Prevalence rates of mucopolysaccharidosis in Iraq: a retrospective cross-sectional observational study

Introduction

Mucopolysaccharidosis (MPS) is a rare inherited metabolic disorder that is the most heterogeneous group of lysosomal storage diseases (LSD). It is characterized by multiorgan impairment caused by glycosaminoglycan (GAG) buildup in various tissues and organs, eventually resulting in severe debilitation and fatality in early life.¹ There are 11 types/sub-types of MPS, each caused by a specific lysosomal enzyme dysfunction or deficiency that contributes to GAG breakdown and, as a result, causes a variety of clinical manifestations such as coarsening of facial characteristics, hepatosplenomegaly, cognitive impairment, dysostosis multiplex, hernias, corneal cloudiness, kyphoscoliosis, cardiac complications, etc.² Different types usually have mutual symptoms, particularly MPS I and II, but MPS III and VII are characterized by severe neurological features and hydrops fetalis, respectively.³ These clinical symptoms are involved in the diagnosis of MPS. However, implementing newborn screening programs and enzymatic and molecular assays for early and precise diagnosis of asymptomatic suspected individuals is imperious for improving therapeutic outcomes.^4,5 Enzyme replacement therapy (ERT) and hematopoietic stem cell transplantation are conventional therapeutic approaches for most MPS types/subtypes. However, the emergence of novel therapeutic strategies like gene therapy, pharmacological chaperone, and substrate reduction therapy is on the way to proving its effectiveness, especially for managing neurological manifestations and other intractable symptoms.⁶ All MPS types are inherited by autosomal recessive inheritance except MPS II, which is inherited as an X-linked pattern.⁷ The first case of MPS was diagnosed in 1917 by Charles Hunter; ethnicity and geographical region may affect the phenotypic characteristics of MPS.⁸ This is the first epidemiological survey regarding MPS in Iraq, although there were similar studies considering the epidemiology of MPS disorders conducted in the province of Arabian nations; this retrospective epidemiological study of MPS was undertaken to calculate the birth prevalence rate and frequencies of different types of MPS for a period of one-decade from 2010 to 2020 in Iraq. In 2017, the overall prevalence of MPS in Saudi Arabia (a neighbor of Iraq) was estimated and calculated by Nouriya A. Al-Sannaa et al. as 15.64 per 100,000 live births.⁹ In 2013, a study of MPS prevalence in the United Arab Emirates (UAE) was achieved by Fatma A. Al-Jasmi et al. and revealed an overall prevalence of 5.5 per 100,000 live births.¹⁰ Ben Turkia H et al. in 2009 surveyed MPS epidemiology with the estimation of a combined MPS majority in Tunisia, and the result revealed 2.3 per 100,000 live births.¹¹ Despite this, the worldwide studies regarding MPS epidemiology were insufficient; the overall birth prevalence of MPS in Portugal, Brazil, the USA, Malaysia, etc., was calculated.¹²

The reported epidemiological surveys are expected to be underestimated; this is attributed to insufficient data regarding the diagnosis of rare diseases.¹³ Therefore, further epidemiological studies regarding the prevalence of different MPS types become essential to estimate both the individual and overall influence of LSDs on patients, their families and the public and decide which therapeutic approach should be commenced to improve the outcomes prior to irreversible impairment effectively ensues. Furthermore, these data will be necessary to accurately assess the cost of these illnesses to community health care organizations, and they will serve as the basis for establishing screening and therapeutic programs.¹⁴

This study was designed to calculate the individual and overall birth prevalence of mucopolysaccharidosis in Iraq and the frequencies of each type. In the discussion, we compare the outcomes with described epidemiological statistics from other Arabian countries.

Methods

Patient recruitment and data extraction

Two types of data were obtained. Firstly, the live births between 2010 and 2020 were obtained from the central registry of the Ministry of Health. The data were obtained as pdf file after direct visit to Ministry of Health, Environment of Iraq. Secondly, from July to October 2022, information was collected and investigated from populations diagnosed with MPS in five metabolic centers (there are only five metabolic centers available in Iraq), listed below, in Iraq, as seen in Figure 1.

• 1. Child’s Central Teaching Hospital/Metabolic diseases unit/Baghdad governorate.

• 2. Al-Kadhimiya Teaching Hospital/Metabolic diseases unit/Baghdad governorate.

• 3. Medical City/Pediatric Teaching Hospital/Baghdad governorate.

• 4. Faiha Specialized Diabetes, Endocrine, and Metabolism Center (FDEMC)/Basra governorate.

• 5. Raparin Children’s Hospital/Erbil governorate.

Figure 1. Enrollment process.

The patients were identified from their patient files at the five centers, and asked to participate in this research during their weekly hospital visits to get ERT supplements. Written informed consent to allow their data records to be used in this research was obtained from the patients. For patients that were minors, parental consent was obtained during these visits. Approval to access the patient records was approved by each center.

Results

Live births documented in the Iraqi’s annual statistic report organized by the Ministry of Health from 2010 until 2020 totaled 12,319,467. In the past decade, we found 367 patients (more than half of them were males and aged older than 10 years as presented in Table 1) diagnosed with MPS I, II, III, IV, and VI, and no individuals have been diagnosed with MPS VII or IX. From our data, the overall birth prevalence of MPS is 2.97 per 100,000 live births; data on the birth prevalence rates are summarized in Table 2. Data regarding different MPS type frequencies are illustrated in Figure 2.

Figure 2. Frequencies of MPS types among the Iraqi population.

Discussion

The overall birth prevalence of MPS in the Iraqi population (2.97 per 100,000 live births), when compared with the birth prevalence of other Arabian countries, such as the UAE (5.5 per 100,000 live births) and Saudi Arabia (15.64 per 100,000 live births), was lower.⁹ However, it is similar to the birth prevalence in Tunisia (2.3 per 100,000 live births).¹⁷ The fact that there are only five specialized metabolic centers for diagnosis and registration of MPS cases in Iraq significantly facilitates data collection for this study; hence, we are highly confident (Poisson Confidence Interval 95%) that only a few instances might be undiagnosed. This could be attributed to several causes, including poor health awareness regarding implementation of newborn screening program, particularly for affected families, even after the first birthed child was diagnosed with MPS, unavailability of specialized centers that perform molecular analysis for diagnosis of suspected cases with an inborn error of metabolism. Therefore, several MPS cases might be undiagnosed.

Additionally, the poor financial status of most affected families may contribute to the underestimation of MPS cases, despite ERT and Diagnostic test presented as free medical services from government, most of poor families refuse to receive these services because they don’t have enough money for transportation and therefore neglect the diagnoses of other children who are recently born to MPS affected families. This fact was identified through phone communication with these families. Various types of MPS show different frequencies. In the Iraqi population, MPS VI was the most frequently reported type (1.32 per 100,000 live births, representing 44.41% of all MPS cases), followed by MPS IV A and MPS I (0.625 and 0.593 per 100,000 live births, respectively). The higher frequency rate of MPS VI among other MPS types was also reported in neighboring countries, including UAE and Saudi Arabia, which were 2.51 and 8.0 per 100,000 live births, respectively.^9,10 Obviously, this could be attributed to the regional effect of similar variants or the high consanguinity rate, which increases the frequency of diseased allele transmission,¹⁸ which could be in accordance with the Iraqi situation. Typically, the correlation between consanguinity and homozygosity should be confirmed by genotyping, but molecular studies are still not available as a diagnostic tool in the Iraqi public health system. It is worth mentioning that the most prevalent type of MPS reported in almost all published studies was MPS III. Poorthuis et al. (1990) said that MPS II was more prevalent; this variation could be attributed to differences in ethnicity and geographical origin. In this study, it is imperative to mention the two children who are females affected by hunter MPS (type II), which attributed to skewed X-chromosomal inactivation and Iduronidase (IDS) de novo mutations, these two cases should receive genetic counseling with regard to their reproductive decisions.¹⁹

A limitation of our study is that there are no specialized laboratories to perform genetic analysis for confirmation of MPS diagnosis; thus, some cases may be missing, particularly mild cases that are difficult to diagnose. As a result, while providing comprehensive data on the epidemiological profile of MPS in Iraq, the total numbers obtained in this study may be underestimated. In addition, access to data at the registration centers was also challenging and time-consuming. This is due to the privacy of data recorded in these centers and the distant regions where the centers are located.

Conclusion

In conclusion, data obtained in this prevalence studies should be highly considered by the health system, including health care specialists, clinical genetics, and workers in laboratories involved in MPS diagnosis. Such information is essential for decision-makers to estimate the disease’s genetic and social burden to the public. Increasing awareness among affected families for early diagnoses, such as newborn screening programs for a new birth family member, may be needed. Estimating prevalence rates is essential and required for calculating the financial burden of therapeutic approaches for stabilizing MPS disorders like ERT.