Mucopolysaccharidoses: Clinical features and diagnosis

INTRODUCTION — The mucopolysaccharidoses (MPS) are lysosomal storage disorders caused by the deficiency of enzymes required for the stepwise breakdown of glycosaminoglycans (GAGs), previously known as mucopolysaccharides (table 1) [1-3]. Fragments of partially degraded GAGs accumulate in the lysosomes, resulting in cellular dysfunction and clinical abnormalities. The clinical features and diagnosis of the MPS are reviewed here. The management of these disorders and associated complications are discussed separately. (See "Mucopolysaccharidoses: Complications".)

EPIDEMIOLOGY — The MPS are rare conditions, with an estimated total incidence of all types of MPS of approximately 1 in 20,000 live births [4-7].

PATHOGENESIS — Glycosaminoglycans (GAGs) are large, complex polymers of linear, repeating sulfated acidic and amino sugar disaccharide units attached to a protein core. They are widely distributed in many tissues, where they play important roles. As examples, they are components of the ground substance of bone and cartilage, lubricant in joint fluid, and the surface coating that initially binds growth factors to cells.

The metabolic recycling of GAGs requires the stepwise degradation of the terminal sulfate, acidic, and amino sugar residues by a series of lysosomal enzymes. The deficiency of one of these enzymes blocks degradation of the substrate and results in a specific disorder. The clinical phenotype of the disorder depends upon both the amount of residual enzyme activity and the distribution and turnover of the substrate affected by the deficiency, rather than the distribution of the enzyme.

GENETICS — All of the MPS are autosomal recessive disorders, with the exception of MPS II, which is X linked. The affected genes and chromosomal locations are shown in the table (table 1).

The phenotype of these disorders covers a broad spectrum, from mild to severe. In general, the severity depends upon the quantity of residual enzyme, which is related to the genotype of the affected patient. Mutations that permit small amounts of residual enzyme activity result in less severe clinical phenotypes [8]. These residual amounts may be less than 1 percent of normal and may not be detectable by routine assay. Mild-to-intermediate forms are also referred to as the "attenuated phenotypes." Phenotype can vary among affected siblings due to other unknown genetic or environmental factors.

CLINICAL CLASSIFICATION AND PRESENTATION — The MPS disorders are classified as types I II, III, IV (A or B), VI, VII, and IX. MPS V (formerly Scheie syndrome) and MPS VIII are no longer recognized. The MPS disorders are differentiated clinically by their clinical features and age of presentation and biochemically by their associated enzyme deficiency. They can be grouped into four broad categories according to their dominant clinical features (table 1):

●Soft tissue storage and skeletal disease with or without brain disease (MPS I, II, VII)

●Soft tissue and skeletal disease without brain disease (MPS VI)

●Primarily skeletal disorders without brain disease (MPS IV A and B)

●Primarily central nervous system (CNS) disorders (MPS III A to D)

Signs and symptoms of MPS are usually not present at birth, with the exception of the more severe forms of MPS VII (table 1). Most types present within the first few years of life, but some of the attenuated forms (MPS I, II, and some cases of MPS VII and MPS VI) can present as late as adolescence to early adulthood.

RADIOLOGIC FINDINGS — The characteristic pattern of skeletal abnormalities in MPS disorders is known as dysostosis multiplex [9-11]. This condition occurs in MPS I, II, IV, VI, and VII and is less extensive in MPS III and milder variants [12-14]. A radiographic skeletal survey should be performed and interpreted by a radiologist experienced with the findings in storage diseases. (See "Mucopolysaccharidoses: Complications", section on 'Dysostosis multiplex'.)

The following are typical radiographic findings of dysostosis multiplex:

●The long bones are short and thick and have an irregular, hyperostotic shaft and metaphysis due to inadequate remodeling. The distal radius and ulna have an abnormal angulation and tilting of the distal epiphyses (image 1). The clavicle is similarly abnormal in shape with widened ends.

●The iliac bones are flared, with a flattened acetabulum and coxa valga deformity (widening of the angle formed by the femoral neck and shaft).

●The metacarpals narrow proximally and widen distally with irregular ends (image 2).

●Hypoplasia of the anterosuperior areas of the lower thoracic and upper lumbar vertebral bodies results in ovoid vertebrae with a beaked appearance of their anterior inferior surfaces on a lateral radiograph and leads to development of vertebral slippage (image 3) and dorsal kyphosis (gibbus deformity) (picture 1A-B).

●The ribs have a characteristic "oar shape" with a narrowing at the takeoff from the vertebral column and a broadening of the anterior distal end. These broadened ribs give the appearance of decreased intercostal spaces and a "beehive" appearance (image 4).

●The skull is large and deformed due to craniosynostosis, with a thickened calvarium and an abnormal "j" or boot-shaped sella turcica (image 5). The basilar skull may impress upon or fuse with the cervical vertebrae. This is associated with a narrowed spinal canal [15,16]. (See "Mucopolysaccharidoses: Complications", section on 'Cervical cord compression'.)

OVERVIEW OF SPECIFIC DISORDERS

MPS type I — MPS type I (MIM #252800) is an autosomal recessive disorder caused by deficiency of lysosomal hydrolase, alpha-L-iduronidase (IDUA), which is needed for the degradation of heparan sulfate and dermatan sulfate [8]. MPS I is caused by mutations in the IDUA gene, located on chromosome 4p16.3 [17]. The syndrome that results depends in part upon the specific combination of mutations on both alleles that determines the level of residual enzyme activity. The latter can also be influenced by the presence of polymorphisms within the gene.

MPS I includes Hurler (MPS I H, MIM #607014), Hurler-Scheie (MPS I H/S, MIM #607015), and Scheie (MPS I S, MIM #607016) syndromes. The clinical phenotype covers a broad spectrum of severity. Patients with severe, intermediate, and mild features were historically classified as Hurler, Hurler-Scheie, and Scheie syndromes, respectively. Hurler-Scheie and Scheie syndromes are referred to as "attenuated phenotypes" [18].

Early recognition of the attenuated phenotypes is critical so that enzyme replacement therapy can be initiated before the development of significant morbidity [18,19]. In one series of 29 patients with attenuated phenotypes, median age of diagnosis was five years (range 1.3 to 40 years) despite onset of symptoms at a median age of two years (range four months to nine years). Presenting symptoms included joint stiffness, corneal clouding, and recurrent sinopulmonary infections with chronic rhinitis. (See "Mucopolysaccharidoses: Treatment", section on 'Enzyme replacement therapy'.)

Hurler syndrome — Hurler syndrome is the severe form of MPS I and is characterized by a broad spectrum of clinical problems, including skeletal abnormalities, hepatosplenomegaly, and severe intellectual disability. The incidence is approximately 1 to 3 in 100,000 births [5,9,20].

Affected infants appear normal at birth. During the first year, they develop the characteristic coarse facial features, wide nasal bridge, and flattened midface. Other signs include hepatosplenomegaly, umbilical or inguinal hernias, and typical skeletal abnormalities, known as dysostosis multiplex (image 3 and image 2 and image 5) [21,22]. Patients typically present at six months to two years of age with developmental delay and recurrent respiratory infections with chronic nasal discharge. Hurler patients may also present with other problems, including rapidly enlarging head size due to hydrocephalus and possibly hyperostosis of the skull, heart failure, hernias, and gibbus deformity of the lower spine, before their facial features and other abnormalities make the diagnosis obvious (picture 1A-B).

Growth, which may be increased during the first year, slows by two to three years of age and becomes minimal. Patients may develop progressive joint stiffness and contractures, which limit mobility and are painful. Development peaks by two to three years, usually with multiword sentences and walking, and then declines. High-pressure communicating hydrocephalus can exacerbate the enlargement and deformity of the head and may accelerate the developmental decline in some Hurler patients (image 6 and image 7) [12,23].

Loss of vision and hearing may worsen the progressive developmental decline. Corneal clouding is a characteristic feature (picture 2). It is caused by structural changes in the corneal stroma, including abnormalities of the size, spacing, and arrangement of collagen fibrils [24]. Blindness may develop due to corneal clouding, retinal disease, optic nerve compression, or primary brain disease [4,25]. Combined conductive and sensorineural hearing loss often occurs [26,27].

Patients often develop frequent ear, sinus, and pulmonary infections with thick secretions that lead to emergency department visits and hospitalizations. Soft-tissue thickening in the nose and pharynx and hypertrophy of the tonsils and adenoids due to storage of glycosaminoglycans (GAGs) in these tissues along with abnormalities in tracheal cartilage cause progressive airway obstruction and sleep apnea and may result in a difficult airway if intubation is required [28]. In some patients, unrecognized sleep apnea can cause significant hypoxemia at night, leading to pulmonary hypertension and cor pulmonale [9]. (See "Mechanisms and predisposing factors for sleep-related breathing disorders in children" and "Evaluation of suspected obstructive sleep apnea in children" and "The difficult pediatric airway for emergency medicine".)

Cardiac abnormalities become apparent between birth and five years of age. These may include cardiomyopathy, endocardial fibroelastosis, and valvular regurgitation, which alone or in combination can lead to heart failure [29]. GAG storage within blood vessels causes irregular and diffuse narrowing of the coronary arteries and irregular lesions of the aorta in untreated patients [29-33].

Other problems include umbilical and inguinal hernias. Gibbus deformity (dorsal kyphosis) can be apparent in the first few months of life. Arthropathy, including the hip joint, is progressive. Joint stiffness is universal and progressive, leading to painful and impaired movement of shoulders and legs. Fixed flexion contracture of the fingers along with carpal tunnel syndrome leads to the typical hand deformity (picture 3). Carpal tunnel syndrome can be severe [34]. It may develop insidiously and without typical symptoms and thus is often unrecognized. Odontoid dysplasia and anterior C1-C2 subluxation occur frequently and can cause cord compression and sudden death (image 8 and image 9).

Lifespan is markedly shortened in Hurler syndrome. The average age at death is five years, and nearly all patients die before 10 years.

Hurler-Scheie syndrome — Hurler–Scheie syndrome is intermediate in severity. It is typically diagnosed by two to six years of age [18]. In one series of 15 patients, joint stiffness was the most frequent presenting complaint (in six patients), followed by recurrent ear, nose, and throat symptoms due to airway narrowing, thicker mucus, and recurrent infections and umbilical hernia (each in four patients) [18]. Hurler-Scheie is less common than Hurler.

Characteristic facial features are less coarsened than in Hurler syndrome and often include a small mandible. Progressive Achilles tendon contractures lead to toe walking. Hepatosplenomegaly can be substantial and can cause discomfort or respiratory compromise. Progressive cardiac valve disease may cause severe aortic and mitral regurgitation [29]. Patients often develop spondylolisthesis (subluxation of the vertebra) and kyphoscoliosis [16]. The meninges are often thickened, causing progressive circumferential compression of the cervical spinal cord (pachymeningitis cervicalis), which may sometimes lead to weakness or paralysis (image 9) [35].

Hurler-Scheie, although severe, progresses less rapidly than Hurler syndrome [36]. Patients usually have normal intelligence, although static learning disabilities are not uncommon. Lifespan is shortened. Patients typically die in their twenties of cardiac disease or respiratory failure.

Scheie syndrome — Scheie syndrome is the least severe form of MPS I, although it is not a mild disease. Patients may be diagnosed as late as the teenage years due in part to their mildly affected facies [18]. In one series of 10 patients, the most frequent presenting features were joint stiffness and corneal clouding (each present in five patients) [18].

Scheie patients suffer from significant joint stiffness and pain, which can be debilitating. Aortic valve disease often requires valve replacement [37-39]. Corneal clouding, optical nerve compression, or other related eye problems can lead to blindness (picture 2). Many problems that occur in Hurler-Scheie syndrome also affect Scheie patients (eg, hydrocephalus or cord compression) (image 10). Most will have carpal tunnel syndrome.

In general, lifespan is longer than with the other MPS I subtypes. Some Scheie patients have a normal lifespan, although they have significant disability. Most die in their middle decades.

MPS type II (Hunter syndrome) — MPS II (MIM #309900) is also known as Hunter syndrome. This X-linked disorder is caused by a deficiency of iduronate 2-sulfatase (IDS), which results in storage of heparan and dermatan sulfate [12]. MPS II is caused by mutations in the IDS gene, located on chromosome Xq28 [40]. Deletion of contiguous genes has been reported in patients with severe Hunter syndrome [41]. Although the disorder is X linked, cases in females have been reported [42-48].

Hunter syndrome occurs as part of a wide clinical spectrum, although the correlation between the somatic and cognitive aspects of the disorder is less clear than in MPS I. [13,49]. The severe form shares features with Hurler syndrome (MPS I), including abnormal facial appearance, hepatosplenomegaly, cardiovascular disorders due to mucopolysaccharide deposits [50], dysostosis multiplex with dwarfism, neurocognitive decline, and deafness (picture 4). However, Hunter syndrome is differentiated by absence of corneal clouding and presence of pearly papules [13]. Distinctive pearly papular skin lesions over the scapulae and on the lateral upper arms and thighs develop in some Hunter patients (picture 5) [51]. Some patients with the severe form have aggressive hyperactive behavior similar to Sanfilippo syndrome (MPS III) [52]. In one series, issues with behavior, sleep, and bowel/bladder training were markers for central nervous system (CNS) involvement and subsequent cognitive dysfunction [53]. Survival to the teens or twenties is common [9].

The attenuated form is similar to Scheie syndrome (MPS I), although Hunter patients often have more coarsened facies (picture 6A-B), and late cardiac issues such as arrhythmia can occur. Affected patients usually have normal intelligence and can survive into the sixth or seventh decade [9].

MPS type III (Sanfilippo syndrome) — MPS III is known as Sanfilippo syndrome. It occurs in four forms (A, B, C, and D) caused by different enzyme deficiencies but with similar clinical features. Each is caused by a deficiency of one of four enzymes involved in the degradation of heparan sulfate, leading to its accumulation. All forms have autosomal recessive inheritance. MPS IIIA is the most common type, with an approximate incidence of 1.16 (range 0.27 to 1.88) per 100,000 birth [5,6].

●MPS III A (MIM #252900) results from mutations in the gene encoding heparan sulfate sulfatase (also known as sulfamidase or N-sulfoglucosamine sulfohydrolase [SGHS]), located at 17q25.3 [54].

●MPS III B (MIM #252920) results from mutations in the gene encoding N-acetyl-alpha-d-glucosaminidase (NAGLU), located at 17q21 [55].

●MPS III C (MIM #252930) results from deficiency of acetyl-CoA:alpha-glucosaminide n-acetyl transferase (HGSNAT), located at 8p11.1 [56,57].

●MPS III D (MIM #252940) is caused by mutations in the gene encoding N-acetylglucosamine-6-sulfate sulfatase (GNS), located at 12q14 [58].

MPS III is characterized primarily by progressive CNS degeneration [59,60]. Typical features of MPS may be present, including musculoskeletal manifestations [61], although to a lesser extent than in other forms. Patients typically present at two to seven years of age with developmental delay and behavior problems, including hyperactivity and aggression [59,62-65]. Sleep disorders are common (78 percent in one series) [66].

Physical findings are milder than in Hurler syndrome but include typical coarse facial features, dysostosis multiplex, hepatosplenomegaly, and hernias [9,67]. Diagnosis may be delayed because the facial coarsening and skeletal disease are initially subtle, and many disorders cause behavioral problems and intellectual disability.

Function progressively declines, with loss of learnt words seen first and loss of motor function appearing later [59]. Hyperactive children become manageable, then sedentary, and finally are confined to bed. The disease often terminates in neurologic devastation and death in the teen years, but survival into early adult life is common.

MPS type IV (Morquio syndrome) — MPS IV (MPS IV A and the less common type B) is also known as Morquio syndrome. This disorder consists of two forms with similar clinical findings and autosomal recessive inheritance. MPS IV A (MIM #253000) results from mutations in the gene encoding galactosamine-6-sulfatase (GALNS), located at 16q24.3 [68]. MPS IV B (MIM #253010) is due to beta-galactosidase (GLB1) deficiency. The clinical features result from accumulation of keratan sulfate and chondroitin-6-sulfate. The incidences of MPS IV A and B are approximately 0.22 (range 0.07 to 1.32) and 0.14 per 100,000 births, respectively [5,6].

Morquio syndrome is characterized by skeletal involvement (picture 7). Patients typically present at approximately one year of age with short stature, primarily due to a shortened neck and trunk, and joint laxity [69-72]. Pectus carinatum (protuberant sternum), kyphoscoliosis, genu valgum (knock-knee deformity), coxa valga, and abnormal gait are common. Dysostosis multiplex occurs early. Spondyloepiphyseal dysplasia and severe flattening of the vertebrae (platyspondyly) develop (image 11). (See "Pectus carinatum and arcuatum".)

Odontoid dysplasia with failure to ossify leads to atlantoaxial instability and C1-C2 subluxation [73-76]. This can result in the insidious onset of cervical cord compression, beginning with fatigue and progressing to weakness [74]. Acute cord compression and respiratory arrest may occur after minor falls [75]. Patients may be confined to wheelchairs by their second or third decade. Respiratory problems often develop due to narrow, floppy airways; cord compression; and the restrictive effects of skeletal disease.

Mild corneal opacities, hepatosplenomegaly, and valvular heart disease may occur in Morquio syndrome [9]. Some patients develop progressive hearing loss. Enamel hypoplasia is seen in MPS IV A but not IV B.

Both types of Morquio syndrome can have severe or attenuated forms, depending upon the amount of residual enzyme activity. In the severe forms, linear growth is minimal after six or seven years of age, and death usually occurs in the third or fourth decade from cardiorespiratory failure [9]. Mildly affected patients may survive into the seventh decade.

MPS type VI (Maroteaux-Lamy syndrome) — MPS VI (MIM #253200) is also known as Maroteaux-Lamy syndrome. This disorder is caused by mutations in the gene encoding arylsulfatase B (ARSB, N-acetylgalactosamine 4-sulfatase), which is located on chromosome 5q11-q13 [77]. The enzyme deficiency results in accumulation of partially degraded GAGs, dermatan sulfate, and chondroitin 4-sulfate [78]. The disorder primarily affects the skeleton and soft tissues. Inheritance is autosomal recessive. The incidence is approximately 0.15 (range 0.05 to 0.48) per 100,000 births [5,6].

Maroteaux-Lamy syndrome occurs in attenuated and severe forms that vary in the extent of findings and age of onset. Severely affected children present at ages one to six years with coarse facial features, severe skeletal disease, joint abnormalities, respiratory disease, and cardiac abnormalities (valvular disorders, such as mitral or aortic insufficiency, and less often cardiomyopathy and endocardial fibroelastosis) (picture 8) [14,79-82]. Obstructive sleep apnea and pulmonary hypertension are common in untreated patients [83]. Corneal clouding can occur.

Intelligence is usually normal, although vision and hearing disorders or hydrocephalus can lead to developmental delay [14,84]. Thickening of the cervical meninges, combined with thickening of tissues anterior to the cord and the posterior longitudinal ligament, may cause stenosis of the spinal canal at the level of the foramen magnum and upper cervical spine and circumferential constriction of the cord, leading to cord compression [85,86]. Death typically occurs in the second or third decade [9].

Disease progression is slower in the attenuated form.

MPS type VII (Sly syndrome) — MPS VII (MIM #253220), also known as Sly syndrome, is a rare disorder caused by mutations in the gene encoding beta-glucuronidase (GUSB), located on chromosome 7q21.11 [87]. The enzyme deficiency results in accumulation of heparan sulfate, dermatan sulfate, chondroitin-4-sulfate, and chondroitin-6-sulfate. Inheritance is autosomal recessive.

The presentation of MPS VII is variable [88-90]. Clinical features and complications may be similar to MPS I, with significant soft tissue and skeletal abnormalities (picture 9) [88,91,92]. As in the attenuated forms of MPS I, intellectual disability may be mild or absent in MPS VII. Hydrops fetalis is a common presentation and may account for a large proportion of patients that are unrecognized because they do not survive to be diagnosed [93,94]. More recent experience suggests that these hydropic infants may not always follow a severe course if they survive the perinatal period. The most attenuated form is limited to skeletal abnormalities [95].

MPS type IX (Hyaluronidase deficiency) — MPS IX (MIM #601492) is an extremely rare autosomal recessive disorder resulting from deficiency of hyaluronidase 1 (HYAL1, hyaluronoglucosaminidase 1) [96]. Deficiency of hyaluronidase leads to accumulation of hyaluronan. The gene encoding the enzyme is located on chromosome 3p21.3-p21.2 [97].

The major clinical features in one reported patient were periarticular soft tissue masses composed of nodular aggregates of histiocytes, erosions of the acetabula, and short stature [96]. Three children in a consanguineous family presented with knee and/or hip pain and swelling (familial juvenile idiopathic arthritis) [98]. All were found to have diffuse joint involvement with infiltration of macrophages in the synovium. Osteoarthritis is the key finding in a mouse model of MPS IX [99].

DIAGNOSIS — An MPS disorder should be suspected in a child with coarse facial features, hepatosplenomegaly, and bone disease, with or without central nervous system (CNS) abnormalities. Rarely, a patient may present before the onset of signs and symptoms of MPS due to the history of an affected family member. Newborn screening is not available for most forms of MPS, except MPS I in some countries. The distinctive skeletal findings may help with diagnosis. As an example, the abnormal ovoid or beaked vertebral bodies and the oar-shaped ribs may be noted on a chest radiograph of an affected infant who has recurrent pneumonia. However, the initial presentation may be subtle, and signs may be variable, depending upon the MPS type and severity, resulting in frequent delays in diagnosis.

As a result, a comprehensive biochemical evaluation may be needed for patients who present early in the course of disease. Measurement of urinary glycosaminoglycan (GAG) concentration, fractionation of GAG by electrophoresis or chromatography, and analysis of oligosaccharides can identify the types of MPS and can also identify oligosaccharidoses and other storage disorders in the differential. Definitive diagnosis requires assay of enzyme activity, usually in peripheral blood leukocytes. (See "Evaluation of the peripheral blood smear", section on 'Presence of abnormal or giant granules'.)

Urinary glycosaminoglycans — The urinary concentration of GAGs should be measured in all patients with a suspected MPS. Both a quantitative test of total GAG and a fractionation method, such as electrophoresis or chromatography, to distinguish among the different types of GAGs should be performed. First morning urine specimens should be tested because they are relatively concentrated. Dilute urine may be falsely negative, especially in disorders with lower levels of urinary GAG, such as MPS III and IV. The test should be performed by a qualified biochemical genetics laboratory experienced with GAG quantitation and electrophoretic or chromatography methods [100-102]. Normal newborns and infants have significantly higher GAG levels than older children. As a result, comparison with age-specific controls and fractionation to verify pathologic GAG (heparan, dermatan, keratan) from common normal GAG (other chondroitins) is important to avoid false-positive results.

Methods that should not be used are spot tests or those that do not fractionate the GAGs. The former, such as the Berry spot test, may give false-positive results due to the normal high excretion of GAG in children younger than one year of age. Tests that do not fractionate GAGs may be falsely positive or negative due to the inability to distinguish abnormal GAG from high turnover of normal GAG or to detect relatively small amounts and fragment sizes of some pathologic species (eg, heparan sulfate and keratan sulfate).

In normal individuals, urinary GAG concentrations are highest at birth, fall substantially during the first few months of age, and then progressively decline during childhood and adolescence. The analysis is usually sensitive in MPS I, II, VI, and VII because urinary GAG excretion is markedly elevated in these disorders, except in attenuated patients.

Urine testing may be falsely negative in MPS III and IV. In MPS III, this is due to lower urinary GAG levels and smaller heparan sulfate fragments than in the other MPS diseases. In MPS IV, analysis of urine may be unreliable because keratan sulfate levels decline with age in this condition [103,104]. Thus, enzyme analysis should be performed when MPS disease is strongly suspected, even when urinary GAG excretion appears to be normal.

Analysis of oligosaccharides — Oligosaccharidoses can masquerade as MPS disease. Thus, the urine in patients with suspected MPS is also tested for oligosaccharides. (See 'Differential diagnosis' below.)

Enzyme analysis — The diagnosis of MPS disorders is confirmed by demonstration of a specific enzyme deficiency, usually in peripheral blood leukocytes, although fibroblasts or dried blood spots can be tested [12,105-107]. Enzyme analysis is available for all types of MPS. Results of the urine GAGs guide enzyme analysis, but enzyme panels can be used if the specific type of MPS is not known.

Tests for the enzymes deficient in MPS I, III B, IV B, and VII, which cleave sugar moieties, are usually available in clinical genetics laboratories. These tests use artificial fluorescent substrates. Assays for sulfatases (MPS II, III D, IV A, and VI), acetylase (MPS III C), and sulfamidase (MPS III A) are more difficult to perform reliably and use radioactive substrates. These tests are available only in specialized laboratories. Tandem mass spectrometry assays using dried blood spots have been developed for a number of subtypes and have the potential to be used for newborn screening [105-107].

Mutation analysis — Genetic testing usually shows the high frequency of rare "private" mutations in these disorders. Molecular analysis can be performed when the mutations are known in affected family members [12,108-110]. In addition to prenatal diagnosis, knowledge of the genotype might be helpful in assessing whether a patient is severely affected (especially in MPS I) and should consider hematopoietic cell transplantation. (See "Mucopolysaccharidoses: Treatment", section on 'Hematopoietic cell transplantation'.)

Prenatal diagnosis and newborn screening — Prenatal diagnosis is usually performed because of a family history of MPS. The other most common indication is hydrops fetalis, which is associated with a number of lysosomal storage disorders. Prenatal testing can be performed for all of the MPS disorders by chorionic villous sampling or amniocentesis. Prenatal testing by genotyping (mutation analysis) is preferred if the respective individual carriers have been tested and the familial mutations are known. Genetic testing can also be performed preimplantation. Enzyme analysis is performed if the specific mutations are not known. Direct enzyme assay on material obtained by chorion villus biopsy is the most commonly used method because it avoids the need for tissue culture, providing results more quickly than amniocytes in culture. Enzyme activity can also be measured in cultured fibroblasts obtained by amniocentesis [108] and in dried fetal blood spots [111,112].

Testing for MPS I was included in the uniform newborn screening panel in the United States in 2016 and is being piloted in several other countries [112]. The indications for testing of fetal blood spots are otherwise limited except in cases of hydrops fetalis, a common presentation in MPS VII, where measurement of enzyme activity in leukocytes obtained by fetal blood sampling can provide faster results [109,113].

Carrier detection — Carrier detection using enzyme assays of leukocytes is not reliable, because of the wide variation in enzyme concentrations [12]. DNA analysis can be used to identify carriers among siblings or other relatives if the mutation is known.

DIFFERENTIAL DIAGNOSIS — MPS is a multisystem disease that can initially present and masquerade as many different diseases. One of the challenges in diagnosing MPS is that the various presenting features initially may be evaluated separately by different specialists, and it may take time to recognize that the seemingly unconnected health problems have a single unifying diagnosis. In the patient whose main presenting feature is hip disease, for example, the differential diagnosis may include Legg-Calvé-Perthes (LCP) disease and spondyloepiphyseal dysplasia (SED). In contrast, if developmental delay and behavior problems are the primary presenting features, then the differential would include attention deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD). There are still other disorders in the differential for corneal clouding, obstructive sleep apnea, hearing loss, and kyphoscoliosis. Once the constellation of findings is recognized as having a common underlying cause, the main disorders in the differential are other storage diseases, including the oligosaccharidoses (eg, alpha- and beta- mannosidosis, fucosidosis, aspartylglucosaminuria), sphingolipidoses (eg, Gaucher type II, Niemann Pick A), and mucolipidoses (eg, I cell disease). Urinary analysis of glycosaminoglycans and oligosaccharides helps differentiate these disorders. (See "Inborn errors of metabolism: Classification", section on 'Lysosomal storage disorders'.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Mucopolysaccharidoses".)

SUMMARY AND RECOMMENDATIONS

●Pathogenesis – The mucopolysaccharidoses (MPS) are lysosomal storage disorders caused by the deficiency of enzymes required for the stepwise breakdown of glycosaminoglycans (GAGs) (table 1). Fragments of partially degraded GAGs accumulate in the lysosomes, resulting in cellular dysfunction and clinical abnormalities. (See 'Introduction' above and 'Pathogenesis' above and 'Genetics' above.)

●Clinical features and classification – The MPS disorders can be grouped into four broad categories according to their dominant clinical features (table 1). The phenotypic severity depends upon the quantity of residual enzyme, which is related to genotype. (See 'Clinical classification and presentation' above and 'Overview of specific disorders' above.)

●Diagnosis:

•When to suspect MPS – An MPS disorder should be suspected in a child with coarse facial features, hepatosplenomegaly, and bone disease (dysostosis multiplex) (image 3 and image 2 and image 5), with or without central nervous system (CNS) abnormalities. (See 'Diagnosis' above and 'Radiologic findings' above.)

•Diagnostic evaluation – Biochemical evaluation includes measurement of urinary GAG concentration, fractionation of GAG by electrophoresis or chromatography, and analysis of oligosaccharides. Definitive diagnosis requires assay of enzyme activity, usually in peripheral blood leukocytes, and confirmed by molecular analysis. (See 'Diagnosis' above.)

•Prenatal diagnosis – Prenatal diagnosis is usually performed because of a family history of MPS. The other most common indication is hydrops fetalis, which is associated with a number of lysosomal storage disorders. Prenatal diagnosis can be performed for all of the MPS disorders, either by molecular testing if the specific mutation is known or by enzyme analysis. (See 'Prenatal diagnosis and newborn screening' above.)

ACKNOWLEDGMENTS — The UpToDate editorial staff acknowledges Ed Wraith, MD; Emil Kakkis, MD, PhD; Robert Wynn, MD, MRCP, FRCPath; and Simon Jones, MD, who contributed to earlier versions of this topic review.