It may seem counterintuitive to delay the onset of treatment in the face of a potentially life-changing diagnosis, but such is the dilemma faced by children diagnosed with late-onset Pompe disease (LOPD). The difficulty here lies in the fact that LOPD can have an extremely heterogeneous presentation, with significant clinical differences existing even among family members.
LOPD differs from infantile-onset Pompe disease (IOPD), which has a more homogenous disease course. Patients with IOPD, for example, are almost always diagnosed with cardiomyopathy. Symptoms emerge early, around 3 months of age; unfortunately, most patients die before their first birthday, with only a 10th of patients living past the 18-month mark.
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In LOPD, the presentation is much more insidious and subtle. Patients tend to present with mild-to-severe muscle weakness, exercise intolerance, and respiratory failure. The areas of muscle involvement are also highly variable, sometimes involving the upper limbs, other times involving the lower limbs.
LOPD may also increase the risk of central nervous system (CNS) pathology, such as cognitive decline and impairments in executive decision-making. Patients may also be at a higher risk of developing secondary subarachnoid brain hemorrhage. The peripheral nervous system is also often involved.
Nevertheless, we must stress again that there is a documented heterogeneity in the clinical presentation of patients with LOPD. Increasingly, medical attention has turned to identifying patients who are at the pre-symptomatic stage of LOPD. These patients may be identified via screening of an affected family individual or through newborn screening.
“The recognition of pre-symptomatic cases has raised the dilemma of when to start treatment,” Faraguna and colleagues wrote in Genes.
The main dilemma here is that while the initiation of enzyme replacement therapy (ERT) can have a positive impact on quality of life and survival, it is also associated with adverse events, the most common being pain, edema, and erythema, as well as anaphylaxis. In addition, long-term ERT usage can cause seroconversion — approximately 95% of individuals become IgG positive.
“Exceptionally high titers of persistent antibodies may occur, and this can activate the complement cascade, neutralizing the recombinant enzyme,” Faraguna et al wrote. “In these rare circumstances, there is a decline in the therapeutic response to ERT, and infusion reactions may be observed.”
Adding to the dilemma of whether prophylactic commencement of therapy is needed is the possibility that a patient’s clinical symptoms may turn out to be mild and be clinically manageable without treatment. To elucidate this heterogeneity in clinical presentation, Faraguna and colleagues presented the case of 3 siblings affected by LOPD.
Family Matters
A 7-month-old male was recently diagnosed with IOPD. He was noted to have significant hypotonia of the head and the trunk. He was thus placed under neurological follow-up. This child has 2 siblings — an older sister (patient 2) and brother (patient 3).
A next-generation sequencing (NGS) was carried out, and clinicians were able to identify a combined heterozygosity: GAA (NM_000152.3):c.2284G>A p.(Glu762Lys) and GAA (NM_000152.3):c.1994G>A p.(Gly665Glu).
In his first visit, the 7-month-old male demonstrated slight hypotonia of the upper back; this was the only sign of Pompe disease present.
The child’s siblings then underwent extensive testing. While asymptomatic, the sister underwent screening for Pompe disease, which revealed the same mutations as her 7-year-old sibling. The only notable finding among the tests carried out was that her lower limb muscle MRI revealed diffuse, slight fat replacement, primarily at the medial and posterior compartments of the gluteus maximus and the thigh. Other testing parameters were normal.
A screening for Pompe disease for the older brother (patient 3) revealed the same mutations as his other 2 siblings. All other tests were normal — echocardiography, neurological assessment, an abdomen ultrasound, electromyography, and muscle MRI. He was a fairly active child, playing sports 3 times a week.
The authors of the study concluded the following:
Patient 1 was symptomatic during the first 3 months of age and is expected to commence ERT soon. Patient 2 had fatigability and muscle MRI consistent with LOPD; she was started on ERT administered every other week. Patient 3 was asymptomatic and placed on close follow-up.
“The 3 siblings reported differ in age at diagnosis, symptoms, and findings,” the authors of the study wrote.
What can we learn about this case report on 3 biological siblings? First, symptoms of Pompe disease can vary widely. Second, treatment should be initiated on a case-by-case basis; however, do we have the protocols in place to dictate when treatment should be started?
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According to a study published by Fatehi and colleagues in Frontiers in Neurology, the team of experts are of the opinion that ERT should not be started in presymptomatic patients. However, all symptomatic patients should be started on recombinant human acid alpha-glucosidase (rhGAA), and that a trial of ERT should be considered in individuals with advanced LOPD.
It is clear from available evidence in medical literature that the guidelines surrounding the initiation of treatment in patients with LOPD (presymptomatic and symptomatic alike) are evolving. The crux of the issue is to avoid doing unnecessary harm by going too aggressive too early. Nevertheless, continuous research into this subject should offer greater clarity in the near future.
References
Faraguna MC, Crescitelli V, Fornari A, et al. Treatment dilemma in children with late-onset Pompe disease. Genes (Basel). Published online January 30, 2023. doi:10.3390/genes14020362
Fatehi F, Ashrafi MR, Babaee M, et al. Recommendations for infantile-onset and late-onset Pompe disease: an Iranian consensus. Front Neurol. Published online September 21, 2021. doi:10.3389/fneur.2021.739931
