Neuromuscular Disorders
Asymptomatic hyperCKemia
Aug. 14, 2022
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Toll Free (U.S. + Canada): 800-452-2400
US Number: +1-619-640-4660
Support: service@medlink.com
Editor: editor@medlink.com
ISSN: 2831-9125
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The authors describe the clinical, pathological, biochemical, and molecular features of Pompe disease, which is a heterogeneous glycogen storage disease. Tremendous advances in infantile Pompe disease have occurred since the development of enzyme replacement therapy--the first FDA-approved treatment for this otherwise lethal disorder. Therapeutic success has subsequently been noted in both infantile and late-onset Pompe disease; those who begin enzyme replacement therapy earlier in the course of disease progression tend to respond better to treatment. However, there are new emerging phenotypes among the survivors of Pompe disease, and therapies must be improved. With the continued development of novel therapies and newborn screening programs, advancements in the management of Pompe disease continue to push the boundaries of modern medicine.
• Pompe disease is a glycogen storage disease that has a wide clinical spectrum and is broadly classified as infantile and late-onset Pompe disease (93). Infantile Pompe disease is further divided into classic and non-classic, based on the presence of a severe (classic) or less severe (non-classic) cardiomyopathy in the first year of life. Late-onset Pompe disease is defined in this article as that which occurs in patients with no cardiac involvement in the first year of life, with an age at diagnosis and a clinical presentation ranging from infancy to as late as the sixth decade of life. | |
• “Classic infantile-onset Pompe disease” is the only term exempt from debate. However, there has been some consensus on the nomenclature for the rest of the clinical continuum in the past few years. | |
• The advent of enzyme replacement therapy with intravenous alglucosidase alfa in 2006 marked the beginning of a shifting natural history, including new phenotypic manifestations, disease complications, and understanding of the clinical spectrum of Pompe disease (94). Presentation continues to diversify by age at onset, extent of organ involvement, and degree of myopathy. | |
• There has been increasing evidence of central nervous system involvement in children with infantile-onset Pompe disease (125; 99; 101). | |
• Across the clinical spectrum, treatment response in patients continues to vary based on several factors, including muscle fiber type, defective autophagy, the degree of disease progression at the time of treatment initiation, cross-reactive immunological material status, antibody response to enzyme replacement therapy, underlying angiotensin-converting enzyme allele (insertion/deletion), ACTN3 variants, nutritional status, and other factors. | |
• Research on enhancing therapeutic efficacy continues as the disease is better understood, including the use of noninvasive adjunctive therapies, immune modulation to suppress or abrogate immune response, and new therapeutic targets. Investigations of the pathology have focused on pinpointing reasons for clinical plateau and the inability of enzyme replacement therapy to minimize the buildup of lysosomal and cytoplasmic glycogen, presence of autophagic material, especially in type 2 muscle fibers, and lipofuscin in late-onset patients. |
In 1932, Pompe and Putschar described case studies on infants with fatal “enlarged heart.” Thirty-three years later, Zellweger, Courtecuisse, and their respective teams recognized the less progressive “muscular form” (143; 148; 36; 202). In 1963, Hers documented the defect of the enzyme acid maltase (alpha-1,4- glucosidase, acid alpha-glucosidase, GAA) in liver, heart, and skeletal muscle of children with "cardiomegalic glycogenosis" and, together with Lejeune and colleagues, showed that GAA was a lysosomal enzyme (114; 74). Thus, Pompe disease became the prototype of inborn lysosomal diseases.
In the years that followed, GAA deficiency was recognized in both children and adults with myopathy, and the main clinical variants of GAA deficiency were categorized as infantile and late-onset forms (53). Over time, the alternate names “Pompe disease,” “acid alpha-glucosidase deficiency,” and “glycogen storage disease type II (GSD II)” have eclipsed the original name, “acid maltase deficiency” (47). The eponym Pompe disease was originally limited to the infantile form of the disease as described by JC Pompe but is now utilized to describe all clinical variants. The disease is more accurately attributed to a deficiency of lysosomal GAA rather than acid maltase because GAA generally functions by breaking down glycogen into glucose, whereas acid maltase specifically dismantles maltose into glucose.
Pompe disease represents a wide clinical spectrum that is now considered a clinical continuum with two subtypes, delineated by presence or absence of cardiomyopathy in the first year of life: infantile-onset Pompe disease and late-onset Pompe disease (93). IPD is further classified as classic and nonclassic. Patients with classic IPD present with severe cardiomyopathy and left ventricular outflow tract obstruction in the first year of life, which is fatal if untreated. Patients with the nonclassic form present with less severe cardiomyopathy than those with the classic form and typically live beyond the first 2 years of life without enzyme replacement therapy. Patients with LOPD (childhood, juvenile, and adult) typically do not have any cardiac involvement in the first year of life, and the age at symptom-onset typically ranges from infancy to the sixth decade of life. Patients with LOPD exhibit variable rates of progression of myopathy and pulmonary compromise.
Importantly, the phenotypic presentations of both the infantile-onset and late-onset forms continue to evolve as patients are living longer due to enzyme replacement therapy with intravenous alglucosidase alfa (rhGAA, Myozyme™) in 2006, the advent of newborn screening for Pompe disease (91; 146; 32), and immune modulation (43; 115). As the phenotypic spectrum continues to evolve, the nomenclature for the disease is struggling to keep pace. The definition of “classic infantile Pompe” is the only term that is currently exempt from criticism. In contrast, the true terminology for the rest of the clinical continuum continues to be debated as the characteristics that at one point helped delineate the groups, namely cardiac involvement, are being proven to exist across the categories. In particular, patients with IPD who are surviving with enzyme replacement therapy have an emerging phenotype that seems to reflect features in the LOPD cohort but also show specific manifestations unique to their group. Based on these features, it is unclear whether the IPD subgroups should be labeled as infantile survivors or a late-onset infantile subgroup. Since the advent of newborn screening, children with LOPD are also now being identified early, and a subset of these children present with subtle clinical signs in infancy. Similarly, it is unclear if this subset should be labeled as an infantile-onset late form of Pompe disease. Consensus on the nomenclature is needed and will continue to be an issue as the full clinical spectrum of Pompe disease is solidified and understood (10; 65).
The advent of enzyme replacement therapy marks the development of a shifting natural history, including new phenotypic manifestations, disease complications, and understanding of the wide clinical spectrum of Pompe disease (94). Clinical presentation continues to diversify by age of onset, extent of organ involvement, and degree of myopathy. The severity of disease manifestations tends to reflect the level of residual enzyme activity, with lower enzymatic activity typically correlating with greater disease burden (93; 104).
Untreated infants: | |
• Hypertrophic cardiomyopathy +/- left ventricular outlet tract obstruction, which can progress to dilated cardiomyopathy in the first year of life | |
• Cardiomegaly | |
• Floppy baby syndrome | |
• Enlarged tongue | |
Long-term survivors on enzyme replacement therapy: | |
• Severe myopathy | |
• Neurologic manifestations, such as sensorineural or mixed hearing loss, foot-slapping gait, white matter hyperintense foci as seen on brain MRI | |
• Manifestations with a neuromuscular involvement, such as bulbar weakness, dysarthria, hypernasal speech, lingual weakness, dysphonia, ptosis, and dysphagia |
Infants with classic infantile Pompe disease in the first days to weeks of life, with cardiomyopathy and features that can range from subtle such as feeding difficulties, cardiac arrhythmias (ie, supraventricular tachycardia), increased creatine kinase (22), aspartate aminotransferase (85), alanine aminotransferase (155), and urinary glucose tetrasaccharide (Glc4, also referred to as hexose tetrasaccharide, Hex4), to the more florid findings of diffuse hypotonia and weakness, giving them a "rag doll" appearance (floppy baby syndrome). Hypertrophic cardiomyopathy, massive cardiomegaly, and diffuse skeletal myopathy are hallmarks of classic infantile Pompe disease. Muscle bulk is often increased secondary to glycogen deposition, especially in the gastrocnemius muscles and tongue (macroglossia). Despite their extreme weakness, these infants are usually alert and interested in their environment. Obstructive sleep apnea and hypoventilation are commonly noted in patients with IPD, even in those who do not have symptoms of sleep-disordered breathing. Without treatment, infants with classic infantile Pompe disease have feeding and swallowing difficulties and failure to thrive and usually succumb to the complications of progressive cardiac or muscle weakness, increased rate of pulmonary infections, and cardiac or respiratory failure before 2 years of age.
In the United States, a study of 11 children with IPD on long-term enzyme replacement therapy (younger than 6 months of age at ERT initiation; average years on ERT = 8 years) showed overall improvement in cardiac and gross motor function and freedom from long-term invasive ventilator support (146). However, proximal and distal muscle weakness in both upper and lower extremities has been noted in enzyme replacement therapy-treated survivors with IPD (26; 186). In addition, as the children with IPD enter adulthood, new phenotypic manifestations include residual muscle weakness, hypernasal speech, hearing loss, dysphagia, dysphonia, gastroesophageal reflux, genitourinary incontinence, and the potential risk for basilar artery aneurysms, arrhythmias, aspiration, and osteopenia (184; 185; 146; 140; 180; 84; 81; 83; 154; 124; 99; 197; 37). These clinical manifestations have been attributed to bulbar weakness and smooth muscle and nervous system involvement, which are not fully amenable to enzyme replacement therapy.
Autopsy findings in patients with IPD have revealed glycogen accumulation in the neurons of the cerebrum and brainstem nuclei, glial cells and astrocytes of white matter, and in the cerebellum and anterior horn cells of the spinal cord (61; 11; 99). Using brain MRI and CT scans, white matter abnormalities have been reported in children with IPD. These range from mild to severe diffuse white matter hyperintense foci, with a predominance and early involvement of the periventricular and subcortical areas rather than the deep white matter areas (49; 99; 101). There can be transient ventricular enlargement and extra-axial cerebrospinal fluid accumulation in infancy, which usually resolve after 2 years of age (125). At this time, further investigation is warranted to determine the cause of these white matter abnormalities on brain MRI and understand their impact on cognition and development.
With the emerging evidence of nervous system involvement, developmental outcomes have become a growing concern. It is important to evaluate cognitive function using standardized verbal and nonverbal assessments, keeping in mind each individual’s motor skills, speech and language abilities, auditory function, and native language (177; 102). This enables an accurate assessment of whether there is a learning disability or an intellectual disability (50; 177). In a pivotal trial of enzyme replacement therapy, 11 of 17 infants with IPD (mean age 5 months, 2 days at baseline) performed at the lower end of the average range on a measure of cognition following 52 weeks of enzyme replacement therapy (175). A strong correlation between cognitive and motor development was found. Similar findings were obtained in a study of 13 infants with IPD identified through newborn screening and treated with enzyme replacement therapy from a very early age (112). Slightly older children (ages 4.9 to 8.9 years) with classic IPD had a median IQ that fell at the lower end of average (176). An additional follow-up study of 11 children and adolescents with IPD (age range = 5.5 to 17 years) highlighted the importance of using both verbal and nonverbal test measures to assess cognition and related skills over time, given potential hearing issues and motor weaknesses (177). This cohort also obtained median scores at the lower end of the average range on cognitive testing. Although there are reports of declining IQ scores in some individuals with IPD (49), this does not appear to be the norm for these individuals. Typically, children with IPD have a wide range of cognitive skills, even though median scores for the group continue to fall at the lower end of average. There is also some evidence of relative weaknesses in processing speed, fluid reasoning, visual perception, and receptive vocabulary (101).
The development of speech and language skills in children with IPD is also impacted by their pulmonary function, respiratory muscle weakness, laryngeal weakness, and neuromuscular control of the larynx. Children with IPD may have mixed and sensorineural hearing losses, which are known to impact speech. However, the hearing loss observed in these children does not fully explain the degree of speech impairment (164; 37). Children with IPD typically present with articulation disorders, hypernasality, and impaired speech intelligibility consistent with flaccid dysarthria (204). Mild to moderate severity of dysphonia is noted in about 80% of individuals with IPD (37).
Parent reports of children and adolescents with classic IPD (ages 5 to 18 years) indicate age-appropriate behavior and emotional functioning compared to age-matched and gender-matched typically developing peers (102). Despite the physical challenges of a chronic illness, increased school absenteeism due to weekly or biweekly enzyme replacement therapy infusions, and frequent clinical appointments, most children attend regular classrooms and receive special accommodations, such as extra time to complete their school work.
• Myopathy | |
• Respiratory insufficiency with early involvement of the diaphragm | |
• Absence of cardiomyopathy in the first year of life; can present later with cardiac involvement, such as varying degrees of left ventricular or septal hypertrophy, Wolff-Parkinson-White (WPW) syndrome, sinus arrhythmias, atrioventricular blocks, and other electrocardiographic abnormalities | |
• Musculoskeletal abnormalities, such as scoliosis, osteopenia, and winged scapulae | |
• Neuromuscular involvement, such as sensorineural, conductive, or mixed hearing loss, oropharyngeal dysphagia, small fiber neuropathy, ptosis, rigid syndrome, and lingual weakness |
Disease onset ranges from infancy to as late as the sixth decade of life (66; 105; 154; 71). Given the typically higher percentage of enzyme activity in LOPD, the disease onset is slower, and the disease progression is less severe and less aggressive than in IPD. Common presentations in the first year of life include swallowing difficulty, feeding difficulty, and sleep apnea. In LOPD, sleep-disordered breathing is common and comprises both hypoventilation and obstructive sleep apnea. Noninvasive ventilation significantly improves respiration and sleep quality (17; 203). However, as the disease progresses, in some instances, noninvasive ventilation becomes insufficient to maintain adequate pulmonary ventilation, and patients require continuous ventilator support such as (124). In addition to presenting with limb-girdle and respiratory involvement, patients can present with ptosis, rigid spine syndrome, lingual weakness, and vascular complications such as basilar artery aneurysms. Children with LOPD may exhibit delayed motor milestones. Common musculoskeletal problems include osteopenia or osteoporosis, kyphosis, scoliosis, chest wall abnormalities, winged scapulae, asymptomatic vertebral fractures, and problems with gait and posture (26; 16; 29).
Data from the Pompe Registry (the largest Pompe database in the world with 742 patients from 28 countries) shows that 89.2% (461 of 517) of patients with LOPD experience proximal muscle weakness in the lower extremities, 72.9% (377 of 517) experience proximal muscle weakness in the upper extremities, and 65.2% (337 of 517) experience muscle weakness in the trunk (24). In terms of respiratory manifestations, 65.6% (339 of 517) experience shortness of breath after exercise, and about 45% (232 of 517) receive respiratory support at some point, mostly in the form of noninvasive ventilation.
Muscle weakness predominates in truncal and proximal muscles (with lower extremities more involved than upper extremities). Clinically significant differences in gait, posture, selective muscle weakness, and contractures in muscle groups in patients with LOPD, when compared to those with IPD, have been extensively reviewed (26). Quantitative MRI data from patients with LOPD reveal significant fatty infiltration of musculature, largely correlating with muscle weakness identified via clinical muscle function assessments; additionally, evidence suggests that MRI data are able to monitor progression of muscle fatty infiltration over time and, in some cases, have been shown to be more sensitive than traditional disease outcome measures, such as physical examination, muscle function tests, or patient-reported outcomes (157; 25; 78; 57; 190; 118; 89). Muscle diffusion tensor imaging (mDTI) has also been used to show significant and early structural abnormalities in the distal muscles in patients with LOPD with or without fat infiltration, much prior to fatty degeneration (159). Nerve conduction abnormalities are also noted, and myotonic discharges may be prevalent and abnormal (01). However, it is unclear whether these abnormalities occur due to damage in a muscle, a nerve, or both.
Respiratory insufficiency may be the presenting complaint and is usually associated with daytime sleepiness, fatigue, morning headache, exertional dyspnea, or sleep-disordered breathing (18; 124). In LOPD, respiratory failure is usually the cause of death (195). Diaphragmatic weakness is a significant feature in Pompe disease and is the major cause of sleep-disordered breathing and early respiratory failure in patients with Pompe disease (172). Forced vital capacity should be monitored at baseline and follow-up assessments (12). A decrease in forced vital capacity from the upright to supine position is characteristic in LOPD and highlights the involvement of the diaphragm (24). There is a direct correlation between forced vital capacity and other important outcome measures, such as the 6-minute walk test, maximal inspiratory/expiratory pressure, Medical Research Council skeletal muscle strength score, and the 36-item short-form survey-physical component score. Therefore, forced vital capacity is a useful measure to monitor disease progression in patients with LOPD over time. Muscle MRI data have shown that respiratory weakness and insufficiency in LOPD is mainly due to diaphragmatic weakness and significant fat replacement in respiratory muscles, such as paraspinal, abdominal, and trunk muscles, and it is important to monitor these changes over time (60; 161).
Although the heart is not extensively involved in LOPD, variable degrees of left ventricular or septal hypertrophy, Wolff-Parkinson-White (WPW) syndrome, sinus arrhythmias, atrioventricular blocks, and other electrocardiographic abnormalities have been seen (133; 58; 03; 113; 05; 29). These cardiac findings are blurring the lines of what was once the definitive feature of classic IPD and reinforcing the idea that Pompe disease is, in fact, a continuous spectrum. Only a subset of individuals with LOPD may have a reversal of the cardiac findings with long-term enzyme replacement therapy (for 3 years) (03). Patients with LOPD with the c.-32-13T>G variant (IVS1 splice site variant) do not have severe cardiomyopathy but can present with arrhythmias and aortic root dilatation in adulthood (72). In the absence of the c.-32-13T>G variant, patients can present with cardiomyopathy. Increased glycogen accumulation in the arterial walls has been observed to cause increased aortic stiffness and blood pressure and dilated arteriopathy, increasing the potential risk of cardiovascular diseases in adult patients with LOPD (137; 52; 193).
Involvement of the central or peripheral nervous system has also been reported. Neuromuscular manifestations include sensorineural, conductive, or mixed hearing loss, oropharyngeal dysphagia, small fiber neuropathy, ptosis, rigid syndrome, and lingual weakness. There is strong evidence of glycogen accumulation in the smooth muscles of the cerebral arteries causing intracranial aneurysms that can lead to early death in LOPD (119; 123; 103; 110; 165). In addition to intracranial aneurysms, dolichoectasia of the vertebrobasilar system may be seen in adults with LOPD (134). White and gray matter abnormalities have been reported on brain MRI from adults with LOPD; however, further research is needed to understand whether these are typical age-related changes (134; 167). It must be remembered that relevant data at this time are sparse, and other causes of cognitive decline have not been excluded or explored. Although cognitive function is largely thought to be unaffected in LOPD, adults with LOPD may present with mild impairment in executive functions, lower than normal IQ scores on cognitive tests, and affected visual-constructive abilities (20; 99; 134). Overall, children with LOPD seem to be less impacted than their peers, with overall higher IQ scores (99; 101; 176). Parent reports on children with LOPD have shown relative weak domains, such as negative mood symptoms and peer relations (102). Smooth muscle function is also impaired in individuals with LOPD (124). Patients can present with urinary incontinence, dribbling, weak urine stream, post-void dribbling, inability to stop urination midstream, bowel incontinence, swallowing difficulty, chronic diarrhea, postprandial bloating, abdominal pain, and irritable bowel syndrome (14; 126). Patients with LOPD have a high prevalence of gas and bloating (98%), gastroesophageal reflux (94%), constipation (84%), diarrhea (72%), belly pain (68%), nausea and vomiting (61%), disrupted swallowing (54%), and bowel incontinence (40%) (100). Patients typically have no change or worsening gastrointestinal and genitourinary symptoms; therefore, it is important to manage these symptomatically.
Due to the multitude of symptoms, patients with LOPD who are on long-term enzyme replacement therapy have a reduced quality of life. Monitoring the physical, mental, and social outcomes and the minimal changes in these outcomes is essential to providing holistic treatment for these individuals (201; 69; 100).
Before the era of enzyme replacement therapy (2006), the natural history of untreated children with infantile Pompe disease revealed a median age of disease onset of 2 months, age at diagnosis of 4.7 months, age at ventilator dependence of 5.9 months, and, eventually, death by 6 to 8.7 months (187; 91). With enzyme replacement therapy, children with IPD are living longer, and the oldest survivors have entered adulthood. The natural history continues to evolve, and the long-term prognosis and complications are still unknown.
Before the enzyme replacement therapy era, patients with late-onset Pompe disease had a median survival of 27 years after the age at diagnosis and had a higher mortality rate compared to the general population, with a median age of death at 55 years (range 23 to 77 years) (64). Additionally, patients with wheelchair or respiratory support had a shorter life expectancy compared to those without wheelchair or respiratory support. The cause of death in patients with LOPD is typically attributed to respiratory complications; however, studies have shown that basilar artery aneurysms are also responsible (67; 127; 110). With enzyme replacement therapy, patients with LOPD had remarkable improvement in ambulatory and ventilation status, with a five-fold lower mortality rate compared to untreated patients (169).
A 31-year-old man presented with pneumonia, at which time considerable wasting of proximal limb and trunk muscles was noted. He also reported difficulty with swallowing food. The patient had steadily progressive muscle weakness since the age of 24 years, but he had been able to work and did not seek any medical advice except for low back pain (his myelogram was normal). In childhood, he reported no issues and was very active. Two of his brothers and both parents did not have similar symptoms.
Neuromuscular examination showed marked atrophy and commensurate weakness of the pelvic girdle and shoulder muscles. Both primary and secondary respiratory muscles were weak. Weakness of trunk muscles was associated with thoracic scoliosis and marked lumbar lordosis. Distal limb muscles and craniobulbar musculature were spared. Deep tendon reflexes in both upper and lower extremities were normal. There were no sensory deficits. Mentation was normal.
Six months later, the patient developed respiratory insufficiency with arterial hypoxemia and respiratory acidosis, necessitating permanent tracheostomy. Pulmonary function tests, electromyography, and punch muscle biopsy were obtained. Pulmonary function test showed a decrease in forced vital capacity both in the upright and supine position, with greater postural drop of forced vital capacity in the supine position. Needle EMG showed abundant spontaneous fibrillations as well as synchronized fibrillations from many proximal and distal muscles. On maximal effort, there was reduced interference. Muscle biopsy, however, was normal.
Laboratory tests showed increased serum creatine kinase (159 IU; reference range < 45 IU) (22). Urinary glucose tetrasaccharide (Glc4) levels and serum aspartate aminotransferase, alanine aminotransferase, and lactate dehydrogenase levels were elevated. GAA activity in dried blood spots showed deficiency. GAA sequencing revealed compound heterozygosity for two pathogenic variants, c.-32-13T>G (IVS1-13T> G) and c.1827del (p.Tyr609X). This was a case of a young man diagnosed with LOPD.
• Autosomal recessive | |
• Acid alpha-glucosidase (GAA) enzyme deficiency | |
• Pathogenic variants in the GAA gene |
Pompe disease is a hereditary condition transmitted as an autosomal recessive disease. The gene encoding acid alpha-glucosidase, GAA, has been localized on chromosome 17q25.3 (107). More genetic information can be accessed at the following website:GAA Chromosome Locus.
Acid alpha-glucosidase (GAA) is a lysosomal enzyme with both alpha-1,4-glucosidase and alpha-1,6-glucosidase activity and is, therefore, capable of digesting glycogen, maltose, and isomaltose completely to glucose (150). Like other lysosomal enzymes, acid alpha-glucosidase is a glycoprotein and is synthesized in the endoplasmic reticulum (ER)-Golgi complex. Before leaving the ER-Golgi complex to be transferred to the lysosomes, the inactive enzyme precursor of about 110 kDa is modified by proteolysis into a 95-kDa intermediate form, which is then further modified to the active forms of 76 and 70 kDa (131).
In agreement with the concept that there are no tissue-specific GAA isozymes, GAA activity in Pompe disease is markedly decreased in all tissues, not only in infantile Pompe disease but across the disease spectrum (48). Fibroblasts from patients with infantile Pompe disease have less than 1% GAA residual activity, whereas fibroblasts from patients with late-onset Pompe disease typically have between 1% and 40% residual GAA activities. However, some reports show a subset of patients (101 patients; 13%) with late-onset Pompe disease could have less than 1% residual activity in cultured skin fibroblasts (08).
Pompe disease is a genetically heterogeneous disorder. A study of 1079 patients from 26 countries reported 2075 GAA variants (80 novel) from the Pompe registry with the largest global repository data (160). Some variants are common in specific population groups, allowing correlations between specific pathogenic variants and clinical severity (76). Other variants are rare, some being reported only in one family.
• The c.-32-13T>G variant (or IVS1 splice site variant) is the most commonly reported variant among patients with LOPD, globally and in specific geographic locations such as Europe, North America, and Latin America but not in Asia-Pacific or Middle East (160). The c.-32-13T>G variant is called a “leaky splice site” variant because in 10% to 20% of splicing events, this variant allows some normal protein to be made, leading to its association with the milder, adult-onset LOPD (19). However, a subset of children with the c.-32-13T>G variant present within the first 2 years of life with symptoms including delayed motor milestones, proximal weakness, swallowing and feeding difficulties, and sleep apnea (71). | |
• The c.510C>T is a genetic modifier in patients with LOPD with compound heterozygous and homozygous c.-32-13T>G variant (13). The c.510C>T variant reduces the extent of leaky wild-type splicing. This decreases the residual GAA enzyme activity, which results in early onset of the disease, compared to patients with LOPD without the modifier variant (13). However, it must also be noted that the absence of this modifier variant does not guarantee that the disease onset is later in life. | |
• Additionally, although cardiac involvement in the form of severe cardiomyopathy is rare in patients with LOPD with the c.-32-13T>G variant, arrhythmias have been reported in patients as young as 8 years old (188; 72). | |
• The c.525delT (9% United States cases, 34% Dutch cases) and exon 18 deletion (5% United States cases, 25% Dutch and Canadian cases) variants predominate among patients with IPD (189; 76). | |
• Common variants due to founder effect in certain ethnic groups include p.Asp645Glu (infantile) in patients of Chinese background, p.Arg854X in patients of African American and African origins, and p.Gly309Arg in patients of European descent (93). |
Understanding of the correlation between the “molecular severity” of variants and severity of the clinical presentation continues to grow (54; 73; 106; 104; 136). This understanding has been facilitated by documentation of clinical severity alongside specific variants in the Erasmus MC database, and by studies that transiently express the pathogenic variant in COS-7 and HEK293T cells and then analyze the activity, quantity, and quality of the GAA enzyme (54; 73; 105; 106; 104). Although there is a correlation between genotype and phenotype, other factors play a role in clinical presentation, emphasizing the clinical and genetic heterogeneity of Pompe disease and reinforcing the idea that disease presentation constitutes a continuum.
The cross-reactive immune material (CRIM) status is established by Western blot analysis and can be used to predict clinical outcomes and response to enzyme replacement therapy in patients with Pompe disease. CRIM-positive patients have detectable GAA protein, whereas CRIM-negative status denotes the absence of GAA protein; thus, CRIM-negative patients tend to have poorer outcomes compared to CRIM-positive patients (92). CRIM-negative patients typically mount an immune response (antibodies) against the infused rhGAA in enzyme replacement therapy and have a poor clinical response to the subsequent doses of enzyme replacement therapy. Approximately 25% of patients with classic infantile Pompe disease are CRIM-negative (07). The most commonly identified variants in CRIM-negative patients are p.Arg854X (32.7%) and c.525delT (4.8%). About 85% of CRIM-negative patients test homozygous or compound heterozygous for nonsense, frameshift, and multi-exon deletion variants, consistent with the inability to make GAA protein. CRIM-positive patients, on the contrary, have one or two missense variants, in-frame deletions, or other variants that are expected to allow for some degree of GAA production. All CRIM-negative and a third of CRIM-positive patients can develop high or sustained immune response to the infused rhGAA in enzyme replacement therapy, leading to a decrease in response to enzyme replacement therapy and a progressive clinical decline (139; 15; 44). New studies suggest that it is important to predict and assess the risk of response to enzyme replacement therapy in each patient with Pompe disease using the Personalized Immunogenicity Risk Assessment (PIMA), which combines information about the patient’s native GAA gene and the body’s own immune response (HLA DR haplotype) (41). A better understanding of the immunogenicity risk in patients with Pompe disease will benefit the development of targeted immune modulation therapy, thereby improving clinical outcomes and response to standard of care.
• Glycogen accumulation in skeletal, smooth, and cardiac muscles as well as brain and spinal cord | |
• Vacuolization of cells | |
• Impaired autophagy |
In muscle biopsies from patients with infantile Pompe disease, there is significant accumulation of free and intra-lysosomal glycogen in most tissues and an abundance of often-confluent vacuoles, resulting in a "lacework" appearance. In LOPD, muscle biopsies may appear normal, despite the marked decrease of GAA activity. Muscle glycogen concentrations are generally lower in those presenting in childhood and may be normal in some patients presenting later in life. If abnormal, vacuoles are less numerous and smaller compared to peers with IPD. The vacuoles contain periodic acid-Schiff-positive material and stain intensely for acid phosphatase, another lysosomal enzyme. The positive acid phosphatase stain can be a useful diagnostic clue in otherwise normal biopsy specimens. Thus, it is important to recognize that a normal muscle biopsy histology does not exclude a diagnosis of Pompe disease; if Pompe disease is suspected, further testing, such as GAA enzyme activity analysis or gene sequencing, is warranted.
Autopsy findings from patients with Pompe disease also suggest a significant amount of glycogen accumulates within the skeletal muscles. Additionally, glycogen accumulation is seen in the smooth muscles of the bladder and other parts of the genitourinary tract, the gastrointestinal tract, respiratory muscles, cardiac conduction tissue, iris sphincter and blood vessels, and skeletal muscles of the tongue and upper esophagus (141).
As expected in a lysosomal disease, electron microscopy shows that much of the glycogen is contained within single membrane-limited lysosomal "sacs," but free glycogen is also present in the cytoplasm, especially in IPD. The buildup of glycogen in the cytoplasm, which one might think would not occur due to the existence of cytoplasmic glycogenolytic enzymes, appears to be due to rupture/leakage of lysosomal glycogen (153). The lack of glycogen clearance from the cytoplasm can also be attributed to dysfunctional autophagy (135). Given that lysosomal storage of any substrate impairs autophagic delivery of bulk cytosolic contents to lysosomes (171), impairment of the autophagic pathway may help explain the relationship between different lysosomal enzyme deficiencies and cell death, secondary to autophagic buildup in all lysosomal disorders (170).
Impaired autophagy in Pompe disease is suggested by detailed studies both in the murine model (59) and in patients (120; 136; 135). In Pompe disease, buildup of autophagic debris in the skeletal muscle of patients and knockout mice appears to be correlated with a decrease in muscle strength, the accrual of defunct mitochondria, and mild muscular atrophy (153). In a study examining human tissues, autophagic buildup progressed over time in both adult and infantile forms (151). Patients with IPD on long-term enzyme replacement therapy (up to 8 years) who were treated early in life had lesser autophagic buildup (147). Another study reported that most adult patients with LOPD (who were on enzyme replacement therapy) had autophagic buildup with lipofuscin inclusions (55). Muscle biopsies before and after enzyme replacement therapy revealed varying amounts of large, autofluorescent inclusions filled with lipofuscin, an indigestible material normally recognized in older patients due to aging. The ramifications of glycogen and autophagic buildup along with lipofuscin accumulation remain under investigation, both in relation to enzyme replacement therapy efficacy and the prevention of normal contractile function.
Research on human-induced pluripotent stem cell-derived cardiomyocytes (iPSC-CM) found that Pompe disease iPSC-CMs produce lysosome-associated membrane proteins lacking glycosylation, revealing a Golgi-based glycosylation deficit most likely secondary to the changes in glycogen metabolism. These data suggest that Pompe disease cardiomyopathy has a glycan processing abnormality and, thus, shares features with hypertrophic cardiomyopathies observed in the congenital disorders of glycosylation (158).
• Genetic variants | ||
• Degree of GAA deficiency | ||
• Degree of disease progression at the time of treatment initiation (ie, age at enzyme replacement therapy initiation) and insufficient enzyme uptake of skeletal muscle | ||
• Environment, diet, exercise | ||
• Genetic modifiers | ||
- The angiotensin-converting enzyme (ACE) variants with genotype DD (deletion/deletion). The DD genotype has been linked to an earlier age of onset, faster rate of progression, and more severe muscle pain (39; 40). Patients with the DD genotype appeared to have a reduced response to enzyme replacement therapy, compared to patients with II (insertion/insertion) or ID (insertion/deletion) genotypes (06). However, irrespective of the ACE variants, a large variation was observed in the disease severity and the enzyme replacement therapy response in patients with the most common genetic variant c.-32-13T>G in LOPD in a European cohort (108). | ||
- The ACTN3 gene. A null polymorphism in the ACTN3 gene was shown to positively affect treatment efficacy with enzyme replacement therapy (156). | ||
• Oxidative stress at the tissue level has been found to be inversely proportional to the treatment response to enzyme replacement therapy in patients with Pompe disease (182). | ||
• Female sex has been identified as a good prognostic factor for the effect of enzyme replacement therapy on muscle strength. | ||
• Immune response and CRIM status | ||
• Dose of enzyme replacement therapy (lower doses less effective than higher) | ||
• Defective autophagy | ||
• Muscle fiber type. Type II muscle fibers have been found to be less responsive to enzyme replacement therapy than type I fibers (149; 152). This can explain the persistent weakness of certain skeletal muscles, such as the anterior tibialis, in patients with IPD who respond well to enzyme replacement therapy (26). The weakness of the anterior tibialis, a muscle with a great number of type II fibers, may be attributed to the notable accumulation of autophagosomes and the subsequent accumulation of the recombinant enzyme within the autophagosomes, preventing glycogen clearance in type II fibers. |
Prior to the advent of newborn screening, Pompe disease was thought to have a combined estimated frequency of 1 in 40,000 live births and had been reported in many countries and different ethnic groups (122). There have been reports of founder effects in Taiwanese, Chinese, and African populations. A newborn screening program implemented in Taiwan uncovered that the prevalence of Pompe disease across the spectrum was approximately 1 in 18,108, of which 1 in 26,466 were LOPD and 1 in 57,343 were IPD. As a result of newborn screening, the prevalence of pseudodeficiency also increased. Pseudodeficiency includes genetic variants that result in lower GAA activity but no clinical manifestations. Individuals with pseudodeficiency have a c.1726 G>A (p.G576S) variant in cis with c.2065 G>A (p.E689K), also known as the c.[1726A; 2065A] haplotype. Pseudodeficiency is common in Asia; it is seen in 3.9% of the healthy Japanese population and 14.5% of the Taiwanese population (30). A newborn screening report in Japan revealed low GAA activity in 71 of 103,204 (0.07%) newborns. Of these 71 patients, 32 (45.1%) were homozygous and 37 (52.1%) were heterozygous for pseudodeficiency alleles c.[1726G>A; 2965G>A] (129). Three newborns were identified with potential LOPD with no symptoms at the time of that publication, and none were diagnosed with IPD.
Since the addition of Pompe disease to the Recommended Uniform Screening Panel (RUSP) in the United States in 2015, more information is available about the incidence of Pompe disease from different states. Missouri was the first state to implement newborn screening for Pompe disease, with an overall incidence rate of about 1 in 10,000 after 6 years of implementation (96). In Pennsylvania, an overall incidence of 1 in 16,095 (n=2, IPD; n=31, LOPD) was observed (56). In Illinois, 10 patients were identified with a confirmed diagnosis of Pompe disease (n=2, IPD; n=8, LOPD), with an incidence of 1 in 21,979 (22). In California, the overall prevalence of Pompe disease was 1 in 25,200, with approximately 1 in 250,000 for IPD and 1 in 37,500 for LOPD (181).
Newborn screening programs have significantly improved clinical outcomes in newborns with IPD. Infants with IPD diagnosed via newborn screening who are treated early have an average lifetime increase of 11.66 quality-adjusted life-years (QALY), compared with their peers diagnosed via symptom-onset (162).
• Newborn screening | |
• Genetic counseling and prenatal testing | |
• Very early diagnosis and treatment with enzyme replacement therapy |
Newborn screening helps in the early detection of Pompe disease, thereby facilitating earlier and more effective treatment (198). In the United States, since March 2015, more and more states have implemented universal newborn screening for Pompe disease. At the time of this publication, in addition to the District of Columbia, the following 28 states have implemented universal newborn screening for Pompe disease: Delaware, Washington, Oregon, California, Nebraska, Minnesota, Missouri, Illinois, Wisconsin, Michigan, Ohio, Kentucky, Mississippi, Tennessee, Virginia, Maryland, Pennsylvania, New York, Vermont, Massachusetts, Florida, Rhode Island, Connecticut, Indiana, Kansas, Maine, New Jersey, and South Carolina. Newborn screening studies from Taiwan show that infants receiving enzyme replacement therapy before 1 month of age show marked clinical improvement (31; 32; 198). Over time, these studies showed that an early initiation of enzyme replacement therapy (median age at initiation of 11.5 days) resulted in a marked improvement in patients with IPD, specifically with regards to their daily activities, motor milestones, muscle weakness and tone, ptosis, speech, echocardiography findings, and other biomarkers of disease progression.
As prenatal diagnosis is feasible using either biochemical or molecular genetic analysis, recurrence of IPD in the same family can be identified through prenatal detection and genetic counseling. There is a 25% recurrence rate with each pregnancy in a couple where one parent is a carrier of a pathogenic variant for Pompe disease (178). Of note, lifespan and phenotypic presentation among siblings with IPD is very similar (173). Siblings with LOPD, in contrast, can present very differently even though they share the same genotype. Phenotypic variation indicates the influence of epigenetic and environmental effects on clinical presentation and disease development (194).
Despite the confirmatory methods of laboratory diagnosis, the rarity of Pompe disease and nonspecific presentation of many symptoms can complicate the clinical diagnostic process. The ACMG Practice Guidelines for Pompe disease offer a clear, concise method for diagnosis, both in infantile- and late-onset forms of the disease (93). The AANEM Consensus Treatment Recommendations for LOPD and Diagnostic Criteria for Late-onset (Childhood and Adult) Pompe Disease also provide useful methodologies (01; 38).
The differential diagnosis for Pompe disease is as follows:
• Spinal muscular atrophy type I (Werdnig-Hoffmann disease) and other metabolic or congenital myopathies (79). Infants present with hypotonia, muscle weakness, delayed motor milestones, respiratory muscle weakness, and swallowing difficulties. Spinal muscular atrophy type I can be differentiated from Pompe disease using cardiac imaging. Patients with classic IPD typically present with massive cardiomegaly, as seen in chest x-ray and echocardiogram. An echocardiogram would reveal hypertrophic cardiomyopathy, occasionally with left ventricular outflow tract obstruction. Later in the disease course, IPD may present with dilated cardiomyopathy and impaired cardiac function. An electrocardiogram can further indicate the diagnosis as patients with IPD typically have short PR intervals with tall QRS complexes. | |
• Cytochrome c oxidase deficiency. Patients with cytochrome c oxidase deficiency have myopathy and cardiomyopathy, but the cardiomegaly seen here is usually less marked than in IPD. Patients with cytochrome c deficiency typically develop lactic acidosis. | |
• Deficiency of AMP-activated protein kinase (AMPK, also known as PRKAG2 cardiac syndrome). Patients with AMPK deficiency can present with massive cardiomegaly in infancy, but muscle weakness is minimal, and muscle biopsy is essentially normal (21). Patients with Pompe disease can have pre-symptomatic (early) myopathic changes and fat infiltration, as seen in electromyogram (EMG) and muscle MRI. | |
• Glycogen storage disease type IV or branching enzyme deficiency. Patients with GSD type IV can present with muscle weakness and cardiomegaly; however, the presence of abnormal glycogen (polyglucosan) in tissues of patients with branching enzyme deficiency distinguishes it from Pompe disease. | |
• Debrancher deficiency (GSD IIIa) myopathy. This condition is often accompanied by hepatomegaly, fasting hypoglycemia, and elevated cholesterol and triglycerides. There is no response of blood glucose to epinephrine or glucagon administration | |
• Danon disease. Danon disease is characterized by cardiomyopathy, intellectual disability, and autophagic vacuolar myopathy. This disorder is caused by pathogenic variants in the gene encoding a lysosome-associated membrane protein known as LAMP-2 (138). | |
• Carnitine uptake disorder. This condition occurs due to biallelic pathogenic variants in the SLC22A5 gene. | |
• Muscle phosphorylase b kinase deficiency. Another rare condition where patients can present with increased hepatic transaminases, myopathy, exercise intolerance, and delays in developmental milestones, which are similar clinical features in Pompe disease. However, both disorders can be distinguished by enzymatic and molecular genetic testing. | |
• Limb-girdle muscular dystrophy or polymyositis, Duchenne muscular dystrophy, or Becker muscular dystrophy. These disorders can be confused with LOPD due to the common presentation of boys with calf pseudohypertrophy and a progressive myopathy. In Duchenne muscular dystrophy, however, family history may suggest X-linked transmission, serum CK tends to be higher, and EMG does not show prominent irritative features (ie, fibrillation or positive sharp wave potentials) or myotonic discharges. EMG features in paraspinal muscles in Pompe disease include fibrillation potentials, positive waves, complex repetitive discharges, and myotonic discharges, which may be useful clues. Muscle biopsy or blood-based enzyme analysis clearly differentiates Duchenne muscular dystrophy and late-onset Pompe disease. |
Pompe disease continues to be underdiagnosed or is often misdiagnosed as another one of these conditions. However, with the implementation of newborn screening programs, the awareness of Pompe disease would increase, over time. Because Pompe disease has a phenotypic overlap with a number of neuromuscular disorders, it is important for clinicians to be aware of unique findings in Pompe disease. Patients with Pompe disease who had a direct referral to expert clinics (metabolic or musculoskeletal) had the lowest diagnostic delay and better clinical outcomes (111). Similarly, lone cardiac involvement may be a preliminary clinical sign in inherited metabolic disorders such as Pompe disease; therefore, a cardiologist should have a high index of suspicion when a patient has higher than normal serum CK levels, abnormal echocardiography, and subtle muscular issues (62).
• GAA deficiency (fibroblasts, muscle, or blood) | |
• Variant analysis of the GAA gene | |
• Targeted gene sequencing, next-generation sequencing, exome sequencing | |
• Cardiac evaluation with ECG, echocardiogram, and chest x-ray | |
• Pulmonary function test | |
• Biomarkers | |
• Muscle function testing |
Confirmation of the diagnosis of Pompe disease requires demonstration of GAA enzyme deficiency or the presence of two pathogenic variants in trans in the GAA gene.
GAA enzyme activity. The GAA enzyme activity can be evaluated in cultured skin fibroblasts, muscle biopsies, or blood.
• Muscle biopsy, although invasive, provides material for histology and electron microscopy studies in addition to GAA activity assay. This can be helpful, especially when the differential diagnosis is wide. However, it should be noted that a normal muscle biopsy does not rule out the diagnosis of Pompe disease and that a positive acid phosphatase stain can help in confirming the diagnosis, particularly in LOPD. | |
• Measurement of GAA activity in cultured skin fibroblasts is time-consuming, requiring the time to culture the cells, but provides an accurate measurement of residual enzyme activity and material for CRIM testing. CRIM status has emerged as an important prognostic factor in patients with IPD and is now part of the recommended diagnostic workup for babies with IPD identified via newborn screening (23). The presence of any amount of GAA activity on Western blot is considered CRIM-positive, and a complete lack of the enzyme or the protein is considered CRIM-negative. It is important to note that the CRIM status should not be interpreted as an “either/or” phenomenon but, rather, a continuum. Hence, the CRIM status should be confirmed based on Western blot and GAA variant analyses or variant analysis alone if there are known pathogenic variants. |
Variant analysis of the GAA gene. Variant analysis of the GAA gene (GAA sequencing) allows identification of the associated DNA changes. GAA pathogenic variants may include missense, nonsense, splicing, frameshift, deletions, and insertions. GAA gene sequencing helps to confirm the diagnosis of Pompe disease, differentiate between IPD and LOPD, and facilitate testing for family members, including carrier testing and prenatal testing (93); it also helps in determining CRIM status and identifying patients with pseudodeficiency of GAA activity (ie, p.Gly576Ser and p.Glu689Lys variants in cis result in high false positives during newborn screening). An algorithm utilizing enzyme analysis, CRIM status analysis, and genotyping would be useful for newborn screening to minimize false-positive rates and correctly identify pseudodeficiency in patients (109; 09; 191).
Targeted gene sequencing. Targeted gene sequencing allows sequencing of regions of particular interest and the identification of common or known familial pathogenic variants. Gene-targeted deletion and duplication analysis is useful when only one pathogenic variant or none is identified.
Next-generation sequencing. Next-generation sequencing methods make it possible to test for several disorders simultaneously. It is particularly useful to narrow the diagnosis when patients present with nonspecific muscle weakness or atypical phenotypes.
Exome sequencing. Exome sequencing sequences all the expressed genes in a genome. This approach may be useful in undiagnosed neuromuscular disorders. However, it does not reliably detect structural variants such as translocations or large deletions or duplications and can, therefore, fail to detect certain pathogenic variants (179; 132).
Biomarkers or biochemical testing. Biomarkers or biochemical testing should include determining the levels of serum creatine kinase (CK), CK-MB, aspartate aminotransferase (AST), alanine aminotransferase (ALT), lactate dehydrogenase (LDH), and urinary Glc4 as part of the diagnostic workup for Pompe disease (85; 155). AST and ALT are often elevated, with AST typically being higher than ALT. Urinary Glc4 is a limit dextrin produced due to the breakdown of glycogen and is excreted in the urine. Urinary Glc4 is a good indicator of the overall disease burden in Pompe disease because its level correlates well with the level of glycogen accumulation in skeletal muscles (199). Urinary Glc4 is found to be elevated as early as in neonates with IPD. Therefore, it could potentially be used as a biomarker for IPD at the time of newborn screening and to monitor response to enzyme replacement therapy (200; 32). Although the serum enzymes creatine kinase, CK-MB, AST, ALT, and LDH are useful in the diagnostic workup of Pompe disease, they are nonspecific biomarkers and should accompany other more specific diagnostic tests.
Cardiac evaluation using ECG echocardiogram. Cardiac evaluations using ECG, echocardiogram, and chest x-rays are useful for diagnosing IPD. Electrocardiography shows short PR interval, giant QRS complexes, and signs of left ventricular or biventricular hypertrophy. An echocardiogram would reveal hypertrophic cardiomyopathy, occasionally with left ventricular outflow tract obstruction in classic IPD. Dilated cardiomyopathy and impaired cardiac function (reduced ejection fraction) can also occur in IPD. Chest x-ray reveals cardiomegaly.
Pulmonary function testing. Pulmonary function testing should be done in both the supine and seated positions as it may reveal diaphragm weakness in LOPD (01). Pulmonary function studies show restrictive ventilatory insufficiency with reduced maximal static inspiratory and expiratory pressures and early diaphragmatic fatigue.
Muscle function testing. Muscle function testing done at regular intervals by experienced physical therapists on the care team is very important to evaluate muscle function and assess response to enzyme replacement therapy. The standardized muscle tests used in patients with Pompe disease include 6-minute walk tests, Gait, Stairs, Gowers, Chair (GSGC) test, Gross Motor Function Measures (GMFM), grip strength, and other age-appropriate measures. EMG of paraspinal muscles in LOPD may reveal irritative features (ie, fibrillation or positive sharp wave potentials) or myotonic discharge. Nerve conduction abnormalities are also noted, and myotonic discharges may be prevalent and abnormal. Muscle MRI may be useful to follow the progression of glycogen deposition, detect early fat-infiltration, and monitor the response to therapeutic interventions.
Whole-body magnetic resonance imaging. Whole-body magnetic resonance imaging (WBMRI) has also been used to measure the amount of fatty infiltration in skeletal muscles in LOPD. A study showed that a methodical evaluation of muscle strength and function (GSGC score) and laboratory biomarkers (urinary Glc4) correlated well with the results from whole-body magnetic resonance imaging and, therefore, can be used to assess the severity of muscle disease and follow patients with LOPD over time (if unable to perform WBRI in patients with Pompe disease) (89).
All patients with infantile or late-onset Pompe disease require a multidisciplinary team approach to manage the disease. The team should include a geneticist, neurologist, pulmonologist, cardiologist, speech and language pathologist, child psychologist, dietician, physical therapist, and others as needed. With time, various treatment options have surfaced.
• Enzyme replacement therapy | ||
- First- and second-generation therapy | ||
• Adjunct therapies using chaperones, immune modulation, diet, and exercise | ||
• Gene therapy | ||
• Stem cell therapy | ||
• Preclinical studies |
• Enzyme replacement therapy with alglucosidase alfa. Enzyme replacement therapy with alglucosidase alfa (in 2006 and 2014, Myozyme™ and Lumizyme™, respectively) changed the treatment landscape of Pompe disease. | |
• Second-generation enzyme replacement therapy. Studies are underway to enhance response to enzyme replacement therapy, focused on targeting and uptake of GAA via the addition of mannose 6-phosphate residues to the engineered alpha-glucosidase (205) and simultaneous administration of pharmacological chaperones to enhance the delivery of enzyme replacement therapy to the lysosomes (145). The Food and Drug Administration (FDA) approved avalglucosidase alfa (neoGAA) in August 2021 for patients with LOPD. NeoGAA is a next-generation enzyme replacement therapy wherein carbohydrates are conjugated to the GAA enzyme to improve its delivery to muscle cells by its increased affinity for cation-independent mannose-6-phosphate receptors (CI-MPR). It has approximately 15 moles of mannose-6-phosphate residues per mole of enzyme (15 M6P, which is a 15-fold increase compared to traditional enzyme replacement therapy or alglucosidase alfa). Clinical trials for avalglucosidase have shown significant improvement in the muscle strength and pulmonary functioning in patients who were enzyme replacement therapy-naïve patients treated with neoGAA, and this drug has been deemed safe and well-tolerated in patients (NCT02782741) (142). | |
• ATB200 (cipaglucosidase alfa). ATB200 is a new rhGAA with high bis-M6P residues. The AT2221 (miglustat, an oral chaperone)/ATB200 combination is being investigated for treating patients with adult LOPD. Initial studies showed marked improvements in functional measures (motor function tests) and key biomarkers (CK, AST/ALT, urine Hex4) when compared to the alglucosidase/placebo group (phase 1/2) (02). A phase 3 trial suggested that it had no superiority for improving 6-minute walk tests clinicaltrials.gov) (168). Further studies are underway to investigate the longer-term safety, efficacy, and benefits (respiratory function) of cipaglucosidase alfa/miglustat (NCT04138277, ongoing phase 3 study). At this time, the drug combination is in phase 3 trial for children with LOPD as well (ages 12 to 18 years) (NCT03911505). |
The pivotal studies of patients with IPD uncovered that enzyme replacement therapy improved survival, cardiac function, and both growth and motor development and that it was important to begin treatment as early as possible for maximum efficacy (91). For IPD, enzyme replacement therapy has clearly shifted the natural history, with survival now extending far beyond the first year of life; older patients in the first cohort are now as old as 22 years. Several long-term issues are emerging, but, in general, the response of patients with IPD has been varied, as illustrated by several studies (94).
The most important lesson learned through these 15 years with enzyme replacement therapy is that early treatment improves long-term outcomes in patients with Pompe disease, and age at the start of enzyme replacement therapy is crucial to reduce muscular weakness and respiratory decline in IPD (33; 34; 91; 28; 196; 198; 197). An important trend to note is that patients with IPD typically reach a clinical plateau with the standard dose of 20 mg/kg every other week, and increasing the dose to 40 mg/kg/week improves clinical outcomes for ventilator-free survival and motor function, lingual strength, pulmonary function measures, and biochemical markers (147; 27; 192; 90). In patients with LOPD, enzyme replacement therapy has improved clinical outcomes (pulmonary, respiratory, and muscular systems) and quality of life, when initiated early. There is a five-fold increase in the survival rate of enzyme replacement therapy-treated patients with LOPD when compared to their untreated peers with LOPD (169). For patients with LOPD, there are no consensus guidelines on when to begin enzyme replacement therapy. The availability of newborn screening will help to understand this knowledge gap. However, to avoid irreversible damage, it is important to initiate enzyme replacement therapy early in the disease course. In addition, due to the emerging phenotypes of IPD survivors and enzyme replacement therapy-treated patients with LOPD, it is clear that a more efficient therapy is the need of the hour. Multiple approaches have been explored, either as adjunct therapies to enzyme replacement therapy, second-generation enzyme replacement therapy, or gene therapy.
• Diet and exercise. Diet and exercise play an essential role in improving the clinical manifestations in patients with Pompe disease on enzyme replacement therapy. A high-protein, low-carbohydrate diet, physical therapy, and supervised or guided aerobic exercises suggested by expert physical therapists are known to improve muscle function. It is suggested that patients with LOPD should be encouraged to engage in low-to-moderate intensity exercises under supervision on most days and that an excessively strenuous regimen, excessive fatigue, and muscle pain should be avoided (183). Patients with IPD and LOPD on enzyme replacement therapy have shown improvement in respiratory strength after undergoing respiratory muscle strength training (RMST) (81; 83; 82; 05). | ||
• Small-molecule or chaperone therapy. High doses of enzyme replacement therapy are required to reduce the abnormal glycogen accumulation in skeletal muscles. This may be due to the low affinity of enzyme replacement therapy for cation-independent mannose 6-phosphate receptor (CI-MPR) on the affected target cells (skeletal muscles) during endocytosis (206). To improve the delivery of enzyme replacement therapy to the target cells, the addition of a high-affinity, small-molecule, chaperone therapy is being explored. Pharmacological chaperones include receptor agonists and antagonists, substrate analogs or other modulators, and ligands. Several preclinical studies have shown that beta-agonists effectively improve the delivery of enzyme replacement therapy into the skeletal muscles. In patients with LOPD who reached a clinical plateau with enzyme replacement therapy, the addition of albuterol showed a remarkable improvement in muscle weakness and pulmonary function tests (97; 98). The addition of clenbuterol has been shown to reduce glycogen content in the vastus lateralis, increase the normal muscle gene expression, and improve muscle function tests. | ||
• Immunomodulation with enzyme replacement therapy. Immunomodulation is used to prevent or reduce the antibody response to enzyme replacement therapy, thereby maximizing the effect of the therapy. It is extremely important to start immunomodulation before the formation of antibodies because the presence of high-sustained antibody titers diminishes enzyme replacement therapy efficacy. Early-treated patients showed significant improvements in left ventricular mass index (LVMI) and motor and pulmonary outcomes (invasive ventilator-free) as well as biomarkers (CK, urinary Glc4), compared with intermediate and late treatment groups (115). Prophylactic immune tolerance induction (ITI + ERT) protocols have been successful in patients with Pompe disease. Immunomodulation with the anti-CD20 monoclonal antibody rituximab, methotrexate, and intravenous immunoglobulin prior to enzyme replacement therapy initiation has been successful in CRIM-negative patients (128; 09; 86; 43). In CRIM-positive patients, a prophylactic ITI protocol with only transient, low-dose methotrexate has been safely administered, resulting in a significant reduction in the number of patients developing high, sustained antibody titers and sustained intermediate titers when compared to a patient cohort treated with enzyme replacement therapy monotherapy (87). | ||
- The use of bortezomib, a proteasome inhibitor, shows promise as an immunosuppressive agent for preexisting antibodies. The addition of bortezomib to immunomodulatory regimens resulted in a rapid reduction of high, sustained antibody titers and a significant improvement in clinical outcomes (09; 88). These patients are then weaned off all immune-tolerance induction protocol medications (bortezomib, rituximab, methotrexate, and intravenous immunoglobulin) and monitored. A high dose of intravenous immunoglobulin was successfully used as a lifesaving measure for a 7-year-old CRIM-negative patient with IPD who did not tolerate the ERT + ITI protocol (154). | ||
- A number of other immunomodulation approaches have been reported in patients with Pompe disease, including the use of rituximab, sirolimus or mycophenolate, and intravenous immunoglobulin (51; 42), plasma exchange, and omalizumab (164; 43). |
In February 2020, the Food and Drug Administration updated the prescription information for enzyme replacement therapy to state that there is a risk of developing anti-rhGAA antibodies (IgG) against enzyme replacement therapy in patients with Pompe disease. More information about Lumizyme can be accessed at the following website:http://products.sanofi.us/Lumizyme/lumizyme.pdf. The prescription information also specifies the need for routine monitoring of these antibody titers. An early assessment of the CRIM status in the disease process and the initiation of immune tolerance induction (ITI) protocol prior to and in conjunction with initiation of enzyme replacement therapy are recommended. CRIM status is to be assessed for all patients every 3 months for the first 2 years (at the start of enzyme replacement therapy) and then annually. Anti-rhGAA antibody testing may also be considered if patients develop hypersensitivity reactions, other immune-mediated reactions, or lose clinical response to enzyme replacement therapy.
Gene therapy has shown promise to correct some of the chronic neuromuscular problems in Pompe disease that persist despite enzyme replacement therapy, and it allows long-term sustained expression of the therapeutic protein. Because a single gene defect causes Pompe disease, replacing this defective gene with a normal one using vectors makes Pompe disease an excellent target for gene therapy.
There are currently four ongoing clinical trials recruiting adults with LOPD for gene therapy. The trials can be accessed at the following websites: Clinical trial A, Clinical trial C, and Clinical trial D. (Clinical trial B is no longer recruiting.)
Further advances in the field include the use of induced pluripotent stem cells (iPSCs) generated from the cells of patients with IPD and LOPD (75; 166). These IPD- and LOPD-specific iPSCs are being used to develop next-generation therapies.
Preclinical studies. Pompe knockout mice (also known as GAA knockout mice) are used to better understand the pathophysiology of Pompe disease and develop new therapies. The role of co-administration of dehydroepiandrosterone (DHEA), salmeterol, formoterol, or clenbuterol with an adeno-associated virus (AAV) vector carrying the GAA transgene has been studied and was found to be successful in reducing glycogen accumulation. Another approach is substrate reduction therapy, which inhibits glycogen biosynthesis. Co-administration of mTORC1 inhibitor rapamycin, an oligonucleotide-suppressing muscle glycogen synthase, or arginine with recombinant human GAA (rhGAA) has shown benefits in Pompe mice (04; 35; 116). The overexpression of transcription factors [EB (TFEB) and E3 (TFE3)] triggers lysosomal exocytosis and results in efficient cellular clearance of glycogen in Pompe cellular models. This offers TFEB and TFE3 as potential therapeutic targets for future advances in the management of Pompe disease (174; 121). In preclinical studies, low-dose gene therapy improved the efficacy of concurrent enzyme replacement therapy, and a higher dose of gene therapy (three-fold) was required to suppress the immune response to enzyme replacement therapy (70; 95; 117).
The quest to perfect the efficacy of enzyme replacement therapy and develop new and improved therapies for Pompe disease continues. This is demonstrated with the ongoing clinical trials using different therapeutic strategies as well as preclinical work in the field of Pompe disease.
Overall, it can be seen that patients with Pompe disease have benefited immensely from early enzyme replacement therapy and that enzyme replacement therapy has improved survival and quality of life. However, as stated above, there is an unmet need to address the residual clinical manifestations and new emerging phenotypes in enzyme replacement therapy-treated patients.
Adenotonsillectomy in children with infantile Pompe disease. Generally, children with recurrent throat infections and sleep-disordered breathing are often recommended to undergo adenotonsillectomy. One main complication of adenotonsillectomy is hypernasality. Most children with IPD already have mild to severe hypernasality and velopharyngeal incompetence that affects their speech and poses feeding difficulties (82). Thus, children with IPD who already have preoperative hypernasality can develop postoperative worsening of hypernasality. Adenotonsillectomy should be avoided in children with IPD, and other alternative approaches should be used to manage sleep-disordered breathing (82).
Enzyme replacement therapy in pregnancy. There is limited experience regarding the effect of enzyme replacement therapy on maternal and fetal outcomes.
Experience from other lysosomal disorders where enzyme replacement therapy is commonly continued during pregnancy, namely Gaucher disease and Fabry disease, is reassuring. Nevertheless, it must be recognized that the dose of enzyme replacement therapy in Pompe disease is up to 20-fold higher than that used in other lysosomal disorders. The Lumizyme package insert states that alglucosidase alfa should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. However, based on our experience in Pompe disease and the risk-benefit considerations, continuation of enzyme replacement therapy appears to be very reasonable (77).
Pregnancy and late-onset Pompe disease. Pregnancy is a state of high physiological and metabolic demand. Women with LOPD have had successful pregnancies. Although there does not appear to be an increased risk for pregnancy or delivery complications in women with Pompe disease, there might be unmasking or worsening of muscle weakness and respiratory complications during and after pregnancy in some women (84). Complications seen with pregnancy or childbirth are not higher in women with LOPD except for an increase in the rate of stillbirths (3.8% compared to the national average of 0.2% to 0.7%) (63). There is no difficulty carrying a pregnancy to term (85). Women on enzyme replacement therapy may have a decline in motor function and worsening respiratory function in the third trimester. However, most women tend to regain their motor and respiratory function, although not to prepregnancy levels in some. Typically, enzyme replacement therapy-treated women with LOPD have had an uneventful course of pregnancy; fetal growth is normal in all gestational stages, and healthy babies are born (85; 63). Thus, a discontinuation of enzyme replacement therapy during pregnancy is not recommended as it can lead to worsening of musculoskeletal and respiratory symptoms. In addition, it can make labor and delivery more challenging. In some pregnant women with LOPD who stopped enzyme replacement therapy during pregnancy, emergence of allergic reactions on enzyme replacement therapy reinitiation has been reported (163). There are no particular dietary recommendations other than what is typically recommended during a pregnancy. As pregnancy is a state of high metabolic demand, a high protein diet should be followed.
Lactation. Alglucosidase alfa has been found to be secreted in breast milk, with activity levels in milk peaking 2.5 hours after the end of infusion. Activity returns to preinfusion levels 24 hours after the infusion. To minimize infant exposure to alglucosidase alfa, a nursing mother may temporarily pump and discard breast milk produced during the 24 hours after administration of alglucosidase alfa. There are no reports of adverse reactions due to increased enzyme activity in infants of these mothers, and there is inadequate evidence to support complete abstinence from breastfeeding (45).
Patients with Pompe disease are known to be at increased risk during anesthesia. Heart conditions in pediatric patients with Pompe disease undergoing procedures should be monitored, as arrhythmias such as ventricular fibrillation have been documented (46). Malignant hyperthermia precautions should be taken. The use of propofol is not recommended as it may lead to myocardial ischemia through reducing myocardial contractility and systemic vascular resistance (80). In pregnancy, anesthesia complications were higher (5%) in women with LOPD when compared to the national data (0.1%) (63).
Organ donation. Very little information is available about the eligibility of patients with Pompe disease as organ donors. A donor with LOPD was successfully used for deceased donor liver and kidney transplantations (68). Also, a 37-year-old, type 2 (ie, category II) non-heart-beating donor with LOPD successfully donated both kidneys to two patients with chronic kidney disease (130). It is clear that, with the increase of life expectancy in patients with Pompe disease, further knowledge is required to understand the suitability of these patients as organ donors.
Priya S Kishnani MD
Dr. Kishnani of Duke University Medical Center received research/grant support from Alexion Pharmaceuticals, Amicus Therapeutics, Pfizer, Sanofi Genzyme, Takeda, and Valerion Therapeutics and consulting fees and honorariums from Alexion Pharmaceuticals, Amicus Therapeutics, AskBio, Sanofi Genzyme, Maze Therapeutics, and Takeda. She is an advisory board member for Amicus Therapeutics, Baebies, and Sanofi Genzyme and has equity in AskBio and Maze Therapeutics.
See ProfileAditi Korlimarla MBBS
Dr. Korlimarla of Duke University Medical Center has no financial disclosures.
See ProfileAravindhan Veerapandiyan MD
Dr. Veerapandiyan of University of Arkansas for Medical Sciences has no relevant financial relationships to disclose.
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