Cardiovascular disease in non-classic Pompe disease: A systematic review

Pompe disease is a rare inherited metabolic and neuromuscular disorder, presenting as a spectrum, with the classic infantile form on one end and the more slowly progressive non-classic form on the other end. While being a hallmark in classic infantile Pompe disease, cardiac involvement in non-classic Pompe disease seems rare. Vascular abnormalities, such as aneurysms and arterial dolichoectasia, likely caused by glycogen accumulation in arterial walls, have been reported in non-classic Pompe patients. With this first systematic review on cardiovascular disease in non-classic Pompe disease, we aim to gain insight in the prevalence and etiology of cardiovascular disease in these patients. Forty-eight studies (eight case-control studies, 15 cohort studies and 25 case reports/series) were included. Fourteen studies reported cardiac findings, 25 studies described vascular findings, and nine studies reported both cardiac and vascular findings. Severe cardiac involvement in non-classic Pompe disease patients has rarely been reported, particularly in adult-onset patients carrying the common IVS1 mutation. There are indications that intracranial dolichoectasia and aneurysms are more prevalent in non-classic Pompe patients compared to the general population. To further investigate the prevalence of cardiovascular disease in non-classic Pompe patients, larger case-control studies that also study established cardiovascular risk factors should be conducted.     

Quantitative computed tomography for enzyme replacement therapy in Pompe disease

Objective: Pompe disease is an autosomal recessive disorder caused by deficiency of the lysosomal enzyme, acid alpha-glucosidase (GAA). To the best of our knowledge, no studies have reported the results of systematic and sequential CT analyses before and during ERT. In this study we have treated three patients with late onset Pompe disease by ERT, and investigated the efficacy of treatment by computed tomography number. Methods: We measured the serial changes in the computed tomography (CT) number of multiple organs in three patients with late onset of Pompe disease during 24 months of enzyme replacement therapy (ERT). Results: Before treatment, the liver and muscle CT numbers were higher in these patients than in the controls. The liver CT number decreased after performing ERT. Furthermore, the urinary glucose tetrasaccharide levels, a biomarker of glycogen accumulation, were elevated before ERT and reduced thereafter. Conclusions: The findings in these cases suggest that the elevation of the liver CT number represents glycogen accumulation in the liver and that the analysis of the liver CT number is therefore a useful tool for assessing the efficacy of ERT.     

Presymptomatic late-onset Pompe disease identified by the dried blood spot test

Pompe disease or glycogen storage disease type II is an autosomal recessive disorder caused by mutations in the GAA gene leading to muscle weakness. Here we describe a 15 years old presymptomatic patient with normal muscle MRI, unspecific muscle biopsy findings but abnormal acid maltase activity in a dried blood spot test. Sequencing the GAA-gene identified a heterozygous novel splice-site and a heterozygous previously described mutation. The case highlights the variability in clinical phenotype and difficulties to diagnose late-onset Pompe disease. Dried Blood Spot (DBS) might be the most sensitive tool to pick up mildly symptomatic patients.     

Pompe disease (glycogen storage disease type II) in Argentineans: clinical manifestations and identification of 9 novel mutations

Pompe disease is an autosomal recessive disorder caused by a deficiency in 1,4-alpha-glucosidase (EC.3.2.1.3), the enzyme required to hydrolyze lysosomal glycogen to glucose. While previous studies have focused on Pompe patients from Europe, the United States, and Taiwan, we have analyzed a group of South American Pompe patients to better understand the molecular basis of their disease. From 14 Argentinean patients diagnosed with either infantile or late-onset disease, we identified 14 distinct mutations in the acid alpha-glucosidase (GAA) gene including nine novel variants (c.236_246del, c.377G>A, c.1099T>C, c.1397T>G, c.1755-1G>A, c.1802C>G, c.1978C>T, c.2281delGinsAT, and c.2608C>T). Three different families displayed the c.377G>A allelic variant, suggesting a higher frequency among a subset of Argentineans. Comparison of patients with similar or identical variations in the GAA gene highlights the phenotypic diversity of late-onset disease and supports a role for other genetic and environmental factors in disease presentation.     

Consensus treatment recommendations for late-onset Pompe disease

Introduction: Pompe disease is a rare, autosomal recessive disorder caused by deficiency of the glycogen‐degrading lysosomal enzyme acid alpha‐glucosidase. Late‐onset Pompe disease is a multisystem condition, with a heterogeneous clinical presentation that mimics other neuromuscular disorders. Methods: Objective is to propose consensus‐based treatment and management recommendations for late‐onset Pompe disease. Methods: A systematic review of the literature by a panel of specialists with expertise in Pompe disease was undertaken. Conclusions: A multidisciplinary team should be involved to properly treat the pulmonary, neuromuscular, orthopedic, and gastrointestinal elements of late‐onset Pompe disease. Presymptomatic patients with subtle objective signs of Pompe disease (and patients symptomatic at diagnosis) should begin treatment with enzyme replacement therapy (ERT) immediately; presymptomatic patients without symptoms or signs should be observed without use of ERT. After 1 year of ERT, patients' condition should be reevaluated to determine whether ERT should be continued. Muscle Nerve, 2012     

Screening for late-onset Pompe disease in Finland

Pompe disease (glycogen storage disease type II) is caused by autosomal recessive mutations in GAA gene. The estimated frequency of late-onset Pompe disease is around 1:60,000. However, only two infantile and one late-onset Pompe patients have been reported in Finland with a population of 5 million. We screened for late-onset Pompe disease in a cohort of undetermined myopathy patients with proximal muscle weakness and/or elevated serum creatine kinase values. Acid α-glucosidase (GAA) activity in dried blood spots was measured and clinical data collected in 108 patients. Four patients had low normal GAA activity; all the others had activities well within the normal range. Re-analyses of these patients did not reveal new Pompe patients. Our findings suggest that Pompe disease is extremely rare in Finland. Finland is an example of an isolated population with enrichment of certain mutations for genetic disorders and low occurrence of some autosomal recessive diseases.     

A Case of Adult-onset Pompe Disease with Cerebral Stroke and Left Ventricular Hypertrophy

Background

Pompe disease is an autosomal recessive glycogen storage disorder caused by a deficiency of the lysosomal glycogen-hydrolyzing enzyme acid α-glucosidase. The adult-onset form, late-onset Pompe disease, has been characterized by glycogen accumulation, primarily in skeletal and smooth muscles, causing weakness of the proximal limb girdle and respiratory compromises.

Pompe disease: a review of the current diagnosis and treatment recommendations in the era of enzyme replacement therapy

Pompe disease, or glycogen storage disease type II, is a rare autosomal recessive disorder caused by mutations in the gene that encodes for alpha-glucosidase. Presentation in infancy is associated with respiratory failure, cardiomyopathy, and severe muscle weakness. Juvenile- or adult-onset cases typically present with proximal muscle weakness and are associated with respiratory insufficiency or exertional dyspnea. Treatment, until recently, was focused on supportive measures, and infants diagnosed with Pompe disease usually died within the first year of life. The recent development of recombinant alpha-glucosidase has dramatically improved the life expectancy and quality of life of infantile-onset disease with improvements in respiratory and motor function observed in juvenile- or adult-onset cases. This review focuses on the presentation, pathogenesis, diagnosis, and treatment recommendations for Pompe disease in this new era of enzyme replacement therapy.     

Swiss national guideline for reimbursement of enzyme replacement therapy in late-onset Pompe disease

Glycogen storage disease type II is a rare multi-systemic disorder characterised by an intracellular accumulation of glycogen due a mutation in the acid alpha glucosidase (GAA) gene. The level of residual enzyme activity, the genotype and other yet unknown factors account for the broad variation of the clinical phenotype. The classical infantile form is characterised by severe muscle hypotonia and cardiomyopathy leading to early death. The late-onset form presents as a limb girdle myopathy with or without pulmonary dysfunction. Enzyme replacement therapy (ERT) with recombinant human GAA (rhGAA) in infants is life saving. In contrast, therapeutic efficacy of rhGAA in the late-onset form is modest. High expenses of rhGAA, on-going infusions and poor pharmacokinetic efficacy raised a discussion of the cost effectiveness of ERT in late-onset Pompe disease in Switzerland. This discussion was triggered by a Swiss federal court ruling which confirmed the reluctance of a health care insurer not to reimburse treatment costs in a 67-year-old female suffering from Pompe disease. As a consequence of this judgement ERT was stopped by all insurance companies in late-onset Pompe patients in Switzerland regardless of their clinical condition. Subsequent negotiations lead to the release of a national guideline of the management of late-onset Pompe disease. Initiation and limitation of ERT is outlined in a national Pompe registry. Reimbursement criteria are defined and individual efficacy of ERT with rhGAA is continuously monitored.     

High-density CT of muscle and liver may allow early diagnosis of childhood-onset Pompe disease

Pompe disease is classified into infantile-, childhood- and adult-onset forms based on onset age and the degree of organ involvement. Differing from the infantile-onset form which is characterized by marked organ involvement, the childhood-onset form usually presents with muscle weakness and elevation of serum creatine kinase (CK), mimicking those of progressive muscular dystrophy. We report our successful early diagnosis and initiation of enzyme replacement therapy (ERT) in a young girl with childhood-onset Pompe disease before the development of skeletal muscle symptoms. She was referred to our hospital at the age of 2 years 4 months because of hyperCKemia detected incidentally. She was active and lacked developmental delay and muscle weakness; however, hepatomegaly was noted. The combination of high-density changes in the liver and skeletal muscle on computed tomography (CT) images was suggestive of glycogen storage disorder, especially childhood-onset Pompe disease. Low alpha-glucosidase (GAA) activity on dried blood spots facilitated the diagnostic process, and genetic analysis of GAA allowed a definitive diagnosis, without performing muscle biopsy. We promptly started ERT at the age of 2 years 6 months. After 1 year, she still had not developed any skeletal muscle symptoms, and serum CK level was almost normal. Since the efficacy of ERT is thought to depend on the extent of muscle damage at its commencement, we expect that ERT may have prevented the manifestation of skeletal muscle involvement in this patient.     

Acid alpha-glucosidase deficiency (Pompe disease)

The development and recent approval of recombinant acid alpha-glucosidase for enzyme replacement therapy have been major milestones in Pompe disease research. Acid alpha-glucosidase is the enzyme responsible for degradation of glycogen polymers to glucose in the acidic milieu of the lysosomes. Cardiac and skeletal muscles are the two major tissues affected by the accumulation of glycogen within the lysosomes. Both cardiomyopathy and skeletal muscle myopathy are observed in patients with complete enzyme deficiency; this form of the disease is fatal within the first year of life. Skeletal muscle myopathy eventually leading to respiratory insufficiency is the predominant manifestation of partial enzyme deficiency. The recombinant enzyme alglucosidase alfa is the first drug ever approved for this devastating disorder. This review discusses the benefits and the shortcomings of the new therapy.     

Temporal neuropathologic and behavioral phenotype of 6neo/6neo Pompe disease mice

Pompe disease (glycogen storage disease II) is caused by mutations in the acid alpha-glucosidase gene. The most common form is rapidly progressive with glycogen storage, particularly in muscle, which leads to profound weakness, cardiac failure, and death by the age of 2 years. Although usually considered a muscle disease, glycogen storage also occurs in the CNS. We evaluated the progression of neuropathologic and behavioral abnormalities in a Pompe disease mouse model (6neo/6neo) that displays many features of the human disease. Homozygous mutant mice store excess glycogen within large neurons of hindbrain, spinal cord, and sensory ganglia by the age of 1 month; accumulations then spread progressively within many CNS cell types. "Silver degeneration" and Fluoro-Jade C stains revealed severe degeneration in axon terminals of primary sensory neurons at 3 to 9 months. These abnormalities were accompanied by progressive behavioral impairment on rotorod, wire hanging, and foot fault tests. The extensive neuropathologic alterations in this model suggest that therapy of skeletal and cardiac muscle disorders by systemic enzyme replacement therapy may not be sufficient to reverse functional deficits due to CNS glycogen storage, particularly early-onset, rapidly progressive disease. A better understanding of the basis for clinical manifestations is needed to correlate CNS pathology with Pompe disease manifestations.     

Screening for pompe disease using a rapid dried blood spot method: Experience of a clinical diagnostic laboratory

Pompe disease (acid maltase deficiency; glycogen storage disease type II) is caused by deficiency of the lysosomal enzyme acid alpha‐glucosidase (GAA). Our clinical laboratory began to offer a fluorometric dried blood spot (DBS)‐based GAA activity assay for Pompe disease in 2006 after the FDA approved GAA enzyme replacement therapy in April of that year. The purpose of this study was to examine the experience of our clinical laboratory in using this assay. Over a 2‐year period, we received samples for the DBS GAA assay from 891 patients referred for possible Pompe disease, of whom 111 (12.5%) patients across the disease spectrum who had results in the affected range. The majority of the patients were referred by neurologists and geneticists. When available, we correlated the results obtained through DBS GAA activity assay with the results from a second DBS, or a second tissue (cultured skin fibroblasts or muscle biopsy). In our experience, the DBS GAA activity assay provides a robust, rapid, and reliable first tier test for screening patients suspected of having Pompe disease. Muscle Nerve 40: 32–36, 2009     

Clinical features of Pompe disease with motor neuronopathy

Pathological studies on rodent models and patients with Pompe disease have demonstrated the accumulation of glycogen in spinal motor neurons; however, this finding has rarely been evaluated clinically in patients with Pompe disease. In this study, we analyzed seven patients (age, 7–11 years) with Pompe disease who received long-term enzyme replacement therapy. In addition to traditional myopathy-related clinical and electrophysiological features, these patients often developed bilateral foot drop, distal predominant weakness of four limbs, and hypo- or areflexia with preserved sensory function. Electrophysiological studies showed not only reduced amplitudes of compound muscle action potential, but also absent or impersistent F waves and mixed small and large/giant polyphasic motor unit action potentials with normal sensory study. Muscle biopsy usually showed the existence of angular fingers, fiber type grouping or group atrophy. Taken together, these features support the co-existence of motor neuronopathy additionally to myopathy.     

A case of Pompe disease treated with acid alpha-glucosidase

Pompe disease (type II glycogenosis--GSD II) is a progressive metabolic myopathy caused by lysosomal storage of glycogen due to deficiency of acid alpha-glucosidase. We present the case of a 32-year-old patient with Pompe disease diagnosed 14 years ago in whom enzyme replacement therapy with recombinant human acid alpha-glucosidase (rhGAA) (20 mg/kg i.v. every 2 weeks) has been administered for about 18 months. Despite the fact that therapy was started in the advanced phase of Pompe disease we observed clinical improvement (increased muscle bulk and muscle strength as well as increased range of movements in the distal parts of limbs). In addition, we noticed less effort dyspnoea and use of a respirator during the day shortened to 2-3 hours (previously 5 hours). According to the observation of our patient, we suggest that enzyme replacement therapy causes clinical improvement.     

Late-onset Pompe disease associated with polyneuropathy

Late-onset Pompe disease is caused by a glycogen deposition involving mainly striated muscle. It may also target many other tissues such as liver, smooth muscles or spine anterior horn. Glycogen accumulation in Schwann cells and in the perineurium of peripheral nerves was shown in Pompe's disease mouse models. Moreover two late-onset Pompe disease patients were reported as having a small fiber neuropathy. To the best of our knowledge an involvement of large nerve fibers was never depicted. We describe four late-onset Pompe disease patients having a concomitant polyneuropathy of undetermined etiology. Our observations reinforce the proof-of-concept supporting a potential involvement of peripheral nerves as additional organ targeted by late-onset Pompe disease. It has clinical care consequences since peripheral neuropathy in late-onset Pompe disease could worsen patient's disability and needs particular care such as proprioceptive physiotherapy.     

New GAA mutations in Japanese patients with GSDII (Pompe disease)

Glycogen storage disease type II (Pompe disease) is inherited by autosomal recessive transmission and caused by a deficiency of acid alpha-glucosidase (GAA), resulting in impaired degradation and lysosomal accumulation of glycogen. The GAA gene, responsible for this disease, has been mapped to chromosome 17q25.2-25.3. To date, more than 70 disease-causing mutations have been identified. In this study, we present four mutations found in three Japanese patients with the juvenile form of glycogen storage disease type II; three of these mutations were new (R224W, S619R, and R660H). The pathogenicity of these new mutations was verified by the loss of function of the mutant enzymes expressed in COS cells.     

Enzyme replacement therapy in a patient with Pompe disease

Pompe disease is a rare autosomal recessive disease caused by the deficiency of acid alpha-glucosidase (GAA), which is required for the degradation of lysosomal glycogen. Glycogen accumulation in heart, muscle and liver eventually leads to muscle weakness, hepatomegaly and cardiomegaly. Although an approved therapy does not exist, the efficacy of enzyme replacement therapy (ERT) has recently been reported in multinational trials in Europe and the US. Here, we present data on the efficacy of recombinant human acid alpha-glucosidase (rhGAA) (provided by Genzyme Corporation) in a patient with Pompe disease. At 5 months of age, motor delay (could not raise his head) and cardiomegaly were observed. A definite diagnosis of Pompe disease was made at 8 months of age after the accumulation of glycogen in a muscle biopsy specimen was observed. This was confirmed by low GAA activity. Since then, motor delay predominated and he was unable to sit independently by age 2.5 years. Every 2 weeks, 20 mg/kg of rhGAA was infused intravenously. To assess the effectiveness, chest X-ray, echocardiography and auditory brain response were recorded. The patient was administered rhGAA for 26 months from 2 years and 8 months of age. Following the initiation of ERT, hepatomegaly and cardiac function (ejection fraction) were rapidly improved and motor function was gradually improved. At 4 years and 10 months, the patient could walk with support. No adverse event has been observed. It can be concluded that ERT with rhGAA is an effective and safe regimen for this case.     

Early pathologic changes and responses to treatment in patients with later-onset Pompe disease

The treatment of later-onset Pompe disease with enzyme replacement therapy may not lead to significant improvement in muscle function, probably because of the irreversible muscle destruction caused by glycogen storage. A prospective study was performed to understand early muscle pathology in patients and the response of these pathologic changes to treatment. Five newborns and one child with later-onset Pompe disease but no signs at time of diagnosis were prospectively followed, and treatment was initiated when signs appeared. Six pretreatment biopsies taken at ages 1.5 months to 7 years indicated glycogen storage, lipid storage, stage 4 myocytes, and autophagic debris. Four 6-month posttreatment biopsies revealed glycogen clearance, but stage 4 myocytes and autophagic debris were still evident in three. In conclusion, among patients with later-onset Pompe disease and very mild signs, advanced pathologic changes were evident in a small portion of their myocytes. Because these pathologic changes may not respond to treatment, early treatment is necessary to achieve the best outcomes.