Mucopolysaccharidosis Type I

Severe MPS I (Hurler Syndrome)

Severe MPS I is characterized by a chronic and progressive disease course involving multiple organs and tissues [reviewed in Clarke 1997, Neufeld & Muenzer 2001, Muenzer et al 2009]. Infants with severe MPS I appear normal at birth but may have inguinal or umbilical hernias. The mean age of diagnosis for severe MPS I is approximately nine months; most affected children are diagnosed before age 18 months. Death, caused by cardiorespiratory failure, usually occurs within the first ten years of life.

Craniofacial and physical appearance. Coarsening of the facial features, caused by storage of GAGs in the soft tissues of the orofacial region and facial bone dysostosis, becomes apparent within the first two years. Thickening of the alae nasi, lips, ear lobules, and tongue becomes progressively more evident. Thickening of the calvarium results in macrocephaly. Scaphocephaly is common. Facial and body hypertrichosis are often seen by age 24 months, at which time the scalp hair is coarse, straight, and thatch-like.

Hepatosplenomegaly. Protuberance of the abdomen caused by progressive hepatosplenomegaly is common [Clarke 1997]. Although organ size may be massive, storage of glycosaminoglycans in the liver and spleen does not lead to organ dysfunction.

Skeletal. Progressive skeletal dysplasia (dysostosis multiplex) involving all bones is seen in all individuals with severe MPS I. Children have significant early bone involvement. Mild dysostosis, particularly of the hip, as well as thickening of the ribs, can be detected on radiographs at birth. Gibbus deformity (dorsolumbar kyphosis) often becomes clinically apparent within the first 14 months; it has been reported as early as age six months [Mundada & D'Souza 2009].

By age three years linear growth decreases. Defective ossification centers of the vertebral bodies lead to flattened and beaked vertebrae and subsequent spinal deformity. Complications may include spinal nerve entrapment, acute spinal injury, and atlanto-occipital instability.

The clavicles are short, thickened, and irregular. Long bones are short with wide shafts; the knees are prone to valgus and varus deformities. Endochondral growth plates are thickened and disordered. Typically, the pelvis is poorly formed. The femoral heads are small and coxa valga is common. Involvement of the femoral heads and acetabula leads to progressive and debilitating hip deformity. Progressive arthropathy leading to severe joint deformity is universal; joint stiffness is common by age two years.

Phalangeal dysostosis and synovial thickening lead to a characteristic claw hand deformity. Carpal tunnel syndrome and interphalangeal joint involvement commonly lead to poor hand function. Carpal tunnel syndrome is often missed because of its insidious onset; it often presents with few symptoms or signs other than thenar atrophy.

Ophthalmologic. Corneal clouding occurs in all individuals with MPS I. Progression can lead to severe visual impairment. Open-angle glaucoma may occur. Retinal degeneration resulting in decreased peripheral vision and night blindness is common. Blindness can result from a combination of retinal degeneration, optic nerve compression and atrophy, and cortical damage.

Cardiovascular. Cardiac involvement is seen in all individuals with severe MPS I. Cardiac involvement is evident by echocardiography much earlier than observed clinically. Progressive thickening and stiffening of the valve leaflets can lead to mitral and aortic regurgitation, which may become hemodynamically significant in the later stages of disease. Mitral valve regurgitation is the more common valvular disease in individuals with severe MPS I [Neufeld & Muenzer 2001]. As lysosomal storage continues in the heart, cardiomyopathy, sudden death from arrhythmia, coronary artery disease, and cardiovascular collapse may occur. A small subset of individuals with severe MPS I have an early-onset fatal endocardiofibroelastosis.

Hearing loss. Hearing loss, which is common in severe MPS I, is correlated to the severity of somatic disease. Hearing loss results from frequent middle-ear infection from eustachian tube dysfunction caused by storage of GAGs within the oro-pharynx, dysostosis of the ossicles of the middle ear, scarring of the tympanic membrane, and damage to the eighth nerve.

ENT (otolaryngologic). Chronic recurrent rhinitis and persistent copious nasal discharge without obvious infection are common. Storage of GAGs within the oro-pharynx with associated enlargement of the tonsils and adenoids can contribute to upper airway complications, along with narrowed trachea, thickened vocal cords, redundant tissue in the upper airway, and an enlarged tongue. This upper-airway involvement leads to noisy breathing, particularly at night, and is a main component of obstructive sleep apnea, a common complication particularly in the later stages of disease. CNS involvement can also contribute to sleep apnea.

The voice may be deep and gravelly.

Gastrointestinal system. Inguinal hernias should be repaired surgically with the expectation that they may recur. Umbilical hernias are generally not treated unless they are exceedingly large and cause problems.

For unknown reasons, many children with severe MPS I periodically experience loose stools and diarrhea, sometimes alternating with periods of severe constipation. These problems may or may not diminish with age; they are exacerbated by muscle weakness and physical inactivity, as well as antibiotic use for other problems [Clarke & MacFarland 2001]. Wegrzyn et al [2005] suggested that atypical gastrointestinal microbial infections may underlie gastrointestinal disturbance in the MPSs. The prevalence of such infections is unknown.

Hydrocephaly. Communicating high-pressure hydrocephalus is common in severe MPS I. Impaired resorption of CSF causes an increase in intracranial pressure, leading to brain compression. Increase in intracranial pressure can cause rapid cognitive decline in some individuals. Symptoms may be difficult to assess and progression insidious. The degree to which hydrocephalus contributes to the neurologic deterioration in children with severe MPS I is unknown.

Intellect. Although early psychomotor development may be normal, developmental delay is usually obvious by age 18 months. A measurable decrease in intellectual capacity occurs monthly thereafter (as graded by the Bayley Mental Development Index) [Krivit et al 1999]. Subsequently, most children do not progress developmentally but plateau for a number of years, followed by a slow decline in intellectual capabilities. By the time of death at age eight to ten years, most children are severely intellectually disabled.

Children with severe MPS I develop only limited language skills, likely related to the triad of developmental delay, chronic hearing loss, and enlarged tongue [Neufeld & Muenzer 2001].

In contrast to MPS II and MPS III, the severe developmental effects in children with MPS I are associated with placid rather than aggressive behavior. Seizures appear to be uncommon even at the end stages of disease [Clarke 1997].

Pathophysiology. Heparan sulphate is found in abundance in the brain as part of the extracellular matrix. Deficiency of α-L-iduronidase (a glycosidase that removes non-reducing terminal α-L-iduronide residues during the lysosomal degradation of the glycosaminoglycans heparan sulphate and dermatan sulphate) results in glycosaminoglycan accumulation in the lysosomes of neurons, leading to secondary accumulation of glycolipids that form zebra bodies through an as-yet-unknown mechanism. The glycosaminoglycan storage and secondary glycolipid storage presumably lead to severe intellectual disability and hydrocephalus.

Attenuated MPS I (Hurler-Scheie Syndrome / Scheie Syndrome)

If development is normal at age 24 months and if moderate somatic involvement is evident, an individual should be classified as having attenuated MPS I. Onset of disease in children with attenuated MPS I is variable, usually occurring between ages three and ten years. The rate of disease progression can range from serious life-threatening complications leading to death in the second to third decades, to a normal life span (albeit with significant disease morbidity). The rarity of MPS I (and specifically attenuated MPS I) leads to difficulty in developing characteristic phenotypic descriptions [Thomas et al 2010].

Although development may be normal in early childhood, children with attenuated MPS I may have detectable learning disabilities. No correlation between the degree of somatic disease and intellectual deficits in attenuated MPS I has been observed [Vijay & Wraith 2005].

Craniofacial and physical appearance. The physical appearance of individuals with attenuated MPS I varies. Coarseness of facial features is less obvious than in severe MPS I. Findings can include a short neck, wide mouth, square jaw, and micrognathia.

Children with attenuated MPS I have variable degrees of growth retardation.

Hepatosplenomegaly. A variable degree of hepatomegaly is seen in individuals with attenuated MPS I.

Skeletal. Skeletal and joint manifestations are the most significant source of disability and discomfort for individuals with attenuated disease, who may have severe bone involvement but no cognitive impairment [Clarke 1997, Vijay & Wraith 2005]. The MPS I Registry showed that more than 85% of persons with attenuated MPS I have dysostosis, primarily in the vertebrae and femur [Thomas et al 2010]. Kyphosis, scoliosis, and severe back pain are common. Spondylolisthesis of the lower spine leading to spinal cord compression can occur.

Progressive arthropathy affecting all joints and eventually leading to loss of or severe restriction in range of motion is universal. Carpel-tunnel syndrome was present at a median age of 13.1 years in approximately 67% of persons with attenuated MPS I included in the MPS I Registry [Thomas et al 2010]. Poor hand function resulting from the characteristic claw hand deformity, carpal tunnel syndrome, and interphalangeal joint stiffness is often observed. Most individuals do not have the characteristic early symptoms of carpal tunnel syndrome (see Management).

More than 90% of persons with attenuated MPS I included in the MPS I Registry had pes cavus, genu valgum, and "toe-walking" [Thomas et al 2010].

Ophthalmologic. Corneal clouding, exhibited by approximately 82% of children with attenuated MPS I, was identified at a median age of 9.1 years [Thomas et al 2010]. Corneal clouding can lead to significant visual disability. Glaucoma, retinal degeneration, and optic atrophy can occur.

Cardiovascular. Cardiac involvement is estimated to occur in approximately 88% of children with attenuated MPS I at a median age of 11.7 years [Thomas et al 2010]. Cardiac involvement can present as progressive disease of the mitral and aortic valves with regurgitation and/or stenosis, for which valve replacement may be necessary. Aortic valvular disease is more likely to occur in children with attenuated MPS I than in those with severe MPS I [Neufeld & Muenzer 2001]; however, in some individuals, all valves are affected. In a group of 78 persons with attenuated MPS I, 40% had involvement of one valve and 60% had involvement of two or more valves [Thomas et al 2010].

Coronary disease may also be a feature of attenuated MPS I.

Hearing loss. Moderate to severe hearing loss develops in many individuals with attenuated MPS I, particularly children with significant somatic disease. Hearing impairment, most commonly in the high frequency range, is likely caused by a combination of eustachian tube dysfunction, dysostosis of the ossicles of the middle ear, and eighth nerve involvement.

ENT (otolaryngologic). Rhinorrhea is common.

Sleep apnea as a result of obstructive airway disease and possibly CNS involvement occurs in attenuated MPS I.

Gastrointestinal system. Hernias were present in approximately 65% of persons with attenuated MPS I included in the MPS I Registry [Thomas et al 2010]. Many have also had inguinal hernias during infancy, often requiring repeated surgical correction.

Respiratory system. Progressive pulmonary disease may manifest as abnormalities of forced vital capacity. Respiratory complications (and cardiac involvement) are one of the leading causes of premature death.

Hydrocephaly. The risk of communicating hydrocephalus and its complications are lower in attenuated MPS I than severe MPS I. However, hydrocephalus may occur with insidious onset.

Other neurologic findings. Arachnoid cysts may develop. The predictive power of changes noted on MRI does not appear to be significant in individuals with attenuated MPS I [Neufeld & Muenzer 2001, Matheus et al 2004].

Progressive compression of the spinal cord with resulting cervical myelopathy caused by thickening of the dura (hypertrophic pachymeningitis cericalis) is common in individuals with attenuated MPS I. Cervical myelopathy may present initially as reduced activity or exercise intolerance and may not be recognized until the injury is irreversible [Neufeld & Muenzer 2001].

Intellect. In attenuated MPS I intellect may be normal or nearly normal. If intellectual abilities decline, the course is more protracted than in individuals with severe disease.

Hematopoietic Stem Cell Transplantation (HSCT)

HSCT is considered standard of care for children with severe MPS I. Outcome from HSCT is significantly influenced by disease burden at the time of diagnosis (and thus, with the age of the patient). Due to the morbidity and mortality associated with HSCT, it is currently recommended primarily for children with severe MPS I.

HSCT should be used only in carefully selected children with extensive pretransplantation clinical assessment and counseling in whom systematic long-term monitoring will be possible [Aldenhoven et al 2015a, Aldenhoven et al 2015b]. Adults have not undergone HSCT.

Pulmonary and cardiac complications in the peri-transplant period appear to be significant predictors of transplant complications [Orchard et al 2010].

In general, the outcome of children undergoing HSCT is varied and depends on the degree of clinical involvement and the child's age at the time of transplantation. It is generally recommended that HSCT be performed before age two years to maximize benefit.

HSCT has been successful in reducing the progression of some findings in children with severe MPS I [Vellodi et al 1997, Guffon et al 1998, Neufeld & Muenzer 2001, Souillet et al 2003, Staba et al 2004, Aldenhoven et al 2015b]. Although the heterogeneity of the disease makes the outcomes of HSCT somewhat difficult to interpret, available data show that:

• Successful HSCT reduces facial coarseness, and hepatosplenomegaly, improves hearing, and maintains normal heart function;
• The skeletal manifestations and corneal clouding continue to progress at the same rate in children treated with HSCT and in untreated children [Weisstein et al 2004, Taylor et al 2008];
• The degree to which HSCT relieves neurologic complications other than progressive intellectual decline is not clear: a few reports suggest improvement [Munoz-Rojas et al 2008, Valayannopoulos et al 2010] whereas others do not [Eisengart et al 2013, Aldenhoven et al 2015b]. In children undergoing HSCT before evidence of significant developmental delay (i.e., usually between ages 12 and 18 months), HSCT appears to slow the course of cognitive decline. Children showing significant cognitive impairment prior to undergoing HSCT do not show correction of existing impairment.

HSCT is not curative and does not ameliorate cardiac valvular or skeletal manifestations.

In individuals predicted to have severe MPS I based on the presence of known severe pathogenic variants, use of HSCT resulted in stabilization and improvement of myocardial function with regression of hypertrophy and normalization of chamber dimensions [Braunlin et al 2003]. In that cohort, HSCT did not appear to show significant effects on the presence and progression of valvular involvement.

In part because of increased longevity after HSCT, treated individuals develop increasing pain and stiffness of the hips and knees, carpal tunnel syndrome, spinal cord compression, and progressive thoracolumbar kyphosis [reviewed in Neufeld & Muenzer 2001]. As a result, various orthopedic procedures intended to maintain function and gait have been performed post-HSCT [Masterson et al 1996, Tandon et al 1996].

Pathophysiology. The beneficial effect of HSCT is thought to result from the replacement of deficient macrophages by marrow-derived donor macrophages (Kupffer cells; pulmonary, splenic, nodal, tonsilar, and peritoneal macrophages; and microglial cells) that constitute an ongoing source of normal enzyme capable of gaining access to the various sites of storage [Guffon et al 1998, Prasad & Kurtzberg 2010]. As existing damage is not reversed, early HSCT is critical for optimal effect.

One hypothesis regarding the failure of HSCT in treating skeletal manifestations is the relatively poor vascularity of bone tissues [Taylor et al 2008].

Enzyme Replacement Therapy (ERT)

Laronidase (Aldurazyme^®) is currently licensed in the US, Europe, and Canada for use in treating non-CNS manifestations of MPS I. The current dose regime involves premedication with an anti-inflammatory and antihistamine drugs and intravenous weekly infusion of 100 U/kg of Aldurazyme^® over four hours. Note that the package insert provides details that may differ by country.

The potential effect of Aldurazyme^® on the progression of somatic findings and (more importantly) the effect that Aldurazyme^® may have when started very early in the treatment of an individual with attenuated disease remain to be answered. The latter is particularly important as early diagnosis is critical. Aldurazyme^® does not cross the blood-brain barrier and thus is not expected to influence the CNS disease in severely affected individuals.

A Phase I open label study included ten individuals with attenuated MPS I treated with human α-L-iduronidase and studied over one year. This study showed improvement in liver size, growth, joint mobility, breathing, and sleep apnea. Increased ability to perform daily functions was reported [Kakkis et al 2001]. A six-year follow up of five of the treated individuals showed sustained improvements in joint range of motion and sleep apnea and no progression of heart disease, but evidence of progression of valvular involvement [Sifuentes et al 2007].

A Phase III double-blind placebo-controlled study included 45 individuals with attenuated MPS I treated for 52 weeks with a 26-week placebo phase [Wraith et al 2005]. This study showed statistically significant improvements in pulmonary function and a six-minute walk test and clear biologic effect with reduction in urinary GAG excretion and liver volume. Patients who had significant sleep apnea at the start of the study improved significantly.

Other case reports representing smaller numbers of treated patients show variable responsiveness to treatment. The heterogeneity of treated patients published to date complicates any conclusions that can be drawn. It appears that the ability of ERT to reverse disease symptoms in individuals with attenuated disease relates closely to the burden of disease prior to commencement of treatment.

All published reports indicate that ERT is well tolerated. Although most individuals treated in either clinical trial developed IgG antibodies, no apparent clinical effects have been reported. These antibodies may, however, hinder therapeutic benefit by promoting more rapid clearance of the enzyme. Follow up of individuals who were part of the Phase I and Phase III studies indicates that immune tolerance is eventually reached [Kakavanos et al 2003, Wraith et al 2005].

A Phase III extension trial included 40 of the individuals from the Phase III trial for an additional four years of treatment [Clarke et al 2009].

• Urinary GAG levels decreased 60%-70% before the reduction rate plateaued after 12 weeks (with 15% of patients achieving normal values).
• Hepatic volume normalized in 92%.
• Respiratory function either improved slightly or remained constant.
• Shoulder joint mobility increased gradually, with larger increases being seen in persons with more severe disease.
• Timed walk measurements remained largely constant.
• Quality of life index improved in most (especially with respect to pain).
• Visual acuity improved in 24% although corneal clouding was unchanged.
• Growth resumed in approximately 70%; although the growth rate increased with treatment, the final height was still reduced.

The most common reactions were of an immune nature; most were not serious, indicating that Aldurazyme^® is generally well tolerated. IgG antibodies to Aldurazyme^® were produced in 93% of patients, in inverse correlation to urinary GAG excretion levels; they were not, however, directly related to adverse immune reactions.

Other studies have shown:

• Improvement in height and cranial diameter with earlier administration of Aldurazyme^® (age <1 year) as compared to later administration (age ≥3 years), despite no measurable improvement in growth rate when treatment was started at age one year [Tylki-Szymanska et al 2010b];
• Improvement of learning performance in one of three patients and noticeable alteration of MRI profile after 3.5-4.5 years of ERT in 3/3 persons with attenuated disease [Valayannopoulos et al 2010]; however, many more individuals would need to be treated to confirm this finding.
• Clear differences between early initiation (age 5 months) and late initiation (age 5 years) of ERT in sibs with attenuated MPS I [Coppa et al 2010].

Pathophysiology. The effectiveness of ERT depends on the ability of recombinant enzymes (supplied intravenously) to enter cells and to localize to the lysosome, the appropriate intracellular site [Russell & Clarke 1999].