Oropharyngeal dysphagia may occur in late-onset Pompe disease,implicating bulbar muscle involvement

Late-onset Pompe disease (presenting after 12 months of age) often presents with limb-girdle and respiratory weakness, but oropharyngeal dysphagia has not been reported previously. A retrospective review of all late-onset Pompe disease patients evaluated in the neuromuscular clinic at Duke University Medical Center from 1999–2010 was performed. Twelve patients were identified and 3 had symptoms of oropharyngeal dysphagia. The medical record was reviewed, including the results of electromyography, videofluroscopic swallow examinations, and motor speech examination including instrumental assessment of lingual force with the Iowa Oral Performance Instrument. Oropharyngeal dysphagia was mild in two cases and severe in one. One of the two patients with mild severity demonstrated oral stage swallow signs; in the other, residual material was observed in the area of the cervical esophagus. In the patient with severe oropharyngeal dysphagia, both the oral and pharyngeal stages of swallowing were affected with penetration and aspiration documented. The degree of swallowing impairment appeared to correlate with overall physical strength and function. Oropharyngeal dysphagia may occur in patients with late-onset Pompe disease, implicating bulbar muscle involvement. Screening for symptoms of dysphagia may help reduce morbidity and mortality, while improving understanding of the late-onset Pompe disease phenotype. Further studies, including examination of the relationship between lingual weakness and oropharyngeal dysphagia, are warranted.     

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.     

Late-onset Pompe disease: a genetic-radiological correlation on cerebral vascular anomalies

Pompe disease is an autosomal recessive disorder in which deficiency of the lysosomal enzyme acid alpha-glucosidase results in the accumulation of glycogen mostly in muscle tissues. Several reports suggest a higher incidence of intracranial vascular abnormalities (IVAs) in this condition, as well as brain microbleeds and cerebral vasculopathy. The aim of our study was to evaluate through neuroimaging studies the incidence of these anomalies in our cohort of late-onset Pompe disease (LOPD) patients asymptomatic for cerebrovascular disease, looking for correlations with clinical and genetic data. We studied 18 LOPD patients with brain magnetic resonance angiography (MRA), or contrast-enhanced computed tomography (CECT). Diameters of individual arteries were measured and compared with average values as proposed in the literature. We found IVAs in 13 of the 18 patients, mostly dilatative arteriopathy affecting the vertebrobasilar system. The anterior circle was involved in seven of the 18 patients. The diameter of the basilar artery at 1 cm was found to correlate both with age (spearman rho, p = 0.037) and disease duration (p = 0.004), but no other statistically significant correlation was documented. The incidence of intracranial dilatative arteriopathy in LOPD was higher than in the general population, confirming the literature data. However, we did not find intracranial aneurysms microbleeds or significant cerebrovascular disease. Abnormalities in the anterior and the posterior circle of Willis correlated with age and disease duration, but not with the severity of muscle/respiratory involvement or with genetic data. Further studies in larger cohorts of patients are needed to confirm these findings.     

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.     

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     

Skeletal alterations,developmental delay and new mutations in juvenile-onset Pompe disease

Pompe disease is an autosomal recessive disorder caused by a deficiency of acid α-glucosidase. In addition to the severe infantile form with cardiac involvement, late-onset variants can affect older children, adolescents (aged >1 year old) or adults. Patients with juvenile (a subgroup of late-onset type) Pompe disease typically do not have cardiac alterations e.g. hypertrophic cardiomyopathy, and the diagnosis is often difficult because it can clinically resemble myriad other neuromuscular disorders. A high level of clinical suspicion is necessary for a timely and accurate diagnosis. We describe 3 interesting cases of patients with juvenile-onset Pompe disease who presented some uncommon clinical features e.g. skeletal alterations and developmental delay, and describe a new genetic variant. Juvenile-onset Pompe disease may be accompanied by uncommon clinical signs that could delay the diagnosis of Pompe disease due to the global pictures resembling other metabolic disorders.     

Late onset Pompe disease: clinical and neurophysiological spectrum of 38 patients including long-term follow-up in 18 patients

To describe the clinical and neurophysiological spectrum and prognosis in a large cohort of biochemically and genetically proven late onset Pompe patients. Thirty-eight diagnosed with late onset Pompe disease at our neuromuscular department during 1985 and 2006 are described in detail. The mean delay from onset of symptoms or first medical consultation until diagnosis was 10.4 and 7.1 years, respectively. A different diagnosis was suggested in 11 of 38 patients. Ten patients underwent repeated muscle biopsies before diagnosis of Pompe disease was established. Limb girdle weakness was the most frequent presenting sign. Six patients complained of myalgia. Wolf-Parkinson-White syndrome was found in 3 of 38 patients. Respiratory failure preceded the onset of overt limb muscle weakness in three patients. The course of the patients was progressive in all, but there was a wide variety of progression, which did not correlate with the age of disease onset. In 71% of the patients, neurophysiological investigations revealed a myopathic EMG pattern, half of the patients had spontaneous activity including complex repetitive discharges. A normal EMG was found in 9% of the patients. Nerve conduction studies were normal in all. Pompe disease should be taken into consideration in patients with unexplained limb girdle muscular weakness with respiratory failure. Cardiac manifestations may not be restricted to infantile Pompe disease.     

SHOULD patients with asymptomatic pompe disease be treated? A nationwide study in france

Introduction: Acid α‐glucosidase deficiency, that is, Pompe disease, is a glycogenosis for which enzyme replacement therapy (ERT) is available. It is not known whether patients diagnosed at an asymptomatic stage should be treated to prevent progression of the disease. Methods: We investigated 7 patients with asymptomatic Pompe disease identified from the French Pompe registry. Results: The patients had a mean age of 45 (range 24–75) years, a median follow‐up duration of 2 (range 1–22) years, and normal clinical examination, pulmonary function tests (PFTs), and echocardiography. All presented with at least 1 subclinical abnormality, including hyperCKemia, vacuolar myopathy, and muscle MRI abnormalities, suggesting that subclinical myopathy was present in all cases. Conclusions: Asymptomatic Pompe disease may remain clinically silent for decades, and affected patients should be monitored closely for overt myopathy using clinical examination, PFTs, and muscle MRI to determine when to start ERT. Muscle Nerve 51 : 884–889, 2015     

Atrio-ventricular block requiring pacemaker in patients with late onset Pompe disease

Enzyme replacement therapy consistently improves cardiac function in infantile and juvenile onset patients with Pompe disease and cardiomyopathy, but is apparently not effective in preventing rhythm disorders, an emerging cardiac phenotype in long term survivors. In patients with late onset Pompe disease cardiomyopathy is an exceptional finding while heart rhythm disorders seem to be more frequent. We retrospectively identified, among a cohort of 131 French late onset Pompe disease patients, four patients with severe atrio-ventricular blocks requiring pacemaker implantation. These patients had no other risk factors for cardiovascular diseases or cardiomyopathy. In one patient the atrioventricular block was discovered while still asymptomatic. Cardiac conduction defects are relatively rare in late onset Pompe disease and may occur even in absence of cardiac symptoms or EKG abnormalities. However because of the possible life-threatening complications associated with these conduction defects, cardiac follow-up in patients with late onset Pompe disease should include periodical Holter-EKG monitoring.     

Cerebral occlusive artery disease in Noonan syndrome

Noonan syndrome is an autosomal-dominant inherited syndrome with variable expression of multiple malformations including cardiovascular and craniofacial anomalies. While cerebrovascular insults due to cardiogenic emboli, coagulation abnormalities or cerebrovascular malformations have been documented before, intracerebral occlusive artery disease is not well recognized as a cause of stroke in this syndrome. A 6-year-old girl with Noonan syndrome presented with repetitive transient ischemic attacks consisting of dysphasia and right-sided central facial and arm weakness. Neuroimaging showed acute ischemic lesions in the left putamen and caudate nucleus. Multiple intracranial stenoses were found during transcranial Doppler examination and MR angiography. Although hypertrophic cardiomyopathy was documented by transesophageal echocardiography, a cardioembolic origin of the ischemic attacks was unlikely in this case. The symptoms resolved and did not recur after antiplatelet and anticoagulant therapy was initiated. Stenoses of intracranial cerebral arteries should be considered among the causes of stroke in young patients with Noonan syndrome.     

Cerebrovascular risk factors and depression in older primary care patients: testing a vascular brain disease model of depression.

The authors examined whether cerebrovascular risk factors (CVRFs) are associated with depressive diagnoses and symptoms in 303 primary-care patients age >/=60 years, as would be consistent with a small-vessel brain disease model of later-life depression. CVRFs were not significantly independently associated with major, minor, or subsyndromal depression, late-onset major depression, or overall depressive symptom severity. These data did not support the notion that a small-vessel brain disease model of depression might apply to the majority of older persons with depressive symptoms and syndromes in primary-care settings. Future work should include longitudinal study with larger sample sizes.     

Recombinant human acid alpha-glucosidase (rhGAA) in adult patients with severe respiratory failure due to Pompe disease

Pompe disease is a rare metabolic myopathy caused by lysosomal ??-glucosidase deficiency. Pompe disease ranges from a rapidly progressive course when symptoms present in infancy to a more slowly progressive rate when symptoms present in childhood or adulthood.This open-label prospective exploratory study investigated the effect of 12 months of recombinant enzyme replacement therapy in 5 adult patients who had already advanced to a very severe stage of Pompe disease.Muscular and respiratory function, quantitative muscle testing and spirometry were assessed. Four patients were tracheostomized. Respiratory parameters did not deteriorate. A moderate improvement in sitting/supine slow vital capacity in 2 patients (from 7% to 11% and 28% to 32% of predicted) and reductions of ventilation support in 2 patients was observed. Three patients, wheelchair bound at baseline, improved sitting and proximal motor function; 2 patients improved in their ability to stand and transfer. The treatment was well tolerated.Alglucosidase alfa may stabilize or even slightly improve muscle strength and respiratory function among patients with severe Pompe disease.     

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.     

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.     

Cessation and resuming of alglucosidase alfa in Pompe disease: a retrospective analysis

Enzyme replacement therapy (ERT) with recombinant human alglucosidase alfa (rhGAA) in late-onset Pompe disease is moderately effective. Little is known about the clinical course after treatment termination and the resumption of ERT. In Switzerland, rhGAA therapy for Pompe disease was temporarily withdrawn after the federal court judged that the treatment costs were greatly out of proportion compared to the benefits. Re-treatment was initiated after the therapy was finally licensed. We retrospectively analysed seven Pompe patients, who underwent cessation and resumption of ERT (median age 43 years). The delay from first symptoms to final diagnosis ranged from 4 to 20 years. The demographics, clinical characteristics, assessments with the 6-min walking test (6-MWT), the predicted forced vital capacity (FVC) and muscle strength were analysed. Before initiation of ERT, all patients suffered from proximal muscle weakness of the lower limbs; one was wheelchair-bound and two patients received night-time non-invasive ventilation. Initial treatment stabilised respiratory function in most patients and improved their walking performance. After treatment cessation, upright FVC declined in most and the 6-MWT declined in all patients. Two patients needed additional non-invasive ventilatory support. Twelve months after resuming ERT, the respiratory and walking capacity improved again in most patients. However, aside for one patient, none of the patients reached the same level of respiratory function or distance walked in 6 min, as at the time of ERT withdrawal. We conclude that cessation of ERT in Pompe disease causes a decline in clinical function and should be avoided. Resuming treatment only partially recovers respiratory function and walking capacity.     

Late-onset seizures and risk of subsequent stroke: A systematic review

Otherwise unexplained late-onset seizures, conventionally defined as epileptic seizures occurring in subjects older than 60 years and in the absence of disorders known to increase the risk of developing epilepsy, have been assumed to be, in most cases, of cerebrovascular origin. We systematically searched the literature to identify the evidence supporting the association between otherwise unexplained late-onset seizures/epilepsy and the risk of subsequent stroke. Most data from the literature indicate that cerebrovascular disease often underlies otherwise unexplained late-onset seizures/epilepsy. Patients presenting with seizures occurring for the very first time in late life and without clinically overt cerebrovascular disease should be considered as at increased risk of stroke. Consequently, these patients should be screened for the presence of vascular risk factors and treated accordingly. Such measures may greatly contribute to prevent strokes in these patients.     

Targeted gene panel screening is an effective tool to identify undiagnosed late onset Pompe disease

Mutations in the GAA gene may cause a late onset Pompe disease presenting with proximal weakness without the characteristic muscle pathology, and therefore a test for GAA activity is the first tier analysis in all undiagnosed patients with hyperCKemia and/or limb-girdle muscular weakness. By using MotorPlex, a targeted gene panel for next generation sequencing, we analyzed GAA and other muscle disease-genes in a large cohort of undiagnosed patients with suspected inherited skeletal muscle disorders (n = 504). In this cohort, 275 patients presented with limb-girdle phenotype and/or an isolated hyperCKemia. Mutational analysis identified GAA mutations in ten patients. Further seven affected relatives were identified by segregation studies. All the patients carried the common GAA mutation c.-32-13T >G and a second, previously reported mutation. In the subcohort of 275 patients with proximal muscle weakness and/or hyperCKemia, we identified late-onset Pompe disease in 10 patients. The clinical overlap between Pompe disease and LGMDs or other skeletal muscle disorders suggests that GAA and the genes causing a metabolic myopathy should be analyzed in all the gene panels used for testing neuromuscular patients. However, enzymatic tests are essential for the interpretation and validation of genetic results.     

24-months results in two adults with Pompe disease on enzyme replacement therapy

Objective

Late-onset Pompe disease is a slowly progressive disorder resulting from deficiency of lysosomal acid alpha-glucosidase (GAA). Since 2006, an intravenous enzyme replacement therapy (ERT) with Myozyme™ (alglucosidase alfa) is available but long-term experience with ERT in late-onset Pompe disease is still limited.

Methods

Two adult patients with impaired walking ability and disease duration of 10 and 13 years, respectively received ERT over a period of 24 months. Clinical and functional parameters including dynamometer-based assessment of proximal muscle strength were registered longitudinally.

Results

In both patients some gain in function and physical endurance could be observed which was collaborated by stable dynamometer tests. No serious adverse events occurred and no patient required de novo ventilation.

Conclusion

The clinical results from our data base imply that long term enzyme replacement therapy seems to somewhat affect functionality and quality of life and can stabilize the otherwise progressive disease course in patients with late-onset Pompe disease.     

Clinical guidelines for late-onset Pompe disease

Before 2006, Pompe disease or glycogenosis storage disease type II was an incurable disease whose treatment was merely palliative. The development of a recombinant human alpha-glucosidase enzymatic replacement therapy has become the first specific treatment for this illness. The aim of this guide is to serve as reference for the management of the late-onset Pompe disease, the type of Pompe disease that develops after one year of age. In the guide a group of Spanish experts make specific recommendations about diagnosis, follow-up and treatment of this illness. With regard to diagnosis, the dried blood spots method is essential as the first step for the diagnosis of Pompe disease. The confirmation of the diagnosis of Pompe disease must be made by means of an study of enzymatic activity in isolated lymphocytes or a mutation analysis of the alpha-glucosidase gene. With regard to treatment with enzymatic replacement therapy, the experts say that is effective improving or stabilizating the motor function and the respiratory function and it must be introduced when the first symptoms attributable to Pompe disease appear.     

Course of disability and respiratory function in untreated late-onset Pompe disease

Fifty-two untreated patients with late-onset Pompe disease completed questionnaires about their clinical condition and level of handicap at baseline and at 1-year (n = 41) and 2-year follow-ups (n = 40). During this period, declines in functional activities, respiratory function, handicap, and survival were recorded on a group level. This study illustrates the progressiveness of late-onset Pompe disease and indicates the need for close clinical follow-up of both children and adults with this disorder.