.
“This is the first study that analyzes the [genetic and clinical profiles] of IOPD patients in Malaysia, and has established the c.1935C > A p.(D645E) mutation as the most common mutation, with an … frequency of 33%,” the researchers wrote.
“Our low survival rate of 29% highlights the importance of early diagnosis and initiation of treatment,” the team wrote, adding that “newborn screening for Pompe disease is the way forward to achieving better survival and long term outcomes.”