Citation

Puckett Y, Pham T, Bui E, Turner L, Zelicoff A (2019) Epidemiology of Mucopolysaccharidoses (MPS) in the United States: A Need for Newborn Screening. Int J Rare Dis Disord 2:010. doi.org/10.23937/2643-4571/1710010

ORIGINAL ARTICLE | OPEN ACCESS DOI: 10.23937/2643-4571/1710010

Epidemiology of Mucopolysaccharidoses (MPS) in the United States: A Need for Newborn Screening

Yana Puckett, MD, MPH1, Theophilus Pham, MBA1*, Eileen Bui2, Laurie Turner3 and Alan Zelicoff, MD1

1TTUHSC School of Medicine, USA

2Saint Louis University School of Medicine, USA

3National MPS Society, USA

Abstract

Introduction

The incidence of MPS in the U.S. was found to be much lower than those reported in other countries. It was 1.16 per 100,000 live births overall with an overall prevalence of 2.9 per 1 million. MPS I had the highest live birth incidence of 0.34/100,000 which accounted for 29.8% of all MPS. The birth incidences of MPS II, III, IV, VI, and VII were 0.29 (28.0% of all MPS), 0.38 (28.0%), 0.09 (7.8%), 0.05 (5.6%), and 0.01 (0.08%) per 100,000 live births, respectively. No cases of MPS IX were identified.

Methods

The incidence of MPS in the U.S. was found to be much lower than those reported in other countries. It was 1.16 per 100,000 live births overall with an overall prevalence of 2.9 per 1 million. MPS I had the highest live birth incidence of 0.34/100,000 which accounted for 29.8% of all MPS. The birth incidences of MPS II, III, IV, VI, and VII were 0.29 (28.0% of all MPS), 0.38 (28.0%), 0.09 (7.8%), 0.05 (5.6%), and 0.01 (0.08%) per 100,000 live births, respectively. No cases of MPS IX were identified.

Results

The incidence of MPS in the U.S. was found to be much lower than those reported in other countries. It was 1.16 per 100,000 live births overall with an overall prevalence of 2.9 per 1 million. MPS I had the highest live birth incidence of 0.34/100,000 which accounted for 29.8% of all MPS. The birth incidences of MPS II, III, IV, VI, and VII were 0.29 (28.0% of all MPS), 0.38 (28.0%), 0.09 (7.8%), 0.05 (5.6%), and 0.01 (0.08%) per 100,000 live births, respectively. No cases of MPS IX were identified.

Conclusion

To date, this is the most comprehensive review of the incidence and prevalence of all MPS in the U.S. Public health policy needs to focus on increased newborn screening for MPS and creating a mandatory national/worldwide registry for all rare diseases.

Introduction

Mucopolysaccharidoses (MPS) are rare, inherited lysosomal storage disorders (LSDs) characterized by progressive multiorgan involvement, leading to severe disability and premature death. There are a total of seven types of MPS variants, caused by defects in the genes coding for different lysosomal enzymes which are used in the degradation of glycosaminoglycans (GAGs). The deficient enzyme activity results in multiorgan storage of GAGs, leading to varied clinical manifestations dependent on many factors. Some factors include the degree of enzyme deficiency and the age of the child and type of MPS disorder. All but MPS II (Hunter Syndrome) are inherited in an autosomal recessive manner; MPS II is inherited as an X-linked recessive disorder [1,2].

MPS I (Figure 1), also known as Hurler's Disease, results from build-up of heparan sulfate and dermatan sulfate due to deficiency of alpha-L-iduronidase (Table 1), an enzyme that is responsible for degradation of mucopolysaccharides in lysosomes [3]. MPS II, also known as Hunter syndrome (Figure 2), is caused by a build-up of heparan sulfate and dermatan sulfate due to lack of the enzyme iduronate sulfatase (Table 1). Many of the clinical features associated with MPS I can be seen in patients with MPS II [4]. MPS III, also known as Sanfilippo syndrome (Figure 3), is classified into four different types based on the type of enzyme missing. MPS IIIA, IIIB, IIIC, and IIIC are caused by missing or altered enzymes: Heparin N-sulfatase, alpha N-acetylglucosaminidase, acetyl-coalpha-glucosaminide acetyltransferase, N-acetylglucosamine 6-sulfatase, respectively [5]. All forms result in accumulation of heparan sulfate (Table 1). MPS IV, otherwise known as Morquio syndrome (Figure 4), is classified depending on the type of enzyme missing: N-acetylgalactosamine 6-sulfatase (GALNS) (Type A) or beta-galactosidase (Type B) [6]. These enzymes are needed to break down keratan sulfate sugar chains, although GALNS also catabolizes chondroitin 6-sulfate (Table 1). The clinical features are similar in both types, with onset between ages of 1 and 3, but appear milder in MPS IVB. MPS VI, also known as Maroteaux-Lamy syndrome (Figure 5), is caused by a deficiency in the enzyme N-acetylgalactosamine 4-sulfatase, leading to buildup of dermatan sulfate and chondroitin sulfate (Table 1) [7]. MPS VII, or Sly syndrome (Figure 6), is caused by deficiency of the enzyme beta-glucuronidase, resulting in accumulation of dermatan sulfate, heparan sulfate and chondroitin sulfate (Table 1) [8]. MPS IX results from hyaluronidase deficiency, leading to an accumulation of hyaluronan (Table 1).

Figure 1: Characteristics of MPS I phenotype. (Photo courtesy of Genzyme.com). View Figure 1

Figure 2: Patient with MPS II, also known as Hunter Syndrome. (Photo courtesy of National MPS Society). View Figure 2

Figure 3: Patient with MPS III, also known as Sanfilippo syndrome. (Photo courtesy of www.phoenixnestbiotech.com). View Figure 3

Figure 4: Patient with MPS IV disease, also known as Morquio syndrome (Photo courtesy of The National MPS Society). View Figure 4

Figure 5: Patient MPS VI disease (Alena Galan, spokesperson for MPS disease (http://www.frompatienttoperson.com). With permission from Alena Galan. View Figure 5

Figure 6: Patient with MPS VII disease, also known as Sly syndrome (Photo courtesy of The National MPS Society). View Figure 6

Table 1: Summary of pathophysiology of Mucopolysaccharidoses I, II, III, IV, VI, VII, and IX. View Table 1

Currently, the U.S. Food and Drug Administration has approved four recombinant human enzymes for enzyme replacement therapy (ERT): Laronidase for MPS I, idursulfase for MPS II, elosulfase alfa for MPS IVA and galsulfase for MPS VI [9,10]. Hematopoietic stem cell transplantation (HSCT), if performed before the age of 2 years, can increase survival and preserve mental abilities in patients with MPS I. HSCT has also been used to clinically treat MPS II and III patients, although there is still controversy surrounding its efficacy [9]. Several case reports have also shown that stem cell transplant in MPS VII patients does have some clinical benefit, although to varying degrees of success [8]. Growing interest in MPS and more patients can play significant roles in exploring experimental therapies. For example, clinical trials in substrate reduction therapy have indicated that it may be effective against MPS III [11]. Gene therapy, while not yet approved for in humans, is also a very promising field for MPS treatment, especially for the neurological manifestations [12].

Several studies have reported the incidence and prevalence of MPS disorders, but the numbers vary greatly depending on the population and area. Incidence is the number of new cases in a population during a specific timeframe, while prevalence is all cases present in a population during that time frame. A disease is considered rare when it affects one person out of 2,000 or less, and it is estimated that about 5,000 to 8,000 rare diseases exist [13]. Data collected on rare diseases is necessary to address the challenge of public health funding for treatment and need for fundamental biomedical research. It must also be specific to the regions or countries in which the diseases exist [14-16].

Unfortunately in the U.S., this data is missing [17,18]. Some reasons cited for missing epidemiologic data on rare diseases are lack of dedicated mandatory registries for such diseases [19]. In addition, lack of epidemiological data on rare diseases also affects the decision to include such diseases on newborn screening (NBS) [20]. The consideration of onset of disease and rather or not it is treatable is also is used when deciding what diseases are added to the screening. NBS allows for the earliest, cost-effective, and least invasive way of screening for a disease. The benefits of early detection of rare disease is early intervention and mitigation of morbidity, and therefore is associated with improved outcomes, better quality of life, and longer survival time [21-24].

Currently, individuals with MPS usually require presentation of a clinical symptom to be diagnosed. However, there is widespread interest in adding MPS to NBS panels to achieve early diagnoses. Several techniques, which measure lysosomal enzyme activity using artificial substrates, have been developed and successfully used in pilot NBS programs. For MPS I, microplate fluorometry, digital microfluidic fluorometry and mass spectrometry (MS/MS) are able to quantify IDUA levels from newborn dried-blood spots, and can also be multiplexed to detect other lysosomal storage disorders [25]. MS/MS in particular has been emerging as a powerful tool due to its ability to not only show sensitivity and specificity for all subtypes of MPS, but also to monitor therapeutic efficacy [26].

However, not every state screens for MPS in NBS in the U.S. While all states in the U.S. require NBS for every infant, the number and types of conditions on a state's screening panel varies depending on the decisions made by each state's public health department [27]. Only sixteen states out of 50 screen for MPS and the screening only includes MPS I, which is the most common MPS variant. Furthermore, only five states screen for other lysosomal storage diseases (Illinois, Kentucky, Missouri, New York, and Pennsylvania) [28]. There are several factors that come into play when it comes for state government to decide which diseases will be screened for in NBS in their state: laws of the state, financial cost of screening, frequency of the disorder in the state, the availability of treatments for each condition, and funding sources for the NBS program. As such, if state public health departments are not aware of the incidence and prevalence rates of a certain disease, the discussion of funding allocation and inclusion of NBS cannot even begin.

To encourage uniform and comprehensive NBS throughout the U.S., the Health Resources and Services Administration (HRSA) issues a report that recommends screening for 34 specific conditions known as the core panel. MPS I was only recently added as a recommended condition [29]. In addition, these are merely recommendations and states are not required by law to follow them [30]. These state-dependent disparities in screening could not only mean delayed diagnosis and therefore heavier disease burdens, but also make it difficult to obtain a complete epidemiological picture of certain diseases.

Although several studies have looked at the epidemiology for MPS in certain countries, not including the U.S., no centralized database or national/worldwide registry exists that mandates reporting of rare diseases [29]. Furthermore, NBS for MPS has only recently been implemented in a few populations, and only for MPS I. This has led to a visible lack of epidemiological data on the incidence and prevalence of MPS disease. As such, there is no true and sure way to collect the number of cases of MPS in the U.S. and/or worldwide accurately.

Here, we implemented a retrospective epidemiological study of MPS in the U.S. We also compared our data with previous reports in different populations from other countries, including populations with NBS for MPS.

A Human Subjects Research Determination Form was obtained from the Institutional Review Board (IRB) at Saint Louis University which determined that our research was exempt from a formal IRB submission due to lack of patient identifiers. A database of over 200 Children's Hospitals was found (Figure 7). Initially, an attempt was made to obtain all cases of MPS by calling all Children's Hospitals. However, there was a lack of consistent source of information from these hospitals. In addition, all hospitals were reluctant to divulge patient information despite being told that no patient identifiers need be revealed. Next, the clinicaltrials.gov website was investigated for number of MPS cases participating in clinical trials and years during which they were active in clinical trials were obtained. The incidences calculated from those results were short of the estimates worldwide. In addition, it was hard to assess whether the same patient belonged to more than one trial.

Figure 7: MPS Incidence by state in the U.S. in our study. View Figure 1

Another attempt to collect MPS cases was made by contacting BioMarin® Pharmaceuticals (which manufacture enzyme treatment for MPS I, IVA, and VI); Shire® Pharmaceuticals (manufactures enzyme treatment for MPS II); Ultragenyx® pharmaceuticals (manufacturer of enzyme treatment for MPS VII), and Genzyme® (manufacturer of enzyme treatment for MPS I). The National MPS Society provided a database of all MPS members. This database included year of birth, year of death, type of disease, and state of residence. National U.S. Census bureau was used to obtain estimates on U.S. population from the years 1995 to 2005. The incidence rate was calculated by dividing the total number of cases by the total number of live births during the study period. Prevalence was calculated by dividing the total number of cases between 1995 and 2005 by the total population during the same time period.

A sub-analysis was performed for incidence based on state location. The number of live births was obtained for each state using the U.S. Census Bureau data between 1995 and 2005. Incidences were then calculated based on number of patients recorded for each state during that time period.

A review of the natural disease process as well as a review of literature was made for incidence numbers to compare to our results. In addition, patient registries from Department of Pediatrics at Saint Louis University and Ultragenyx® Pharmaceutical database were used for MPS VII patients. The Ultragenyx® data was for MPS VII only and is thought to be the most comprehensive database in the U.S. As such, the incidence and prevalence results of our study for MPS VII are most likely complete. A literature review of incidences for MPS I disease was performed to compare our results to other countries. In addition, a review of methods of incidence and prevalence outcome was made in other countries with incidence and prevalence data published on PubMed® for MPS diseases. Finally, a literature review of incidences for newborn screening programs for MPS was then performed.

Results

Incidence in the United States

Between 1995 and 2005, there were a total of 474 patients with MPS disorders registered with the National MPS Society. The total number of live births in the U.S. 1995-2005 was 39,578,840. The average total population in the U.S. between 1995 and 2005 was 268,436,968. The corresponding incidence based on this data is shown in Table 2.

Table 2: Overall incidence and prevalence rates of MPS in United States (1995-2005). View Table 2

The combined incidence for all Mucopolysaccharidoses was 1.2 per 100,000 live births. MPS I had the highest calculated incidence of all MPS variants of 0.34 per 100,000, comprising 29.8% of all MPS diagnoses. MPS II, III, IV, VI, and VII variants had incidences of 0.29, 0.38, 0.09, 0.05, and 0.05 per 100,000 live births. No cases of MPS IX were identified. Our overall prevalence was found to be 1.8 per million.

A sub-analysis of incidence of MPS was performed per state (Table 3) and subsequently plotted on a color map of the incidence by state (Figure 6). Wide disparities in incidence were noted throughout the U.S. with no pattern to substantiate the differences.

Table 3: Incidence rates of MPS by state in the United States per 100,000 live births (1995-2005). View Table 3

Incidence in other countries

The overall incidence of MPS ranges worldwide between 1.93 to 4.50 per 100,000 live births compared to our result of 1.2 [31-41]. A review of literature for MPS I disease reveals incidences that vary between 0.11 (Taiwan) to 3.85 (Northern Ireland) (Table 4) [31-42]. Our result of 0.34 per 100,000 for MPS is on par with Taiwan (0.11) and Poland (0.22) (Table 4).

Table 4: Published incidence per 100,000 for MPS I disease from other countries. View Table 4

A review of countries with incidence and prevalence data of MPS disease was performed to distinguish ways other countries collect epidemiological data and to see whether a method can be implemented in the U.S. that would allow recording of incidence and prevalence of all rare diseases (Table 5).

Table 5: Review of methods of incidence collection for MPS by country. Wide discrepancies are seen in the incidence and prevalence data of MPS worldwide. View Table 5

Australia

Six sources were used

1. Medical records from Princess Margaret Hospital for Children and King Edward Memorial Hospital for Women, Perth.

2. Medical records from the Disability Services Commission of Western Australia.

3. Laboratory records from the Department of Chemical Pathology.

4. Laboratory records from the department of Clinical Biochemistry from Princess Margaret Hospital for Children.

5. Membership list of the Society for Mucopolysaccharide Disease.

6. Records of Birth Defects Registry of Western Australia [37].

British Columbia, Canada

All patients were born in British Columbia, Canada. Birth records of the British Columbia Vital Statistics Agency was used [31].

Ireland

Data was obtained from a retrospective database and chart review of patients with MPS collected from the National Center for Inherited Metabolic Disorders, Children's University Hospital and the Oncology Unit [35,36].

Northern Ireland

Three main sources were used

1. Hospital records (only two hospitals in the region)

2.The Diagnostic indices of the Department of Medical Genetics.

3. Laboratory records of hospitals [35,36].

The Netherlands

Records from the laboratories of the clinical genetic centers involved in the post and prenatal diagnosis of LSD in the Netherlands were used as the sole source of ascertainment [38].

Poland

Three main sources were used

1. Patient records from the Department of Metabolic Diseases at the Children's Memorial Health Institute in Warsaw.

2. Laboratory records from the Department of Genetics at the Institute of Psychiatry and neurology.

3. Membership list of the Polish MPS Society [42].

Scandinavian countries

In Sweden, two laboratories are responsible for the diagnosis of lysosomal storage disorders during the last three decades. In Norway, diagnosis is carried out by one cytopathology hospital. In Denmark, two cytopathology laboratories performed diagnoses for MPS disorders until 2003: The Kennedy Institute in Glostrup and the Department of Clinical Genetics at Rigshospitalet since 2003 [33].

Taiwan

Five sources were used

1. Membership of Taiwan MPS society members.

2. Medical records from 10 Taiwan hospitals.

3. Laboratory records from Department of Medical Research.

4. Records of Taiwan Foundation for Rare Disorders.

5. Records of Bureau of Health Promotion, Department of Health [33].

UK

The Society for Mucopolysaccharide Diseases UK made available anonymized records of MPS I patients held in its registry. The Society aimed to collect data on every UK patient with MPSI. Most patients with MPS I are seen at a small number of designated centers in the UK and are automatically registered into the society registry. As such, the database is thought to be considered complete [41,43].

Incidence in programs with newborn screening for MPS

Only four newborn screening programs for MPS with public data were found, all of which were pilot programs. The data from 3 of these programs indicate higher incidences than current epidemiological studies identify (Table 6). Taiwan's MPS-I NBS program analyzed 35,285 infants with a fluorescence enzyme assay for Iduronidase (IDUA) activity levels. Two cases of MPS-I were identified with diagnosis confirmed by molecular genetic analysis, yielding an estimated incidence of 5.67 per 100,000 [44]. This figure is significantly higher than the reported 0.11 per 100,000 in the 2009 epidemiological study [32].

Table 6: Incidence rates of MPS-I from pilot studies of newborn screenings. View Table 6

In the United States, 3 pilot programs have been conducted. In Missouri, a full-population pilot study examined 149,500 specimens using a multiplexed fluorometric enzymatic assay [45]. One individual with confirmed severe MPS-1 was identified, yielding an incidence of 0.67 per 100,000. In Illinois, one individual with confirmed severe type MPS-I was identified from the sample population, yielding an incidence of 1.59 per 100,000 [46]. The study performed at the University of Washington did not do a clinical follow-up and thus lacks phenotype information; however, they did identify 3 with mutations/nucleotide changes that are "consistent with MPS I disease", yielding an incidence of 2.8 per 100,000 [47]. The Missouri study indicates a lower incidence than our study, while the Illinois and Washington study reveal higher incidences.

Discussion

There are relatively few published studies examining the epidemiology of MPS in the United States. Upon comparison of our incidence rates with those available in the literature, there appear to be significant differences. For MPS I, a paper by Beck, et al. 2014 published data citing North America with 343 patients with MPS I between 2003 and 2013 [48]. The total number of live births in the U.S. between 2003 and 2013 was 45,138,496. A calculation of the incidence of this paper results in the incidence of 0.76 per 100,000. This is much higher than our incidence for MPS I disease of 0.34. However, this paper lists patients from all of North America, which could mean that Canada and Mexico may be included in that number. As such, it may be overinflated. However, the rate of incidence for MPS I in the U.S. is estimated to be somewhere between 0.34-0.76 per 100,000.

For MPS II disease, the Hunter Outcome Survey (HOS) was used to estimate incidence in the U.S. for comparison. The HOS is a global, multi-center, long-term, observational survey that is overseen by national, regional, and global scientific advisory boards [49]. The HOS reports a total of 45 patients with MPS II in North America as of 2007. The calculated incidence of this paper between 1995 and 2007 would be 0.11 per 100,000. However, our incidence rate was found to be higher (0.29 per 100,000). Thus, an estimated incidence rate in the U.S. is somewhere between 0.11-0.29 per 100,000.

One study out of Utah, U.S., published in 1964, cited MPS III incidence between 0.5-1 per 100,000 [50]. Our incidence of MPS III was calculated to be 0.38 per 100,000. This number is close to the cited incidence in Utah, but falls slightly short. The estimated incidence rate of MPS III in the U.S. is somewhere between 0.38-1.0 per 100,000.

For MPS IVA, a paper published on the International Registry for Morquio A Disease showed a total of 87 patients located in the U.S. with the disease between 1998 to 2006 [51]. The total number of live births in the U.S. between 1998 and 2006 was 36,313,349. This calculates to an incidence of 0.24 per 100,000. This was higher than our calculated incidence for MPS IV from the National MPS Society, at 0.09 per 100,000. Thus, the incidence rate of MPS IV in the U.S. is somewhere in the range of 0.09-0.24 per 100,000.

No publications reporting MPS VI incidence rates in the U.S. were found.

For MPS VII, a patient registry thought to be complete for the U.S. from the Department of Pediatrics at Saint Louis University was used to compare incidence rates to those obtained from the National MPS Society [8]. This database contained 10 patients between 1995 and 2005. Ultragenyx® Pharmaceuticals, manufacturer of enzyme for MPS VII ERT generously provided their database for us, which is thought to be a complete count of all MPS VII patients in the US [9]. This brings the incidence rate for MPS VII to 0.05 per 100,000. Papers on incidence and prevalence of MPS out of Scandinavian countries, Ireland, Northern Ireland, Taiwan, and Western Australia had no patients to report for MPS VII [32,33,36,37]. As such, our paper is one of the few that reports data on accurate incidence and prevalence of MPS VII. The Netherlands cited their incidence rate for MPS VII as 0.24 per 100,000 [38].

Our calculation of the prevalence of MPS disease overall was found to be 1.8 per million. This is almost half less as the prevalence for all MPS disorders in Scandinavian countries, which were cited as 4.24, 7.06 and 6.03 per million inhabitants in Sweden, Norway and Denmark respectively [49]. It is likely that our prevalence rate is low due to the fact that we lack complete data, having only primarily used three sources.

Overall, the results of our study in terms of incidence and prevalence fall short of the estimates of other countries with more unified healthcare systems. The smaller size of European countries and lack of state fragmentation may have made it easier to estimate incidence and prevalence data. Medical records are easier to obtain if only two hospitals exist in the country and there are more national hospitals with better medical record data. Nevertheless, wide discrepancies were still seen in incidence and prevalence data of MPS worldwide (Table 5) and as such, the accuracy of the data is questionable. This may in part be due to methods of obtaining incidence and prevalence data being inconsistent. Understanding which methods are most effective at obtaining complete and accurate data is vital to obtaining cohesive epidemiological statistics and therefore, better scientific, economic and social efforts in relieving rare disease burden.

Upon review of these methods, Scandinavian countries have perhaps the best system of keeping rare disease records; they have few cytopathology laboratories nationwide and diagnose all patients born in Scandinavian countries. To accommodate for the U.S. much larger and divided population, the best method of record keeping for rare diseases would be a mandatory national rare disease registry which every state would have to report to. This centralized data collection would allow a more comprehensive and complete picture of U.S. MPS patients, and perhaps also overcome the data analysis limitations resulting from patients moving between states.

It is possible that variability in incidences may be due to ethnicity differences, as due to the nature of Mendelian genetic inheritance of the disease, locations that are enclosed and with little migration in and out of the population to increase genetic pool diversity are likely to have a higher incidence of MPS. For instance, the highest incidence of MPS I was 3.8 and was found to be in Northern Ireland. Northern Ireland has a high rate of Irish traveler population that tends to stay and intermarry within group [38]. U.S. is a very large and diverse country and this may explain our low incidence and prevalence rates of MPS. However, without a national registry for rare disease it is hard to say that our incidence and prevalence rates are accurate. Even in countries with more comprehensive published data on incidence and prevalence of MPS, review of the methods for finding incidences is highly variable and likely not definite (Table 5).

The U.S. lacks any comprehensive epidemiological data on MPS. Some obstacles encountered in obtaining data on MPS in the U.S. include its fragmentation into 50 states. The large size of the country with countless cytopathology laboratories available nationwide make it difficult to gather data accurately and effectively. Over 200 Children's hospitals exist in the U.S. that are reluctant to divulge patient information. Strict patient health information protection laws further limit any information that can be obtained in the U.S. Pharmaceutical companies that manufacture enzymes for ERT protect patient identity and registry.

The only source of solid information was the National Society of MPS and Ultragenyx® Pharmaceuticals. However, analysis of the data from the National MPS Society may not include all patients with MPS in the U.S. as it is not a requirement to be a member of the society. It is also important to consider that patients recorded in a specific state were not specified to have been born there. Therefore, it is difficult to determine if some of the discrepancies are due to patients moving states. In addition, the data provided demonstrated statewide disparities (Figure 7). The suspected reason for the discrepancies is lack of homogeneous knowledge about the MPS Society in all 50 states. Interestingly, states with high rural populations such as Oklahoma, Kansas, Indiana, New Mexico, Montana, and South and North Dakota had some of the highest incidences of MPS overall (Figure 7).

Rare diseases place a huge burden on the patient, the caregiver, and the society. Knowledge of the incidence and prevalence of disease dictates how much research, funding, and other resources will be allotted to the disease [52]. The fragmented health care information system in the U.S. has made obtaining basic information about incidence and prevalence of rare diseases difficult. Without such knowledge, the aforementioned efforts to fight MPS will always lag behind other countries.

Perhaps critical to achieving accurate epidemiological data is newborn screening (Figure 8), which allow examination of an entire population without needing patients to first present specific clinical symptoms. Pilot NBS programs for MPS I in Taiwan, Washington and Illinois have indicated incidence rates higher than those reported in the literature and our study (Table 6). This suggests that current methods of collecting epidemiological data are insufficient at identifying all possible cases of MPS. Several factors may contribute to this insufficiency, many of which can be eliminated with NBS. For example, patients diagnosed with MPS do not register with the institutes that collect data. Physicians may be unable to diagnose the clinical presentation of MPS patients as MPS. Furthermore, patients with milder phenotypes may not be diagnosed at all. NBS can allow data collection to be more comprehensive and accurate, and identify patients without requiring a clinical diagnostic evaluation.

Figure 8: Summary of methodology. View Figure 8

The Missouri program indicated a lower incidence than what we identified in our study. However, these preliminary pilot study results do not reflect the screening protocol in Missouri, and the authors have stated that they should not be generalized [50]. Nevertheless, data obtained from identifying MPS I disease on screening may allow a more detailed understanding of MPS I within a population-level context, and provide opportunities to examine discrepancies in incidence rates when comparing newborn screening and clinical diagnoses [32,40-42].

In fact, beyond providing valuable epidemiological data, implementation of MPS into NBS panels can also have significant net benefits over standard clinical assessments. Key impact is on the time to diagnosis, which under current conditions, varies depending on timing and nature of symptom presentation. Individuals with MPS then undergo treatment and follow-up, but delayed diagnosis can have significant implications on intermediate measures of health (ex. biomarkers) and primary health outcomes (ex. morbidity). Evidence has already shown that earlier treatment can result in improved cognitive and other health outcomes [26], and several studies suggest that morbidity and mortality may also be reduced [52]. Pilot studies on NBS for MPS are also capable of revealing carriers for MPS, providing valuable information to these individuals in the future for family planning purposes. Unfortunately, there are relatively few studies that can estimate and quantify anticipated benefits of early treatment, given the small numbers of patients currently receiving early treatment.

NBS may change the landscape of MPS in the context of both epidemiology and clinical intervention. In the United States, only sixteen states have implemented NBS, all examining only MPS I and all implemented within the last 5 years. Therefore, major public health policy implications are called for. Specifically, the authors of this paper recommend all NBS for MPS in all states and mandatory registration of every diagnosis of MPS into a national MPS registry. If NBS for MPS becomes widespread, patients on the later onset portion of the spectrum may be identified earlier and prognostic biomarkers will be vital in determining which patients will progress rapidly and need to start therapy immediately and which will require monitoring for symptom onset.

Currently, there is the National MPS Society in the U.S., established to provide support for those diagnosed with MPS and their families and loved ones. Benefits of being in the society include staying current on the latest treatments, research, and publications, and resource guides specific to certain syndromes and treatments. In addition, members are provided with networking opportunities with each other, researchers, physicians, and families of other MPS patients. NBS programs can facilitate the connection between MPS patients with this support system early on, to more quickly ease quality of life. It is highly important to locate any patients who are not currently members of the National MPS Society, such that patients can begin treatment immediately, if not already done. ERT therapy is currently effective in controlling some somatic manifestations of MPS patients. However, it is important to note that there are high costs associated with ERT. Not only does this pose challenges to the patient, but also to the inclusion of MPS in NBS since the treatments may be too expensive. Thus, more discussion is needed to address the socioeconomic issues that MPS patients face even after they have been located.

This study initially began as the search for the incidence and prevalence rate of MPS disease in the U.S. revealed that membership to the National MPS Society is not uniform throughout the U.S. with no pattern to explain the disparities [53]. Some reasons that may explain the state differences may be lack of knowledge by medical professionals and inadequate or improper diagnosis. The differences in NBS standards across states may also be an important factor for lower numbers, as MPS may not be included in the screening process at all. Another reason may be lack of acceptance of the diagnosis by families and reluctance to join the membership secondary to that. Finally, it may be that families are simply not aware of the MPS society's existence.

Conclusion

To date, this is the most comprehensive review of the incidence and prevalence of all MPS in the U.S. Policy advocacy is needed to establish NBS of MPS in all states. Furthermore, a national registry for all rare diseases is needed to ensure accurate epidemiologic information.

Acknowledgements

We would like to thank the staff of the National Society of MPS and Ultragenyx® Pharmaceuticals for generously providing their database information for our study.

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Citation

Puckett Y, Pham T, Bui E, Turner L, Zelicoff A (2019) Epidemiology of Mucopolysaccharidoses (MPS) in the United States: A Need for Newborn Screening. Int J Rare Dis Disord 2:010. doi.org/10.23937/2643-4571/1710010