James Edmond Wraith
The mucopolysaccharidoses (MPS) are a family of disorders that are caused by inherited defects in the catabolism of sulfated components of connective tissue known as glycosaminoglycans (GAGs). In affected patients, one or more of three specific polymers—dermatan sulfate (DS), heparan sulfate (HS), and keratan sulfate (KS)—accumulate within the cells, interfering with normal function, and are excreted in excess in the urine.
The enzymes associated with GAG catabolism are all lysosomal hydrolases, and patients with an MPS disorder usually have less than 1% residual enzyme activity. Heterozygote detection based on enzyme activity alone is inaccurate and is now, fortunately, no longer necessary, as the genes encoding the enzymes involved in GAG catabolism have been identified and sequenced. Phenotypic variability (heterogeneity) is very much a feature of MPS disease, and within each specific enzyme deficiency there is a very wide spectrum of clinical effects. Although the disorders are most often known by their eponymous titles (eg, Hurler syndrome), this has led to an oversimplification in the classification of the subtypes, which should be kept in mind when interpreting the data in Table 160-1. A comprehensive review of the biochemistry and molecular biology of these disorders can be found in Neufeld and Muenzer, 2001.1
MPS disorders, like all lysosomal storage diseases, are progressive conditions. Affected infants are usually normal at birth, and the disease is suspected only as the phenotype evolves with time. Infants with an MPS-like phenotype present at birth are most likely to have mucolipidosis type II (I-cell disease) or GM1 gangliosidosis.
Table 160-1. The Mucopolysaccharidoses
The MPS disorders tend to present in one of three ways:
• As a dysmorphic syndrome (eg, MPS IH, MPS II, MPS VI)
• With learning difficulties, behavioral disturbance, and dementia (eg, MPS III)
• As a severe bone dysplasia (eg, MPS IV)
The diagnosis is based on clinical suspicion, supported by appropriate clinical and radiological examinations followed by urinary examination for GAG excretion and then by specific enzyme assay, usually on white blood cells. Urinary screening tests for MPS disorders may be inaccurate, and false-negative results, especially in MPS III and IV, are well recognized. Furthermore, patients with mucolipidosis or glycoproteinoses do not have excessive excretion of GAG. Therefore, a negative screening test should not dissuade the clinician from vigorously pursuing a diagnosis in a clinically suspicious case. Although algorithms aimed at helping the diagnostic process have been developed, their use in clinical practice is limited by the extreme heterogeneity in this group of disorders.
If urinary GAG analysis by electrophoresis is negative, one needs to consider other diagnostic possibilities. 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. Radiographs should be reviewed to confirm the presence of dysostosis multiplex (Fig. 160-1), 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 nonlysosomal disturbances can mimic storage disease (eg, Coffin-Lowry syndrome, Williams syndrome, and geleophysic dysplasia).
All MPS disorders are multisystem diseases, and effective management depends on a multidisciplinary approach involving many different clinical specialties and access to expert support services. The pediatrician has a major role in orchestrating the various members of the therapeutic team. Anesthesia is particularly difficult in these patients, and surgery should be performed only in centers in which there is access to anesthetists who are used to dealing with difficult pediatric airways and who have access to pediatric intensive care. Many patients survive through adolescence and into adult life, and careful planning of the transition between pediatric and adult services is necessary.
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 a gross oversimplification; it is preferable to consider the disorders on a clinical spectrum. Although many conditions are compatible with prolonged survival, for the majority of patients, these are not benign conditions.
MUCOPOLYSACCHARIDOSIS TYPE I
Patients with MPS IH (Hurler syndrome) are usually diagnosed toward the end of the first year of life, when the facial phenotype becomes obvious (Fig. 160-2). The younger a patient presents, the more likely he or she is to have a severe form of MPS I (Hurler syndrome).3 Many will have presented with inguinal and umbilical hernias and with recurrent respiratory infections before the diagnosis is established. Parents often notice the lower thoracicupper lumbar gibbus but are usually reassured that the abnormality is only postural and not of importance. A number of patients will have a large head circumference, and communicating hydrocephalus will develop in up to 40% of patients. The early clinical picture is dominated by the upper respiratory tract obstruction secondary to the midface hypoplasia, the large tongue, and the infiltration of the respiratory tract by accumulating GAG. Obstructive sleep apnea is usual, and all affected children require expert ear, nose, and throat (ENT) assessment; most require ENT surgery. Although growth for the first 12 to 18 months of life is normal, the effects of the skeletal dysplasia eventually lead to severe growth restriction. In addition, all patients have a dysplastic odontoid process and are at risk of sudden and severe spinal cord damage secondary to atlantoaxial subluxation (eFig. 160.2 ). Hepatosplenomegaly and progressive cardiac disease develops, and corneal deposition of GAG becomes clinically apparent as corneal clouding during the second year of life in most patients. Although learning difficulties are a feature of all patients with the severe forms of iduronidase deficiency, developmental progress can be surprisingly good over the first 2 or 3 years and often contrasts greatly with the affected child’s physical appearance. Deafness is usually present and must be diagnosed early and treated appropriately.
FIGURE 160-1. A: Dysostosis multiplex. Hypoplastic and hooked lumbar vertebral body (arrowed) at the site of thoracolumbar gibbus in a patient with 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).
Although corneal clouding can be significant, severe visual loss is usually due to retinal or postretinal involvement. Sudden blindness can occur due to compression of the optic nerve within the optic sheath. Although glaucoma is said to be common, this is often over-diagnosed as increased corneal thickness gives rise to erroneous measurements of intraocular pressure. The ophthalmic and otolaryngological complications of the mucopolysaccharidoses have been reviewed recently.4,5
Prognosis depends upon the severity of cardiac involvement. This can range from a very severe cardiomyopathy, causing death in the early months of life, to progressive valve involvement (usually mitral and aortic) with relatively good left ventricular function and survival up to the end of the first decade and occasionally beyond. Coronary artery disease can be severe, and episodes of cardiac ischemia and infarction can occur.
At the other end of the clinical spectrum from Hurler syndrome are those patients diagnosed in late childhood or early adult life, usually because of their orthopedic or oph-thalmologic problems. In MPS IS (Scheie syndrome), intellectual development is normal, and the disorder is compatible with 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 this type of MPS disorder. In some patients, corneal haze 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 retinop-athy, which also occurs in MPS IS. The clinical presentation of this form of MPS I has recently been reviewed.6
FIGURE 160-2. Facial features in MPS IH at diagnosis, age 12 months. Mid-face hypoplasia, “button” nose, thick lips.
Between these two extremes is a continuous clinical spectrum that is often labeled MPS IH/S (Hurler/Scheie syndrome; see Fig. 160-3). These patients may develop late-onset neurological deterioration, but most of the active clinical problems relate to the progressive joint stiffness and the degenerative bone disease that commonly occurs. Spondylolisthesis of L5/S1 is very common and requires surgical repair (eFig. 160.4 ). Progressive visual loss due to a combination of corneal clouding (eFig. 160.5 ) and retinal disease is usual, and many patients will develop progressive cardiac disease. Frequent chest infections, limited chest expansion, and upper respiratory obstruction are common. In addition, many patients have a relative micrognathia (eFig. 160.6 ) and are unable to open their mouths widely. Sleep apnea can be troublesome, and routine pulse oximetry overnight during sleep should be performed annually. Some patients 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, and it is often associated with an increase in airway secretions that requires frequent suction.
The gene coding for a-L-iduronidase is on chromosome 4p16.3 and consists of 14 exons. Many different mutations have been described, especially in the more severe forms of MPS I. Two nonsense mutations—p.W402X and p.Q70X—are relatively common in Europe, although their incidence varies from country to country. The molecular biology of MPS I has been reviewed recently.7
FIGURE 160-3. A patient with an intermediate form of MPS I (MPS IH/S, Hurler-Scheie disease). Note the joint stiffness and the relatively normal facial appearance.
FIGURE 160-4. A lateral MRI scan of the craniocervical junction in a patient with MPS II. Notice the lack of CSF around the cervical cord (arrowed) due to thickening of ligaments and dura. The odontoid is also dysplastic.
MUCOPOLYSACCHARIDOSIS TYPE II
The clinical features in MPS II are even more heterogeneous than in MPS I. At the severe end of the clinical spectrum, the disorder is very similar to MPS IH but is generally milder, allowing for survival into the mid teens. At the other end of the spectrum, survival into adult life with reproduction is possible. There are two important differences from MPS I: First, the disorder is inherited as an X-linked recessive condition (it is the only X-linked MPS disorder; all the rest are recessives), and, second, corneal clouding does not occur to any significant degree in the vast majority of patients.
In severely affected patients, the diagnosis is usually established around the second birthday because of a combination of learning difficulties, middle-ear disease, a history of hernia repairs, and a coarse facial appearance. Many patients have troublesome diarrhea, and most develop joint stiffness and organomegaly. A nodular rash around the scapulae and on the extensor surfaces is considered pathognomonic of the disorder but is actually rare in childhood. The learning difficulties are different from those in MPS IH, as most patients with MPS II make more developmental progress than the typical MPS IH patient. The behavioral phenotype is also different, with challenging behavior, attention deficit disorder, and seizures being much more common in MPS II than in MPS IH. Cardiomyopathy (apart from asymmetric septal hypertrophy) is rare in MPS II, but progressive valve lesions can occur, although these rarely lead to symptoms.
In patients with less severe forms of MPS II, cervical cord compression due to hyperplasia of the dura and ligamentum flavum can lead to a progressive cervical myelopathy (Fig. 160-4). This usually presents with decreasing exercise tolerance that can be mistaken for a progression of the joint stiffness unless a careful neurological examination is performed. 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 all patients with cervical compromise. Fortunately, atlantoaxial instability is usually not a feature of MPS II, as the odontoid is usually well developed; therefore, spinal fusion in addition to the decompression is usually not required.
Despite often gross abnormality on cerebral imaging, intellectual development is normal in this form of MPS II, but the severe somatic features present in some intellectually normal men lead to considerable psychosocial problems, which require sensitive and careful handling.
Most adults with MPS II develop upper respiratory obstruction and sleep apnea. Many benefit from the use of nasal CPAP devices, although the nasal masks often have to be shaped individually because of the abnormal facial anatomy.
Although MPS II is an X-linked disorder, an occasional affected female patient has been described. This can occur as a result of chromosomal translocation or nonrandom X-inactivation. Most affected girls have an intermediate phenotype with preserved cognitive function (eFig. 160.7 ).
The MPS II gene is large and is located at Xq27-28. In affected boys, a whole range of molecular pathologies have been described, including insertions, deletions, point mutations, and splice-junction mutations. There are no common mutations, and it is often difficult to predict severity from the molecular lesion. In some patients, no abnormalities are detected despite sequencing of the whole coding region, and it is assumed that other regulatory elements must be involved in the disease. The molecular biology of MPS II has been recently reviewed.9
MUCOPOLYSACCHARIDOSIS TYPE III
This MPS disorder is a clinically similar but biochemically heterogeneous group of four recognized conditions all associated with an inability to catabolize heparan sulfate. MPS IIIA is the most common MPS disorder in the UK (and many other countries) and accounts for 80% of all MPS III patients in this population. The remaining patients are mainly MPS IIIB; types IIIC and IIID are rare.
The hallmark of MPS III is severe central nervous system (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),12 when compared to other MPS disorders, and the condition is less heterogeneous than MPS I or II. In a typically affected patient, a triphasic illness can be recognized. The first phase, often before diagnosis, consists of only developmental delay. There is often a history of recurrent upper respiratory infections, 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.
Gradually the characteristic behavioral phenotype evolves as the second phase of the illness starts, usually in late infancy. This comprises severe challenging behavior with extreme hyperactivity and often aggression. In addition, there is a complete disregard for danger, and the children are a risk to themselves and others and need constant attention. Temper tantrums are frequent, and normal family life for many families becomes impossible. It is during this phase that the diagnosis is established in the majority of patients. As the disease advances, developmental milestones are lost and increasing spasticity leads to progressive loss of motor skills. Precocious pubertal development is a well-recognized association.
The third and final stage of the illness usually begins in the early teenage years and is characterized by further loss of skills leading to swallowing dysfunction; eventually the disorder culminates in a vegetative existence in the mid-to-late teens. Death usually occurs around the second decade, although patients with MPS IIIC may have a more attenuated course and can survive in to the third or fourth decade.
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 disturbance with prolonged crying can be extremely distressing for the parents of affected children.
Somatic features are usually mild (Fig. 160-5), except in some patients from the Asian subcontinent who can develop severe cardiac involvement (usually mitral valve disease but occasionally a dilated cardiomyopathy).
The disorder is probably underdiagnosed at the less severe end of the clinical spectrum, as these patients may have only mild learning difficulties until the age of 20 to 30 years.
Mutation analysis has been performed extensively in MPS IIIA and IIIB. The MPS IIIA gene is located on chromosome 17q25.3 and consists of eight exons. Considerable genetic heterogeneity has been demonstrated and a wide range of mutations described; p.R245H and p.R74C have a combined frequency of over 50% in some European populations. The MPS IIIB gene is situated on chromosome 17q21.1 and consists of six exons. An even greater degree of genetic heterogeneity is seen in this disorder, and there are no common mutations.
The MPS IIIC gene has recently been cloned,13 and the MPS IIID gene is of academic interest only because so few patients with MPS IIID have been identified.
MUCOPOLYSACCHARIDOSIS TYPE IV
Patients with MPS IV have a severe skeletal dys-plasia and, unlike the other MPS conditions, are not dysmorphic. In addition, CNS involvement does not occur, and the clinical course is dominated by the severe bone disease and resulting extreme short stature. The diagnosis can be established in the newborn period but more commonly is made toward the end of the first year of life, when the sternal protrusion, which occurs as a result of the short trunk, becomes obvious. The radiological 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 (see Fig. 160-6).
FIGURE 160-5. Facial features in a 7-year-old MPS III boy at diagnosis.
Most severely affected adults are under 105 cm in height and have a typical clinical phenotype of fixed hip flexion, genu valgum and pes planus with midthoracic gibbus, sternal protrusion, and a very short neck. The greatest immediate danger to these patients is the inevitable odontoid dysplasia that is present in all severely affected patients (Fig. 160-7). Without treatment, 60% of MPS IV patients suffer an irreversible neurological deficit by age 6 years. 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.
FIGURE 160-6. Lateral spine x-ray of MPS IV. Generalized vertebral abnormality (platyspondyly) is present in contrast to the single vertebral anomaly seen in MPS IH (Fig. 160-1).
FIGURE 160-7. Odontoid dysplasia (arrowed) in a patient with MPS IV.
Flexion/extension radiographic views of the cervical spine are helpful in identifying those 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 following diagnosis. The timing of cervical fusion remains contentious, but most groups are moving toward prophylactic fusion in those patients whose radiographs show atlantoaxial subluxation. 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 the 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 in this group of patients (Fig. 160-8).
Although this disorder is commonly reported to be associated with “ligamentous laxity,” this is not the case. The ligaments and tendons are generally stiffer than normal (similar to other MPS disorders), but the skeleton is poorly ossified. The excess movement present at the wrist is due to the cartilaginous nature of the carpal bones, as readily demonstrated by x-rays of the hand.
Dental decay is common, secondary to enamel hypoplasia, and the teeth are generally pointed and widely spaced.
A number of patients will develop aortic insufficiency or mild corneal haze as adults, but these rarely need treatment. The biggest problem for older patients is the restrictive respiratory disease that often leads to respiratory failure in adult life and is the most common cause of death.
At the less severe end of the spectrum, the odontoid is not dysplastic, and the patients are not at risk of cervical myelopathy. Growth may be normal or marginally affected, and the usual complaints relate to hip involvement that may require corrective surgery.
The MPS IVA gene is located on chromosome 16q24, and extensive allelic heterogeneity has been demonstrated on mutation analysis. In British/Irish patients, the p.I113F mutation is relatively common (20%) and produces a severe form of the disease when homoallelic. For a comprehensive review of MPS IVA, the reader should consult a recent review.14
MUCOPOLYSACCHARIDOSIS TYPE VI
MPS VI is an uncommon disorder (1:500,000) and, like other MPS conditions, is associated with considerable heterogeneity. In the typical or severe form of the disease (sometimes referred to as the “rapidly progressing” form), the clinical phenotype is similar to MPS IH, but the intellect is preserved. All patients, even those at the less severe end of the clinical spectrum (“slowly progressing” form of the disease), are at risk from 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 patients with cervical cord disease until the time of operation.
Upper respiratory obstruction, middle-ear disease, corneal clouding, and progressive joint stiffness all occur. Cardiac involvement is universal and can be severe, including a neonatal presentation with endocardial fibroelastosis. In severely affected patients, diffuse airway narrowing can lead to cor pulmonale with age.
The MPS VI gene is located on chromosome 5q13-q14. No common mutations have been detected, and the mutations identified have been reviewed recently.17
MUCOPOLYSACCHARIDOSIS TYPE VII
MPS VII is a rare disorder, and its importance is largely due to the research work that has been done on the murine model of the disease. This work has provided important information about therapeutic options in MPS disorders in general, including response to bone marrow transplantation, enzyme replacement therapy, and gene augmentation. Affected patients are few in number, as one of the main modes of presentation is with hydrops fetalis. Patients who survive to delivery often have a severe Hurler phenotype, although, like other MPS disorders, there is considerable heterogeneity.
FIGURE 160-8. A 10-year-old girl with MPS IV. The immobility leads to obesity in many affected children.
The MPS VII gene is located on chromosome 7q21.1-q22 and consists of 12 exons. The relative rarity of MPS VII has rendered mutation analysis to be of academic interest only.
MUCOPOLYSACCHARIDOSIS TYPE IX
A 14-year-old girl with mild short stature and multiple periarticular soft-tissue masses has been described.22 There was no other visceral or CNS involvement, although synovial histology revealed abundant lysosomal storage. The patient was subsequently shown to have a mutation in the HYAL1 gene on chromosome 3p21.3, which results in a deficiency of hyalu-ronidase and an accumulation of hyaluronic acid (hyaluronan [HA]), a large GAG abundant in the extracellular matrix. The disorder has been labeled MPS IX; as yet, no further patients have been described.
MANAGEMENT OF MPS
Definitive/curative treatment for most MPS disorders affecting the brain is still not possible despite numerous recent advances. However, 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 pediatric review.
Palliative therapies in severe MPS I, II, and VI include treating hydrocephalus, middle-ear disease, and regular analgesia for joint pain and stiffness. Because of the limited life expectancy in patients with severe MPS I and II, more aggressive therapies such as surgical correction of the gibbus abnormality or cardiac surgery are not indicated. Appropriate education, speech therapy, physiotherapy, and occupational therapy should be offered, and parents should be given help with regard to appropriate financial support, aids, and adaptations.
In patients with less severe forms of these disorders, a more aggressive approach is justified. These individuals may require neurosurgical interventions to prevent cervical cord disease, and many require regular ENT and orthopedic assessments. Cardiac status requires monitoring, and in patients with MPS I and VI, oph-thalmologic follow-up is essential.
Patients with MPS III provide a very different clinical challenge. The behavioral problems and sleep disturbance require attention, although both are resistant to treatment. It is preferable to try improving the child’s sleep pattern first, as the parents are more able to deal with the challenging behavior if fully rested. Chronic exhaustion due to sleep deprivation magnifies the clinical problems and creates an unsuitable therapeutic environment within the home. Hypnotic medication can be successful but is usually only of transient benefit. 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. The challenging behavior responds poorly to a psychological or behavioral approach, and the children are effectively “un-trainable.” In some patients, the hyperactivity can be extremely intense and completely resistant to treatment. The use of a major tranquil-izer is often necessary to modify aggressive or destructive behavior, and the hyperactivity generally responds poorly to amphetamine derivatives. In patients with the most severe behavioral disturbance, oversedation or other side effects of medication are constant risks. Environmental modification within the home is an essential part of management. Seizures usually respond well to a normal anticonvulsant regimen, although there are exceptions.
When swallowing dysfunction starts to produce coughing, often with drinks before solids, a formal assessment from a speech-language pathologist should be done. This usually involves performing a special radiological study of the swallowing process (videofluoroscopy). If the child is at risk from aspiration, nonoral feeding should be instituted; most parents prefer a surgically placed gastrostomy tube rather than a naso-gastric tube for this purpose.
In MPS IV, attention should be focused on the cervical cord and the prevention of irreversible neurological disease. In older patients, managing the respiratory failure is difficult, as the patients do not respond well to nasal continuous or bilevel positive airway pressure (CPAP or BiPAP). It is important to ensure that the patients receive influenza vaccine and that any respiratory infection is treated with the utmost seriousness. Efforts to improve sitting posture and breathing exercises may be helpful for patient morale but probably achieve very little clinically. Very careful attention to weight management is essential. In view of the patient’s immobility, calorie needs are very low; unfortunately, obesity is very common and compounds the motor and respiratory difficulties.
Hematopoietic Stem Cell Transplant (HSCT) Since 1980, bone marrow transplantation (BMT) has been used as a crude form of “gene therapy” in patients with MPS.24 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, there is no doubt that BMT will alter the natural history 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 likely to be reserved for patients with severe MPS I alone.
In MPS IH, the prime objective is to avoid the intellectual deterioration; consequently, BMT must be performed at an early age (< 18 months). Following a successful BMT, urinary GAG excretion quickly increases and then falls to the normal range after 3 to 6 months. Organomegaly resolves and there is incomplete clearing of the cornea. Cardiomyopathy, if present, is also successfully treated. 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 the long bones grow better, 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 them their only chance of long-term survival.
Enzyme Replacement Therapy Enzyme replacement therapy (ERT) is intuitively attractive as a treatment, and the relevant enzymes can now be manufactured in large quantities by molecular means. Proof of principle in animal models has been followed by successful clinical trials in MPS I,29 MPS II,30 and MPS VI.31 In treated patients, an improvement in endurance (as measured by a 6- or 12-minute walk test) and respiratory function has been demonstrated. It is becoming clear that 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 (BBB), and some patients have immune-mediated reactions to the protein infusion, although these have generally tended to be mild. The treatments are very expensive and are therefore not readily available in countries that have other pressing health care needs.
MUCOLIPIDOSES, GLYCOPROTEINOSES, AND RELATED DISORDERS
The disorders to be considered in this section are summarized in Table 160-2.
The terminology used for this group of conditions is confusing, and mucolipidoses (ML) I and IV are very different conditions from ML II and III, which are allelic. The conditions are considered together for simplicity, but it is important to note that the enzyme basis, stored material, and clinical disturbance is very different despite common use of the term mucolipidosis.
Mucolipidosis Type I (Neuraminidase Deficiency; Sialidosis I, Cherry-Red Spot-Myoclonus Syndrome, ML I)
This is a very heterogeneous disorder that ranges in presentation from hydrops fetalis to a more chronic disorder (juvenile sialido-sis) that presents with myoclonus and ataxia associated with a macular cherry-red spot. Dementia occurs very late, if at all, in this variant, and prolonged survival is usual. The most common mode of presentation is between these two extremes (childhood sialidosis), which produces a mild Hurler-like phenotype, mild dysostosis multiplex, and a cherry-red spot. Death usually occurs in the late teenage years.
Mucolipidosis Types II and III (UDP-N-Acetylglucosamine:Lysosomal Enzyme N-Acetylglucosaminyl-L-Phosphotransferase Deficiency; I-Cell Disease: ML II; Pseudo-Hurler Polydystrophy: ML III)
ML II and ML III represent two ends of the same disease spectrum. 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, where they are inactive. As a result, a variety of substrates accumulate within the ly-sosomes and interfere with normal cellular function.
Table 160-2. The Mucolipidoses, Glycoproteinoses, and Other Related Disorders
ML II produces very severe clinical and radiological abnormalities and can present in the newborn period with a Hurler phenotype and with a severe dysostosis that may be associated with intrauterine or neonatal fractures. Periosteal new bone formation is often very prominent. Hyperplastic gums soon after birth are an important clue to diagnosis (Fig. 160-9). Affected patients often make little developmental progress and are often extremely difficult to feed; some succumb early to cardiomyopathy and may have significant coronary artery disease (eFig. 160-12 ). 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.
ML III, on the other hand, can be a very mild disorder with survival into the fifth and sixth decades of life. Mild developmental problems are usual, although not present in all patients. The disorder produces severe orthopedic problems secondary to the progressive joint stiffness. The underlying dysostosis differs from that seen in MPS and characteristically affects the ball-and-socket joints most severely. Affected patients are unable to raise their arms above their heads, and progressive hip dysplasia (Fig. 160-10) often leads to severe problems with mobility by early adult life. Most patients have carpal tunnel syndrome, and cardiac valve lesions (usually aortic incompetence) can develop later in life.
FIGURE 160-9. Hyperplasia of the gums in a neonate with mucolipidosis II (I-cell disease).
Mucolipidosis Type IV
ML IV is a very rare disorder that is most commonly seen in children of Ashkenazi-Jewish extraction. The disorder is due to defects in the MCOLN1 gene (Ashkenazi common mutations: IVS3-2A > G and 511 > 6944del), which encodes for a 65-kDa protein known as mucolipin 1, a member of the transient receptor potential ion channel family (TRP). This cation channel appears to be important in the acidification and maintenance of normal endosomal function.38
Affected Ashkenazi children 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. Severe visual loss is due to a combination of corneal opacity and retinal degeneration. There is no organomegaly or dysostosis and no deficiency of any lysosomal hydrolase. In non-Ashkenazi children, the disorder can be more variable; some attenuated patients have been described with a much slower progression of the disease and prolonged survival. In most patients, gastric parietal cell involvement leads to achlorhydria, and the subsequent rise in plasma gastrin levels can be a useful diagnostic clue. In Ashkenazi patients, diagnosis is best achieved by specific gene mutation studies that look for the common mutations. In non-Ashkenazi patients, diagnosis depends on clinical suspicion and electron microscopy of skin fibroblasts demonstrating storage vacuoles.
Management of Mucolipidoses
Unfortunately, there is no effective curative treatment for any of the mucolipidoses, and palliative care is all that can be offered. Some patients with ML have received HSCT treatment, although this has never been associated with any improvement in cognitive abilities.
FIGURE 160-10. X-ray of hips and pelvis in a patient with mucolipidosis type III (pseudo-Hurler polydystrophy). The femoral heads have been completely eroded.
GLYCOPROTEINOSES AND OTHER RELATED DISORDERS
Mannosidoses (α-Mannosidase Deficiency, α-Mannosidosis; β-Mannosidase Deficiency, β-Mannosidosis)
The term mannosidosis usually refers to α-mannosidosis, which is the most common of the mannosidoses. In this heterogeneous disorder, presentation can be severe in the first months of life with a Hurler-like disorder, or much later with a more prolonged clinical course with survival into middle age. Immunologic abnormalities are noted in most patients. Severe middle-ear and respiratory infections are common, and immune deficiency caused by inadequate antibody production and decreased white-cell killing has been demonstrated in affected patients.
α-Mannosidosis was known to exist in goats long before it was identified in humans. The clinical phenotype is not well characterized, as there have been very few reported cases in humans. The first patients described with an isolated deficiency of β-mannosidase were adults who presented with angiokerato-ma and mild learning difficulties. A severe presentation with infantile epileptic enceph-alopathy has also been reported.
Fucosidosis (a-Fucosidase Deficiency)
Fucosidosis is a rare disorder that produces symptoms and signs similar to mannosidosis, although the neurodegeneration has a tendency to be more aggressive in progression. In addition, the dysostosis and somatic abnormalities tend to be less obvious than in mannosidosis. Angiokeratoma can be extensive in some older patients with less severe forms of the disease (sometimes called fucosidosis type II, see eFig. 160.14 ).
Schindler Disease (α-N-Acetylgalactosaminidase Deficiency)
Although only a few patients with this disorder have been reported, a wide clinical spectrum has been described. The condition was first described in infants with severe neurological involvement, including myoclonus, spasticity, and rapidly progressive dementia. Histologic studies suggested a form of neu-roaxonal dystrophy. Subsequent patients have been described with a very mild disorder consisting of angiokeratoma but no overt neurological disease.42
Aspartylglucosaminuria (Aspartylglucosaminidase Deficiency)
Although this disorder occurs in all ethnic groups, it is relatively more common in the Finnish population. The disorder usually presents in infancy or early childhood with speech delay, middle-ear disease, and behavioral disturbance that can mimic Sanfilippo syndrome (eFig. 160.15 ). With time, however, the somatic features become more obvious, with facial coarsening and dysostosis multiplex; by the teenage years, these features are usually well developed. Survival well into adult life is usual.
GM1 Gangliosidosis (Isolated β-Galactosidase Deficiency)
β-Galactosidase activity is required for the catab-olism of GM1 ganglioside, galactose-containing glycoproteins, and keratan sulfate. Different mutations in the β-galactosidase gene appear to affect activity toward these substrates differently, resulting in a tremendous variability in clinical effect in β-galactosidase-deficient patients. The most severely affected patients present in the newborn period with generalized gangliosidosis. In this rapidly progressive disorder, a Hurler phenotype can be noted at or soon after birth. Most severely affected infants make little or no developmental progress and die in infancy from progressive neurodegeneration. Half of the patients with this early onset variant will have macular cherry-red spots (CRS), and there is usually visceromegaly and dysostosis multiplex. Later-onset variants known as late-infantile or juvenile and adult GM1gangliosidosis have been described.
Finally, as previously described, several patients with a phenotype indistinguishable from that of MPS IVA (Morquio syndrome) have been described. Here, the β-galactosidase mutation seems to predominantly affect keratan sulfate catabolism.
Galactosialidosis (Sialidosis Type II, Combined Neuraminidase and β-Galactosidase Deficiency)
Galactosialidosis is a heterogeneous disorder that manifests in utero with hydrops fetalis or later in infancy (infantile), childhood (juvenile), or adult life. The basic biochemical defect is in protective protein/cathepsin A (PPCA), which, when defective, leads to an intralysosomal pro-teolysis of β-galactosidase and neuraminidase. The majority of reported patients are of Japanese ancestry and present with mild clinical features. The clinical features are similar to the cherry-red spot myoclonus syndrome, although the skeletal disease is usually more obvious. Mental retardation is usually mild, and the disorder is only slowly progressive.
Multiple Sulfatase Deficiency
Mucosulfatidosis results from a deficiency of all sulfatases, both lysosomal and microsom-al. The multiple enzyme insufficiency results from a deficiency of a protein (sulfatase-modifying factor-1 coded for by the SUMF1 gene) that converts a specific cysteine thiol residue to an aldehyde, an essential and limiting factor for the activity of all seven sulfatases. Coexpression of SUMF1 with sulfatases results in a strikingly synergistic increase of enzymatic activity.
Biochemical testing reveals accumulation of GAGs, sulfatides, and gangliosides in the brains of affected children. Cerebral white-matter histology and biochemistry reveals features similar to those in metachromatic leukodystrophy. Clinically affected patients are ichthyotic due to a deficiency in steroid sulfatase and have a profound neurological handicap. Mild dysmorphism is usually present along with radiological evidence of dysostosis multiplex. Death usually occurs in childhood.
Salla Disease (Sialic Acid Transporter Defect, Infantile Sialic Acid Storage Disease [ISSD])
ISSD and Salla disease (so called because it is seen in the Salla area of Finland) are variants of the same basic defect: a deficiency in the transport of free sialic acid across the lysosomal membrane. Along with excessive intracellular accumulation of sialic acid is excessive urinary excretion that is readily detected by urinary oli-gosaccharide analysis.
In ISSD, a dramatic neonatal presentation can occur with hydrops fetalis, hypopigmentation, recurrent severe infection, and failure to thrive (eFig. 160.16 ). Dysostosis multiplex, vacuolated lymphocytes, and cardiac disease are usual, and the facial features are often coarse. Most affected patients die in the first year of life.
Salla disease is a less severe presentation of the same disease. Most patients of Finnish origin present in the first year or two of life with learning difficulties, but progression is slower and patients survive well into adult life.
Management of Glycoproteinoses and Related Disorders
For the majority of disorders, treatment is palliative only. BMT has been performed in α-mannosidosis, fucosidosis, and aspartylglucosaminuria, and although the numbers treated remain small, HSCT may prove to be a useful therapy in carefully selected patients.
GENETIC COUNSELING, PRENATAL DIAGNOSIS
All of the conditions discussed in this chapter are genetic, and diagnosis within a family should be followed by referral for appropriate counseling. In some conditions (eg, the X-linked disorder MPS II [Hunter syndrome]), carrier detection may be a priority within the family. Prenatal diagnosis is possible for all the disorders. In some conditions, this can be done by direct enzyme assay on uncultured chorion villus material, which provides a speedy result at an early stage in pregnancy (10–12 weeks). In other disorders, cultured cells or analysis of am-niotic fluid may be more relevant. Because of the clinical overlap between these disorders, it is imperative that an accurate biochemical diagnosis be established in the index case before embarking on prenatal testing and that the various possibilities be discussed with the metabolic laboratory before samples are collected.
Because these disorders are relatively rare, management should be centralized within the regional metabolic or genetics unit.