Mucopolysaccharidoses

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Chapter 82 Mucopolysaccharidoses

Mucopolysaccharidoses are hereditary, progressive diseases caused by mutations of genes coding for lysosomal enzymes needed to degrade glycosaminoglycans (acid mucopolysaccharides). Glycosaminoglycan (GAG) is a long-chain complex carbohydrate composed of uronic acids, amino sugars, and neutral sugars. The major GAGs are chondroitin-4-sulfate, chondroitin-6-sulfate, heparan sulfate, dermatan sulfate, keratan sulfate, and hyaluronan. These substances are synthesized and, with the exception of hyaluronan, linked to proteins to form proteoglycans, major constituents of the ground substance of connective tissue, as well as nuclear and cell membranes. Degradation of proteoglycans starts with the proteolytic removal of the protein core followed by the stepwise degradation of the GAG moiety. Failure of this degradation due to absent or grossly reduced activity of mutated lysosomal enzymes results in the intralysosomal accumulation of GAG fragments (Fig. 82-1). Distended lysosomes accumulate in the cell, interfere with cell function, and lead to a characteristic pattern of clinical, radiologic, and biochemical abnormalities (Table 82-1, Fig. 82-2). Within this pattern, specific diseases can be recognized that evolve from the intracellular accumulation of different degradation products (Table 82-2). As a general rule, the impaired degradation of heparan sulfate is more closely associated with mental deficiency and the impaired degradation of dermatan sulfate, chondroitin sulfates, and keratan sulfate with mesenchymal abnormalities. Variable expression within a given entity results from allelic mutations and varying residual activity of mutated enzymes. Allelic mutations of the gene encoding L-iduronidase may result in severe Hurler disease with early death or in mild Scheie disease manifesting only with limited joint mobility, mild skeletal abnormalities, and corneal opacities. Mucopolysaccharidoses are autosomal recessive disorders, with the exception of Hunter disease, which is X-linked recessive. Their overall frequency is between 3.5/100,000 and 4.5/100,000. The most common subtype is MPS-III, followed by MPS-I and MPS-II.

Figure 82-1 Degradation of heparan sulfate and mucopolysaccharidoses resulting from the deficiency of individual enzymes. Some of the enzymes are also involved in the degradation of other glycosaminoglycans (not shown).

Table 82-1 RECOGNITION PATTERN OF MUCOPOLYSACCHARIDOSES

Figure 82-2 Patients with various types of mucopolysaccharidoses. I: Hurler disease, 3 yr; II: Hunter disease, 12 yr; III: Sanfilippo disease, 4 yr; IV: Morquio disease, 10 yr; VI: Maroteaux-Lamy disease, 15 yr.

Table 82-2 MUCOPOLYSACCHARIDOSES: CLINICAL, MOLECULAR, AND BIOCHEMICAL ASPECTS

Clinical Entities

Mucopolysaccharidosis I

MPS I is caused by mutations of the IUA gene on chromosome 4p16.3 encoding α-L-iduronidase. Mutation analysis reveals 2 major alleles, W402X and Q70X, that account for more than the MPS-I alleles in the white population. The mutations introduce stop codons with ensuing absence of functional enzyme (null alleles); homozygosity or compound heterozygosity gives rise to Hurler disease. Other mutations occur in only one or a few individuals.

Deficiency of α-L-iduronidase results in a broad clinical spectrum, from severe Hurler disease to mild Scheie diseases. Homozygous or double heterozygous nonsense mutations result in severe forms of MPS I, whereas missense mutations are more likely to preserve some residual enzyme activity associated with a milder form of the disease. Varying efficacy of GAG synthesis may also influence the prognosis.

Hurler Disease

This form of MPS I (MPS I-H) is a severe, progressive disorder with multiple organ and tissue involvement that results in premature death, usually by 10 yr of age. An infant with Hurler syndrome appears normal at birth, but inguinal hernias are often present. Diagnosis is usually made between 6 and 24 mo of age with evidence of hepatosplenomegaly, coarse facial features, corneal clouding, large tongue, prominent forehead, joint stiffness, short stature, and skeletal dysplasia (see Fig. 82-2). Acute cardiomyopathy has been found in some infants <1 yr of age. Most patients have recurrent upper respiratory tract and ear infections, noisy breathing, and persistent copious nasal discharge. Valvular heart disease with incompetence, notably of the mitral and aortic valves, regularly develops, as does coronary artery narrowing. Obstructive airway disease, notably during sleep, may necessitate tracheotomy. Obstructive airway disease, respiratory infection, and cardiac complications are the common causes of death.

Most children with Hurler syndrome acquire social but only limited language skills because of developmental delay, combined conductive and neurosensory hearing loss, and an enlarged tongue. Progressive ventricular enlargement with increased intracranial pressure caused by communicating hydrocephalus may be responsible for headache and sleep disturbance. Corneal clouding, glaucoma, and retinal degeneration are common. Radiographs show a characteristic skeletal dysplasia known as dysostosis multiplex (Figs. 82-3 and 82-4). The earliest radiographic signs are thick ribs and ovoid vertebral bodies. Skeletal abnormalities in addition to those shown in the figures include enlarged, coarsely trabeculated diaphyses of the long bones with irregular metaphyses and epiphyses. With progression of the disease, macrocephaly develops, with thickened calvarium, premature closure of lambdoid and sagittal sutures, shallow orbits, enlarged J-shaped sella, and abnormal spacing of teeth with dentigenous cysts.

Figure 82-3 Dysostosis multiplex. A, Sanfilippo disease, 4 yr: The ribs are wide. B, Sanfilippo disease, 4 yr: immature, ovoid configuration of the vertebral bodies. C, Hurler disease, 18 mo: anterior-superior hypoplasia of L-1 resulting in hook-shaped appearance.

Figure 82-4 Dysostosis multiplex. A, Mucopolysaccharidosis (MPS) I-H, 10 yr. The inferior portions of the ilia are hypoplastic with resulting iliac flare and shallow acetabular fossae. The femoral necks are in valgus position. B, MPS I-H, 4 yr. Metacarpals and phalanges are abnormally short, wide, and deformed with proximal pointing of the metacarpals and bullet-shaped phalanges. Bone trabeculation is coarse and the cortices are thin. C, MPS I-S, 13 yr. The carpal bones are small leading to a V-shaped configuration of the digits. The short tubular bones are well modeled. Flexion of the middle and distal phalanges II-V is caused by joint contractures.

Hurler-Scheie Disease

The clinical phenotype of MPS I-H/S is intermediate between Hurler and Scheie diseases and is characterized by progressive somatic involvement, including dysostosis multiplex with little or no intellectual dysfunction. The onset of symptoms is usually observed between 3 and 8 yr of age; survival to adulthood is common. Cardiac involvement and upper airway obstruction contribute to clinical morbidity. Some patients have spondylolisthesis, which may cause cord compression.

Scheie Disease

MPS I-S is a comparatively mild disorder characterized by joint stiffness, aortic valve disease, corneal clouding, and mild dysostosis multiplex. Onset of significant symptoms is usually after the age of 5 yr, with diagnosis made between 10 and 20 yr of age. Patients with Scheie disease have normal intelligence and stature but have significant joint and ocular involvement. A carpal tunnel syndrome often develops. Ophthalmic features include corneal clouding, glaucoma, and retinal degeneration. Obstructive airway disease, causing sleep apnea, develops in some patients, necessitating tracheotomy. Aortic valve disease is common and has required valve replacement in some patients.

Mucopolysaccharidosis II

Hunter disease (MPS II) is an X-linked disorder caused by the deficiency of iduronate-2-sulfatase (IDS). The gene encoding IDS is mapped to Xq28. Point mutations of the IDS gene have been detected in about 80% of patients with MPS II. Major deletions or rearrangements of the IDS gene have been found in the rest; these are usually associated with a more severe clinical phenotype (see Fig. 82-2). Hunter disease manifests almost exclusively in males; it has been observed in a few females and this is explained by skewed inactivation of the X chromosome carrying the normal gene.

Marked molecular heterogeneity explains the wide clinical spectrum of Hunter disease. Patients with severe MPS II have features similar to those of Hurler disease except for the lack of corneal clouding and the somewhat slower progression of somatic and central nervous system (CNS) deterioration. Coarse facial features, short stature, dysostosis multiplex, joint stiffness, and mental retardation manifest between 2 and 4 yr of age. Grouped skin papules are present in some patients. Extensive Mongolian spots have been observed in African and Asian patients since birth and may be an early marker of the disease. Storage in gastrointestinal cells may produce chronic diarrhea. Communicating hydrocephalus and spastic paraplegia may develop due to thickened meninges. In severely affected patients, extensive, slowly progressive neurologic involvement precedes death, which usually occurs between 10 and 15 yr of age.

Patients with the mild form have a prolonged life span, minimal CNS involvement, and slow progression of somatic deterioration with preservation of intelligence in adult life. Survival to ages 65 and 87 yr has been reported; some patients had children. Somatic features are Hurler-like but milder with a greatly reduced rate of progression. Adult height may exceed 150 cm. Airway involvement, valvular cardiac disease, hearing impairment, carpal tunnel syndrome, and joint stiffness are common and can result in significant loss of function in both the mild and severe forms.

Mucopolysaccharidosis III

Sanfilippo disease (MPS III) makes up a genetically heterogeneous but clinically similar group of 4 recognized types. Each type is caused by a different enzyme deficiency involved in the degradation of heparan sulfate (see Fig. 82-1). Mutations have been found in all the MPS III disorders for which the genes have been isolated.

Phenotypic variation exists in MPS III patients but to a lesser degree than in other MPS disorders. Patients with Sanfilippo disease are characterized by slowly progressive, severe CNS involvement with mild somatic disease. Such disproportionate involvement of the CNS is unique to MPS III. Onset of clinical features usually occurs between 2 and 6 yr in a child who previously appeared normal. Presenting features include delayed development, hyperactivity with aggressive behavior, coarse hair, hirsutism, sleep disorders, and mild hepatosplenomegaly (see Fig. 82-2). Delays in diagnosis of MPS III are common due to the mild physical features, hyperactivity, and slowly progressive neurologic disease. Severe neurologic deterioration occurs in most patients by 6-10 yr of age, accompanied by rapid deterioration of social and adaptive skills. Severe behavior problems such as sleep disturbance, uncontrolled hyperactivity, temper tantrums, destructive behavior, and physical aggression are common. Profound mental retardation and behavior problems often occur in patients with normal physical strength, making management particularly difficult.

Mucopolysaccharidosis IV

Morquio disease (MPS IV) is caused by a deficiency of N-acetylgalactosamine-6-sulfatase (MPS IV-A) or of β-galactosidase (MPS IV-B). Both result in the defective degradation of keratan sulfate. The gene encoding N-acetylgalactosamine-6-sulfatase is on chromosome 16q24.3 and the gene encoding β-galactosidase, GLB1, on chromosome 3p21.33. β-Galactosidase catalyzes G_M1 ganglioside in addition to keratan sulfate, and most mutations of GLB1 result in generalized gangliosidosis, a spectrum of neurodegenerative disorders associated with dysostosis multiplex. A W273L mutation of the GLB1 gene, either in the homozygous state or as part of compound heterozygosity, commonly results in Morquio B disease.

Both types of Morquio disease are characterized by short-trunk dwarfism, fine corneal deposits, a skeletal dysplasia that is distinct from other mucopolysaccharidoses, and preservation of intelligence. MPS IV-A is usually more severe than MPS IV-B, with adult heights of <125 cm in the former and >150 cm in the latter. There is considerable variability of expression in both subtypes, however. The appearance of genua valga, kyphosis, growth retardation with short trunk and neck, and waddling gait with a tendency to fall are early symptoms of MPS IV (see Fig. 82-2). Extra skeletal manifestations include mild corneal clouding, small teeth with abnormally thin enamel, frequent caries formation, and, occasionally, hepatomegaly, and cardiac valvular lesions. Instability of the odontoid process and ligamentous laxity are regularly present and can result in life-threatening atlantoaxial instability and dislocation. Surgery to stabilize the upper cervical spine, usually by posterior spinal fusion before the development of cervical myelopathy, can be lifesaving.

Mucopolysaccharidosis VI

Maroteaux-Lamy disease (MPS VI) is caused by mutations of the ARSB gene on chromosome 5q11-13 encoding N-acetylgalactosamine-4-sulfatase (arylsulfatase B). It is characterized by severe to mild somatic involvement, as seen in MPS I, but with preservation of intelligence. The somatic involvement of the severe form of MPS VI is characterized by corneal clouding, coarse facial features, joint stiffness, valvular heart disease, communicating hydrocephalus, and dysostosis multiplex (see Fig. 82-2). In the severe form, growth can be normal for the 1st few years of life but seems virtually to stop after age 6-8 yr. The mild to intermediate forms of Maroteaux-Lamy disease can be easily confused with Scheie syndrome. Spinal cord compression from thickening of the dura in the upper cervical canal with resultant myelopathy is a frequent occurrence in patients with MPS VI.

Mucopolysaccharidosis VII

Sly syndrome (MPS VII) is caused by mutations of the GUSB gene located on chromosome 7q21.11. Mutations result in a deficiency of β-glucuronidase, intracellular storage of GAG fragments and a very wide range of clinical involvement. The most severe form presents as lethal nonimmune fetal hydrops and may be detected in utero by ultrasound. Some severely affected newborns survive for some months and have, or develop, signs of lysosomal storage including thick skin, visceromegaly, and dysostosis multiplex. Less severe forms of MPS VII present in the 1st years of life with features of MPS-I but slower progression. Corneal clouding varies. Patients with manifestation after 4 yr of life have skeletal abnormalities of dysostosis multiplex but normal intelligence and usually clear corneae. They may be found incidentally on the basis of a blood smear that shows coarse granulocytic inclusions.

Mucopolysaccharidosis IX

The disorder is caused by a mutation in the HYAL1 gene on chromosome 3p21.2-21.2 encoding 1 of 3 hyaluronidases. Clinical findings in the only known patient, a 14 yr old girl, were bilateral nodular soft tissue periarticular masses, lysosomal storage of GAGs in histiocytes, mildly dysmorphic craniofacial features, short stature, normal joint movement, and normal intelligence. Small erosions in both acetabulae were the only radiographic findings.

Diagnosis and Differential Diagnosis

Radiographs of chest, spine, pelvis, and hands are useful to detect early signs of dysostosis multiplex (see Figs. 82-3 and 82-4). Semiquantitative spot tests for increased urinary GAG excretion are quick, inexpensive, and useful for initial evaluation but are subject to both false-positive and false-negative results. Chemical quantification of uronic acid–containing substances is required to assess the total urinary excretion of GAG. Quantitative analysis of single GAG by various methods, or of oligosaccharides by tandem mass spectrometry, reveals type-specific profiles. Morquio disease is often missed in urinary assays but can reliably be diagnosed in serum using monoclonal antibodies to keratan sulfate. Any individual who is suspected of an MPS disorder based on clinical features, radiographic results, or urinary GAG screening tests should have a definitive diagnosis established by enzyme assay. Serum, leukocytes, or cultured fibroblasts are used as the tissue source for measuring lysosomal enzymes (see Table 82-2). Prenatal diagnosis is available for all mucopolysaccharidoses and is carried out on cultured cells from amniotic fluid or chorionic villus biopsy. Measurement of GAGs in amniotic fluid is unreliable. Carrier testing in Hunter syndrome, an X-linked disorder, requires analysis of the IDS gene once the specific mutation or chromosome arrangement in the family under consideration is known. Molecular analysis in patients with other mucopolysaccharidoses or in known carriers requires a specific rationale. Attempts are being made to develop methods for routine newborn screening.

Mucolipidoses and oligosaccharidoses manifest with the same clinical and radiographic features as mucopolysaccharidoses (Chapters 80.4 and 80.5). In these conditions, the urinary excretion of GAGs is not elevated. Hurler-like facial features, joint contractures, dysostosis multiplex, and elevated urinary GAG excretion differentiate the mucopolysaccharidoses from other neurodegenerative and dwarfing conditions.

Treatment

Hematopoietic stem cell transplantation results in significant clinical improvement of somatic disease in MPS I, II, and VI. Clinical effects include increased life expectancy, resolution or improvement of growth failure, upper airway obstruction, hepatosplenomegaly, joint stiffness, facial appearance, pebbly skin changes in MPS II, obstructive sleep apnea, heart disease, communicating hydrocephalus, and hearing loss. Enzyme activity in serum and urinary GAG excretion normalize. Transplantation prevents neurocognitive degeneration but does not correct existent cerebral damage. Hence, the main target group are young children with severe MPS I, anticipated neurodegeneration, who undergo transplantation before 24 mo of age and have a baseline mental development index >70. In children with anticipated normal neurodevelopment the benefits of transplantation must be weighed against its complications, including transplantation-related death or primary graft failure, which occurs in ≈30% of the patients.

Stem cell transplantation does not correct skeletal and ocular anomalies; they have to be treated with appropriate orthopedic and ophthalmologic procedures.

Enzyme replacement using recombinant enzymes is approved for patients with MPS I, MPS II, and MPS VI. It reduces organomegaly and ameliorates rate of growth, joint mobility, and physical endurance. It also reduces the number of episodes of sleep apnea and urinary GAG excretion. The enzymes do not cross the blood-brain barrier and do not prevent deterioration of neurocognitive involvement. Consequently, this therapy is the domain for patients with mild central nervous involvement. To stabilize extraneural manifestations, it is also recommended in young patients before stem cell transplantation. The combination of enzyme replacement therapy and early stem cell transplantation may offer the best treatment. Recombinant iduronate-2-sulfatase ameliorates the non-neurologic manifestations of Hunter disease, and recombinant N-Ac-gal4-sulfatase has been successfully tested in patients with MPS VI.

Primary prevention through genetic counseling and tertiary prevention to avoid or treat complications remains the mainstay of supportive pediatric care. Multidisciplinary attention to respiratory and cardiovascular complications, hearing loss, carpal tunnel syndrome, spinal cord compression, hydrocephalus, and other problems can greatly improve the quality of life for patients and their families (Table 82-3). The progressive nature of clinical involvement in MPS patients dictates the need for specialized and coordinated evaluation (Table 82-4).

Table 82-3 MANAGEMENT OF MUCOPOLYSACCHARIDOSES

PROBLEM	PREDOMINANTLY IN	MANAGEMENT
NEUROLOGIC
Hydrocephalus	MPS I, II, VI, VII	Fundoscopy, CT scan, ventriculoperitoneal shunting
Chronic headaches	All	See behavioral disturbances
Behavioral disturbance	MPS III	Behavioral or medication therapy, sometimes CT scan, ventriculoperitoneal shunting
Disturbed sleep/wake circle	MPS III	Melatonin
Seizures	MPS I, II, III	EEG, anticonvulsants
Odontoid hypoplasia	MPS IV	Cervical MRI, upper cervical fusion
Spinal cord compression	All	Laminectomy, dural excision
OPHTHALMOLOGIC
Corneal opacity	MPS I, VI, VII	Corneal transplant
Glaucoma	MPS I, VI, VII	Medication, surgery
Retinal degeneration	MPS I, II	Night light
EARS, AIRWAYS
Recurrent otitis media	MPS I, II, VI, VII	Ventilating tubes
Impaired hearing	All except MPS IV	Audiometry, hearing aids
Obstruction	All except MPS III	Adenotomy, tonsillectomy, bronchodilator therapy, CPAP at night, laser excision of tracheal lesions, tracheotomy
CARDIAC
Cardiac valve disease	MPS I, II, VI, VII	Endocarditis prevention, valve replacement
Coronary insufficiency	MPS I, II, VI, VII	Medical therapy
Arrhythmias	MPS I, II, VI, VII	Antiarrhythmic medication, pacemaker
ORAL, GASTROINTESTINAL
Hypertrophic gums, poor teeth	MPS I, II, VI, VII	Dental care
Chronic diarrhea	MPS II	Diet modification, loperamide
MUSCULOSKELETAL
Joint stiffness	All except MPS IV	Physical therapy
Weakness	All	Physical therapy, wheelchair
Gross long bone malalignment	All	Corrective osteotomies
Carpal tunnel syndrome	MPS I, II, VI, VII	Electromyography, surgical decompression
ANESTHESIA	All except III	Avoid atlantoaxial dislocation, use angulated videointubation laryngoscope and small endotracheal tubes