Deficiency of alpha-L-iduronidase can result in a wide range of multisystem involvement. Hurler and Scheie syndromes represent phenotypes at the severe and mild ends of the MPS-I clinical spectrum, respectively, and the Hurler-Scheie syndrome is an intermediate phenotype (McKusick, 1972). Patients of Hurler type usually have early manifestations of umbilical or inguinal hernia, frequent upper respiratory tract infections before the age of 1 year. Progressive coarsening of facial features, skeletal deformities, intellectual disability, cardiorespiratory involvement, hepato-splenomegaly, hearing loss, corneal clouding and visual impairment are observed as they grow. Death commonly occurs due to cardiorespiratory failure within the first ten years of life. Patients with Hurler-Scheie syndrome / Scheie syndrome have an onset between three to ten years with variable severity ranging from death at the second to third decade or a normal life span with progressive manifestations. Psychomotor development can be normal in early childhood but it may deteriorate later in life (Clarke, 2002, Viskochil et al., 2019, van den Broek et al., 2020).
Parental consanguinity was found in 68.9% of the current studied cases. Fateen et al. (2021) reported a higher rate of parental consanguinity (82.5%) among the diagnosed Egyptian cases of MPS-I. The difference could be related to the larger size and duration of that study. However, both studies revealed the role of the relatively high consanguinity rate in the Egyptian society (Temtamy and Aglan, 2012).
The patients in this study represented all manifestations of MPS-I. Hurler and Hurler-Schei were more common than Schei syndrome, in consistence with Fateen et al. (2014). Corneal opacity was the most common ocular abnormality in our patients followed by glaucoma, papilledema, pale optic disc then cataract as GAGs deposition can involve the cornea, sclera, trabecular meshwork, retina and optic nerve even in attenuated phenotypes of MPS-I (Del Longo et al., 2018). GAGs deposits occur first in the tympanic membrane, then in the inner ear (Gökdoğan et al., 2016), conductive hearing loss was more common than neurosensorial or mixed type in our patients.
Bay et al. (2021) reported that after the first two years of nearly average mental development, a fast-cognitive deterioration occurs; approximately 20 IQ points and 9 IQ points are lost per year in the severe MPS-I form and attenuated form, respectively. This is due to the neurotoxic effect of deposited heparan sulfate which induces ectopic dendritogenesis and abnormal synaptogenesis. In our study, Vineland scale revealed an IQ score between 40 and 68 in Hurler patients and 64 and 90 in patients with the attenuated type. Mentality was more deteriorated in Hurler patients and the late presenting older patients of the attenuated type in accordance with previous studies (Aldenhoven et al., 2015).
A study of the basic characteristics of body height in MPS-I patients revealed that the growth pattern could be faster than average until 24 months then it drops below the 3rd percentile at 30 months for the severe type (Różdżyńska-Świątkowska et al., 2015). Regarding our patients and regardless of the type, short stature was more frequent in patients who presented at an older age in agreement with a previous study conducted by Laraway et al. (2016). Follow up of height SDS of our patients during ERT revealed a decrease in the mean from − 2.72 to -2.99 in severe patients and from − 2.21 to -2.73 in intermediate patients. The difference between patients’ ages at initiation of ERT, the irregular ERT intake and associated progressive hip and knee contracture deformities are important factors that can explain the decline in height. Height deterioration was reported by Polgreen et al. (2008) and Hampe et al. (2021) in Hurler patients who were treated by hematopoietic stem cell transplantation. Kakkis et al. (2001) and Sifuentes et al. (2007) reported that ERT had resulted in increased growth velocity (height and weight) in MPS-I pediatric patients, particularly in those who started ERT before the age of puberty. In our study, some weight improvement was noticed in both the severe and attenuated types during ERT. Hampe et al. (2021) reported that the combination of ERT and hematopoietic stem cell transplantation was more effective. The differences emerge the need for larger, age and sex MPS-I specific growth curves to be helpful for the evaluation of long-term outcomes of ERT interventions in agreement with Viskochil et al. (2019).
Four patients with Hurler type in this study have an associated communicating hydrocephalous. Although, they had early surgical intervention, the condition was progressive despite ERT. In a 14-year follow-up study in MPS-I patients, who received ERT, Eisengart et al. (2018) reported a 37% cumulative incidence of communicating hydrocephalus. The pathophysiology of hydrocephalus in MPS patients is complex. CSF dynamic disturbances may be related to impaired CSF absorption, engorgement of the arachnoid granulations by accumulated GAGs, obliteration of the subarachnoid space by GAGs and reduced venous drainage through the skull base due to anatomical abnormalities (Alden et al., 2017).
All our studied patients had different degrees of bone deformities and typical radiology of dysostosis multiplex clarifying the importance of radiological studies in MPS patients. X-ray hands can identify the early phalangeal abnormalities, the bullet-shaped phalanges sign, and could facilitate the early diagnosis (Martins et al., 2018). A limited effect or even no effect of ERT on joint stiffness was reported (Concolino et al., 2018), in our study, no effect was noted too.
Elevated urinary GAGs levels were evident in our patients and were reduced rapidly after initiation of ERT. Clinical study data corroborate that urinary GAG reduction is directly associated with clinical benefit as it accurately reflect tissue GAG storage and predict treatment efficacy (Kakkis & Marsden, 2020).
As GAGs are normal components of cardiac tissue, echocardiographic evaluation of patients with MPS-I is mandatory to detect cardiac abnormalities (Hampe et al., 2020). Cardiovascular system involvement occurs when GAG-laden interstitial cells and collagen deposit in excess in the valvular tissues and myocardium which lead to thickening of such tissues. It ends in valvular heart disease as well as myocardial abnormalities and pulmonary hypertension (Sugiura et al, 2020).
In the present study, mitral valve (with regurgitation rather than stenosis) was the most affected valve followed by aortic regurgitation. Regurgitation in the pulmonary valves, found in 77.4% of patients, was trivial to mild which could be considered as a normal finding in our age group. Myocardial disease in the form of dilatation or hypertrophy was detected in a small percent of our patients with the more severe types of Hurler and Hurler–Scheie. The percentage of valve affection increased with the aforementioned forms of the disease (41.8% and 50%, respectively). In accordance with our results, Martins et al. (2009) mentioned that valvular affection (regurgitation, stenosis, or both) was the most prominent feature in MPS-I. They mentioned that the most common lesion is thickening of the mitral valve with regurgitation or stenosis followed by aortic lesion. Laraway et al. (2016) reported that valvular insufficiency starts early at young age in MPS-I patients. Severe forms of MPS-I presented by hypertrophic rather than dilated cardiomyopathy with reduced ejection fraction and pulmonary hypertension.
ERT reduces lysosomal GAGs storage which results in some clinical improvement. However, it might be difficult to prevent the progression of pre-existing cardiac disease due to irreversible changes in heart valves and chordae tendinae (Sugiura et al, 2020). Follow-up after one year of ERT revealed a stationary course for most of our patients with non-significant differences in all measured echocardiographic parameters. In a study by Laraway et al. (2016) valvular functions remained stable in 65% of treated patients, deteriorated in 32% and improved in 3% of patients. Moreover, Hampe et al. (2021) confirmed that ERT had no significant effect on cardiac valve thickening. They noticed valvular function deterioration in children aged more than 10 years at the time of ERT initiation. Lin et al. (2018) suggested that better results may be associated with starting ERT at a younger age. ERT stabilization of valvular disease, over a limited study period, has been observed in several studies (Braunlin et al. 2006, Fesslova et al. 2009, Okuyama et al. 2010, Boffi et al., 2018).
Concerning the ventricular function, several studies have shown resolution of ventricular hypertrophy in adults and children with MPS-I with preserving or even improving the systolic ventricular function after long term ERT (Braunlin et al. 2006, Okuyama et al. 2010). Congestive heart failure is one of the common causes of death in these patients, especially the severe type of MPS-I (Braunlin et al., 2018); in our study one patient was on anti-failure measures before he started ERT and died after uncontrolled heart failure following chest infection.
Respiratory problems are frequent in MPS patients and cause premature mortality in individuals with the disease (Cantú-Reyna et al., 2023). Few published reports on the prevalence and severity of pulmonary dysfunction in MPS are present. Standard normal values for spirometry cannot be applied in MPS patients due to the disease induced growth impairment and expressing VC as a % of normal is of limited value (Swiedler et al 2005, Hampe et al., 2021) and spirometry may not be possible in children who are very young to cooperate and in patients with cognitive impairment (Lin et al, 2014). However, spirometry has been commonly recommended for screening, to determine disease progression and assess response to therapy (Harmatz et al, 2010, Muhlebach et al, 2011). PFT results were expressed as the percentage of predicted values based on spirometry reference equations that takes into account, age, height and gender (Miller et al, 2005).
Despite limitations encountered because of poor cooperation and capability to follow instructions to perform spirometry, our results report a high prevalence of restrictive (61.1%) and obstructive lung disease (20%) among MPS-I patients and demonstrated improved pulmonary functions after enzyme replacement. Our findings are in accordance with previous studies showing that restrictive lung disease is common in MPS patients with severe skeletal involvement including MPS-I (Lin et al, 2010, Muhlebach et al, 2011, Lin et al, 2014).
Obstructive airway diseases were less common (20%) in our patients. Few published reports on the prevalence of obstructive lung disease in MPS are present. Lin et al. (2014) referred this to the paucity of literature reporting the occurrence of small airway disease in these patients; as FEF25–75% may be a more sensitive parameter than FEV1 to detect obstructive small airway disease (Simon et al, 2010). In our study the mean value of FEF25–75% was normal in more than 65% in the studied population.
Follow up spirometry in 5 MPS-I patients treated with ERT demonstrated improvement of all parameters of pulmonary functions. Although the duration of ERT in our cases was shorter compared to other studies; our findings were consistent with previous studies that demonstrated improvement of PFT after ERT (Lin et al, 2005, Wraith et al, 2008, Clarke et al, 2009, Harmatz et al, 2010, Rodriguez et al, 2010, Lin et al, 2011, Muenzer et al, 2011, Muenzer et al, 2017, Hendriksz et al, 2011, Parini et al, 2015, Concolino et al., 2018). Studies attributed the improved pulmonary function in MPS patients receiving ERT to reduced glycosaminoglycan storage in the airways and increased chest wall compliance, respiratory muscle strength and endurance, and diaphragmatic excursion (Swiedler et al 2005; Harmatz et al 2010).
Abdominal ultrasound results showed that hepatosplenomegaly was more common in Hurler syndrome. Follow up of hepatosplenomegaly after ERT, revealed a statistically significant reduction in hepatic and splenic size. These results are in concordance with other long-term observational studies confirming a progressive reduction of liver and spleen size with a tendency to normalization. (Wraith et al.,2004, Clarke et al.2009, Sifuenteset al., 2007, Wraith et al., 2007, Lin et al., 2019, Dornelleset al., 2014, Concolino et al., 201).
Clarke et al. (2009) had reported that approximately 50% of MPS-I patients treated with laronidase had variable infusion adverse reactions. Additionally, Hampe et al. (2021) documented that up to 90% of patients produced IgG antibodies to laronidase. In the present study, ten patients (26.3%) experienced mild infusion adverse reactions such as fever, rash and high blood pressure that were successfully controlled by interrupting or slowing the rate of infusion and the administration of anti-histaminic, antipyretic and/or corticosteroids. We agree that ERT- pre-medication can effectively prevent severe hypersensitivity reactions. Nan et al. (2020) stated that ERT has an acceptable safety profile.
Patients with MPS-I have reduced life expectancy. Without treatment, patients with the most severe form of the disease have a median survival of 6.8 years (Martins et al., 2009). In our study, seven patients passed away from disease comorbidities mainly due to respiratory infection with mean age at death of 5.83 years. These patients received ERT in an irregular course for an average duration of 8 months. Jurecka et al. (2012) stated that discontinuation of ERT in MPS-I patients may worsen their condition and even lead to their death.
In a large Brazilian study, Giugliani et al. (2021) reported that the age at diagnosis for the severe type of MPS-I was less than 1 year and median time between diagnosis and first treatment was less than 3 months, throughout a 15-years observation period. While for the attenuated type, the age at diagnosis ranged between 4.5 and 6 years while the duration from diagnosis to first ERT was 5.42 years in 2004 then decreased to 2.4 years from 2014–2017. In our study, we experienced the problems of late presentation and diagnosis and the time consuming procedures to get approval for ERT (mean: ≈2 years) thus, leading to delayed ERT initiation (mean: ≈7 years) in addition to irregular interrupted ERT courses due to delay in treatment renewal approvals and difficulties in patient’s transportation from far governorates.
In conclusion, we report our experience with ERT in MPS-I in our center and the challenges faced. ERT is an effective well tolerated treatment in the management of MPS-I patients. Early diagnosis, initiation of ERT and tackling the obstacles regarding drug approval and supply are essential to get better response for our patients. This study provides direction for better future disease management in our country.