Treatment Dilemma in Children with Late-Onset Pompe Disease

Abstract

In recent years, there has been a significant increase in the diagnosis of asymptomatic Late-Onset Pompe Disease (LOPD) patients, who are detected via family screening or Newborn Screening (NBS). The dilemma is when to start Enzyme Replacement Therapy (ERT) in patients without any clinical sign of the disease, considering its important benefits in terms of loss of muscle but also its very high cost, risk of side effects, and long-term immunogenicity. Muscle Magnetic Resonance Imaging (MRI) is accessible, radiation-free, and reproducible; therefore, it is an important instrument for the diagnosis and follow-up of patients with LOPD, especially in asymptomatic cases. European guidelines suggest monitoring in asymptomatic LOPD cases with minimal MRI findings, although other guidelines consider starting ERT in apparently asymptomatic cases with initial muscle involvement (e.g., paraspinal muscles). We describe three siblings affected by LOPD who present compound heterozygosis and wide phenotypic variability. The three cases differ in age at presentation, symptoms, urinary tetrasaccharide levels, and MRI findings, confirming the significant phenotypic variability of LOPD and the difficulty in deciding when to start therapy.

Omics-Based Approaches for the Characterization of Pompe Disease Metabolic Phenotypes

“…or efficacy of therapies could be very valuable for the management of LSDs patients and for guiding treatment decisions [ 41 ]. This would be especially relevant in LSDs such as PD [ 63 ], where both diagnosis and treatment at the earliest possible stage is critical for patient prognosis [ 26 , 56 ], and where there is a poor correlation between genotype and clinical manifestations of the disease [ 15 , 143 , 144 , 145 , 146 ].…”

“…Finally, the integration of data from different omics experimental approaches (e.g., genomics, transcriptomics, proteomics and metabolomics) may represent a powerful strategy to parse the genotype–phenotype complexity of PD. Particularly, another experimental approach that has proven its value in characterizing CNS progression [ 155 ] and response to therapy [ 156 , 157 ], but also in defining when to start therapy [ 26 ] in PD patients, is magnetic resonance imaging (MRI). Hence, the development of new bioinformatics tools for the integration of radiomics and metabolomics data, directed to the characterization of the prognostic profile associated with different subgroups of PD patients, would be of benefit for the identification of specific phenotypes that could be clinically exploited for improving the management of PD patients [ 158 ].…”

“…In 2015, PD was added to the Recommended Uniform Screening Panel (RUSP) [ 16 , 22 ]. Since then, PD has been included in public newborn screening (NBS) programs in many countries, and has contributed to the identification of PD patients, even in asymptomatic cases [ 23 , 24 , 25 , 26 ].…”

“…Moreover, it is not clear whether these patients would benefit from prophylactic treatment to delay or prevent symptoms. Thus, there is no uniform consensus on the optimal time to initiate treatment in these patients [ 26 , 40 ].…”

“…Also, different factors (e. g., age at start of treatment, CRIM (cross-reactive immune material) status, extra lysosomal glycogen accumulation in muscle) are thought to be correlated with the high variability of response to ERT in PD patients [ 14 , 35 , 59 , 60 , 61 , 62 ]. Additionally, there is a current need to develop newer and more sensitive biomarkers related to disease burden, disease progression, optimal time to initiate ERT and response to current treatments [ 26 , 63 , 64 , 65 , 66 , 67 ]. Thus, metabolic phenotyping represents a powerful and promising approach for the characterization of clinically relevant PD metabolic phenotypes that could be translated to therapeutic benefits for these patients.…”