Deniz Güngör

How to describe the clinical spectrum in Pompe disease

Pompe disease, which is also known as acid maltase deficiency and glycogen storage disease type II, derived its name from the Dutch pathologist Dr J.C. Pompe, who described it in a 7-month-old girl in 1932. In the same year, Dr Putschar presented an equally detailed report on a similar case. Both patients died in their first year of life due to generalized glycogen storage—later named glycogen storage disease type II – that affected mainly heart and skeletal muscle function. The underlying lysosomal a-glucosidase deficiency was discovered in 1963. Originally, Pompe disease was thought to be a disease of early infancy leading to death in the first year of life. However, the acid a-glucosidase deficiency turned out to occur in different degrees, with the first symptomsmanifesting at various ages, and the disease progressing at various speeds [Engel et al., 1973, 2004; Hirschhorn and Reuser, 2001]. Pompe disease is now considered to be a continuous spectrumof phenotypes, with the clinically severest, rapidly progressive phenotypes in the ultra violet, and the least severe, slowly progressive phenotypes extending into the infra red (Fig. 1). Boundaries between clinical subtypes cannot be set, although this is desirable for unraveling the genotype-phenotype correlation, discovering the factors contributing to disease progression, and judging the effects of therapeutic interventions such as enzyme replacement therapy. The recent series of ten articles on advancements in Pompe disease in the American Journal of Medical Genetics [Kishnani et al., 2012] reflects a struggle with nomenclature. Even among experts, a rich variety of nuanced terms are used to subdivide the clinical spectrum. One article distinguishes infantile onset Pompe disease (IOPD) from late onset Pompe disease (LOPD) with a caesura at the age of 1 year, while late onset Pompe disease is historically synonymous with adult onset Pompe disease—which is how it is used in the context of other articles. Terms such as classic infantile, infantile (onset), non-classic (infantile), atypical (infantile), non-infantile, and muscular variant, childhood, juvenile, adult, late(r) onset is used, sometimes to describe the same phenotypes and sometimes to describe different ones. Though consensus on nomenclature is clearly lacking, most experts seem to agree that the term classic infantile Pompe disease represents onset of symptomswithin the first year of life; it is always associated with hypertrophic cardiomyopathy, and it is always associated with virtually total lack of acid a-glucosidase activity. But late onset Pompe disease is ill defined:

Pain in adult patients with Pompe disease A cross-sectional survey

BACKGROUND Pompe disease is a rare hereditary metabolic myopathy caused by a deficiency of acid-α-glucosidase. We investigated the presence and severity of pain and its interference with daily activities in a large group of adults with Pompe disease, who we compared with an age-matched control group. METHODS Data were collected in a cross-sectional survey in Germany and The Netherlands. Pain was assessed using the short-form brief pain inventory (BPI). Patients also completed the Short Form-36 item (SF-36v2), the Hospital Anxiety and Depression Scale (HADS) and the Rotterdam Handicap Scale (RHS). RESULTS Forty-five percent of the 124 adult Pompe patients reported having had pain in the previous 24h, against 27% of the 111 controls (p=0.004). The median pain severity score in Pompe patients reporting pain was 3.1 (on a scale from 0 to 10), indicating mild pain; against 2.6 amongst controls (p=0.06). The median score of pain interference with daily activities in patients who reported pain was 3.3, against 1.3 in controls (p=0.001). Relative to patients without pain, those with pain had lower RHS scores (p=0.02), lower SF-36 Physical and Mental component summary scores (p<0.001 and p=0.049), and higher levels of depression and anxiety (p=0.005 and p=0.003). CONCLUSIONS To date, this is one of the largest studies on pain in a specific neuromuscular disorder. Nearly one in two Pompe patients had experienced pain in the previous 24h. Although pain severity and its interference with daily life were mild, pain was related to a reduced quality of life, less participation in daily life, and greater depression and anxiety. Its management should therefore be seen as part of clinical practice involving Pompe patients.

Severely impaired health status at diagnosis of Pompe disease: A cross-sectional analysis to explore the potential utility of neonatal screening

Since the introduction of enzyme replacement therapy for Pompe disease, awareness and early diagnosis have gained importance. Because the therapy is most effective when started early and methods for dried bloodspot screening for Pompe disease are currently being explored, neonatal screening is getting increased attention. The objective of this study was to investigate the gains that might be achieved with earlier diagnosis by neonatal screening. For this purpose we analyzed the health and functional status of non-screened patients with Pompe disease at the time of diagnosis. Previously collected clinical data and results of an international patient-reported questionnaire were used. Cross-sectional data of 53 patients with Pompe disease diagnosed between 1999 and 2009 (aged 0-64 years) were analyzed. According to the World Health Organizations International Classification of Functioning, Disability and Health the following domains are described: body function, activity, participation and contextual factors. In all patients with classic infantile Pompe disease cardiac function, hearing, muscle strength and motor development were considerably impaired at the time of clinical diagnosis. The use of oxygen and/or nasogastric tube-feeding was reported in more than 70% of these cases. Most children, adolescents and adults had advanced muscle weakness and impaired respiratory function at the time of their diagnosis, causing varying degrees of handicap. About 12% of them used a walking device and/or respiratory support at the time of diagnosis. The severely impaired health status reported here provides a strong argument for earlier diagnosis and to further explore the potential of neonatal screening for Pompe disease.

Pain in adult patients with Pompe disease.

Abstract Background Pompe disease is a rare hereditary metabolic myopathy caused by a deficiency of acid-α-glucosidase. We investigated the presence and severity of pain and its interference with daily activities in a large group of adults with Pompe disease, who we compared with an age-matched control group. Methods Data were collected in a cross-sectional survey in Germany and The Netherlands. Pain was assessed using the short-form brief pain inventory (BPI). Patients also completed the Short Form-36 item (SF-36v2), the Hospital Anxiety and Depression Scale (HADS) and the Rotterdam Handicap Scale (RHS). Results Forty-five percent of the 124 adult Pompe patients reported having had pain in the previous 24h, against 27% of the 111 controls (p=0.004). The median pain severity score in Pompe patients reporting pain was 3.1 (on a scale from 0 to 10), indicating mild pain; against 2.6 amongst controls (p=0.06). The median score of pain interference with daily activities in patients who reported pain was 3.3, against 1.3 in controls (p=0.001). Relative to patients without pain, those with pain had lower RHS scores (p=0.02), lower SF-36 Physical and Mental component summary scores (p Conclusions To date, this is one of the largest studies on pain in a specific neuromuscular disorder. Nearly one in two Pompe patients had experienced pain in the previous 24h. Although pain severity and its interference with daily life were mild, pain was related to a reduced quality of life, less participation in daily life, and greater depression and anxiety. Its management should therefore be seen as part of clinical practice involving Pompe patients.

A conceptual disease model for adult Pompe disease

BackgroundStudies in orphan diseases are, by nature, confronted with small patient populations, meaning that randomized controlled trials will have limited statistical power. In order to estimate the effectiveness of treatments in orphan diseases and extrapolate effects into the future, alternative models might be needed. The purpose of this study is to develop a conceptual disease model for Pompe disease in adults (an orphan disease). This conceptual model describes the associations between the most important levels of health concepts for Pompe disease in adults, from biological parameters via physiological parameters, symptoms and functional indicators to health perceptions and final health outcomes as measured in terms of health-related quality of life.MethodsThe structure of the Wilson-Cleary health outcomes model was used as a blueprint, and filled with clinically relevant aspects for Pompe disease based on literature and expert opinion. Multiple observations per patient from a Dutch cohort study in untreated patients were used to quantify the relationships between the different levels of health concepts in the model by means of regression analyses.ResultsEnzyme activity, muscle strength, respiratory function, fatigue, level of handicap, general health perceptions, mental and physical component scales and utility described the different levels of health concepts in the Wilson-Cleary model for Pompe disease. Regression analyses showed that functional status was affected by fatigue, muscle strength and respiratory function. Health perceptions were affected by handicap. In turn, self-reported quality of life was affected by health perceptions.ConclusionsWe conceptualized a disease model that incorporated the mechanisms believed to be responsible for impaired quality of life in Pompe disease. The model provides a comprehensive overview of various aspects of Pompe disease in adults, which can be useful for both clinicians and policymakers to support their multi-faceted decision making.

Impact of enzyme replacement therapy on survival in adults with Pompe disease

Background Since 2006, enzyme replacement therapy (ERT) has been available as a treatment for patients with Pompe disease. ERT has shown efficacy concerning muscle strength and pulmonary function in adult patients. However, no data on the effect of ERT on the survival of adult patients are currently available. Our objective was to assess the effect of ERT on survival in adult patients with Pompe disease.

Prevalence of vitamin D deficiency in Samarkand, Uzbekistan

Background. Clinical rickets is a childhood bone disorder that is infrequently seen in the Western World. It is still frequently seen in Uzbekistan, Eastern Europe. This is the first study undertaken to estimate the prevalence and factors associated with deficiency of vitamin D in infants in this region of Eastern Europe.Methods. Information was obtained by parental questionnaires for 474 infants aged 5–61 weeks attending rural out‐patient clinics in Samarkand. Blood was assayed for 25‐OHD and ferritin concentration.Results. Prevalence of vitamin D deficiency (25‐OHD <30 nmol l−1) was 78.7% and was significantly associated with continued breastfeeding (p<0.05), lack of vitamin supplementation (p<0.05), residence in a rural area (p<0.05) and reduced time spent outdoors (p<0.05). Maternal characteristics did not differ between mothers of infants with and without biochemical rickets. Possible causes are a combination of factors including vitamin D deficiency in pregnancy, prolonged breastfeeding without supp...

Ten Years of The International Pompe Survey: Patient Reported Outcomes As A Reliable Tool for Studying Treated and Untreated Children and Adults With Non-Classic Pompe Disease

Pompe disease is a rare, progressive lysosomal storage disorder for which enzyme therapy (ERT) became available in 2006. Four years earlier, the IPA/Erasmus MC survey, an international longitudinal prospective survey, was established to collect information on the natural course of the disease and its burden on patients. The survey is a collaboration between Erasmus MC University Medical Center and the International Pompe Association (IPA) and comprises an annual questionnaire that was specifically designed to assess the symptoms and problems of the disease. Here we review our results of over 10 years of follow-up, and discuss the survey’s contribution to the field. Tracking 408 Pompe patients between 2002 and 2013, the cumulative data reveals the broad range of clinical manifestations that interfere with patients’ lives. The survey allowed us to quantify the rate of disease progression and the positive effects of ERT on patients’ quality of life, fatigue, and participation in daily life. Furthermore, it showed for the first time that survival is reduced in adult Pompe disease and improved by ERT. Our results show that a patient survey can serve as a valuable and reliable tool for obtaining quantifiable information on the natural course of a rare disease and on the effects of therapy in a large cohort over a very long time. Most importantly, by working with patient reported outcomes, the survey provides the data that is truly relevant to the patient and complementary to clinical datasets.

Quality of Life and Participation in the Daily Life (Activities) of Adults with Pompe Disease Receiving Enzyme Replacement Therapy: 10 Years of International Follow-Up.

Responses were available for 174 adult patients. In the periods before and after the start of ERT, the median follow-up times were 4 years each (range 0.5– 8). The SF-36 Physical Component Summary measure (PCS) deteriorated before ERT (−0.73 score Quality of Life and Participation in the Daily Life (Activities) of Adults with Pompe Disease Receiving Enzyme Replacement Therapy: 10 Years of International Follow-Up

Ten Years of the International Pompe Survey: Patient-Reported Outcomes as a Reliable Tool for Studying Treated and Untreated Children and Adults with Non-Classic Pompe Disease

Pompe disease is a rare, progressive, lysosomal storage disorder for which enzyme replacement therapy (ERT) became available in 2006. Four years earlier, the International Pompe Association (IPA)/ Erasmus MC survey, an international prospective survey, was established to collect information on the natural course of the disease and its burden on patients. The survey is a collaboration between Erasmus MC University Medical Center and the IPA, and comprises an annual questionnaire that was specifi cally designed to assess the symptoms and problems of the disease. Here we review our results of over 10 years of follow-up, and discuss the survey’s contribution to the fi eld. Tracking 408 patients with Pompe disease between 2002 and 2013, the cumulative data reveal Ten Years of the International Pompe Survey: Patient-Reported Outcomes as a Reliable Tool for Studying Treated and Untreated Children and Adults with Non-Classic Pompe Disease