MPS IVa and MPS VI in Saudi Arabia

MPS IVa and VI represent significant health challenges in Saudi Arabia for affected individuals, their families, and the wider healthcare system. Both conditions have a diverse phenotypic spectrum and are associated with significant debilitation and impairment [10, 24]. Moreover, the landscape of MPS in Saudi Arabia is nuanced, with unique challenges that warrant specific considerations.

Screening and diagnosis of MPS IVa and VI

Clinical presentations of MPS IVa and VI are heterogenous with non-specific, multisystemic symptoms that can vary in severity among patients [10, 16,17,18,19]. Patients may present with an attenuated phenotype, characterized by residual enzyme activity and slower disease progression compared with classical MPS IVa and VI phenotypes [4, 9, 18]. This variability coupled with inadequate disease awareness frequently hinders timely diagnosis, which is especially critical in cases of rapidly progressing skeletal dysplasia [4, 24]. Early recognition and treatment initiation can improve patient quality of life by delaying the development of irreversible pathologies [24, 33]. Additionally, many typical features of MPS IVa and VI are shared among other MPS subtypes, other LSDs such as multiple sulfatase deficiency, mucolipidosis, Fabry disease, hereditary skeletal dysplasias, and some metabolic and connective tissue disorders [19, 24, 46,47,48]. Accurate diagnosis is therefore essential to ensure that patients receive appropriate care and disease-specific treatment [24].

Biochemical diagnostic approaches for MPS encompass urine testing and enzyme activity analysis. Urine tests allow for non-invasive assessment of abnormalities in GAG excretion. The accumulation of GAGs is a hallmark of MPS, and urine testing can provide a useful initial indication, guiding further diagnostic evaluation. However, urine testing in isolation is insufficient to establish a diagnosis, and in cases of clinical suspicion of MPS IVa, it is strongly recommended to proceed to enzyme activity analysis even if urinary GAG levels appear normal [25, 49]. Enzyme activity analysis is a vital diagnostic approach that involves assessing the activity of specific enzymes, such as GALNS for suspected MPS IVa and ARSB for suspected MPS VI [24, 25, 49]. Reduced enzyme activity in leukocytes or cultured fibroblasts are key diagnostic markers for these disorders. Enzyme activity assays can help confirm a diagnosis and distinguish between different MPS subtypes as well as other disorders, providing critical insights to guide management decisions. Fluorometric techniques are most commonly used for enzyme assays, though recent LC-MS/MS technologies allow for more precise and sensitive quantification of enzyme levels [4, 27, 50].

Molecular genetic analysis can be used as a confirmatory diagnostic approach when a pathogenic variant is present on each allele of GALNS or ARSB for MPS IVa and VI, respectively. A large number of pathogenic mutations in these genes have been characterized, including missense and nonsense mutations, rearrangements, insertions, and deletions [25, 49, 51, 52]. Molecular analysis can be conducted using leukocytes from whole blood and DNA from saliva samples, and can facilitate phenotype prediction, carrier testing, prenatal testing, and genetic counseling [24, 46, 53]. Specific mutations have been demonstrated to correlate with residual enzyme activity in MPS IVa and this can be used to predict clinical severity [4, 51, 54,55,56,57]. Molecular genetic analysis can also be used to discriminate between pseudodeficiency, carrier status, and normal status in cases wherein there is low enzyme activity and normal urinary GAG levels [58]. Molecular analysis is a precise and essential component of the diagnostic process for MPS IVa and MPS VI, enabling appropriate care and management for affected individuals when considered together with clinical and biochemical findings. However, molecular analysis is generally more costly than other diagnostic tests and may uncover novel variants of unknown significance.

DBS-based assays allow for multiple enzyme activity tests as well as molecular analysis and offer several logistical advantages in terms of sample collection, storage, and transport [24]. While these assays are generally sensitive and specific if performed with appropriate controls, they are insufficient to confirm a diagnosis of MPS IVa or VI in isolation due to the limited number of cells present in the sample and the risk of a false positive result due to sample degradation [46, 49]. Confirming results obtained from DBS assays via enzyme activity analysis in other tissues and/or molecular analysis is strongly recommended. Furthermore, a combination of clinical findings and biochemical/molecular genetic test results is crucial to ensure an accurate diagnosis in all cases of suspected MPS IVa and VI.

In Saudi Arabia, there is a significant disparity in access to specialized laboratory tests. Urinary GAG assays and enzyme activity tests are unavailable in remote areas where some centers lack necessary laboratory facilities, trained personnel, or logistical capabilities for send-out testing. These tests are mostly available in established tertiary centers as send-out tests. The shortage of specialized staff in some regions represents another challenge in carrying out critical laboratory tests and interpreting results accurately. Therefore, there is an urgent need to improve the accessibility and availability of biochemical diagnostic and monitoring tests for MPS IVa and VI across treatment centers in Saudi Arabia. Furthermore, there was a consensus among the expert voting panel that molecular testing should be made available to all individuals with suspected MPS IVa and VI to identify the causative pathogenic variant. This should be coupled with genetic counseling, which should also be available and easily accessible.

Premarital screening

The expert panel highlighted that premarital screening initiatives should be reinforced among select families with a history of MPS IVa and/or MPS VI in Saudi Arabia. This proactive approach to primary prevention can have a profound impact on reducing the occurrence of these rare genetic disorders within affected communities. Premarital screening allows prospective couples to assess their genetic compatibility and the risk of passing on these inheritable conditions to their offspring. By identifying carriers of MPS IVa and MPS VI, individuals can make informed decisions regarding family planning, consider genetic counseling, and explore options such as prenatal testing or assisted reproductive technologies if appropriate [22]. Premarital screening initiatives can empower families with essential genetic information and contribute to the prevention and management of MPS IVa and VI.

Newborn screening for MPS IVa and MPS VI

Newborn screening has the potential to transform the landscape of MPS detection in Saudi Arabia. Establishing a correct diagnosis for MPS IVa and VI usually takes several years [46]. In most cases of MPS, patients are asymptomatic at birth and subsequently experience the onset of clinical symptoms [50]. Moreover, patient outcomes for some MPS subtypes are significantly improved with early detection and timely intervention prior to the development of irreversible pathologies and debilitating manifestations [53, 59]. It is therefore recommended that pilot newborn screening initiatives are implemented in Saudi Arabia to assess impacts on long-term outcomes of MPS IVa, MPS VI, and other LSDs. It has been demonstrated that novel LC-MS/MS methods are more precise than traditional fluorometric assays and can support multiplex newborn screening [27]. Additionally, LC-MS/MS can be integrated with DBS testing for newborn screening [46]. DBS represents the preferred sample for this purpose as it offers several logistical advantages [60].

Raising awareness of MPS IVa and VI

There was a consensus among the expert voting panel that there is a need to raise awareness of different LSDs, including MPS IVa and VI, among healthcare professionals across various subspecialties in Saudi Arabia. Improving awareness can raise clinical suspicion of these conditions when appropriate, potentially allowing for the detection of cases that would otherwise be undiagnosed [22]. Establishing clinical suspicion when appropriate is critical, as initial signs and symptoms may vary among patients and the presence or absence of any particular feature is insufficient to confirm or rule out MPS [61]. Patients may initially be seen by family physicians in primary healthcare, surgeons, or ear, nose and throat (ENT), pediatric, orthopedic, ophthalmologic, cardiac, or rheumatologic specialists, who may not have familiarity with MPS presentations, particularly attenuated phenotypes [24, 49, 62]. Increased awareness of MPS among these specialties is required to facilitate timely referral to a clinical geneticist or metabolic specialist. Potential initiatives to improve awareness of different LSDs include conducting periodic lectures and workshops, disseminating educational material to medical staff, and promoting bilateral communication between different subspecialties [22].

Furthermore, there are sociocultural issues associated with rare, inherited diseases in Saudi Arabia. Patients and families often face stigmatization and isolation, and this can lead to denial and non-disclosure of these diseases. These sociocultural challenges can also have a negative impact on treatment adherence and psychological well-being [22]. To combat these issues, the expert panel recommends that community-based initiatives are conducted, such as general awareness campaigns with specific messaging, and the provision of tailored education and psychological support for patients and their families.

ERT for MPS IVa and MPS VI

Early intervention is key to optimizing treatment outcomes in MPS IVa and VI [10, 17, 28, 33, 53]. As such, it is recommended that treatment is initiated immediately after confirmation of a diagnosis and family counseling to discuss treatment options and expected outcomes. This recommendation is in alignment with international guidelines for the management of MPS IVa and VI [28, 63]. ERT with elosulfase alfa, a recombinant form of GALNS, is the primary disease-specific treatment option for MPS IVa. The aim of treatment with elosulfase alfa is to prevent lysosomal accumulation of keratan sulfate and chondroitin-6-sulfate and thus prevent disease manifestations. In a phase III, randomized, placebo-controlled study of the efficacy and safety of elosulfase alfa for MPS IVa, patients who received 2.0 mg/kg/week over 24 weeks experienced reductions in urinary GAGs and improvements in endurance related to enhanced respiratory function [64]. Other studies have demonstrated minor benefits in some other domains such as daily activities and motor skills [65,66,67]. These findings are indicative of partial recovery of functionality following treatment with elosulfase alfa for MPS IVa [63]. Elosulfase alfa also demonstrates an acceptable safety profile [68]. While HSCT may be a viable treatment option for select patients with MPS, it is thought to be ineffective in MPS IVa [35, 36]. As per a survey conducted among members of the expert voting panel, the majority of respondents “strongly agreed” with the statement “HSCT is ineffective in MPS IVa and is not recommended for these patients” (Fig. 1) [22].

Fig. 1

Level of agreement with the statement “HSCT is ineffective in MPS IVa and is not recommended for these patients” as per a panel of consultant geneticists in Saudi Arabia (number of respondents = 6) [22] HSCT, hematopoietic stem cell transplantation; MPS, mucopolysaccharidoses

Figure 1: Perceptions of effectiveness of HSCT in treating MPS IVa among the expert panel.

In addition to HSCT, ERT with galsulfase is the primary disease-specific treatment option for MPS VI. Treatment with galsulfase, a recombinant form of ARSB, aims to prevent lysosomal accumulation of dermatan sulfate and chondroitin-4-sulfate and thus prevent MPS VI disease manifestations [28]. Several studies have demonstrated reduced urinary GAGs and improved endurance and pulmonary function in patients receiving ERT with galsulfase [29, 69,70,71,72]. It is also thought that galsulfase is associated with improved growth and mobility, delayed progression of cardiac abnormalities and bone disease, and improved quality of life in patients with MPS VI [73,74,75,76,77]. It is noteworthy that several adverse safety events have been reported in clinical trials involving galsulfase, including fever, nausea, vomiting, headache, respiratory distress, and infusion-site reactions [28].

ERT outcomes in MPS IVa and VI are significantly improved when treatment is initiated early in life [10, 17, 28, 63]. There was a consensus among the expert panel that ERT (elosulfase alfa for MPS IVa and galsulfase for MPS VI) should be accessible to all eligible patients in Saudi Arabia. ERT represents a treatment option in the management of these rare LSDs and can restore partial function, slow the progression of disease manifestations, and improve patient quality of life in MPS IVa and VI [28, 63]. Response to treatment is variable, with less severely affected patients more likely to benefit from ERT. To maximize its benefits, it is crucial that ERT is readily available to all eligible patients across the country. In all cases, treatment plans in MPS IVa and VI should be highly individualized. Informed decision-making should be promoted with extensive patient/family counseling in close consultation with a genetic/metabolic specialist to address the specific needs and clinical profile of each patient. Moreover, it is recommended that formal standards of care for MPS IVa and VI are established in Saudi Arabia, encompassing clear guidelines that specify when ERT is indicated as a viable treatment option and when treatment cessation is warranted [22].

ERT home infusion programs

It is recommended that ERT home infusion programs are established along with clear selection criteria and guidelines to improve adherence among patients and combat sociocultural and logistical challenges [22]. Home infusion programs may enhance patient adherence by reducing the burden of frequent hospital visits and improving self-perceived quality of life [78, 79]. As per local experience, home infusion programs clearly improve adherence, with some patients demonstrating full treatment compliance over a long-term period. Moreover, these initiatives can help address sociocultural issues such as stigma or apprehension related to healthcare facilities, which may discourage individuals from pursuing treatment. By promoting a patient-centric approach and addressing cultural and logistical nuances, ERT home infusion programs can significantly improve treatment adherence and thus enhance clinical outcomes for individuals with MPS IVa and MPS VI in Saudi Arabia. As per a survey conducted among the expert panel, the majority of respondents “strongly agreed” that the provision of ERT home infusion solutions can improve adherence and health outcomes for patients with MPS IVa and MPS VI in the country [22].

Multidisciplinary care approach for MPS IVa and MPS VI

Promoting multidisciplinary care for MPS IVa and VI in Saudi Arabia is crucial to enhance patient quality of life and overall outcomes. The utilization of multidisciplinary care teams that encompass metabolic specialists, surgeons, nurses, physiotherapists, occupational therapists, psychologists, audiologists, and speech pathologists can significantly alleviate the burden of these diseases on individuals and on the healthcare system via improved health outcomes and optimized resourcing. To address the multisystemic manifestations of MPS IVa and VI, care teams should also engage pulmonology, dental, orthopedic, pediatric, ENT, ophthalmology, cardiology, anesthesiology, and neurology specialists as required [22]. Patients should also have access to extensive psychological support and education to address issues such as stigmatization and isolation as part of a comprehensive care approach for MPS IVa and MPS VI in Saudi Arabia. Adopting a holistic, patient-centric approach goes beyond addressing the medical aspects of MPS IVa and MPS VI and encompasses the broader spectrum of physical, psychological, and social needs of affected individuals [28, 63]. An integrated model of care can be instrumental in minimizing complications by addressing multisystemic manifestations and improving psychological well-being and quality of life for patients [17]. This recommendation is in alignment with recognized international management guidelines for MPS IVa and VI [17, 28,