How many people have pompe disease

Data of patients were collected in a prospective international observational study conducted between and Survival analyses from time of diagnosis and from time of study entry were performed using Kaplan-Meier curves and Cox-proportional-hazards regression.

Median age at study entry was 48 years range years. Median survival after diagnosis was 27 years, while median age at diagnosis was 38 years. During follow-up, twenty-three patients died prior to ERT, with a median age at death of 55 range years. In a Dutch subgroup of 99 patients, we compared the observed number of deaths to the expected number of deaths in the age- and sex-matched general population. During a median follow-up of 2. These results may be of relevance when addressing the effect of ERT or other potential treatment options on survival.

Pompe disease, synonymously 'acid maltase deficiency' or 'glycogen storage disease type II', is a metabolic myopathy caused by deficiency of the enzyme acid alpha-glucosidase and resulting in intralysosomal accumulation of glycogen. This autosomal recessive disorder is mainly characterized by progressive loss of muscle strength and respiratory function due to destruction of muscle tissue [ 1 , 2 ]. Because of its low frequency of approximately 1 in 40, births and the broad ethnic spreading [ 3 — 5 ], Pompe disease is a true orphan disease with the associated problem of collecting data in sufficiently large groups.

Clinical heterogeneity is an additional complicating factor [ 5 , 6 ]. Classic infantile Pompe disease, the most severe form, presents in the first months of life with generalized muscle weakness and cardiac hypertrophy. Without treatment these infants die before age one.

Later-onset forms of Pompe disease comprise childhood, juvenile, and adult cases. The majority of these patients present with symptoms in adulthood with limb- girdle weakness and respiratory problems [ 5 ]. For a long time, supportive care such as respiratory support was the only way of managing Pompe disease, but in the course of enzyme replacement therapy ERT with recombinant human alpha-glucosidase became available.

Clinical trials showed that ERT can ameliorate motor outcome, improve cardiomyopathy and prolong survival in classic infantile Pompe disease [ 7 — 11 ]. In children and adults treatment with ERT has been shown to stabilize respiratory function and to improve muscle function [ 12 — 16 ]. In contrast to classic infantile Pompe disease, in which survival is a key outcome measure to describe the natural course of the disease and to evaluate the effects of treatment, information on mortality in adults with Pompe disease has been lacking.

The present study was performed to fill the gap of knowledge on the impact of Pompe disease on survival in untreated adult patients, using data collected prospectively in an international patient survey prior to the introduction of ERT. The objective was to determine natural course survival in adult patients with Pompe disease, to compare this to the general population and to assess differences in survival between subgroups of patients. Data were collected between May and December as part of an ongoing study on the natural course of Pompe disease 'Pompe Survey' e.

Inclusion criteria for the Pompe Survey were a diagnosis of Pompe disease and an age above 2 years. The present analyses only include patients of 18 years and older with late-onset Pompe disease. For the Dutch patients, more information was available as Erasmus MC was designated as the single referral center for treatment and longitudinal follow-up of Pompe patients in the Netherlands.

Written informed consent was obtained from all patients. For the international participants in the Pompe Survey, the date of the last completed questionnaire before December was considered as the date of last follow-up. For the Dutch subgroup, the date of last follow-up was the last visit at our hospital in or the date of the last completed questionnaire, whichever came last. When the date of death for the deceased was not exactly known it was estimated to be halfway between the date of the last completed questionnaire and the date at which the next questionnaire should have been completed.

The date of diagnosis was estimated as precisely as possible according to the information provided in the questionnaires. To assess the level of participation defined as a person's involvement in life situations; previously called 'Handicap' [ 18 , 19 ], the Rotterdam Handicap Scale RHS was used. The RHS consists of 9 questions on the topics of mobility, kitchen tasks, domestic tasks, leisure activities, travelling and work or study.

The scores per item range from 1 'unable to fulfil the task or activity' to 4 'complete fulfilment of the task or activity'. If an item is not applicable to a patient, a score of 0 is given. The RHS score thus ranges from 9 to 36 and in the present analysis the number of items necessary to calculate a score was 5 out of 9 questions.

To assess disability level at study entry patients were divided into four groups: 1 no wheelchair or respiratory support, 2 only wheelchair, 3 only respiratory support and 4 both wheelchair and respiratory support. No division was made between partial and fulltime respiratory support, or whether it was invasive or non-invasive. Survival was calculated from the date of diagnosis or study entry until the date of last follow-up, start of ERT or death.

The survival times of patients who were alive at study end or lost to follow-up were censored. The survival times of the patients were also considered censored at the initiation of ERT. For survival from diagnosis and from study entry, the influence on survival was tested for the following variables: gender, age at diagnosis, and nationality. The variables age at entry, disability level and RHS score were only tested for survival from study entry.

This means that the data are 'left-truncated', as opposed to usual time-to-event data where all patients are followed from diagnosis. Estimates of survival from diagnosis in case not all patients enter the cohort study at the time of diagnosis require special calculations as described by Kurtzke [ 21 ].

Univariate analysis for survival from study entry was estimated by using the Kaplan-Meier method. Factors influencing survival were identified with the log-rank test. Multivariate analysis was performed with the Cox proportional-hazards method. Death probabilities from study entry were compared between the Dutch Pompe patients and the general population using death probabilities derived from the Dutch Central Bureau of Statistics CBS [ 22 ].

For each case of our study population, the death probability per follow-up year of someone of the same age and gender from the general population was taken for comparison.

Annual death probabilities per person were summed up and the sum of these cumulative death probabilities of the matched persons from the general population was used as the expected number of deaths.

This was then compared to the observed number of deaths in our own cohort using the Poisson distribution. This finding from the Registry is supported by a previous study of 15 LOPD patients conducted in Taiwan which reported a median age at symptom onset and diagnosis of 15 range, 10—35 and 21 10—38 years, respectively [ 17 ].

Furthermore, Chinese LOPD Registry patients also had a younger age at death compared with their counterparts from the rest of the world, although due to the small number of Chinese patients who had died, this should be interpreted cautiously. This may have contributed to the younger mean age at symptom onset and diagnosis. Therefore, it is encouraging that the diagnosis gap in the present study is shorter than previous observations, and is similar for Chinese patients and those from the rest of the world.

This finding may also reflect the high proportion of Chinese patients diagnosed using the relatively fast blood spot analysis or other blood-based assays. Although, it should be noted that DNA analysis is also an effective method for fast diagnosis.

Despite the apparent improvement in time to diagnosis, a delay of several years between symptom onset and diagnosis remains suboptimal considering that disease duration is a key factor for severity of Pompe disease, [ 19 ] and that ERT treatment with rhGAA has been shown to slow the progress of disease progression in adults and older children [ 20 ]. The main reason for the low rates of ERT treatment observed among Chinese patients in the Registry is that ERT was not available in China until May and the cutoff for the present analysis was September It should also be mentioned that the high prevalence of dried blood spot analysis in China may reflect that many Chinese patients with suspected Pompe disease are managed by long distance and send dry blood spots for screening, whereas in Chinese hospitals whole blood is more commonly used for enzyme analyses.

In addition, there are only four laboratories in China which can perform the GAA enzyme test which also makes dry blood spot testing more practical for screening.

Nevertheless, it is also best practice that diagnoses of Pompe disease are confirmed by a traditional assay, molecular analysis or both. Furthermore, FVC in the upright position for Registry patients from the rest of the world was These results suggest that Chinese patients with LOPD have greater diaphragm weakness compared with patients from the rest of the world, which aligns with the higher rates respiratory distress Our results found that c.

This difference in mutational frequency may explain the worse pulmonary function observed in Chinese patients versus their non-Chinese counterparts. Furthermore, other factors such as living conditions, smoking status of the patient or their immediate family smoking is more prevalent in China versus many Western countries , and history of lung infections or disease may have influenced these results and further studies are required to clarify this.

It is important to recognize the limitations of the analyses conducted when interpreting the findings presented in this report. The Registry is voluntary and not all patients with Pompe disease have been identified, nor do all wish to participate in the Registry. Therefore, patient numbers for some analyses are very small.

Furthermore, although the Registry provides a recommended schedule of assessments, patients and their treating physicians ultimately determine the assessments and the time intervals at which they are carried out. Thus, clinical data may be incomplete for some patients and some assessments or events may be under-reported.

Analysis of Registry data will become more meaningful as increased longitudinal clinical data become available for patients in China. In conclusion, this first report of Chinese patients in the Registry represents the largest data set currently available on the characteristics of patients with Pompe disease in China. Overall, Chinese Registry patients had a high burden of disease, and the most common mutations were c. Compared with patients from the rest of the world, Chinese patients with LOPD appear to be younger at symptom onset and diagnosis, have lower lung function, and are not receiving treatment with ERT.

The delay between symptom onset and diagnosis for Chinese patients with LOPD was similar to that in patients from the rest of the world and suggests that even with the common use of blood-based assays there is still room for improvement in the delay between symptom onset and diagnosis. The methodology for data collection by the Registry has been described in detail previously [ 18 ].

In brief, the Registry is an on-going, international, multi-center, observational program that tracks the routine clinical outcomes for patients with Pompe disease, irrespective of patient age, clinical manifestations or treatment status. However, it should be noted that due to the young age of death associated with IOPD, many patients with this form of Pompe disease are not entered into the Registry.

Patient participation is voluntary, and written informed consent is obtained from all participants. The Registry was established in September and the Registry protocol is registered at ClinicalTrials. A recommended schedule of assessments is provided by the Registry [ 18 ]. However, the assessments and data collected reflect regional clinical practices, standards of care, and available testing resources.

Safety data are not collected by the Registry and healthcare providers are advised to report any spontaneous adverse drug reactions and pregnancy exposures related to ERT directly to the Sanofi Global Pharmacovigilance and Epidemiology Department. Scientific guidance is provided to the Registry by an independent Registry Board of Advisors comprising physicians and healthcare professionals with extensive scientific and clinical expertise.

More than one type of assay may have been used to diagnose individual patients. All patients with LOPD included in the Registry as of September were eligible for inclusion in the present analysis. Patient demographics and clinical characteristics are presented using summary statistics.

Variables are summarized as mean SD unless otherwise stated. Percentages reported for individual measures reflect the proportion of patients with available data for each measure, and are not percentages of the total number of patients included in the analysis. Since all analyses were descriptive, statistical tests were not conducted. All analyses were conducted using SAS 9. Manganelli F, Ruggiero L. Clinical features of Pompe disease. Acta Myol. Hirschhorn R, Reuser AJ. Glycogen storage disease type II: acid alpha-glucosidase acid maltase deficiency.

The accumulation of glycogen in certain organs and tissues, especially muscles, impairs their ability to function normally. Researchers have described three types of Pompe disease, which differ in severity and the age at which they appear.

These types are known as classic infantile-onset, non-classic infantile-onset, and late-onset. The classic form of infantile-onset Pompe disease begins within a few months of birth. Infants with this disorder typically experience muscle weakness myopathy , poor muscle tone hypotonia , an enlarged liver hepatomegaly , and heart defects.

Affected infants may also fail to gain weight and grow at the expected rate failure to thrive and have breathing problems. If untreated, this form of Pompe disease leads to death from heart failure in the first year of life. The non-classic form of infantile-onset Pompe disease usually appears by age 1. It is characterized by delayed motor skills such as rolling over and sitting and progressive muscle weakness. The heart may be abnormally large cardiomegaly , but affected individuals usually do not experience heart failure.

The muscle weakness in this disorder leads to serious breathing problems, and most children with non-classic infantile-onset Pompe disease live only into early childhood. The late-onset type of Pompe disease may not become apparent until later in childhood, adolescence, or adulthood.

Late-onset Pompe disease can present at various ages with muscle weakness and respiratory insufficiency. Progression of the disease is often predicted by the age of onset, as progression is more rapid if symptoms present in childhood.

Cardiomegaly is not typically seen, but progressive muscle weakness resulting in motor delays, swallowing difficulties, and respiratory insufficiency usually occurs as in the infantile form, only at a slower rate. Clinical manifestations of late-onset Pompe disease include the following 1 :.

The current worldwide prevalence of Pompe disease is estimated at 1 in 5, to 10, people 4, 5. The prevalence is variable, depending on ethnicity and geographic region, and it is estimated from , in African Americans 6 to , in individuals of European descent 7. Pathogenic variants in the GAA gene that result in the deficiency or absence of acid alpha-glucosidase GAA results in progressive expansion of glycogen-filled lysosomes in multiple tissues, with cardiac and skeletal muscle being the most severely affected.

The severity of clinical presentations, tissue involvement, and age of onset generally correlate well with the nature of the variant and the degree of residual enzyme activity 1, 8. It is assumed that biallelic GAA pathogenic variants which produce essentially no enzyme activity result in infantile-onset Pompe disease.