Diagnostic and Clinical-Epidemiological Insights into Pompe Disease: A Retrospective Analysis at a Reference Center for Inborn Errors of MetabolismAbstract
Pompe disease (PD) is characterized by an inborn metabolic error resulting from the deficiency of the enzyme acid alpha-glucosidase, leading to glycogen accumulation within lysosomes. The severity of the disease is related to the age of symptom onset and the time to diagnosis. This study aimed to retrospectively evaluate the clinical and epidemiological profile of patients with suspected PD referred for diagnosis at a reference center for Inborn Errors of Metabolism in Brazil, between 2005 and 2010. Most diagnostic requests came from the Southeast region of Brazil, made by geneticists (29.2%), neurologists (21.3%), and pediatricians (14.4%) for infantile-onset phenotypes, and by pediatric neurologists (31.4%) and geneticists (28.9%) for late-onset phenotypes. Enzyme testing revealed 5.5% of positive cases for PD, of which 38.5% were classified as infantile-onset and 61.5% as late-onset. A high prevalence of muscular abnormalities was observed in all cases, with cardiac manifestations predominating in infantile-onset and neurological and neuromuscular symptoms in late-onset. These findings are relevant for improving early diagnostic and therapeutic strategies. Moreover, the data underscores the importance of multidisciplinary collaboration among medical specialists, in facilitating a more comprehensive and effective approach to managing PD.
Keywords:
Pompe disease; dried blood testing; enzyme assays; medical specialties; rare diseases
Introduction
Pompe disease (PD), also known as glycogen storage disease type II (GSD II) or acid maltase deficiency (OMIM 232300), is an autosomal recessive lysosomal storage disorder caused by deficiency of the enzyme acid alpha-glucosidase (GAA; EC 3.2.1.20). This deficiency leads to progressive intralysosomal glycogen accumulation in multiple tissues and cell types, predominantly affecting cardiac, skeletal, and smooth muscle [1,2]. The disease presents with a broad clinical spectrum, with symptoms that may manifest at any age.
Patients with the infantile-onset form (IOPD) typically present within the first months of life with hypotonia, generalized muscle weakness, and hypertrophic cardiomyopathy, often progressing to death from cardiorespiratory failure or respiratory infection within the first year of life [3,4] According to the Brazilian consensus on the management of Pompe disease [5], classification may also consider the presence or absence of cardiomyopathy, regardless of age at symptom onset. Patients presenting with cardiomyopathy (dilated or hypertrophic), hypotonia, rapidly progressive muscle weakness, and delayed motor milestones are classified as having early-onset Pompe disease [5].
Late-onset Pompe disease (LOPD) is generally characterized by the absence of serious cardiac involvement and a more variable clinical course, with symptom onset ranging from early childhood to late adulthood. Disease progression is typically slower, and mortality is often related to respiratory complications [1-3,6]. Skeletal muscle weakness and respiratory involvement are the most commonly recognized manifestations [7,8]. However, additional features-such as low body mass index, tongue weakness, urinary incontinence, and hearing impairment-have also been reported, contributing to the clinical heterogeneity of the disease and often delaying clinical suspicion and diagnosis [9].
Clinical suspicion and differential diagnosis are important tools for the accurate diagnosis of LOPD [10]. The correct interpretation of symptoms leads to appropriate patient management and drastically reduces the so-called diagnostic odyssey - a prolonged and often exhausting journey between the onset of initial symptoms and the definitive diagnostic confirmation [11]. In addition, it allows for the establishment of therapeutic measures and appropriate interventions, including enzyme replacement therapy (ERT) [12,13].
Despite advances in newborn screening and increased awareness of Pompe disease, early diagnosis still depends largely on clinical suspicion, particularly in settings where screening programs are not universally implemented. Newborn screening for Pompe disease in Brazil was incorporated in a limited manner only in 2021 [14] and remains available in just a few municipalities. Given this restricted coverage, many patients continue to experience delayed diagnosis, with potential impact on clinical outcomes. In this context, understanding which clinical features raise suspicion and which medical specialties are involved in initiating diagnostic investigation is essential. Therefore, the aim of this study was to analyze the clinical manifestations and referral patterns associated with requests for enzymatic testing of acid alpha-glucosidase (GAA) activity in a real-world cohort, in order to identify factors that may support earlier recognition and diagnosis of Pompe disease and help reduce diagnostic delay. This retrospective study analyzed individuals with suspected Pompe disease referred between 2005 and 2010 to a Brazilian reference center, focusing on diagnostic requests, confirmation by dried blood spot (DBS) testing, clinical manifestations, referring specialties, and geographic origin, with the aim of providing insights into the clinical recognition of patients not identified through newborn screening.
Materials and Methods
Study design
This was a cross-sectional study based on the analysis of test request forms for biochemical investigation of Pompe disease from samples submitted between December 2005 and December 2010 to the Laboratory of Inborn Errors of Metabolism (LIEM), a reference center at the Universidade Federal de São Paulo.
LIEM performs diagnostic investigations for several lysosomal storage disorders using dried blood spot (DBS) samples. A standardized test request form was used, which included a clinical information section with predefined categories to be selected if present in the patient, such as cardiac manifestations, skeletal manifestations, neurological manifestations, muscle manifestations, gastrointestinal manifestations, ophthalmological manifestations, and hypotonia, as well as an open-text field in which the referring physician could provide additional clinical information. Completion of clinical information section was not mandatory.
The results of the fluorometric assay of acid alpha-glucosidase (GAA) activity in DBS were obtained from the LIEM database. This study was approved by the Ethics Committee of the Universidade Federal de São Paulo (protocol no. 0149/10).
DBS enzymatic testing
The DBS enzyme activity assay was adapted from the method described by Chamoles et al. [15]. The main difference in the techniques was that we used acarbose to inhibit the activity of total acid alpha glucosidase [16]. Briefly, DBS samples treated with 20 μL of 0.4M sodium acetate buffer, pH 4.0 and 6.5, 20 μL of fluorogenic substrate 4-methylbeliferyl-alpha-D-glucopyranoside (2.8 mM), and 40 μL of acarbose (μM) as inhibitor of total acid alpha-glucosidase activity in 96-well microplate, for 24 hours at 37°C in a shaker. Followed by 20 μL of the fluorogenic substrate solution and the 10% ethylenediamine stop buffer 1.32 M pH 11.3. The enzyme product 4-methylumbeliferone was detected (excitation 365 nm, emission 450 nm) in a SpectraMax M2 fluorometer (Molecular Devices). Samples fluorescence determined by correction of the background of the reaction and the results were compared with a 4-methylumbeliferone calibration curve. The results were expressed as the ratio between the neutral and lysosomal isoforms (NaG/AaGIA) and the percentage of inhibition of the total acid fraction (% INH). The samples were evaluated in duplicate in parallel to enzymatic control and the results were determined as positive (NaG/AaGIA >40 and % INH >87), negative (NaG/AaGIA > 40 and % INH < 87) and indeterminate (NaG/AaGIA < 40 and % INH > 87).
Descriptive analytics and Database
Patients were categorized according to their age at sample collection. A descriptive analysis was performed based on demographic and clinical data obtained from the Pompe disease test request forms. Data collected included place of origin, enzyme test result (DBS), age, reported clinical manifestations, and referring medical specialty. Medical specialties were standardized according to those listed by the Federal Council of Medicine. DBS enzymatic results were obtained from the LIEM database and inserted into a database of this research, using Microsoft Excel® software. Categorical variables were expressed as percentages. Figures were generated using GRAPHPAD PRISM 6.0 software (GraphPad Prism, San Diego, CA).
Results
Geographic distribution of diagnostic requests
Between December 2005 and December 2010, 734 diagnostic requests accompanied by DBS samples were submitted for enzymatic testing to GAA activity. The samples originated from all regions of Brazil, as well as from some Latin American countries. The frequencies of requests by Brazilian macro-region are presented in Figure 1.
A total of 728 requests/samples were from Brazil, with the Southeast region recording the highest number of requests (50%), followed by the Northeast (20%), South (17%), Central-West and the Federal District (7%), and finally, the North region (6%). Additionally, six samples originated from other Latin American countries, including one from Colombia and five from Chile.
Frequency (%) of laboratory test requests for Pompe disease by Brazilian macro-region of origin.
Sample characterization
Of the 734 DBS-based diagnostic requests referred during the study period, duplicates were excluded, yielding 706 unique samples, each corresponding to a single patient with suspected PD. Tests performed using DBS samples to determine GAA enzymatic activity revealed that 39 (5.5%) patients had positive results, 12 (1.7%) had indeterminate results (gray zone), and 654 (92.6%) showed negative results. In one case (0.2%), the analysis could not be performed due to poor sample quality.
Among the patients with positive results (n = 39), 15 (38.5%) were under 1 year of age, nine (23%) were between 1 and 17 years old, and 15 (38.5%) were 18 years or older, corresponding to 38.5% and 61.5% of cases consistent with IOPD and LOPD, respectively. The characteristics and results of the samples are shown in Figure 2.
Flowchart of DBS screening submitted to the enzymatic assay for GAA activity, aiming to identify cases of PD. N = number of samples/patients.
Profile of medical specialties requesting laboratory diagnosis for PD
Of the 706 diagnostic requests, only 655 contained complete data regarding the referring medical specialty. The medical specialties listed on the request forms were compiled, categorized by the patients' age group, and represented by frequency (%). The medical specialties present on the diagnostic requests were categorized according to the patient's age at the time of sample collection (<1 year, 1-17 years, and ≥18 years), corresponding to the phenotypes: IOPD (<1 year), LOPD (1-17 years and ≥18 years). The results are presented in Table 1.
Frequency (%) of medical specialties present in the diagnostic requests. Frequencies by age group (<1 year, 1-17 years, >18 years) and total.
In the <1 year age group, 18 medical specialties were involved in raising clinical suspicion of PD. The most frequent were geneticists (29.2%), pediatric neurologists (21.3%), pediatricians (14.4%), pediatric cardiologists (8.4%), and pediatric gastroenterologists (6.9%). Other specialties contributed at lower frequencies, ranging from 0.5% to 3.5%.
Similarly, in the 1-17 year age group, 18 medical specialties were identified. The most frequent pediatric neurology (31.4%), genetics (28.9%), neurology (10%), physical medicine and rehabilitation (8.8%), pediatrics (6.3%) and pediatric cardiology (4.6%). Other medical specialties appeared at lower frequencies, ranging from 0.4% to 1.3%.
In patients over 18 years of age, nine medical specialties were identified, with the most frequent being neurologists (57.5%), geneticists (22.9%), pediatric neurologists (7.9%), and pulmonologists (3.3%). The frequency of other specialties in the request forms ranged from 0.5% to 1.9%. Among the 15 patients aged ≥18 years with confirmed Pompe disease, 10 were referred by neurologists, 3 by medical geneticists, and 2 by pulmonologists.
Symptom profiles described in requests for laboratory diagnosis of PD
The information from diagnostic requests was used to establish the frequency of symptoms/clinical manifestations in patients suspected of having PD. The requisition form used in the study included a section with predefined clinical categories, previously selected based on characteristic manifestations of the investigated condition. Additionally, the form contained an open field for the description of other clinical manifestations not previously listed, aiming to capture atypical, complementary, or variably presented signs and symptoms. For this analysis, data from 602 request forms containing information about symptoms/clinical manifestations were used. The frequency of standardized symptoms and the frequency of other clinical manifestations are shown in Figures 3 and 4.
Frequency (%) of standardized symptoms/clinical manifestations in diagnostic requests for suspected PD. Groups: < 1 year; 1 - 17 years; ≥ 18 years.
Frequency (%) of symptoms/clinical manifestations classified as "other" in diagnostic requests for suspected PD. Groups: < 1 year; 1 - 17 years; ≥ 18 years.
The analysis of laboratory diagnostic requests for PD revealed variations in the frequency of symptoms and clinical signs according to the patients' age group. Among patients under 1 year old, the most frequently reported symptoms were cardiac manifestations (50%), neurological manifestations (47.9%), and hypotonia (30.7%). In the age group of 1 to 17 years, the predominant symptoms included neurological manifestations (50%), hypotonia (23.6%), and cardiac manifestations (20.2%). For patients over 18 years old, the most frequently reported symptom was neurological manifestation, with a frequency of 55.7%.
In all age groups, other symptoms were reported at lower proportions, generally below 10%. It is noteworthy that neurological manifestations were a recurring symptom across all three evaluated age groups, with a frequency greater than 50% in all groups.
The symptoms classified as "other" showed distinct frequencies across the age groups analyzed. Among patients under 1 year old, the observed prevalences were: myocardial involvement (18.1%), musculoskeletal involvement (3.8%), hyporeflexia (1.3%), respiratory involvement (7.1%), other clinical manifestations (11.3%), and absence of clinical information (12.2%).
In the 1 to 17-year-old age group, musculoskeletal involvement was the most frequent (19.8%), followed by the absence of clinical information (17.4%), other clinical manifestations (7.8%), myocardial involvement (5%), respiratory involvement (1.6%), and hyporeflexia (1.2%).
For patients over 18 years old, the reported symptoms included musculoskeletal involvement (31.9%), absence of clinical information (23.4%), hyporeflexia (4.7%), other clinical manifestations (3.4%), and respiratory involvement (3%). No cases of myocardial involvement were reported in this age group.
Symptom profile in PD positive samples
The diagnostic requisition forms for PD allowed for the determination of the symptom profile in positive samples, enabling a more precise characterization of the clinical signs associated with the disease. Frequency is shown in Figure 5.
Frequency (%) of symptoms/clinical manifestations reported in diagnostic requests for positive PD. Groups: IOPD and LOPD.
Among the positive samples of patients under 1 year old (IOPD), the description of symptoms was present in 73.4% of the requisitions, while it was absent in 26.6%. Two requisitions (13.3%) indicated diagnosis based on family history. Cardiac involvement, including hypertrophic cardiomyopathy, septal hypertrophy, and unspecified cardiac involvement, was observed in 66.7% of the requisitions. Muscular involvement, such as hypotonia, macroglossia, and unspecified myopathy, was present in 46.7% of the requisitions, followed by neurological involvement in 26.7%, and ocular changes and hepatomegaly in 6.7%. The presence of multiple symptoms was reported in 60% of the patients.
For patients over 1 year old (LOPD), the description of symptoms was present in 75% of the requisitions, while it was absent in 25%. Approximately 20.8% of the diagnostic requisitions were based on family history. Neurological involvement was the most frequent symptom (54.10%), followed by muscular involvement (including muscle weakness, unspecified myopathy, glycogen accumulation in muscle fiber lysosomes, Gower's sign, and muscular dystrophy) in 45.8% of the requisitions. Cardiac involvement was described in 12.5% of the requisitions, while hepatomegaly, failure to thrive, hyporeflexia, ocular changes, exercise intolerance, and respiratory insufficiency were described with a frequency of 4.2%. The presence of multiple symptoms was observed in 54.1% of the requisitions analyzed.
Discussion and Conclusion
We analyzed 734 diagnostic requests from patients with clinical suspicion of PD, originating from all regions of Brazil, between 2005 and 2010. Overall, the results indicated that half of the requests came from the Southeast region, and the GAA activity results in DBS samples revealed positive findings compatible with both IOPD and LOPD phenotypes.
The analysis of the geographic origin of diagnostic requests for PD revealed a predominant concentration in the Southeast region, followed by the Northeast, South, Central-West, and North regions. This pattern partially reflects disparities in access to healthcare services, suggesting greater availability of specialized centers in the Southeast. The low representation of other regions suggests the influence of factors such as limited availability of medical and diagnostic centers, logistical challenges, and lower awareness among healthcare professionals, which hinder access to diagnosis and treatment of rare diseases. The demographic profile observed in our results is consistent with previously reported diagnostic barriers in the literature, as demonstrated in a study involving 1,128 participants with rare diseases in the United States. In that study, Bogart et al. [17] identified that the main difficulties in accessing healthcare included the absence or delay of referrals and the lack of specialized centers.
Clinical suspicion of PD appears to be strongly associated with physicians’ prior knowledge of the condition. In cases of IOPD, most diagnostic requests were submitted by clinical geneticists and pediatric specialists, reflecting the familiarity of these specialties with the disease. In contrast, for LOPD, neurologists played a predominant role in patient referral, particularly due to the presence of concurrent muscle manifestations. These referral patterns suggest that specific clinical experience directly influences diagnostic suspicion.
These findings are largely consistent with data from a retrospective study conducted using medical records from a reference laboratory in the United States, which employed DBS samples for the enzymatic diagnosis of PD. In that study, the medical specialties that most frequently requested testing were genetics for patients under 1 year of age (55%) and between 1 and 17 years (59.7%), and neurology for patients over 18 years (56.6%) [18].
In LOPD, diagnostic requests were primarily made by neurologists and geneticists, both in patients aged 1 to 17 years and in adults. These findings highlight the need to raise awareness of LOPD among specialists from fields other than genetics and neurology. The delay in LOPD diagnosis is a well-documented challenge: patients often undergo a long journey before receiving a definitive diagnosis, taking an average of 7 to 9 years after the onset of initial symptoms and consulting multiple specialists-frequently receiving incorrect diagnoses [9,18].
Despite the predominant role of clinical geneticists in diagnostic requests for IOPD, other specialties such as neurology, pediatrics, and cardiology were also involved. These results are relevant for two main reasons: they confirm the critical role of clinical geneticists in raising suspicion for PD and highlight the limited participation of cardiologists in this process. This finding is particularly noteworthy given that in IOPD, cardiac involvement is severe and prominent, which should warrant greater involvement of cardiology in the diagnostic process. Moreover, access to genetic services in Brazil is largely restricted to regions with higher socioeconomic development, with a greater concentration of specialized centers in the South and Southeast regions [19,20].
The diversity of medical specialties involved in the diagnosis of PD reflects, in part, the challenges associated with recognizing this condition. Patients with PD often consult multiple specialists and undergo inappropriate treatments before receiving a correct diagnosis. A clear example of this difficulty is illustrated by a case report of a patient diagnosed with LOPD only at the age of 58, despite presenting with signs and symptoms suggestive of the disease [21]. This case highlights the complexity of the diagnostic process, in which the patient received multiple incorrect diagnoses and ineffective treatments until, following a thorough clinical history, LOPD was finally confirmed.
Across all diagnostic requests evaluated, the most frequently reported symptom was related to neurological involvement, regardless of age group. Clinical suspicion of IOPD was primarily based on the presence of cardiac, neurological, and muscular abnormalities, whereas suspicion of LOPD was predominantly associated with neurological manifestations. The enzymatic testing of DBS samples revealed a positivity rate of 5.5% in the studied population-lower than that observed in a study conducted at a national reference center for PD diagnosis in the United States, which reported 12.5% positive samples [18]. Thuriot et al. [22] identified reduced enzymatic activity in 4.1% of analyzed samples, of which 24.1% were confirmed cases of PD. In a cohort study involving 7,340 patients, Lukacs et al. [23] detected 8% PD cases using enzymatic testing with DBS samples. As illustrated, GAA enzyme activity assays using DBS are widely employed as a screening method for PD. Variations in positivity rates may be attributed to methodological sensitivity or to specific characteristics of the populations or samples analyzed [18,24].
The samples identified as positive were compatible with PD phenotypes, with a higher frequency observed among patients with the LOPD phenotype. This scenario highlights the negative impact of the absence of PD testing in neonatal screening programs for most of the Brazilian population. Early diagnosis is crucial not only for defining effective therapeutic strategies but also for reducing morbidity and mortality in the affected population. In this context, clinical suspicion plays a central role in guiding the process toward definitive laboratory diagnosis.
The inclusion of PD in neonatal screening tests proves to be an important tool for the early diagnosis of late-onset forms. This is supported by data from a study evaluating indications for ERT initiation in PD patients diagnosed through neonatal screening between 2016 and 2021, which enabled early identification and treatment of LOPD in approximately 44% of cases [25].
Our results indicated that most of the diagnostic requests analyzed that returned positive results were for the LOPD phenotype. The most common symptoms observed in the clinical suspicions of PD were neurological and cardiac, with requests predominantly made by geneticists and neurologists.
Across all age groups, clinical geneticists and neurologists (pediatric and adult) were consistently involved in raising diagnostic suspicion. In contrast, primary care-particularly family and community medicine, the cornerstone of the Brazilian Unified Health System-was notably underrepresented, with no recorded participation across age groups, while general pediatrics appeared only marginally. This pattern suggests a potential gap in awareness of Pompe disease at the primary care level. Given that primary health care is the main entry point and coordinating axis of care within the Brazilian health system [26], this gap may contribute to delayed recognition, particularly in LOPD cases not identified through newborn screening. For patients not identified through neonatal screening, clinical suspicion remains the critical starting point for diagnosis; failure to consider rare diseases is a well-recognized contributor to the diagnostic odyssey, which has been associated with substantial delays in diagnosis and initiation of treatment [9,11]. These findings underscore the need for targeted educational strategies to improve early clinical suspicion in frontline medical settings.
A relevant limitation of this study is the level of detail available in the clinical information provided in the test request forms. Although a standardized form was implemented, including predefined categories (e.g., neurological, cardiac, gastrointestinal, and psychiatric manifestations) and an optional open-text field for additional clinical details, a substantial proportion of requests (12.2% < 1y, 17.4% 1-17y, and 23.4% in adults) were submitted without any clinical information. This limitation restricted the ability to further characterize the reported manifestations but also highlights persistent challenges in clinical documentation and communication, even when structured tools are available.
Acknowledgments
The authors would like to sincerely thank the students and technicians from LEIM, as well as all the physicians who entrusted us with the diagnosis of their patients. We are also grateful for the support provided by FAPESP (K.B.M. scholarship), CAPES, CNPq (grant no. 501248/2005-6), AFIP, and IGEIM. V.D’A. is a recipient of a CNPq research fellowship. The authors acknowledge the editorial assistance of Invitare Pesquisa Clínica in the preparation of this manuscript.
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Data Availability
The dataset supporting the findings of this study is not publicly available because it contains clinical information derived from patient test request forms and is subject to ethical and privacy restrictions. Anonymized data may be made available by the corresponding author upon request, subject to applicable ethical, institutional, and data protection requirements.
The dataset supporting the findings of this study is not publicly available because it contains clinical information derived from patient test request forms and is subject to ethical and privacy restrictions. Anonymized data may be made available by the corresponding author upon request, subject to applicable ethical, institutional, and data protection requirements.
