MPS I is a heterogeneous disease spanning a spectrum of severity.
Individuals with the most severe form of MPS I typically suffer from a number of progressively debilitating symptoms, including mental retardation. Their maximum lifespan is approximately 8 to 10 years. 8
Individuals at the opposite end of the disease spectrum have physical symptoms that can be as severe, but they generally retain normal intellect and stature, and may have a normal lifespan.
MPS I is considered to be the prototypical lysosomal storage disorder with progressive multi-systemic disease and presenting features that vary depending on where a patient is on the disease continuum.
Mucopolysaccharidosis I (MPS I) is a rare, autosomal
recessive disease with pathologic manifestations in multiple organ systems and tissues. The disease is caused by a defect in the gene coding for the lysosomal enzyme
alpha-L-iduronidase; as a result, the cells of affected individuals either are unable to produce the enzyme or produce it in low amounts. This results in an inability
of the lysosome to effect the stepwise degradation of certain glycosaminoglycans (GAGs) - namely dermatan sulfate and heparan sulfate - a process essential for normal
growth and homeostasis of tissues. These glycosaminoglycans, which are important constituents of the extracellular matrix, joint fluid, and connective tissue throughout
the body, progressively accumulate in the lysosome, ultimately causing cell, tissue, and organ dysfunction by largely unknown pathophysiological mechanisms.
The historical classifications of MPS I, Hurler, Hurler-Scheie
and Scheie syndromes do not adequately reflect the tremendous variation in clinical symptoms. The manifestations seen with each classification are not mutually distinct
and often overlap. Therefore the disease is best characterized as alpha-L-iduronidase deficiency with or without CNS involvement. Because the disease generally affects many organ systems and can present in a variety of ways, diagnosis and treatment of
MPS I disease may require collaboration and communication among geneticists, neurologists, pediatricians, developmental specialists, surgeons, cardiologists,
gastroenterologists, physiotherapists, and primary care providers.
General Physical Appearance
The physical appearance for MPS I is quite variable:
- Coarse facial features
- Broad mouth, square jaw, and receding chin
- Large tongue
- Excess facial and body hair
- Large, scaphocephalic head
- Corneal clouding
- Short neck
- Stocky build with short trunk
- Joint deformities (see picture below)
Developmental Delay and Severe Mental Retardation
Patients with MPS I manifest a wide range of intellectual involvement. Some MPS I patients will suffer progressive and
profound mental retardation while others will exhibit little or no intellectual dysfunction. In severe patients, early development may be normal but
developmental delay is usually suspected by 12 months. Thereafter, there is usually progressive deterioration, and by 18 months, developmental delay
is usually apparent. From this point on, patients generally do not progress in development but plateau for a number of years followed by a slow decline
in intellectual capabilities.
Structural CNS Manifestations
In addition to the direct CNS effects of MPS I, communicating hydrocephalus is common.
Decreased resorption of cerebrospinal fluid by arachnoid villi causes an associated increase in intracranial pressure, leading to brain compression.
Rapidly increasing pressure may be the cause of acute developmental decline in some patients. Symptoms may be difficult to assess and progression
can be insidious and is often under-appreciated. Lumbar puncture with opening pressure is a preferred method for assessing the degree of pressure
elevation. Shunting procedures may be beneficial. Another recognized complication is spinal cord compression, which can result from thickening
of the dura or subluxation of vertebrae.
Peripheral Nervous System
Some patients with MPS I may have poor hand function, in part as a result of
carpal tunnel syndrome (median nerve entrapment). This syndrome is due to pressure on the median nerve as a result of thickened
ligaments within the wrist; it may cause pain, and loss of feeling in the fingertips, but most patients lack these typical symptoms
(pain, tingling, or numbness). Because of the high incidence of the syndrome, routine electromyographic/nerve conduction velocity
testing is typically recommended by the treating physician, even in the absence of patient complaints.
Moderate to severe hearing loss, which correlates with the severity of somatic
disease, can occur in patients with MPS I. Hearing loss may be sensorineural or conductive, but is typically mixed. Hearing
impairment is most common in the high frequency range and thus can lead to significant difficulties in social interaction.
Corneal clouding is a feature of all MPS I patients and can lead to significant visual
disability. Open-angle glaucoma is also a common complication. Retinal degeneration associated with loss of peripheral
vision and night-blindness may occur and can be assessed by an electroretinogram. Visual disturbances can progress to
blindness from a combination of retinal pigmentary degeneration, optic nerve compression and atrophy, and cortical damage.
Skeletal and joint manifestations represent the most significant disability and discomfort for patients with MPS I.
In severe cases, skeletal involvement in MPS I patients can be detected in the first year of life by radiological methods. Clinically, skeletal
involvement does not usually become obvious until the age of 10-14 months when a gibbus deformity of the back, or dorsolumbar kyphosis, is observed.
MPS I can be associated with different degrees of growth retardation, typically involving the trunk more than the limbs. Eventually, progressive
skeletal dysplasia involving all bones is seen in all patients.
Interphalangeal joint involvement along with carpal tunnel syndrome commonly lead to poor hand function. Diagnosis
of carpal tunnel syndrome is often missed because its onset is insidious and often presents with few or no symptoms except thenar atrophy.
Patients should be evaluated for this, as they may benefit from carpal tunnel release.
Kyphosis, scoliosis, and severe back pain are also common in MPS I patients. Progressive arthropathy affecting
all joints, and eventually leading to the loss of, or severe restriction of, range of motion is universal.
Chronic rhinitis and rhinorrhea without obvious infectious etiology are common
features of MPS I. Storage within the oro-pharynx with associated enlargement of the tongue, tonsils, and adenoids can lead to significant
upper airway complications. In addition, a narrowed trachea, thickened vocal cords, and redundant tissue in the upper airway may contribute
to airway obstruction and can result in sleep apnea.
Lung volumes are often reduced because of the
small thorax and hepatosplenomegaly that may limit excursion of the diaphragm. Recurrent respiratory infections are common, and respiratory
insufficiency is a major cause of mortality.
Clinical complications related to heart disease occur in some patients with MPS I,
particularly during the later stages of the disease. In these patients, evidence of cardiovascular involvement by echocardiography can
be demonstrated much earlier than that derived from clinical observations. Storage of glycosaminoglycans (heparan sulfate and dermatan sulfate)
within and around the valve leaflets results in their thickening and stiffening, which can lead to progressive mitral and aortic regurgitation.
Mitral regurgitation is the most common valvular disease in severely affected MPS I patients.
Hypertrophic cardiomyopathy may be diagnosed by
echocardiography. Pulmonary hypertension, which can progress to cor pulmonale, may occur as a consequence of sleep apnea.
A distended abdomen is
commonly observed in patients with severe MPS I and is typically caused
by the progressive enlargement of the liver and/or spleen. Storage of
glycosaminoglycans in the liver and spleen does not generally lead to
organ dysfunction; however, organ size may be enlarged. Some children
with MPS I suffer periodically from loose stools and diarrhea, sometimes
alternating with periods of severe constipation due to storage within
ganglion cells of the enteric nervous system. Hernias, both inguinal
and umbilical, are common in patients with MPS I.
The diagnosis of MPS I relies on demonstrating a deficiency of the lysosomal enzyme alpha-L-iduronidase.
This enzyme activity can be measured in most tissues; however, diagnosis is usually made with the use of either peripheral blood
leukocytes, plasma, or cultured fibroblasts.
Findings in MPS I may overlap with those of other lysosomal storage disorders, particularly other
mucopolysaccharide diseases and multiple sulfatase deficiency. Detailed clinical findings and biochemical testing is
necessary for their differentiation. There are some early clinical signs and symptoms, which alone are not diagnostic, but
may warrant more definitive testing. Although findings at presentation will vary with the severity of the disorder, MPS I should be
suspected in individuals with coarse facial features, hepatosplenomegaly, as well as characteristic skeletal, joint, or ocular findings.
Confirmation of an Initial Diagnosis
Analysis of urinary glycosaminoglycans (heparan sulfate and dermatan sulfate) was the earliest method
available for diagnosis of MPS I and remains useful as a preliminary investigative test. However, definitive diagnosis can now
be established by enzyme assays using fluorogenic substrates specific for alpha-L-iduronidase. Cultured fibroblasts, leukocytes,
or plasma are generally used, the choice of which depends on the preference of the testing laboratory.
Accurate testing is critical to ascertain the diagnosis, as I-cell disease and MPS II exhibit clinical
features similar to those of MPS I.
Carrier testing is a service often requested by MPS I families, second only to the demands for effective
therapy. However, to date, the analysis of alpha-L-iduronidase enzyme activity does not provide definitive carrier information.
This is related to the fact that there is considerable overlap between the normal and heterozygous ranges and that pseudodeficiency
of alpha-L-iduronidase has been reported. Thus, there may be issues associated with interpreting results of enzyme levels in
the general population.
Carrier testing is most often performed if the family mutation is known. However, the large number
of mutations that underlie MPS I, and the technologies available to assess gene mutations, do not currently allow for routine
carrier detection by molecular methods. The value of carrier testing for the purpose of identifying couples who may be a risk
of having an affected child is also limited. This is because, even if one can accurately determine the carrier status of a
relative of an MPS I patient, the determination of the carrier status of the unrelated spouse is difficult.
Prenatal diagnosis is routinely carried out on cultured cells from amniotic fluid or
biopsies using the same enzyme assay that is used for monitoring alpha-L-iduronidase in cultured fibroblasts or leukocytes. Measurement
of glycosaminoglycans in amniotic fluid (or alpha-L-iduronidase activity) is complicated by the high glycosaminoglycan excretion of
fetuses. Measurement of radiolabeled 35S-glycosaminoglycan accumulation by cultured cells, while perhaps not practical, may be useful
for establishing cases of pseudodeficiency. Molecular-based prenatal diagnosis can be done, if the mutations carried by the parents are known.
Molecular Genetic Testing and Molecular Diagnosis
When considering DNA-based tests one must take into account the great heterogeneity of mutations underlying MPS I.
Mutant alleles need to be identified for the specific family before molecular diagnosis can be undertaken for members at risk. Many patients
will likely be compound heterozygotes; thus both mutant alleles must be known for carrier testing to be helpful for the family. Once the
mutant allele(s) are identified (either by the mutation itself, or by an intragenic polymorphism), molecular diagnosis may become easier
and require less material, which is important for prenatal testing. However, the large number of private mutations may keep mutation
analysis impractical for some families. Until mutation analysis becomes more readily available, diagnosis should be established by enzyme
assay. DNA-based diagnosis is the only definitive test for determining carrier status but will likely have limited value in individuals
who are at low risk of being carriers.
Genotype-phenotype correlations in MPS I are complex and further research is required before they can be clinically useful.
To date, research has indicated that all nonsense mutations (including the two most common mutations, W402X and Q70X) when present in a homozygous
or compound heterozygous state always confer a phenotype with severe disease and CNS involvement. The clinical consequences of other types of mutations
(missense, deletion, insertion and splice-site mutations) are not as straight forward and have been identified in patients with severe, intermediate,
and mild disease in the homozygous and heterozygous form, even when in association with a known severe nonsense allele. Thus, prediction of phenotype
in patients shown to have at least one missense, deletion, insertion, or splice-site mutation can only be made by looking at the phenotype of patients
who have previously presented with the mutations.
The 2 most common mutations identified in patients with a less severe phenotype without CNS involvement are the missense and
splice-site mutations R89Q and 678-7g>a, respectively. Together they account for 30-40% of mutations in such individuals.
Established mutations represent only a fraction of known cases, and as these studies progress, it is expected that
more mutations will be discovered that are null (mutations resulting in complete absence of alpha-L-iduronidase activity) and lead to severe MPS I disease with CNS involvement. Mutations that cause less severe forms of MPS I disease without CNS involvement are expected to be limited and mostly of the missense type. Although some genotype-phenotype correlations have been established, some striking variations in disease manifestation have also been reported in affected siblings with the same mutations. In general, patients with slight residual enzyme activity will have a less severe phenotype.
Enzyme replacement therapy
A recombinant polymorphic variant of the human enzyme deficient in MPS I, alpha-L-iduronidase,
[Aldurazyme® (laronidase)*], has been approved as a treatment option for individuals with MPS I.
Symptomatic management for MPS I generally includes using supportive care and the treatment of complications - with
attention to the respiratory and cardiovascular complications, skeletal manifestations, arthropathy, loss of hearing and vision, gastrointestinal
symptoms, and communicating hydrocephalus. While these treatments are appropriate strategies in managing MPS I and typically improve the quality of
life for patients and their families, they do not address the underlying cause of MPS I -- the alpha-L-iduronidase deficiency leading to progressive
cellular accumulation of GAG throughout the patient's body.
Examples of symptomatic management techniques may include:
- Oxygen for respiratory insufficiency
- Continuous positive airway pressure (CPAP machines)
- Tracheostomy for severe airway obstruction
- Physical therapy for joint stiffness
- Cardiac valve replacement therapy
Bone marrow transplant
For the most severe patients, bone marrow or umbilical cord blood transplantation may be an option.
transplantation (BMT) may improve some physical (especially facial) features and may stabilize CNS disease in some patients. With engraftment
of donor marrow, the derived monocytes/macrophages enzyme activity is corrected.
However, BMT is usually reserved for the most severe MPS I patients because of the risks associated with this procedure.
In general, the clinical outcome of BMT in patients with MPS I is varied and depends on the degree of clinical involvement and the age of the child
at the time of transplantation. Failure to achieve stable engraftment and graft-vs.-host disease can represent significant barriers to success for
many patients. For patients with MPS I, BMT carries a high risk of morbidity and mortality. Due to the risks, BMT is primarily used to treat selected
severe patients with MPS I.
While BMT has modified disease progression and improved survival in some cases, it is not curative.
MPS I Registry
Access to information is critical to providing the best care to patients. However, information on MPS I disease is limited because of its rarity. Now there is a global resource dedicated to improving the understanding of MPS I disease - the MPS I Registry, sponsored by Genzyme.
By contributing patient clinical data to the registry, health care professionals can have access to aggregate data on MPS I disease from around the world. The MPS I Registry is your resource.