Mucopolysaccharidosis 1 is a rare lysosomal storage disease provoked by mutations of the gene encoding for alpha-L-iduronidase, an enzyme required for the breakdown of determined glycosaminoglycans. Depending on the severity of the disease, patients may be diagnosed with Scheie syndrome, Hurler Scheie syndrome or Hurler syndrome.
In general, MPS 1 is a multisystem disorder that follows a progressive course. Although coarse facial features, short stature, skeletal dysplasia reminiscent of dysostosis multiplex, cardiac and respiratory disease as well as corneal clouding are universal, there are considerable differences regarding the clinical presentation of MPS-IS and MPS-IH patients. These especially refer to the involvement of the central nervous system and corresponding deficits. Thus, these entities shall be presented separately.
Clinical presentation is particularly heterogeneous in MPS-IS patients. Median age at symptom onset is 5 years, but due to rather mild symptoms and insufficient awareness of the disease, most patients are not diagnosed with MPS-IS until late adolescence . Joint contractures, cardiac valve abnormalities and corneal clouding are most frequently reported and about half of MPS-IS patients present the complete symptom triad . Further common findings are coarse facial features, carpal tunnel syndrome, umbilical and inguinal hernia, and hepatomegaly. Bone deformities like kyphosis or gibbus, scoliosis, genu valgum, pes cavus have been described and may cause gait disturbances. Sleep disturbances due to respiratory insufficiency may be experienced and patients may claim a hearing loss. Some patients present with macroglossia. Patients may develop myelopathy, but this condition does generally not manifest before puberty. MPS-IS patients are of normal intelligence; the absence of cognitive developmental delays at the age of two years has been proposed as a clinical feature to distinguish MPS-IS from MPS-IH.
Children suffering from MPS-IH develop first symptoms during their first year of life, and the disease is usually confirmed within months afterwards . Affected individuals may present with any of those symptoms listed for MPS-IS. However, disease progression occurs rapidly and additional symptoms manifest early in life. The major difference between MPS-IH and less severe forms of the disease is profound intellectual disability due to neuronal loss, premature closure of cranial sutures, and possibly hydrocephalus and increased intracranial pressure. Developmental delays, hearing loss and macroglossia contribute to severely reduced language acquisition. Coarse facial features are more pronounced than in MPS-IS patients and may be accompanied by facial and body hypertrichosis. Besides corneal clouding, glaucoma and retinopathy may develop and may eventually cause complete vision loss. Of note, visual impairment may also result from central nervous system involvement. Skeletal dysplasia is striking and although neonates may appear healthy, radiographic studies may reveal signs of dysostosis multiplex at birth. Atlantoaxial subluxation and stenosis of the spinal canal are observed in about a third of MPS-IH patients and results in spinal cord compression and early cervical myelopathy . Vertebral hypoplasia may be observed along the spinal column.
Most patients suffering from MPS 1 have a family history of complaints consistent with this disease. Even if such data are not available, findings of general, ophthalmological and neurological examination, as well as radiographic studies, may prompt a strong suspicion of mucopolysaccharidosis. Clinical features of distinct types of mucopolysaccharidosis may overlap, though, and a target-oriented workup is necessary. The assessment of glycosaminoglycan excretion in urine is helpful to diagnose and distinguish related entities. Qualitative and quantitative analyses should be performed; MPS 1 patients typically excrete excess dermatan and heparan sulfate. However, this approach has limited sensitivity and it is strongly recommended to either determine IDUA activity or to employ molecular biological techniques to demonstrate gene defects consistent with MPS 1. With regards to the former, IDUA activity may be evaluated in leukocytes, dried blood spots or fibroblasts. Recently, a modified IDUA assay has been described that allows for the precise quantification of residual IDUA activity, and such results may enable the physician to predict the course of the disease .
Enzyme replacement therapy and hematopoietic stem cell transplantation are the mainstays of treatment of attenuated MPS 1 and MPS-IH, respectively. Hematopoietic stem cell transplantation has been shown to improve the neurological outcome and to increase survival times in patients suffering from the most severe form of the disease. Nevertheless, long-term follow-ups revealed disease progression years after the successful realization of this procedure . Stem cell transplantation should be performed as early as possible, ideally in infants aged less than four months. Due to morbidity and mortality associated with this therapeutic measure, it is currently not recommended for MPS-IHS and MPS-IS patients. Enzyme replacement therapy consists of weekly administration of 100 U/kg recombinant IDUA (laronidase; Aldurazyme®) per kg body weight; this compound has obtained approval for MPS 1 treatment in 2003 . Patients should be prepared for intravenous laronidase application with antihistamines and/or antipyretics that are to be administered one hour prior to treatment with recombinant IDUA. Of note, laronidase is also given to patients diagnosed with MPS-IH after stem cell transplantation. Although the compound does not cross the blood-brain barrier and thus cannot prevent glycosaminoglycan accumulation within the central nervous system, it is likely to have a positive effect on the patient's quality of life .
In any case, supportive care should be provided to MPS 1 patients. It should be adjusted to the individual needs of the affected person and may comprise physiotherapy, orthopedic measures, provision of hearing aids, analgesia, prophylactic administration of antibiotics, supplementation of oxygen, and psychological support. Surgical interventions may become necessary to remedy joint contractures, skeletal deformities, cardiac valve insufficiency or stenosis, spinal cord compression, and other pathological conditions. A multidisciplinary team is required to support the patient and their family, and this team should be consulted in regular follow-ups. Periodic performance of pulmonary function tests, echocardiography, and neurological evaluation, among others, are of major importance to estimate disease progression and the patient's risk of complications.
As has been indicated above, only confirmation of nonsense mutations on both alleles allows for the prediction of a patient’s phenotype from their genotype. If so, the patient is likely to develop MPS-IH. Otherwise, the heterogeneity of underlying phenotypes has not yet allowed for establishing unequivocal genotype-phenotype correlation . In contrast, residual activity of IDUA directly correlates with the outcome. Quantification of low IDUA activity requires a very sensitive assay, but has been achieved: Dutch researchers have proven MPS-IS patients to show residual IDUA activity of 0.8% of control values, while MPS-IHS and MPS-IH were associated with a residual activity of 0.3% and <0.2%, respectively . Still, more extensive studies on this subject are required to provide general reference ranges.
Patients suffering from MPS-IS may have a near-to-normal life expectancy, but the disease is still associated with considerable morbidity. Individuals affected by MPS-IHS often die in early adulthood. To date, the prognosis of MPS-IH patients is poor. Most patients die within their first decade of life from respiratory or heart failure. Hematopoietic stem cell transplantation is the treatment of choice, and if performed at a very young age when cognitive function is not yet impaired, this therapy may improve survival and neurodevelopment .
All forms of MPS 1 are caused by mutations in the IDUA gene. This gene is located on the short arm of chromosome 4 and encompasses approximately 18 kb, which include 14 exons that are assembled to a 653-amino acid precursor protein. To date, more than 200 distinct mutations have been described in MPS 1 patients . The majority of known sequence anomalies corresponds to missense mutations, while nonsense mutations and gene variants leading to alternative splicing, deletions and insertions account for minor shares of MPS 1-related defects . Genotype-phenotype correlations have been established insofar as nonsense mutations generally trigger MPS-IH; affected patients carry such mutations on both alleles and are unable to synthesize functional IDUA. In contrast, residual activity of IDUA may be detected in patients with missense mutations of the respective gene, and it may attenuate the severity of the disease. In this context, only trace amounts of functional IDUA are encountered in MPS-IHS patients, while enzymatic activity is maintained to a greater degree in MPS-IS patients. According to the current knowledge, enzymatic activity as assessed in an individual patient determines the course of the disease. Moreover, modifying factors have not been identified so far; all forms of the disease are inherited as an autosomal recessive trait.
The overall incidence of MPS 1 has been estimated to 1 in 100,000 live births . About 61% of affected neonates develop MPS-IH, while MPS-IHS and MPS-IS account for 23% and 13% of all cases, respectively. In the cited study, the remainder of cases was classified as undetermined. While Caucasians were overrepresented in the MPS 1 Registry, this may be due to most study participants being Europeans or North Americans. A literature review reveals that people of all races and both genders may be affected by the disease.
IDUA is a lysosomal enzyme catalyzing the hydrolytic cleavage of dermatan sulfate and heparan sulfate. In MPS 1 patients, IDUA activity is severely reduced and thus, glycosaminoglycans accumulate in lysosomes. This condition initially disturbs lysosomal function, but the progressive enlargement of these cell organelles eventually has detrimental consequences for the whole cell and the tissue it forms part of. Furthermore, glycosaminoglycans may alter gene expression and thus affect the composition of the extracellular matrix. Recent studies have shown such pathophysiological events to be involved in MPS 1-associated cartilage and bone damage , but it is tempting to speculate that these mechanisms also contribute to lesions of other organs. In fact, inappropriate accumulation of dermatan sulfate and heparan sulfate is mainly observed in connective tissue and the wide distribution of connective tissue in the human body explains why affected individuals develop multisystem sequelae.
Affected families may benefit from genetic counseling. Furthermore, chorionic villus sampling and amniocentesis allow obtaining specimens suitable for enzyme activity assessment and genetic screens. Thus, prenatal diagnosis of MPS 1 is feasible. In the case of positive results, parents-to-be may be offered the possibility of a premature termination of pregnancy. Neonates born to families with a history of MPS 1 should be tested as early as possible. This way, treatment may be initialized before irreversible organ damage occurs. This is of particular importance for individuals suffering from MPS-IH since this disease requires hematopoietic stem cell transplantation within the first months of life. With regards to milder forms of the disease, pediatricians are encouraged to realize regular examinations, to monitor development and growth, and to refer their patients to specialists if doubts arise.
Mucopolysaccharidosis 1, also referred to as MPS 1, is a lysosomal storage disease. MPS 1 is inherited as an autosomal recessive trait and is triggered by distinct mutations of the gene encoding for the enzyme α-L-iduronidase (IDUA). This enzyme is expressed in lysosomes and catalyzes the breakdown of determined glycosaminoglycans, namely of dermatan sulfate and heparan sulfate. In MPS 1 patients, a functional deficiency of α-L-iduronidase results in the progressive accumulation of glycosaminoglycans in lysosomes, and this condition eventually interferes with cellular, tissue and organ functions. Because this entity affects virtually all organ systems, affected individuals may present complex and heterogeneous symptoms. Depending on the severity of the disease, the following forms of MPS 1 may be distinguished:
Of note, MPS-IS and MPS-IHS correspond to attenuated MPS 1.
Mucopolysaccharidosis 1 (MPS 1) is a rare genetic disorder. It is provoked by mutations of the gene encoding for the enzyme α-L-iduronidase (IDUA), and this enzyme is required for the breakdown of determined glycosaminoglycans, namely of dermatan sulfate and heparan sulfate. These may be encountered in virtually any tissue and because MPS 1 patients are unable to synthesize functional IDUA, these molecules accumulate within cell organelles called lysosomes. In fact, MPS 1 is commonly classified as a lysosomal storage disease. Eventually, build up of glycosaminoglycans interferes with cellular, tissue and organ function. This leads to complex and heterogeneous symptoms, and MPS 1 patients may present with coarse facial features, short stature, skeletal dysplasia, cardiac and respiratory disease as well as corneal clouding. Those suffering from the most severe form of the disease, which may be referred to as Hurler syndrome, also show developmental delays and intellectual disability.
Hematopoietic stem cell transplantation in early infancy is recommended to patients diagnosed with Hurler syndrome, and these individuals may subsequently receive recombinant IDUA. The latter replaces the defective enzyme and thus allows for partial degradation of glycosaminoglycans. Thereby, the patient's quality of life is improved. Unfortunately, there is no cure for MPS 1 and while mild forms of the disease are associated with a near-to-normal life span, they are also related to significant morbidity. Patients diagnosed with Hurler syndrome may live to their twenties if hematopoietic stem cell transplantation is performed early and successfully.