Summary Report of the 4th Steps Forward in Pompe Disease Symposium

Category: Archive
May 3, 2011

November 19-20, 2010, London, UK


This Symposium that further strengthened relations within the Pompe community was attended by over 180 caregivers, caretakers and scientists from all over the world. The Symposium was energetically hosted by Dr. Steven Waldek and Dr. Mark Roberts, both from the Hope Hospital in Manchester. The scientific sessions were chaired by an international faculty and encompassed a broad range of topics from Pompe disease fundamentals, the clinical spectrum of disease, review of Myozyme® outcomes in patient cohorts representing the broad clinical spectrum, and factors to improving the therapeutic outcomes.

A keynote presentation on the basic pathophysiology of Pompe disease was delivered by Dr. Raben. Several presenters reviewed the phenotypic presentations of Pompe disease.

Prof. Dr. van der Ploeg and Dr. Jones reviewed current knowledge about the classic infantile-onset Pompe disease and the clinical presentations of late-onset Pompe disease were reviewed by Dr. Laforêt.

Given the heterogeneous clinical presentation, it can be challenging to diagnose Pompe disease early. The presenting signs and symptoms of late-onset Pompe disease usually do not lead to prompt diagnosis. Prof. Dr. Schoser discussed current diagnostic screening strategies. Dr. Lukacs and Dr. Laforêt both discussed diagnostic laboratory methods.

According to Dr. Pomponio (Genzyme Corp.), around 300 mutations have been listed in the two large Pompe disease mutation databases (www.pompecenter.nl, https://research.cchmc.org/LOVD/home.php?select_db=GAA) as of May 2010. Dr. Pomponio encouraged the audience to contribute genotypic data from all known patients to the Pompe Registry, as these data will allow more meaningful analysis of frequency and genotype-phenotype correlations.

Dr. Willis reviewed the published literature on muscle MRI (magnetic resonance imaging) which has proven to be particularly useful in neuromuscular disorders. It represents a non-invasive imaging modality that is not reliant on patient cooperation or effort.

Prof. Dr. van der Ploeg presented the ERT outcomes in classically affected infants of whom the oldest patient in now 12 years old.

Dr. Semplicini reviewed Myozyme data in juvenile and adult patients including unpublished data from the Italian Group. Dr. Laforêt presented the preliminary results of a French study in 26 late-onset patients treated with Myozyme for a minimum of 18 months (mean 37 months).

Dr. Jones and Dr. Kishnani reviewed issues in relation to anti-alglucosidase IgG antibodies.

Dr. Llerena, Dr. Toscano and Dr. Waldek highlighted the importance of national and international treatment guidelines in enhancing best practices.

Dr. Kaye (Genzyme Corp.) reviewed Genzyme’s undertakings to develop a next generation ERT.

Dr. Tarnopolsky reviewed the role of nutrition and exercise therapy in the management of Pompe disease.

The Pompe Registry is the largest repository of worldwide longitudinal data on Pompe disease and includes patients from the whole clinical spectrum. The Registry is essential to 1) further enhance the understanding of the variability, progression, identification, and natural history of the disease; 2) assist the Pompe medical community with development of recommendations for monitoring patients and reporting on outcomes; and 3) evaluate long-term effectiveness/safety of available treatment and support options. Currently, over 870 patients from 25 countries are enrolled in the Registry.

Newborn Screening Debate

There was a lively debate, chaired by Dr. Mark Roberts, with speakers pleading in favor (Dr. Hwu and J. Keutzer, Genzyme Corp.) or against (D. Hilton-Jones and Dr. Waldek) the motion of introducing newborn screening universally.

Selected Presentation Summaries
(not all abstracts were available for publication)

Enzyme replacement therapy in infants in children with Pompe disease
Ans T. van der Ploeg, Erasmus MC-Sophia Children’s Hospital, Rotterdam, The Netherlands

In this session, Dr. van der Ploeg discussed her experiences with treating patients with enzyme replacement therapy (ERT). She stated that Myozyme/Lumizyme has increased survival in patients.  Infants that were in the first clinical trial in the Netherlands are now twelve years old.  When compared to the natural history of Pompe Disease, this is a clear indicator of increased survival as a result of ERT.

In terms of initiation of treatment, Dr. van der Ploeg said that early treatment results in a better clinical outcome for patients.  In addition, she also noted that it takes up to five years of therapy to see the full effects.

In her presentation, Dr. van der Ploeg also discussed the hearing loss that is seen in some patients.  According to her, this deafness is a result of glycogen deposits in the outer ear cells.  In terms of managing this condition, Dr. van der Ploeg advocated for intervention by speech and language therapists.

Another aspect of disease management that Dr. van der Ploeg discussed was the initiation of ventilation.  In effect, Dr. van der Ploeg stated that in order to achieve the most optimal clinical outcome, ventilation should not be started until after the first year of age.

Treatment challenges in Pompe Disease
Priya Kishnani, Duke University, Raleigh/Durham, North Carolina

The main focus of Dr. Kishnani’s presentation was how to manage CRIM- patients. According to Dr. Kishnani, the clinical response of infantile onset patients is related to their CRIM status.  In effect, CRIM- patients (as opposed to CRIM+ patients) have a poorer clinical response as a result of sustained high antibody titers.

In order to mediate the effect of high antibodies in CRIM-patients, Dr. Kishnani discussed using immune modulation and immune suppression in these patients.  She presented data at the meeting regarding these approaches in several patients, and suggested the approach could result in an antibody-free CRIM- patient.

To date, the data presented at the meeting has not been published.

Muscle biopsy as a diagnostic tool in Pompe disease
Benedikt Schoser, Friedrich Baur Institute and the Department of Neurology, Ludwig-Maximilians University Munich, Germany.

In this session, Dr. Schoser discussed the history of using muscle biopsies to diagnose Pompe disease, focusing primarily on the benefits and failings of this method of diagnosis.  Acknowledging the growing need for a precise diagnostic tool, Dr. Schoser suggested that in light of the alternatives available, muscle biopsies may not be the best diagnostic choice.
In terms of benefits gained from muscle biopsies, Dr. Schoser pointed to the fact that the pathological markers are well established for Pompe disease, as muscle biopsies have been used as a diagnostic tool for decades.  However, he acknowledged that the reliability of muscle biopsies as a diagnostic tool varied depending on the onset of the patient.  In effect, it is extremely effective at detecting infantile onset Pompe, due in large part to the extreme severity of the disease.  However, as you move further down the disease spectrum it becomes less reliable.  This is due in part to the fact that later onset patients do not generally have the same degree of wide-spread muscle damage as infantile onset patients.  Therefore, the chances that the particular muscle chosen for biopsy will be affected decrease.  If an unaffected muscle is biopsied, it is possible that a patient will go undiagnosed.

Therefore, Dr. Schoser suggested that in light of the new diagnostic tools available, it may be more prudent for doctors to utilize a dry blood spot test (DBS), and confirm the diagnosis with genetic analysis.  However, he cautioned that muscle biopsies may still play an essential role in accurately diagnosis some patients.

Does ERT change the phenotype in children over a long period of time?
Carine van Capelle, Erasmus MC-Sophia Children’s Hospital, Rotterdam, The Netherlands

This session focused on long-term treatment effects of enzyme replacement therapy (ERT) in patients with the classic-infantile form of Pompe disease. One of our key questions was: are we modifying classic-infantile patients into childhood-onset patients by administering ERT? To answer this question, we highlighted several clinical issues that are being observed now that patients are living longer, such as cardiac disease, hearing difficulties, speech difficulties, dysphagia, and increased incidence of osteoporosis.

Although clinical symptoms are to some extent comparable to those of patients with more attenuated forms of Pompe disease, we also found differences. For example: our studies revealed that while hearing problems are sporadically present in patients with milder phenotypes of Pompe disease (a conductive hearing loss were found in 1 of 13 juvenile patients), 10 out of 11 classic infantile patients had sensorineural hearing loss. The latter patients also had a high prevalence of conductive hearing loss. Hearing loss persisted during therapy in all patients. We therefore emphasized the need for careful monitoring of auditory function in classic infantile Pompe patients. Early implementation of hearing aids is mandatory to protect speech and language development.1

In addition, we found facial muscle weakness, speech disorders and dysphagia to be more frequent in classic infantile patients. We recommend that infantile patients are evaluated by a speech therapist and that regular swallowing assessments are performed to assess the risk for aspiration of feeding residue.

Finally, we addressed our recently published manuscript on bone mineral density (BMD)2, which showed that the majority of patients with Pompe disease had a decreased BMD. This was found in both classic infantile patients as well as in patients with milder forms of the disease. A low BMD increases the risk for fractures. Training programs may help to improve BMD.

In conclusion, ERT has considerably improved the life expectancy and motor condition of patients. To further improve the quality of life and outcome, we draw attention to other aspects of the disease.

1 van Capelle, CI et al; Hearing loss in Pompe disease revisited: results from a study of 24 children. J Inherit Metabol Dis 2010; 33(5): 597-602.
2 van den Berg, LE et al; Low bone mass in Pompe disease: muscular strength as a predictor of bone mineral density. Bone 2010 47(3):643-9.

Applications of imaging/MRI
Tracey Willis, Institute of Human Genetics, Newcastle University, Newcastle upon Tyne, United Kingdom

In this presentation Dr. Willis discussed the use of MRI’s as a possible diagnostic tool, as well as a tool to monitor disease progression.

In effect, Dr. Willis suggested that the MRI is a non-invasive tool that can be used to measure disease severity and monitor changes in condition.  In addition, Dr. Willis proposed that it could be used as a tool for diagnosis as there are certain patterns of muscle wasting that are routinely noticed in Pompe patients.

However, the use of the MRI is still relatively new and further studies need to be conducted to properly determine the accuracy of this technique in monitoring and diagnosing Pompe patients.

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