Visual system
Diffuse corneal clouding is the most common ocular finding in MPS IVA, although it occurs to a lesser extent and is more slowly progressive than in other MPS diseases (Danes
1973). A retrospective review of 20 patients with MPS IV (subtype A or B not specified), ages 1–65 years, identified 10 eyes with no corneal clouding, 17 eyes with mild corneal clouding, 4 with moderate corneal clouding, and 4 with severe corneal clouding (corneal clouding was not graded in 5 eyes); the severity of corneal clouding was generally related to increasing age of the patient and resulted in reduction in visual acuity (Couprie et al.
2010). The diffuse, finely granular corneal deposits are best visualized with slit-lamp biomicroscopy but when more severe, can be observed with a bright penlight held at an oblique axis to the eye. The corneal deposits may also interfere with examination of other ocular structures, e.g., the trabecular meshwork, the retina, and the optic nerve. Electron microscopy has shown that the corneal clouding is primarily due to fibrillogranular, as well as multimembranous, membrane-bound inclusions in the keratocytes, representing GAGs and complex lipids/glycolipids, respectively; in addition, extracellular granular material has been reported (Ghosh and McCulloch
1974; Iwamoto et al.
1990). This disruption of the normal corneal lamellae results in light scattering and can cause the patient to be photosensitive (Leslie et al.
2005). While the inclusions can also be found in the conjunctiva, sclera, trabecular meshwork, and retinal pigment epithelium, the primary effect is in the cornea (Iwamoto et al.
1990).
Glaucoma or ocular hypertension seems to be unusual in MPS IVA (Davis and Currier
1934). Case reports of corneal clouding and glaucoma in 35-year-old and 36-year-old siblings with MPS IV (subtype A or B not specified) found that the glaucoma was open angle (likely due to accumulation of GAG in the trabecular meshwork over time, obstructing aqueous outflow), was associated with visual field constriction, and was managed with topical medications (Cahane et al.
1990). This is in contrast to the closed/narrow angle glaucoma that has been reported in MPS VI (Cantor et al.
1989; Sato et al.
2002). Electron microscopy has shown distended trabecular endothelial cells with a thickened basement membrane in MPS IVA. The inclusions in the trabecular meshwork are primarily multimembranous, whereas other types of MPS have more fibrillogranular inclusions, perhaps explaining the reduced prevalence of ocular hypertension and glaucoma in individuals with MSP IVA (Iwamoto et al.
1990; Leslie et al.
2005).
While visual acuity is generally better in MPS IVA compared with other types of MPS, corneal clouding, refractive errors, glaucoma, and cataracts can affect visual acuity as the patient matures. Patients with MPS IV (subtype A or B not specified) tend to have astigmatism in addition to myopia and hyperopia (Couprie et al.
2010), in contrast with hyperopia alone as has been reported in patients with other types of MPS (Fahnehjelm et al.
2010). Different types of cataracts or lens opacities have been reported in MPS IV (subtype A or B not specified): punctate lens opacities in six individuals ages 6–45 years, “small” lens opacities in a 9-year-old, nuclear sclerosis in a 65-year-old, and lamellar/zonular cataracts in three individuals ages 8–15 years (Couprie et al.
2010; Iwamoto et al.
1990; Olsen et al.
1993). With progression of the cataracts, visual acuity may be affected.
Optic nerve atrophy may rarely occur due to glaucoma, optic nerve infiltration, or retinal dystrophy (Dangel and Tsou
1985; Abraham et al.
1974; Käsmann-Kellner et al.
1999). When retinal dystrophy is present, the patient may note nyctalopia (night blindness), and funduscopic examination can show constricted arterioles (Abraham et al.
1974; Dangel and Tsou
1985; Käsmann-Kellner et al.
1999). Electroretinography is needed to assess retinal function and make a diagnosis of a retinal dystrophy, typically reported as a reduction in the scotopic responses, in addition to possible delay in photopic implicit times (Dangel and Tsou
1985; Käsmann-Kellner et al.
1999; Abraham et al.
1974). Electroretinography has rarely been documented in MPS IVA, perhaps related to infrequent electrophysiology, absent or mild symptoms, or to the relative sparing of the retina and central nervous system as compared to other MPS disorders. One study, reporting reduced and delayed b-wave scotopic responses in a 43-year-old with MPS IV (subtype A or B not specified), noted that the retinal changes in these patients are insidious and might not be seen in younger patients (Dangel and Tsou
1985). Indeed, essentially normal retina and central nervous system tissue has been reported in MPS IVA with histopathology (Koto et al.
1978), and some clinical reports have documented normal electroretinography into the fourth decade of life (Cahane et al.
1990; Gills et al.
1965; Leung et al.
1971). Interestingly, no inclusions in retinal neurons and rare fibrillogranular inclusions in the retinal pigment epithelial cells were reported by one study (Iwamoto et al.
1990). The two cases with MPS IVA in this study, ages 18 and 19 years, also showed no optic nerve abnormalities on post-mortem examination (Iwamoto et al.
1990). Lastly, similar to other types of MPS, the eyes may appear prominent (pseudoexopthalmos) in MPS IVA due to shallow orbits (Käsmann-Kellner et al.
1999).
Auditory system
As in all forms of MPS, reduction in hearing in patients with MPS IVA can be attributed to multiple causes. Firstly, conductive hearing loss can be present and is most likely secondary to recurrent upper respiratory tract infections and frequent serous otitis media (Schlieier and Steubel
1976). Conductive loss can also be caused by deformity of the ossicles (Barranger and Cabrera-Salazar
2002). Secondly, sensorineural loss may occur as a result of GAG accumulation. Abnormal auditory brainstem response (ABR) results have been described and are thought to be a combination of middle ear, cochlear, eighth nerve, and lower brainstem pathology (Leroy and Crocker
1966).
Hearing loss in MPS IVA usually begins in adolescence, however the conductive element caused by frequent upper respiratory tract infections and serous otitis media can be present anytime from birth onwards. The hearing loss is progressive, and once the sensorineural element is present, it can be severe and is almost universally found in patients who survive beyond the second decade (Bredenkamp et al.
1992; Keleman
1977).
Most patients with MPS IVA have a “mixed hearing loss” attributed to the combination of a conductive element and a sensorineural element. Ventilation tubes can be used to treat aspects of the conductive hearing loss, but the patient is likely to still have a conductive loss if there is ossicular involvement and most patients will have an underlying progressive sensorineural loss.
Abnormal vestibular function has also been reported in a patient with MPS IV (subtype A or B not specified) (Sataloff et al.
1987).
Digestive system
The digestive system is also affected by MPS IVA. According to data from the International Morquio A Registry conducted by the International Morquio Organization, some MPS IVA patients have reported hernias among their initial and current symptoms (Tomatsu et al.
2011). Although umbilical and inguinal hernias are the most common hernia types in patients with MPS disorders (Ashworth et al.
2006), an MPS IV (subtype A or B not specified) patient with bilateral diaphragmatic hernias has also been reported (Nursal et al.
2000).
Another element of the digestive system that may be affected is the liver. Although not as common as in other MPS disorders, hepatomegaly has been reported in patients with MPS IVA (Nelson et al.
1988) and was reported as an initial and current symptom in the International Morquio A Registry (Tomatsu et al.
2011). Hepatosplenomegaly has also been reported (Holzgreve et al.
1981), although it seems to be less common and was not found in all studies in which it was evaluated (Nelson et al.
1988). The liver manifestations are likely a direct result of GAG accumulation as keratan sulfate and chondroitin-6-sulfate are known to accumulate in the liver (Minami et al.
1979). Interestingly, when analyzed, the keratan sulfate found in the liver of a patient with MPS IVA appeared to be structurally similar to the keratan sulfate found in bone (Minami et al.
1983).
In addition to hernias and hepatomegaly, generalized stomach problems were also reported by patients in the International Morquio A Registry (Tomatsu et al.
2011). While gastrointestinal dysfunction and chronic diarrhea have been reported in other MPS disorders (Wraith
1995; Sibilio et al.
2009), the specific stomach problems experienced by MPS IVA patients have not been described in the literature.
Overall, digestive system manifestations appear to be less prominent in MPS IVA than in other MPS disorders. However, there is one exception: dental abnormalities are a particular feature of MPS IVA (James et al.
2012). Due to the integral role of teeth in the digestive system and the importance of oral health in maintaining quality of life (Sheiham
2005), dental abnormalities are included here even though they could also be classified as a skeletal manifestation. Through in situ hybridization of a day 1 mouse incisor it has been shown that GALNS mRNA is most abundant in secretory ameloblasts indicative of a developmental disturbance during the secretory stage of enamel formation (Yamakoshi et al.
2002). This disturbance manifests as dental abnormalities in patients with MPS IVA including spaced dentition (Kuratani et al.
2005), pointed cusps (Rolling et al.
1999; Kinirons and Nelson
1990), spade-shaped incisors (Rolling et al.
1999; Kinirons and Nelson
1990), dental pitting with a band of increased porosity just below the surface of the enamel correlating to the positions of striae of Retzius (Rolling et al.
1999), enamel hypoplasia (Kuratani et al.
2005; Rolling et al.
1999; Kinirons and Nelson
1990), developmental abnormalities of primary and permanent dentition (James et al.
2012), and an increased risk of dental caries (James et al.
2012). In addition, a scanning electron microscopy study has revealed that MPS IV teeth possess a thin layer of amorphous material between the normal prismatic enamel and the dentine surface, believed to be the result of poorly mineralized tissue produced at the earliest stages of amelogenesis (Lustmann
1978). A recent study found that patients with MPS IVA have increased caries rates and enamel defects as compared to both the general population and patients with other MPS disorders (James et al
2012). In concurrence with this finding, there appears to be a marked difference in the orientation distribution of enamel crystallites between enamel affected by MPS IVA and healthy enamel (Al-Jawad et al.
2011).
Cardiovascular system
Cardiac involvement in MPS IVA has previously been thought to be mild (Northover et al.
1996) or uncommon (Montaño et al.
2007). Accurate understanding of the cardiac findings in MPS IVA patients has been hampered by small patient numbers (Schieken et al.
1975; Gross et al.
1988), absence of supporting biochemical documentation of diagnosis (Schieken et al.
1975), failure to differentiate between MPS IVA and MPS IVB (Schieken et al.
1975; Gross et al.
1988; Wippermann et al.
1995; Dangel
1998; Mohan et al.
2002; Fesslová et al.
2009; Lael et al.
2010), and evolving cardiac ultrasound technology (Schieken et al.
1975; Gross et al.
1988; John et al.
1990; Dangel
1998). The single cardiac ultrasound study specifically addressing MPS IVA lacks the color flow Doppler technology that improves the detection of valve stenosis and insufficiency (John et al.
1990). Conversely, the studies that do utilize color Doppler technology do not differentiate between MPS IVA and MPS IVB (Schieken et al.
1975; Gross et al.
1988; Wippermann et al.
1995; Dangel
1998; Mohan et al.
2002; Fesslová et al.
2009; Lael et al.
2010).
Remarkably, despite the absence of color Doppler, cardiac valve disease was found to be quite common in the single study devoted to MPS IVA (John et al.
1990). Five of the 10 patients studied (50%) had mitral valve regurgitation (one of whom had mitral valve stenosis as well), 30% had aortic valve regurgitation, and 20% had both mitral and aortic regurgitation in conjunction with left ventricular hypertrophy. Aortic and/or mitral valve thickening was present in 40% of patients. The average age of patients within the study was 12.5 years although the range was broad (3–40 years). Valve dysfunction occurred in all three adults, but was also present in two patients aged 11 and 13 years. Studies that did not differentiate between MPS IVA and MPS IVB showed a comparable incidence of aortic and mitral valve thickening (40%) and valve stenosis (7–9%) but a somewhat lesser incidence of valve regurgitation (17–26%) (Supplemental Table
1).
It is generally thought that cardiac valves most affected in the MPS syndromes are those associated with dermatan sulfate deposition (Dangel
1998). However, keratan sulfate and chondroitin-6-sulfate are both found within normal cardiac valves (Latif et al.
2005), so it is not surprising that the gross and histological appearances of the MPS IVA cardiac valves are similar to the patterns found in MPS I, II, and VI. Valve thickening, seen on cardiac ultrasound, has been found to be nearly as common in patients who do not accumulate dermatan sulfate as in those who do (Lael et al.
2010). All MPS IVA cardiac valves may show GAG deposition, although the left-sided cardiac valves are more severely affected. Excess GAG is present within MPS IV (subtype A or B not specified) cardiac valve tissue obtained during valve replacement (Barry et al.
2006) and at post mortem examination (Ireland and Rowlands
1981). Mitral valve chordae are thick and shortened, valve edges are thickened and rolled. The aortic valve cusps are thickened throughout and some fusion of the commissures has been noted (Ireland and Rowlands
1981). Characteristic vacuolated cells deep within the valve tissue (likely valvular interstitial cells), appear to be present as well (Barry et al.
2006; Factor et al.
1978). The myocardium can be hypertrophied (Ireland and Rowlands
1981), and coronary intimal sclerosis may be present (Factor et al.
1978), even at a young age.
Respiratory system
Alterations in respiratory function are common in patients with MPS IVA (Montaño et al.
2007). Respiratory impairment occurs due to direct involvement of respiratory tissues and as a consequence of involvement in other body systems. Thus, the etiology for respiratory impairment is multifactorial and attributable to upper and lower airway obstruction, cervical myelopathy, and chest wall restriction. Alteration in growth and development provides an additional mechanism for respiratory impairment due to the short stature and skeletal dysplasia that is frequently noted in these patients (Tomatsu et al.
2011). Patients with MPS IVA are at increased risk for complications that include recurrent infections, progressive loss of respiratory function, sleep disordered breathing, and ultimately respiratory failure (Montaño et al.
2007; Tomatsu et al.
2011; Pelley et al.
2007).
As in other MPS diseases, pulmonary involvement occurs in part due to GAG accumulation throughout the respiratory system (Peters et al.
1985; Semenza and Pyeritz
1988; Walker et al.
2003). GAG accumulation is prominent in the upper airways and tonsils leading to an increased risk for development of obstructive sleep apnea (Montaño et al.
2007). During wakefulness, collapse of the upper airway has been documented upon neck flexion (Pritzker et al.
1980). Hyperextension of the neck (the sniff position) may occur in order to maintain airway patency. GAG accumulation has also been documented in the intrathoracic airways (Semenza and Pyeritz
1988). Tracheal and bronchial wall abnormalities have been noted on post mortem examination (Walker et al.
2003). Tracheomalacia and bronchomalacia with associated airway collapse have been documented upon fiber optic bronchoscopy (Walker et al.
2003). Recognition of this complication is imperative as airway obstruction may persist after therapeutic tracheostomy due to persistent airway collapse distal to the tip of the endotracheal tube (Pelley et al.
2007). Lastly, although the incidence and magnitude of GAG accumulation in pulmonary parenchyma are unknown, if present, this complication would further compromise pulmonary function and gas exchange.
Respiratory compromise also occurs in patients with MPS IVA due to involvement of the chest wall and neuromuscular systems (Buhain et al.
1975; Sly
1980; Ashraf et al.
1991). Chest wall deformities including pectus carinatum and kyphoscoliosis can limit lung expansion and produce a restrictive impairment that manifests as a reduction in lung volume. Displacement of the diaphragm into the thoracic cavity may occur due to short stature coupled with hepatic and/or splenic enlargement, further compromising respiratory function. In addition to the previously stated chest wall abnormalities, atlantoaxial instability and spinal cord compression are common in patients with MPS IVA (Tomatsu et al.
2011) and may result in respiratory muscle weakness. Spinal cord compression can to lead to phrenic nerve dysfunction and inspiratory muscle weakness potentially impairing patient ability to maintain ventilation in the setting of reduced chest wall compliance. Furthermore, impairment of the expiratory muscle strength due to thoracic and/or lumbar involvement impairs cough and clearance of secretions, thereby predisposing patients to infections. The combined effects of these alterations are recognized mechanisms for development of respiratory failure in otherwise healthy subjects and, therefore, are likely to result in reduced ventilation rates and development of respiratory failure in patients with MPS IVA.
Respiratory function is also altered by the short stature and skeletal dysplasia characteristic of patients with MPS IVA. In other MPS disorders associated with short stature (e.g., MPS VI), patient height is the primary determinant of vital capacity (Swiedler et al.
2005). In addition, improvement in pulmonary function during enzyme replacement therapy (ERT) in other MPS disorders is frequently associated with growth and increased stature (Harmatz et al.
2010). While corresponding data in patients with MPS IVA are not available, a similar pattern is likely to occur, suggesting that measures targeted to promote growth and development may have a beneficial effect on the respiratory dysfunction characteristic of MPS IVA.
Sleep disordered breathing (SDB) is common in all MPS diseases (Semenza and Pyeritz
1988) and may precede development of overt respiratory failure during wakefulness. Ventilatory abnormalities during sleep include obstructive sleep apnea as a consequence of GAG accumulation in the upper airway and sustained hypoventilation due to the chest wall deformity and/or respiratory muscle weakness.
If chronic respiratory insufficiency and sleep disordered breathing remain unrecognized and untreated, progression to development of cor pulmonale may occur. The combined primary and secondary effects of GAG accumulation in patients with MPS IVA can result in impairment of respiratory function to a degree that can ultimately lead to respiratory failure and early demise (Pelley et al.
2007; Walker et al.
2003).
Overall quality of life
As the MPS IVA disease process progresses, quality of life for the patient declines. Patients become progressively more dependent on care givers as deteriorating vision, hearing, oral health, respiratory and cardiac function, muscular strength, and endurance make routine daily activities increasingly difficult to accomplish. A description of the endurance and mobility challenges faced by MPS IVA patients is provided online as supplemental material (S1). Ultimately, in the absence of treatment, patient quality of life continuously decreases as the disease progresses.