The mucopolysaccharidoses (MPS) are a family of rare, progressive, multisystem lysosomal storage disorders that are caused by defects in the enzymes that catabolize glycosaminoglycans (GAGs). These disorders are clinically heterogeneous, but some common features include coarse facial features, hepatosplenomegaly, developmental delay/regression, umbilical/inguinal hernias, and a constellation of radiographic bone abnormalities known as dysostosis multiplex. There are 7 clinically defined MPS syndromes (MPS I, II, III, IV, VI, VII, and IX), which are caused by pathogenic variants in 1 of 11 genes (Table 155-1). Within each disorder, there is a wide spectrum of clinical effects ranging from mild to severe (phenotypic heterogeneity) depending on the degree of residual enzymatic activity. Intravenous enzyme replacement therapy is available for many of the MPS and is aimed at reducing the progression of non–central nervous system (CNS) symptoms. Hematopoietic stem cell transplantation (HCST), which is associated with substantial risks, may preserve cognitive function if performed early during the course of the disease.
PATHOGENESIS AND EPIDEMIOLOGY
With the exception of MPS II (Hunter syndrome; X-linked), MPS are inherited in an autosomal recessive manner. In affected individuals, 1 or more specific GAGs—dermatan sulfate (DS), heparan sulfate (HS), keratan sulfate (KS), and chondroitin-6-sulfate—accumulate within the lysosomes, interfering with recycling of cellular material (Fig. 155-1). GAGs build up in the lysosome over time, affecting cellular function. Different GAGs are expressed in different tissues, leading to the variable manifestations seen in each of the MPS disorders. The estimated prevalence of MPS in the United States is approximately 1 in 25,000, although prevalence estimates vary in different parts of the world. Prevalence varies by disease and ethnicity.
A: The catabolism of dermatan sulfate. B: The catabolism of heparan sulfate. C: The catabolism of keratan sulfate.
MPS disorders, like all lysosomal storage diseases, are progressive conditions. Infants typically do not manifest signs or symptoms at birth, and the disease is suspected as the phenotype evolves over time.
MPS disorders tend to present in 1 of 3 ways:
With “coarse” facial features (eg, MPS IH, MPS II)
With learning difficulties, behavioral disturbances, and developmental delay/regression (eg, MPS III)
As a skeletal dysplasia (eg, MPS IV, VI)
When an MPS is suspected from clinical, laboratory, and radiologic findings, the diagnosis can be confirmed by enzyme assay on white blood cells or skin fibroblasts or by the identification of biallelic pathogenic variants in the particular gene. While qualitative or quantitative demonstration of increased urinary GAG excretion is supportive evidence of an MPS, urinary screening tests for MPS disorders have reduced sensitivity, particularly with dilute specimens and in individuals with mild disease. False-negative results, especially in MPS III and IV, are well recognized; therefore, a negative screening test should not dissuade the clinician from pursuing a diagnosis of an MPS disease when the clinical suspicion is high. Although algorithms aimed at helping the diagnostic process have been developed, their use in clinical practice is limited by the clinical heterogeneity in this group of disorders.
If urinary GAG analysis is normal and enzyme and molecular testing has not yielded a diagnosis of an MPS, other diagnostic possibilities should be considered. Urine oligosaccharide and sialic acid analysis should be undertaken to exclude oligosaccharidoses and other glycoproteinoses. White cell and plasma lysosomal enzyme studies should be performed to confirm abnormalities and to exclude galactosialidosis, mannosidosis, and related disorders. Radiographs should be reviewed to confirm the presence of dysostosis multiplex (Fig. 155-2), and abnormal lysosomal storage should be confirmed by examining a skin biopsy under electron microscopy. If all these investigations are normal, it is important to remember that some non-lysosomal disturbances can mimic storage diseases (eg, geleophysic dysplasia, Coffin-Lowry syndrome, Williams syndrome, and Costello syndrome).
A: Dysostosis multiplex. Hypoplastic and hooked lumbar vertebral body (arrowed) at the site of thoracolumbar gibbus in a patient with mucopolysaccharidosis (MPS) IH. B: Dysostosis multiplex. Shallow acetabulum and flattened femoral head (arrowed) in a patient with MPS IH. C: Dysostosis multiplex. Skull x-ray with thickened calvarium and J-shaped sella turcica (arrowed).
There is a tendency to classify the individual MPS disorders into “mild” and “severe” subtypes, based either on survival or on the presence or absence of CNS disease. This is in reality a gross oversimplification; it is preferable to consider the disorders on a clinical spectrum. Although many are compatible with prolonged survival, for the majority of individuals, these are not benign conditions.
TABLE 155-1THE MUCOPOLYSACCHARIDOSES (MPS) ||Download (.pdf) TABLE 155-1THE MUCOPOLYSACCHARIDOSES (MPS)
|Disease (Eponym) ||Gene ||Inheritance ||Enzyme Deficiency ||Airway Obstruction ||Behavioral Problems ||Cardiac Valve Disease ||Cardiomyopathy ||Carpal Tunnel ||Coarse Facies ||Corneal Clouding ||Developmental Delay ||Developmental Regression || |
|MPS IH (Hurler) ||IDUA ||AR ||α-L-iduronidase ||+++ ||+/– ||+++ ||+ ||+++ ||+++ ||+ ||+++ ||+++ || |
|MPS IH/S (Hurler-Scheie) ||IDUA ||AR ||α-L-iduronidase ||– ||– ||+++ || ||+++ ||+/– ||+ ||– ||+/– || |
|MPS IS (Scheie) ||IDUA ||AR ||α-L-iduronidase ||– ||– ||+++ || ||+++ ||– ||+ ||– ||– || |
|MPS II (Hunter) ||IDS ||XL ||Iduronidate-2-sulfatase ||+ ||+ ||+ ||+ ||+ ||+ ||– ||+ ||+ || |
|MPS IIIA (Sanfilippo A) ||SGSH ||AR ||Heparan-N-sulfatase ||+/– ||+++ ||+/– ||+/– ||– ||+ ||– ||+++ ||+++ || |
|MPS IIIB (Sanfilippo B) ||NAGLU ||AR ||N-Acetylglucosaminidase ||+/– ||+++ ||+/– ||+/– ||– ||+ ||– ||++ ||++ || |
|MPS IIIC (Sanfilippo C) ||HGSNAT ||AR ||Acetyl-CoA:α-glucosaminide acetyltransferase ||+/– ||++ ||+/– ||+/– ||– ||+ ||– ||++ ||++ || |
|MPS IIID (Sanfilippo D) ||GNS ||AR ||N-Acetylglucosamine 6-sulfatase ||+/– ||+++ ||+/– ||+/– ||– ||+ ||– ||++ ||++ || |
|MPS IVA (Morquio A) ||GALNS ||AR ||Galactose-6-sulfatase ||++ ||– ||+ ||+ ||– ||+ ||+ ||– ||– || |
|MPS IVB (Morquio B) ||GLB1 ||AR ||β-Galactosidase ||++ ||– ||+ ||+ ||– ||+ ||+ ||– ||– || |
|MPS VI (Maroteaux-Lamy) ||ARSB ||AR ||N-Acetylgalactosamine-4-sulfatase ||+ ||– ||++ ||++ ||– ||+ ||+ ||– ||– || |
|MPS VII (Sly) ||GUSB ||AR ||β-Glucuronidase ||+/– ||+/– ||+ ||+/– ||– ||+ ||+++ ||+ ||+/– || |
|MPS IX (Natowicz) ||HYAL1 ||AR ||Hyaluronidase ||– ||– ||– ||– ||– ||– ||– ||– ||– || |
Mucopolysaccharidosis Type I
MPS I is traditionally divided into 3 different disorders: Hurler (MPS IH; Mendelian Inheritance in Man [MIM] no. 607014), Scheie (MPS IS; MIM no. 607016), and Hurler-Scheie (MPS IH-S; MIM no. 607015). Hurler is considered the most severe, with onset in the first few years of life, and Scheie the least severe, with onset in the second or third decade. With Hurler-Scheie, the age of onset and severity of symptoms are intermediate between Hurler and Scheie. All 3 diagnostic entities are caused by enzymatic deficiency of α-L-iduronidase, which is encoded by the IDUA gene. The diagnosis can be suggested by the finding of dermatan and heparan sulfate in the urine. Infants with Hurler syndrome appear normal at birth. Early manifestations may include inguinal/umbilical hernias, frequent upper respiratory infections, and otitis media. Coarsening of the facial features, caused by infiltration of GAGs in the soft tissues and dysostosis of the facial bones, emerges during the first 2 years of life and results in thickened lips, ear lobules, nose, and tongue (Fig. 155-3). Although growth for the first 12 to 18 months of life is normal, the skeletal deformities eventually lead to severe growth restriction. Although initially development may be normal, developmental delay is usually present by age 18 months, which may be followed by developmental plateauing and/or developmental regression. Upper respiratory tract obstruction may occur secondary to midface hypoplasia, enlarged tongue, and infiltration of the respiratory tract by accumulating GAGs. Obstructive sleep apnea is usual, and affected children require ear, nose, and throat (ENT) assessment. Hearing loss is common due to GAG accumulation, frequent otitis media, and damage to the eighth cranial nerve. A number of patients will have a large head circumference, and communicating hydrocephalus will develop in up to 40% of patients. The abdomen may become protuberant secondary to hepatosplenomegaly. Diarrhea is also a frequent complication of Hurler syndrome. Corneal deposition of GAGs becomes clinically apparent as corneal clouding during the second year of life (Fig. 155-4). Individuals may have a dysplastic odontoid process and are at risk of sudden and severe spinal cord damage secondary to atlantoaxial subluxation (Fig. 155-5). Carpal tunnel syndrome is frequent. Cardiac involvement, which includes progressive thickening of cardiac valves, is nearly universal and may lead to mitral/aortic regurgitation and cardiomyopathy. Prognosis depends on the severity of cardiac and respiratory involvement. Death typically occurs within the first 10 years of life due to cardiorespiratory complications.
Facial features in mucopolysaccharidosis (MPS) IH at diagnosis, age 12 months: mid-face hypoplasia, “button” nose, and thick lips.
Mucopolysaccharidosis (MPS) I corneal clouding.
Lateral x-ray of the cervical spine taken in flexion. The first cervical vertebra (arrowed) has slipped anteriorly over the top of C2 because of odontoid dysplasia and subsequent instability at the craniocervical junction.
At the other end of the clinical spectrum from Hurler syndrome are patients diagnosed in late childhood or early adult life with Scheie syndrome, usually because of orthopedic or ophthalmologic problems. In MPS IS, cognition is normal, and individuals may have a normal life span. Some patients require cardiac valve surgery, but the clinical picture tends to be dominated by bone and joint involvement. Carpal tunnel syndrome is almost universal. In some patients, corneal clouding limits vision to such a degree that corneal transplantation is necessary. Most patients tolerate this procedure well, and the transplanted cornea remains clear. However, before a patient undergoes this surgery, a careful assessment of retinal function is necessary to ensure that the visual loss is not secondary to retinopathy, which also occurs in MPS IS. Hearing loss is also common.
Between these 2 extremes is a continuous clinical spectrum that is often labeled Hurler-Scheie syndrome (Fig. 155-6). Symptoms typically develop between 3 and 10 years of age. These patients may develop late-onset neurologic deterioration, but most of the active clinical problems relate to progressive joint stiffness and degenerative bone disease. Hepatosplenomegaly may occur, but is less common than in Hurler syndrome. Spondylolisthesis of L5/S1 is very common and may require surgical repair (Fig. 155-7). Progressive visual loss due to a combination of corneal clouding and retinal disease is common, and many patients will develop progressive cardiac disease. Frequent chest infections, limited chest expansion, and upper respiratory obstruction are known complications. Sleep apnea can be troublesome, and routine pulse oximetry overnight during sleep should be performed annually. Some require continuous positive airway pressure (CPAP) via a nasal mask. In patients who cannot tolerate the tight-fitting mask or the noise of the machine, tracheostomy remains the only alternative. In general, this is poorly tolerated in MPS disorders, as it is often associated with an increase in airway secretions that requires frequent suction.
An individual with an intermediate form of mucopolysaccharidosis (MPS) I (MPS IH/S, Hurler-Scheie disease). Note joint stiffness and relatively normal facial appearance.
Lateral magnetic resonance imaging scan of the lumbar-sacral spine in a patient with mucopolysaccharidosis (MPS) I H/S. The fifth lumbar vertebra (arrowed) has slipped anteriorly over the top of the sacrum.
Enzyme replacement therapy (laronidase) is available for the nonneuronopathic manifestations of MPS I via a weekly infusion of 0.58 mg/kg over 4 hours. Laronidase does not cross the blood-brain barrier; therefore, it is thought that any apparent effect on neurologic function occurs through improvement in the patient’s general condition. In most treated patients, there is a rapid reduction in urinary GAGs, followed by a much slower decline after the first 6 months of treatment. After 6 years of treatment, there is continued improvement in growth, shoulder flexion, and sleep apnea. Early treatment is essential to prevent some complications such as cardiac valve lesions. Most infusion-associated reactions have been mild and easily managed either by slowing the rate of infusion or premedicating with an antihistamine or corticosteroid. Anaphylaxis has been reported in a few patients. HSCT is recommended only for severe MPS I (Hurler) given the morbidity and mortality associated with this procedure.
Mucopolysaccharidosis Type II
The enzyme deficiency in MPS II is iduronidate 2-sulfatase, which is encoded by the IDS gene. In contrast to MPS I, MPS II (MIM no. 309900) is X-linked, meaning that males are typically affected, while females are carriers; however, a few cases have been described in females. Lack of significant corneal clouding distinguishes MPS II from MPS I. Like MPS I, there is significant heterogeneity in the age of onset as well as in severity and progression of symptoms. In severely affected patients, the diagnosis is usually established in the second year of life. The diagnosis can be suggested by the finding of dermatan and heparan sulfate in the urine. Symptoms include coarse facial appearance, hepatosplenomegaly, and joint contractures, particularly of the phalangeal joints. A nodular ivory rash around the scapulae and on the extensor surfaces is considered pathognomonic of the disorder but is rare in childhood. Most patients have short stature and macrocephaly. Additional findings include frequent upper respiratory infections, umbilical/inguinal hernias, and frequent otitis media. Dysostosis multiplex may develop over time. Developmental delay and/or regression may be present in more severe forms of the disease. The behavioral phenotype includes sleep disturbance, challenging behavioral problems, and attention deficit disorder. Diarrhea is common in the early-onset form of the disease. Cardiac valvar disease and cardiomyopathy may cause early morbidity and mortality. Carpal tunnel syndrome is frequent. It should be routinely screened for using a nerve conduction velocity test, and release should be performed when identified.
In individuals with less severe forms of MPS II, intelligence may be preserved into adulthood. Cervical cord compression due to hyperplasia of the dura and ligamentum flavum can lead to a progressive cervical myelopathy (Fig. 155-8). This usually presents with decreasing exercise tolerance that can be mistaken for progression of joint stiffness. From the age of 10 years, these patients should have the craniocervical junction routinely evaluated by magnetic resonance imaging (MRI), and posterior decompression should be performed in those with cervical compromise. Atlantoaxial instability is usually not a feature of MPS II, as the odontoid process is usually well developed; therefore, spinal fusion in addition to the decompression is usually not required. Most adults with MPS II develop upper respiratory obstruction and sleep apnea. Many benefit from the use of nasal CPAP devices, although the masks often have to be shaped individually because of the abnormal facial anatomy.
A lateral magnetic resonance imaging scan of the craniocervical junction in a patient with mucopolysaccharidosis (MPS) II. Notice the lack of cerebrospinal fluid around the cervical cord (arrowed) due to thickening of ligaments and dura. The odontoid is also dysplastic.
Idursulfatase is approved for enzyme replacement therapy for MPS II at 0.5 mg/kg/wk. Treatment results in improvements in the 6-minute walk test, reductions in the degree of hepatosplenomegaly, decreased urinary GAG excretion, improved hearing, and improved joint range of motion. Like laronidase, it does not cross the blood-brain barrier and thus has no effect on cognitive function. HCST has shown promise in smaller studies, but requires further study to determine long-term efficacy in this group of patients.
Mucopolysaccharidosis Type III
MPS III, or Sanfilippo syndrome, is a clinically identical but biochemically heterogeneous group of 4 conditions all associated with an inability to catabolize heparan sulfate. MPS IIIA (MIM no. 252900) is the most common, caused by variants in the gene SGSH, which encodes for heparin-N-sulfatase. The next most frequent is MPS IIIB (NAGLU, N-acetylglucosaminidase; MIM no. 252920). Types IIIC (HGSNAT, acetyl-CoA:α-glucosaminide acetyltransferase; MIM no. 252930) and IIID (GNS, N-acetylglucosamine 6-sulfatase, MIM no. 252940) are very rare. In contrast to other MPS diseases, the hallmark of MPS III is prominent CNS involvement in the presence of a mild somatic phenotype. Because of this combination, the diagnosis is usually established much later in life (4–5 years) compared to other disorders. The diagnosis can be suggested by the finding of heparan sulfate in the urine. In a typically affected patient, the initial presentation is usually with developmental delay and mildly coarse facial features with dry, coarse hair, usually without hepatosplenomegaly. Somatic features are usually mild (Fig. 155-9). There is often a history of recurrent upper respiratory infections and hernias, and most patients have troublesome diarrhea. Sleep disturbance can present early in life and, in its extreme form, produces a reversal of the normal sleep/wake cycle.
Facial features in a 7-year-old boy with mucopolysaccharidosis (MPS) III at diagnosis.
Gradually, the behavioral phenotype evolves into severely challenging behaviors with extreme hyperactivity, aggression, and temper tantrums. During this phase, the diagnosis is established in the majority of individuals. As the disease advances, developmental milestones are lost and increasing spasticity leads to a progressive loss of motor skills. Behavioral problems and sleep disturbance require attention, although both are resistant to treatment. The challenging behavior responds poorly to a psychological or behavioral approach. In some individuals, benzodiazepines are used to modify aggressive or destructive behavior. Environmental modification within the home is an essential part of management. It is preferable to try improving the child’s sleep pattern first, as the parents are better able to deal with the challenging behavior if fully rested. The use of melatonin has been encouraging, with a positive response obtained in at least 75% of those treated. Regular respite care is essential to allow the parents time for themselves and for normal siblings.
In the early teenage years, patients may progressively lose more skills and experience swallowing dysfunction. Seizures are common in the later stages in some patients and can be difficult to control, while other patients develop a severe movement disorder resistant to treatment. Mood disturbances with prolonged crying can be extremely distressing for the parents of affected children. Eventually, the disorder culminates in a vegetative existence in the mid-to-late teens. Death usually occurs around the second decade for patients with MPS IIIA, although patients with MPS IIIB-D may have a more attenuated course and can survive into the third or fourth decade. The disorder is probably underdiagnosed at the less severe end of the clinical spectrum, as these individuals may have only mild learning difficulties until the age of 20 to 30 years.
Enzyme replacement therapy has not been approved in MPS III by the US Food and Drug Administration (FDA), as it does not cross the blood-brain barrier. There are several ongoing clinical trials involving intrathecal administration of enzyme and intrathecal gene therapy. Intravenous enzyme products that are able to cross the blood-brain barrier are also being investigated. HCST does not ameliorate the neurologic outcomes in patients with MPS III.
Mucopolysaccharidosis Type IV
Individuals with MPS IV, or Morquio syndrome, present primarily with a severe skeletal dysplasia. MPS IVA (galactose-6-sulfatase, GALNS; MIM no. 253000) accounts for 95% of cases, and MPS IVB (β-galactosidase; MIM no. 612222) accounts for 5%; they are clinically indistinguishable. Individuals with MPS IV appear normal at birth. Like other MPS, there is a wide range of phenotypic variability ranging from severe early-onset to mild, slowly progressive disease. Unlike other MPS, these individuals do not have coarse facial features, and developmental delay/intellectual disability does not occur. Instead, the clinical course includes severe bone disease and short stature. Affected individuals have loose peripheral joints (especially the wrists) with some limitation in range of motion in large joints; this joint phenotype distinguishes individuals with MPS IV from patients with other MPS diseases. The diagnosis can be suggested by the finding of keratan and chondroitin-6-sulfate in the urine. The severe form of the disease is diagnosed between 1 and 3 years of life, and initial presentation includes kyphoscoliosis, genu valgum, severe pectus carinatum, and decreased growth velocity. The radiologic abnormalities are different from the classic dysostosis multiplex seen in MPS I, II, VI, and VII and are characterized by vertebral platyspondyly and other features of a generalized spondyloepiphyseal dysplasia (Fig. 155-10). Severely affected males have an average adult height of 123 cm and females 117 cm. The greatest immediate danger is the inevitable odontoid dysplasia that is present in all severely affected patients (Fig. 155-11). Without treatment, MPS IV patients may suffer irreversible neurologic deficits. Care must be taken not to hyperextend the neck, especially during intubation for surgical procedures. Chronic cervical myelopathy presents with an insidious loss of motor function and evolves into a slowly progressive tetraparesis unless the instability in the cervical region is detected and corrected. Flexion/extension radiographic views of the cervical spine are helpful in identifying patients likely to benefit from early spinal fusion. MRI scanning of the cervical region will demonstrate the degree of cervical involvement and should be performed at regular intervals. The timing of cervical fusion remains controversial, with some recommending prophylactic fusion in patients whose radiographs show atlantoaxial subluxation, while others would not recommend intervention until there are clinical signs or symptoms. The situation requires continual vigilance, as instability may develop farther down the vertebral column. Very little else can be done for the bone deformities present in this condition. Corrective surgery for genu valgum often produces only a temporary cosmetic improvement and does not greatly improve mobility. Most adults with the severe form of this disease prefer to use a motorized wheelchair, and because of their lack of mobility, obesity is a major problem (Fig. 155-12).
Lateral spine x-ray of mucopolysaccharidosis (MPS) IV. Generalized vertebral abnormality (platyspondyly) is present in contrast to the single vertebral anomaly seen in MPS IH (Fig. 155-2).
Odontoid dysplasia (arrowed) in a patient with mucopolysaccharidosis (MPS) IV.
A 10-year-old girl with mucopolysaccharidosis (MPS) IV. The immobility leads to obesity in many affected children.
Individuals with MPS IV have a high risk of respiratory complications due to GAG accumulation in the upper respiratory tract, leading to tissue hypertrophy, airway obstruction, and obstructive sleep apnea. Restrictive lung disease results from a small thorax and thoracic spinal anomalies, which can lead to respiratory failure, and is the most common cause of death in adulthood. Cardiac complications, including valvar regurgitation or stenosis and ventricular hypertrophy, may occur. Dental decay is common, secondary to enamel hypoplasia, and the teeth are generally pointed and widely spaced. A number of patients will develop mild corneal haze as adults, but this rarely needs treatment. Mild to moderate hearing loss is common.
Enzyme replacement therapy (elosulfase alfa) is available for MPS IVA. It is administered at a dose of 2 mg/kg weekly and leads to an improvement in the 6-minute walk test and quality of life. Serious adverse events are not common, but as with other forms of enzyme replacement therapy, premedication with an antihistamine and antipyretic may help reduce infusion-associated reactions.
[MPS V was originally Scheie disease, but when it was recognized that this was a milder form of MPS I, it was renamed MPS IS; therefore, there is no MPS V.]
Mucopolysaccharidosis Type VI
MPS VI, also known as Maroteaux-Lamy disease (MIM no. 253200), is due to pathogenic variants in the gene ARSB that encodes the enzyme N-acetylgalactosamine-4-sulfatase. Like other MPS conditions, MPS VI is associated with considerable clinical heterogeneity. In the typical or severe form of the disease (sometimes referred to as “rapidly progressing”), the clinical phenotype includes short stature, coarse facial features, hepatosplenomegaly, dysostosis multiplex, corneal clouding, and cardiac abnormalities. Other associated features include upper respiratory obstruction, middle-ear disease, corneal clouding, and progressive joint stiffness. Cardiac involvement is universal and can be severe and is a leading cause of death in rapidly progressing MPS VI in the second or third decade of life. The diagnosis can be suggested by the finding of dermatan and chondroitin-6-sulfate in the urine. In severely affected individuals, diffuse airway narrowing can lead to cor pulmonale over time. All individuals, even those at the less severe end of the clinical spectrum (“slowly progressing” form of the disease), are at risk of cervical myelopathy secondary to dural and ligamentous hyperplasia. Atlantoaxial subluxation is variable, and it is often not possible to predict whether cervical fusion will be necessary in addition to decompression in individuals with cervical cord disease until the time of operation. People with MPS VI are at risk of 2 complications that are seen particularly in this MPS: sudden blindness due to optic nerve compression and intracranial venous hypertension secondary to the compression at the craniocervical junction. Regular ophthalmologic assessments are mandatory.
Figure 155-13 illustrates 2 patients of approximately the same age, one with rapidly progressing disease (Fig. 155-13A) and the other with a more slowly progressing variant (Fig. 155-13B).
A: A 14-year-old boy with rapidly progressive mucopolysaccharidosis (MPS) VI. B: A 15-year-old girl with slowly progressive MPS VI.
Prior to the advent of enzyme replacement therapy, patients with MPS VI were successfully treated with HCST. However, galsulfase is approved for enzyme replacement therapy for Maroteaux-Lamy disease and is administered intravenously at a dose of 1 mg/kg weekly and results in significant improvements in endurance.
Mucopolysaccharidosis Type VII
MPS VII, or Sly syndrome (MIM no. 253220), is due to pathogenic variants in the gene GUSB (β-glucuronidase deficiency). This disorder is very rare, occurring in < 1 in 250,000 live births. Because one of the main modes of presentation is nonimmune hydrops fetalis, affected individuals are few in number. Infants with hydrops fetalis surviving delivery have a wide spectrum of disease severity. MPS VII can also present in the absence of hydrops fetalis, and in these individuals, the initial presenting symptoms are short stature, coarse facial features, cognitive impairment, hepatosplenomegaly, and dysostosis multiplex. Other common features can include corneal clouding, restrictive lung disease, cardiac valvar disease, and joint contractures. Visual impairment, sleep apnea, and cardiomyopathy occur in approximately one-third of patients. Spinal stenosis may occur. A diagnosis can be suggested by the finding of dermatan, heparan, and chondroitin-6-sulfate in the urine. There are no treatments for MPS VII approved by the FDA; however, a recombinant human β-glucuronidase (rhGUS) is in phase III clinical trials at the time of the writing of this chapter.
Mucopolysaccharidosis Type IX
MPS IX (MIM no. 601492), or Natowicz disease, is vanishingly rare. Thus far, only 4 patients from 2 families have been described with HYAL1 variants leading to deficiency of hyaluronidase. The first was a 14-year-old girl with mild short stature and multiple periarticular soft tissue masses. There was no other visceral or CNS involvement, although synovial histology revealed abundant lysosomal storage and abundant GAGs in the extracellular matrix. A second family with 3 affected children was later described as having joint pain, swelling, and proliferative synovitis with normal stature and no soft tissue masses. The diagnosis can be suggested by the finding of hyaluronic acid in the urine. No FDA-approved treatment exists for MPS IX.
|Dysostosis Multiplex ||Diarrhea ||Frequent Otitis Media ||Hearing Loss ||HSM ||Hernias ||Joint Contractures ||Macrocephaly ||Restrictive Respiratory Disease ||Seizures ||Short Stature ||Sleep Disturbance ||Soft Tissue Swelling ||Synovitis |
|+++ ||+++ ||+++ ||+ ||+++ ||+ ||+++ ||+++ ||+++ ||– ||+++ ||– ||– ||– |
|+ ||+ || || ||+ || || || || ||– ||++ ||– ||– ||– |
|+ ||+ || || || || || || || ||– ||+ ||– ||– ||– |
|+ ||++ ||+ ||+ ||+++ ||+ ||+++ ||+ ||+ ||– ||+ ||+ ||– ||– |
|+ ||+++ ||+ ||+ ||+ ||+ ||+/– ||+/– ||– ||+ ||+ ||+++ ||– ||– |
|+ ||+++ ||+ ||+ ||+ ||+ ||+/– ||+/– ||– ||+ ||+ ||+++ ||– ||– |
|+ ||+++ ||+ ||+ ||+ ||+ ||+/– ||+/– ||– ||+ ||+ ||+++ ||– ||– |
|+ ||+++ ||+ ||+ ||+ ||+ ||+/– ||+/– ||– ||+ ||+ ||+++ ||– ||– |
|+ ||+ ||+ ||+ ||+/– ||– ||– ||– ||++ ||– ||+++ ||– ||– ||– |
|+ ||+ ||+ ||+ ||+/– ||– ||– ||– ||++ ||– ||+++ ||– ||– ||– |
|+ ||+ ||+ ||++ ||+ ||– ||– ||– ||+ ||– ||+++ ||– ||– ||– |
|+++ ||– ||+ ||+ ||+++ ||+ ||+++ ||+ ||++ ||– ||+++ ||+ ||– ||– |
|– ||– ||– ||– ||– ||– ||– ||– ||– ||– ||+/– ||– ||+ ||+ |
Despite recent advances, definitive or curative treatment for most disorders affecting the brain is still not possible. However, enzyme replacement therapy and HSCT can slow or halt the progression of disease in some patients. Even in the most severely affected patients, careful attention to palliative therapies can have a beneficial effect on quality of life, and all patients should be under regular specialist care.
Hematopoietic Stem Cell Transplantation (HSCT)
Since 1980, bone marrow transplantation (BMT) has been used as a cell-based form of “gene therapy” in patients with MPS. Initially, many different types of MPS disease were treated, but it is now generally accepted that the therapy is of no benefit in MPS III and IV, and there remains considerable doubt about its efficacy in severe MPS II. In carefully selected patients with MPS IH and VI, BMT alters the course of the disease, although the indications for treatment in both disorders differ. In addition, now that recombinant enzyme replacement therapy is available for MPS VI, transplantation is typically reserved for patients with severe MPS IH alone. In MPS IH, the primary objective is to avoid intellectual deterioration; consequently, BMT must be performed at an early age (< 18 months). Following successful BMT, urinary GAG excretion quickly increases and then falls to the normal range after 3 to 6 months. Organomegaly resolves, and there is partial clearing of the cornea. Cardiomyopathy, if present, is also successfully reversed. In MPS IH, developmental progress is maintained in the majority of patients who receive BMT earlier than 18 months of age, and the final DQ (developmental quotient) is usually identical to the DQ at the time of BMT. The skeletal disease, however, is very resistant to correction. Although remodeling of the facial bones can change the coarse facial appearance and growth of long bones is improved, the vertebral bodies are not significantly improved, and marked spinal deformity can result over time. Almost all patients with MPS IH who have had a successful BMT require complex corrective spinal surgery. Despite this, the majority of successfully transplanted patients have a good quality of life, and this therapy can no longer be regarded as experimental. For many patients, it offers their only chance of long-term survival. Figure 155-14 depicts MPS IH patients after HSCT.
A, B, and C: An 8-year-old male patient with mucopolysaccharidosis (MPS) IH. Severe spinal deformity after hematopoietic stem cell transplantation.
Recent advances in transplantation for MPS disorders have included enzyme replacement therapy (ERT) as an adjunct to transplant; the increasing use of alternative donor cell sources, especially umbilical cord blood cells (UCB); and new, less toxic induction regimens. The major barriers to success following HSCT in MPS are the high rate of graft rejection and the toxicity associated with the treatment. There is some evidence that using ERT before transplant may lessen this risk. Experience suggests that the combination of ERT and HSCT is safe, and in some patients, pretreatment with ERT can be life-saving and can allow the patient to then go on to successful HSCT. The early results of using UCB as a cell source for HSCT seem promising. UCB is usually rapidly available from UCB banks. Characteristics of this cell source are delayed engraftment, better reconstitution of progenitors, higher thymic function, and a lower incidence of graft-versus-host disease. When a choice is available, most centers transplanting many MPS I patients are using UCB over matched unrelated bone marrow donors.
Enzyme Replacement Therapy (ERT)
ERT replaces the deficient enzyme via weekly intravenous infusions. Clinical trials in MPS I, II, IV, and VI have resulted in improvements in organomegaly, endurance, and respiratory function. The best results are obtained when treatment is started early in the course of the disease. However, ERT has some limitations; none of the products can cross the blood-brain barrier, and some patients have immune-mediated reactions to the protein infusion. Anaphylaxis is an uncommon but serious complication in some individuals. The treatments are very expensive and are therefore not readily available in countries that have other pressing health care needs. Table 155-2 gives an overview of the available therapies.
TABLE 155-2ENZYME REPLACEMENT THERAPY FOR MUCOPOLYSACCHARIDOSES ||Download (.pdf) TABLE 155-2ENZYME REPLACEMENT THERAPY FOR MUCOPOLYSACCHARIDOSES
|Disorder ||Product ||Dosage per Week by Intravenous Infusion |
|MPS I ||Laronidase ||0.58 mg/kg |
|MPS II ||Idursulfase ||0.5 mg/kg |
|MPS IVA ||Elosulfase alpha ||2 mg/kg |
|MPS VI ||Galsulfase (Naglazyme) ||1 mg/kg |
Future Developments with ERT
It is likely that further studies will be done in MPS I, II, and III to determine whether ERT can offer effective delivery to the CNS. This may include direct convective delivery to the brain, injection into the ventricles or lumbar space with or without increases in dosage, or the addition of an immunosuppressant. Clinical trials are already under way for intrathecal administration in the case of MPS IIIA.
Substrate Reduction Therapy
Substrate reduction therapy (SRT) using an inhibitor of glycosphingolipid synthesis (by inhibiting glucosylceramide synthase) is a licensed treatment for managing a different lysosomal storage disorder, type 1 Gaucher disease (see Chapter 156). The approved drug miglustat (Zavesca, Actelion) is active orally, and because it is a small molecule, it can cross the blood-brain barrier. As a result, trials of miglustat are under way in several other lysosomal storage disorders that affect the brain, including MPS III; however, it has not ameliorated neurologic symptoms in individuals with neuronopathic Gaucher disease.
Genistein, an isoflavone found to be abundant in soybeans, has many important potential cellular effects. One of these is to inhibit the function of the epidermal growth factor receptor, which is required for full expression of genes coding for enzymes involved in GAG production; in turn, this leads to an inhibition of the synthesis of GAGs within the cell. However, clinical trials of genistein supplementation in MPS IIIA have yielded conflicting results about efficacy.
Appropriate education, speech therapy, physiotherapy, and occupational therapy should be offered to all patients, and parents should be given help with regard to appropriate financial support, aids, and adaptation. When dysfunctional swallowing is suspected, a formal assessment from a speech-language pathologist should be undertaken and videofluoroscopy performed if appropriate. If the child is at risk from aspiration, nonoral feeding should be instituted; most parents prefer a surgically placed gastrostomy tube rather than a nasogastric tube for this purpose.
ERT can be used as a symptomatic therapy in several situations. Intravenous ERT can rapidly reduce the size of the liver and spleen of affected patients and can improve joint stiffness. This leads to an improved quality of life and may be considered a justifiable reason for prescribing ERT in this group of patients, even though this therapy will not improve CNS disease. A clinical trial of ERT in patients under age 5 with MPS I (most of whom had the Hurler variant) describes a wide range of clinical effects across many organ systems.
MUCOLIPIDOSES, GLYCOPROTEINOSES, AND RELATED DISORDERS
The mucolipidoses are a rare group of disorders originally named because they were clinically intermediate between MPS and lipidoses. However, mucolipids do not exist in nature. Mucolipidoses (ML) I and IV are very different conditions from ML II and III. The conditions are considered together for simplicity, but it is important to note that the enzymatic basis and the clinical phenotype are very different in these conditions despite the common use of the term mucolipidosis.
PATHOGENESIS AND EPIDEMIOLOGY
All ML are inherited in an autosomal recessive manner. Prevalence varies with ethnicity; ML IV is more common in individuals of Ashkenazi Jewish ancestry. Males and females are equally affected.
Mucolipidosis Type I (ML I, Sialidosis)
ML I (sialidosis; MIM no. 256550) is a very rare, heterogeneous disorder caused by pathogenic variants in NEU1, leading to deficiency of the neuraminidase enzyme. Classically, there are 2 major phenotypes described: sialidosis type I, or cherry-red spot myoclonus syndrome (CRSM), and sialidosis type II, which is more severe. CRSM usually presents toward the end of the first decade of life with myoclonus and ataxia associated with a cherry-red spot in the macula. In the second decade of life, affected individuals typically develop ataxia, myoclonic epilepsy, and progressive vision loss. Macular cherry-red spots are always present, and in addition, small punctate opacities in the anterior and posterior subcapsular regions are usually found on ocular examination. Hepatosplenomegaly may occur. Action myoclonus can be exacerbated by excitement, stress, lack of sleep, and other factors. It may be very disabling and respond very poorly to treatment. If present, dysostosis multiplex is typically mild. There is no cognitive impairment. Eventually, affected individuals become wheelchair-bound and unable to use their hands. Feeding is disrupted, and dysarthria eventually makes communicating very difficult. Despite these profound abnormalities, patients survive well into middle age. A milder phenotype, with adult-onset myoclonus with or without mild ataxia and without cherry-red spots, has been described. The more common presentation is sialidosis type II, which may present with hydrops fetalis or after birth with cherry-red spots, coarse facial features, hepatosplenomegaly, dysostosis multiplex, short stature, and severe intellectual disability. Seizures and hearing loss may occur. Death usually occurs in the late teenage years. Currently, there is no treatment for ML I.
Mucolipidosis Type II (ML II, I-Cell Disease, Leroy Disease)
ML II (I-cell disease; MIM no. 252500) is caused by pathogenic variants in GNPTAB, which encodes for the enzyme N-acetylglucosamine 1-phosphotransferase. I-cell disease refers to inclusions observed in affected cells by microscopy. The basic biochemical defect involves an abnormality in the posttranslational modification of lysosomal enzymes in which a targeting sequence (mannose-6-phosphate) fails to be added to the maturing enzyme. Consequently, lysosomal enzymes are not routed to the lysosome but are lost to the extracellular spaces and are not able to degrade material that accumulates in lysosomes. As a result, plasma levels of several lysosomal hydrolases, including β-D-hexosaminidase, β-D-glucuronidase, β-D-galactosidase, α-L-fucosidase, and arylsulfatase A are elevated in ML II and III.
In contrast to other lysosomal storage disorders, symptoms of I-cell disease are often present at birth. Patients may have low or low-normal birth weight with poor postnatal growth. Coarse facial features may occur in infancy and progress over time. Hyperplastic gums are an important clue to diagnosis and are often noted at birth or soon after (Fig. 155-15). Otitis media occurs frequently, and the cry/voice is hoarse. Periosteal new bone formation is often prominent. Cardiac valvar disease affecting the mitral and, less frequently, aortic valves is common. Affected individuals have developmental delay, involving motor more often than speech deficits, and exhibit poor feeding. Hepatosplenomegaly is not common. In contrast to other storage disorders, the head circumference in patients with ML II is usually small, and premature sutural synostosis can occur. Death usually occurs in infancy due to cardiac failure or infection. Pulmonary hypertension may occur in individuals with longer survival.
Hyperplasia of the gums in a neonate with mucolipidosis II (I-cell disease).
Mucolipidosis Type III (ML III α/β, Pseudo-Hurler Polydystrophy)
Like ML II, ML III (MIM no. 252600) is a recessive disorder caused by pathogenic variants in GNPTAB. The GNPTAB gene encodes α and β subunits, which can lead to either ML II or a ML III clinical phenotype. The N-acetylglucosamine 1-phosphotransferase enzyme has a multisubunit structure with an α2β2γ2 structure. In contrast to ML II, ML III may also be due to pathogenic variants in GNPTG.
ML III, also known as pseudo-Hurler polydystrophy, is a slowly progressive disorder with onset in early childhood. Clinical features include short stature, slow growth, and mild-moderate dysostosis multiplex, which characteristically has the greatest impact on the ball-and-socket joints. Other features include course facial features, mild hepatosplenomegaly, and mild developmental delay. The disorder produces severe orthopedic problems secondary to progressive joint stiffness. Affected individuals are unable to raise their arms above their heads, and progressive hip dysplasia (Fig. 155-16) often leads to severe problems with mobility by early adult life. Most have carpal tunnel syndrome, and cardiac valvar lesions (typically leading to aortic incompetence) can develop later in life, requiring surgical repair.
X-ray of hips and pelvis in a patient with mucolipidosis type III (pseudo-Hurler polydystrophy). The femoral heads have been completely eroded.
Mucolipidosis Type IV (ML IV)
ML IV (MIM no. 252650) is due to defects in the MCOLN1 gene, which encodes for mucolipin 1. Affected individuals present in the first year of life with corneal opacity and severe developmental delay, and they generally reach a maximum developmental age of around 18 months for verbal and motor skills. Affected individuals experience difficulties with speech, chewing, and swallowing. Hypotonia is usually present. Although vision is usually normal at birth, severe progressive visual loss occurs due to a combination of dystrophic retinopathy and corneal opacity. Production of stomach acid may be impaired (achlorhydria), and anemia may occur due to poor gastric absorption. Progressive renal failure has been observed beginning in the third decade. There is no organomegaly or dysostosis. Affected individuals may survive into adulthood, although survival is usually attenuated. Some individuals with an attenuated phenotype have been described. Typically, they have a much slower progression of the disease and prolonged survival; clinical features include mild developmental delay and mild progressive visual loss. Management consists of physical therapy and iron supplementation to prevent iron deficiency anemia, secondary to achlorhydria.
Unfortunately, there currently is no effective cure or treatment for any of the mucolipidoses, and supportive care is all that can be offered. Some individuals with ML have received HSCT treatment, although this has not been associated with an improvement in cognitive abilities.
GLYCOPROTEINOSES AND OTHER RELATED DISORDERS
Mannosidoses (α-Mannosidase Deficiency, α-Mannosidosis; β-Mannosidase Deficiency, β-Mannosidosis)
α-Mannosidosis (MIM no. 248500) is caused by pathogenic variants in MAN2B1 and, like many lysosomal storage disorders, has a range of clinical presentation from severe to mild. Most individuals have the moderate form, diagnosed before the age of 10 years, which is characterized by coarse facial features, hearing loss, ataxia, intellectual disability, immunodeficiency, skeletal abnormalities, and rarely a beaten copper appearance to the skull x-ray. In the severe form, early death results from progressive nervous system dysfunction. In the mild form, diagnosis occurs after age 10, lacks skeletal abnormalities, and is more slowly progressive. The diagnosis can be suggested by oligosaccharide analysis of the urine. HCST has been used as a therapy in the severe and moderate forms in a few cases.
Figure 155-17 shows the characteristic clinical phenotype of a child with α-mannosidosis at presentation.
A 6-year-old boy with mannosidosis at presentation.
The clinical phenotype is not well characterized, as there have been very few reported cases. The first patients described with an isolated deficiency of β-mannosidase were adults who presented with angiokeratoma and mild learning difficulties. A severe presentation with infantile epileptic encephalopathy has also been reported.
Fucosidosis (a-Fucosidase Deficiency)
Fucosidosis (MIM no. 230000) is a rare autosomal recessive disorder due to pathogenic variants in FUCA. Neurologic characteristics include developmental delay, intellectual disability that may progress to dementia, spasticity, and seizures. Other features include dysostosis multiplex and angiokeratomas (Fig. 155-18).
Extensive angiokeratomas on the leg of a patient with fucosidosis.
Schindler Disease (α-N-Acetylgalactosaminidase Deficiency)
Although only a few patients with this disorder have been reported, a wide clinical spectrum has been described. Schindler disease (MIM no. 609241) is autosomal recessive, due to pathogenic variants in NAGA. The condition was first described in infants with severe neurologic involvement, including developmental regression, myoclonus, spasticity, and rapidly progressive dementia. Subsequent patients have been described with a mild disorder, also known as Kanzaki disease (MIM no. 609242) consisting of adult-onset angiokeratomas, hearing loss, and mild cognitive impairment. An intermediate phenotype, with cardiomyopathy and hepatomegaly, has also been described.
Aspartylglucosaminuria (Aspartylglucosaminidase Deficiency)
Although this disorder occurs in all ethnic groups, it is more common in the Finnish population. Aspartylglucosaminuria (MIM no. 208400) is an autosomal recessive disorder due to pathogenic variants in the AGA gene. Initially, development is usually normal and patients present in early childhood with speech delay. Intellectual disability worsens over time, and seizures or movement disorders may occur. Other associated features are angiokeratomas, dysostosis multiplex, joint hypermobility, osteoporosis, short stature, and dysmorphic facial features (ocular hypertelorism, small ears, sagging cheeks, full lips, short nose; Fig. 155-19).
Facial features of aspartylglucosaminuria at diagnosis, age 4 years.
Galactosialidosis (Sialidosis Type II, Combined Neuraminidase and β-Galactosidase Deficiency)
Galactosialidosis (MIM no. 256540) is an autosomal recessive disease due to pathogenic variants in CTSA, encoding the protective protein/cathepsin A (PPCA). In the neonatal form, individuals may present with hydrops fetalis, hepatosplenomegaly, inguinal hernia, coarse facial features, macular cherry-red spots, cardiomegaly, and kidney failure. The infantile form includes short stature, hepatosplenomegaly, cherry-red spots, inguinal hernia, coarse facial features, and cardiac valvular disease. In contrast, the juvenile and adulthood forms are characterized by ataxia, myoclonus, and progressive cognitive impairment. Angiokeratomas, coarse facial features, and vision/hearing loss may also be present.
Multiple Sulfatase Deficiency (MSD)
MSD (MIM no. 272200) is a very rare disorder that results from a deficiency of all lysosomal sulfatases. It is to a deficiency of the formylglycine modifying enzyme, encoded by the SUMF1 (sulfatase-modifying factor-1) gene, that converts a specific cysteine thiol residue to an aldehyde, an essential factor for the activity of all sulfatases. Most of these sulfatases are enzymes responsible for other lysosomal storage disorders. As a result, the clinical features of MSD are a heterogeneous combination of several disorders, including metachromatic leukodystrophy, Maroteaux-Lamy syndrome, X-linked ichthyosis, Hunter syndrome, Sanfilippo A syndrome, and Morquio syndrome. Consequently, individuals may have developmental delay/regression, coarse facial features, dysostosis multiplex, ichthyosis, and hepatosplenomegaly. Corneal clouding, hearing loss, and cardiac abnormalities may occur. MRI shows evidence of white matter changes similar to metachromatic leukodystrophy. Biochemical testing reveals accumulation of GAGs, sulfatides, and gangliosides. The severity of the condition can vary from a neonatal form, with death occurring in the first few years of life, to a rare adult-onset disease with attenuated symptoms.
Free Sialic Acid Storage Disorders (Salla Disease and Infantile Sialic Acid Storage Disease [ISSD])
ISSD (MIM 269920) and Salla disease (sialuria, Finnish type; MIM no. 604369) are allelic autosomal recessive disorders due to a defect in the transport of free sialic acid across the lysosomal membrane caused by mutations in SLC17A5. Salla disease is considered to be milder than ISSD, and both conditions exhibit excessive free sialic acid in the urine. In ISSD, neonatal presentation includes hydrops fetalis, hypopigmentation, recurrent severe infection, and failure to thrive (Fig. 155-20). Dysostosis multiplex, vacuolated lymphocytes, and cardiac disease are usual features, and the facial appearance is often coarse. Most affected patients die in the first year of life. Salla disease is characterized by progressive neurologic symptoms including developmental delay or regression, spasticity, seizures, and athetosis. Progression is slower than for ISSD, and patients may survive to adulthood.
An infant with infantile sialic acid storage disease. Note mild facial dysmorphism and fair hair.
MANAGEMENT OF GLYCOPROTEINOSES AND RELATED DISORDERS
For the majority of disorders, treatment is symptomatic only. ERT has not yet been developed for these disorders. HCST has been performed in α-mannosidosis, fucosidosis, and aspartylglucosaminuria and may be a useful therapy in carefully selected patients.
GENETIC COUNSELING AND PRENATAL DIAGNOSIS
All of the conditions discussed in this chapter are genetic, and diagnosis within a family should be followed by referral for appropriate genetic counseling. Prenatal diagnosis is possible for all the disorders. In some conditions, this can be done by direct enzyme assay on uncultured chorionic villus material at an early stage in pregnancy (10–12 weeks). In others, cultured cells or analysis of amniotic fluid may be more diagnostic. Genetic testing for known pathogenic variants may be performed as well. Preimplantation genetic diagnosis is also a possibility. Because of the clinical overlap between these disorders, it is imperative that an accurate diagnosis be established in the index case, before embarking on prenatal testing during subsequent pregnancies.
RM. Lysosomal storage diseases—the horizon expands. Nat Rev Neurol.
A. Lysosomal storage disorders: molecular basis and laboratory testing. Hum Genomics.
A. Lysosomal storage diseases: from pathophysiology to therapy. Annu Rev Med.