Morquio Syndrome (Mucopolysaccharidosis Type IV)

Morquio syndrome (mucopolysaccharidosis type IV [MPS IV]) is a rare lysosomal storage disease (LSD) that is inherited in an autosomal-recessive fashion. Morquio syndrome is classified into two types, Morquio A syndrome (mucopolysaccharidosis type IVA [MPS IVA]; OMIM 253000) and Morquio B syndrome (mucopolysaccharidosis type IVB [MPS IVB]; OMIM 253010), based on a deficiency of different lysosomal enzymes—N-acetylgalactosamine-6-sulfate sulfatase (GALNS) and β-galactosidase, respectively. GALNS deficiency induces the accumulation of glycosaminoglycans (GAGs), keratan sulfate (KS), and chondroitin-6-sulfate (C6S) in multiple tissues, particularly bone, cartilage, heart valves, and cornea, while β-galactosidase deficiency induces the accumulation of only KS in those tissues.[1, 2, 3, 4]

Morquio syndrome is characterized by a unique skeletal dysplasia with excessive accumulation of KS and/or C6S. Although most individuals with Morquio syndrome appear normal at birth, skeletal abnormalities often develop within the first year of life. At birth, some affected newborns may have a minor skeletal phenotype, such as hump back, chest protrusion, and prominent forehead, as confirmed with radiography.[1, 2, 3, 4]

Skeletal dysplasia is characterized by incomplete ossification and successive imbalance of growth, which results in a prominent forehead, abnormal face with a large mandible, short neck, cervical spinal cord compression, tracheal obstruction, disproportionate short-trunk dwarfism, pectus carinatum, flaring of the rib cage, coxa valga, genu valgum, hypermobile joints, and pes planus.[1, 2, 3, 4, 5, 6, 7, 8] The severity of bone and cartilage damage differs by the type of bone affected. Affected bone with growth plate is affected more severely.

In 1929, Morquio first reported four Swedish patients with MPS IV (now classified as MPS IVA).[1] The same year, Brailsford also reported a patient with MPS IV.[2] Clinical features of MPS IV described at the time included prominent forehead, abnormal face with a large mandible, short neck, pectus carinatum, flaring of the rib cage, hypermobile joints, genu valgum, disproportionate short-trunk dwarfism, and pes planus; however, aortic valve disease and corneal clouding were not described in the original publication.[1]

In 1962, Pedrini et al isolated and identified KS in the urine of three patients with Morquio syndrome and reported that this metabolic disorder differs from that observed in Hurler syndrome (mucopolysaccharidosis type I [MPS I]).[3] In 1965, McKusick et al classified Morquio syndrome, as well as Hurler and Hunter syndromes, as hereditary acid mucopolysaccharidoses (MPS I to MPS VI).[9]

In 1971, Orii et al reported an attenuated (intermediate) form of MPS IVA.[4] At age 5 months, adduction of both thumbs was recognized, and, at age 18 months, a chest abnormality was noticed. At age 3 years, the patient had kyphosis, and an abnormal gait was present by age 5 years. The patient had keratosulfaturia and was diagnosed enzymatically with Morquio A syndrome at age 15 years. At age 18 years, he was 135 cm tall and showed milder skeletal deformities, such a pectus carinatum, hypermobile joints, and genu valgum, in addition to corneal clouding.

In 1974, GALNS enzyme and its deficiency were discovered and identified using oligosaccharide substrate prepared from C6S containing N-acetylgalactosamine-6-sulfate.[8] In 1976, O’Brien et al reported a patient with a mild clinical status similar to that of Morquio A syndrome. However, this patient was deficient in β-galactosidase.[10] In 1977, Arbisser et al reported a similar case with mild Morquio A syndrome–like symptoms resulting from a deficiency of β-galactosidase, described as MPS IVB.[11] Since then, Morquio syndrome has been differentiated into two forms, Morquio A syndrome and Morquio B syndrome.

In 1981, Orii et al reported a very mild form of Morquio A syndrome in two siblings.[12] Their initial symptom was hip joint pain at age 8 years; thus, both patients underwent femoral osteotomy at age 13 years. Both patients had keratosulfaturia, mild thorax changes, and corneal clouding, although they did not show unique pectus carinatum, genu valgum, excessive joint laxity, or facial changes. Initial radiographic studies in both cases revealed mild platyspondyly, slight anterior wedging of the lumbar vertebra, and minimal odontoid hypoplasia, as well as subtle capital femoral epiphyses. However, when they were aged 18 and 22 years, respectively, the ossified femoral heads had disappeared with erosion and widening of the femoral necks. These signs were more significant in the older brother. The two brothers were not diagnosed with Morquio A syndrome until age 29 and 25 years, respectively, and their heights were 147 and 157 cm, respectively. In 2015, they were age 52 and 57 years, respectively, and their clinical conditions were stable at the time. GALNS enzyme activity in fibroblasts of these patients was about 10% of that seen in cells from healthy controls.[13]

Morquio A syndrome varies from severe systemic bone dysplasia to a lesser form of the disease, including only mild bone involvement.[4, 5, 6, 7, 12, 13, 14, 15, 16, 17] See the image below.

Individuals with untreated severe Morquio A syndrome die of respiratory obstruction, cervical spinal cord complications, or heart valve disease in their second or third decade of life. The lifespan of individuals with the attenuated form of Morquio A syndrome has been noted to be as long as 70 years.[7] The height prognosis is poor among individuals with severe bone dysplasia. Intellectual impairment does not occur in Morquio A syndrome.

Historically, Morquio B syndrome was considered to have milder manifestations than Morquio A syndrome. The clinical manifestations of Morquio B syndrome include platyspondyly, femoral epiphyses, atlanto-occipital instability, genu valgum, gait abnormalities, and cornel clouding. Morquio B syndrome is associated with normal or near-normal stature with normal neck development and absence of hearing loss and hepatomegaly.[10, 11] The skeletal involvement in Morquio B syndrome is not as pronounced as in Morquio A syndrome. However, radiographic and other phenotypical analysis cannot be used to differentiate between Morquio A and Morquio B syndrome because of the extensive overlap, which depends on the skeletal symptoms, the enzyme activity, recognition of complications, and response to surgery, among other factors.

Mucopolysaccharidoses (MPS) are a group of lysosomal storage diseases caused by a deficiency of lysosomal enzyme(s). Excessive accumulation of GAGs such as dermatan sulfate (DS), heparan sulfate (HS), chondroitin sulfate (CS), and KS in multiple tissues leads to coarse facial features, CNS damage, organomegaly, connective tissue disorders, and skeletal dysplasia. GAGs accumulate in lysosomes, intracellular matrix, and extracellular matrix. MPS is categorized into 7 groups, with 11 different deficient lysosomal enzymes.

In Morquio syndrome, the degradation of KS is defective because of deficiency of either GALNS in Morquio A syndrome or β-galactosidase in Morquio B syndrome. Deficiency of GALNS also influences the catabolism of C6S. KS and C6S have various physiological and biological functions. Both Morquio A syndrome and Morquio B syndrome are inherited through an autosomal-recessive trait. KS is closely involved in cellular motility, embryo implantation, wound healing, corneal transparency, and nerve regeneration.[18] C6S is also involved in embryo development, maintaining mechanical skin strength and cell proliferation.

Morquio A Syndrome

The incidence of Morquio A syndrome is 1 per 216,000 births in the British Columbia,[19] 1 per 76,000 births in Northern Ireland,[20] 1 per 201,000 births in Australia,[21] 1 per 450,000 births in Portugal,[22] 1 per 640,000 births in Western Australia,[23] and 1 per 625,000 births in Japan.[7] Data on Morquio A syndrome incidence in the United States are not available.

Morquio B Syndrome

To date, no epidemiological studies on the incidence of Morquio B syndrome have been conducted. However, the incidence of Morquio B syndrome is much lower than that of Morquio A syndrome.

Patients with the severe form of Morquio syndrome can develop cervical myelopathy early.[24, 25] Those with the severe form do not survive past their second or third decade of life if untreated.[25] Two-thirds of patients die of respiratory distress followed by cardiac issues.[26] A shorter-than-usual lifespan might also be attributed to paralysis caused by myelopathy, restrictive chest movement, and valvular heart disease.[24, 26] Owing to advancements made in comprehensive care, the lifespan among patients with Morquio syndrome is improving.

Patients with mild manifestations of Morquio syndrome (mucopolysaccharidosis type IV), regardless of type, have been reported to survive into the seventh decade of life.

Patients with severe manifestations, primarily related to cervical instability and pulmonary compromise, often do not survive beyond the second or third decade of life.

The length of survival may improve with the improved comprehensive care available to these patients today.

Many resources are available to patients with Morquio syndrome and their families to increase their understanding of the disorder, including the following:

• National MPS Society
• The National Organization for Rare Disorders, Inc.
• International Morquio Organization ( The Carol Ann Foundation)
• Little People of America, Inc.
• Society for the Study of Inborn Errors of Metabolism
• National Institute of Neurological Disorders and Stroke
• Online Mendelian Inheritance in Man

It is also important to educate the patient’s primary physicians, teachers, counselors, school administrators, and classmates to help them understand the unique needs of an individual with Morquio syndrome.

Morquio syndrome does not affect fertility, and a child born to a parent with Morquio syndrome will be a carrier but will not have Morquio syndrome unless he or she partners with another Morquio syndrome carrier. Then, the risk is 25% that their offspring will have Morquio syndrome. As in all autosomal-recessive conditions, if both parents have the same subtype of Morquio syndrome, they will have a 100% chance of having offspring with Morquio syndrome.

Morquio A Syndrome

Initial clinical signs and symptoms of Morquio A syndrome (mucopolysaccharidosis type IVA [MPS IVA]) vary depending on severity.[14] Infants with Morquio A syndrome usually appear normal at birth and often develop skeletal problems within the first few years of life (see image below).

Among individuals with mild Morquio A syndrome, initial symptoms may not appear until later in childhood or during adolescence. The most common initial symptoms of Morquio A syndrome include pectus carinatum, kyphosis, genu valgum, joint laxity, short stature, abnormal gait, and spinal complications. Odontoid hypoplasia, cervical compression/instability, kyphosis, and scoliosis are among the spinal complications (see image below).[7, 27, 28, 29]

Individuals with severe Morquio A syndrome often develop kyphoscoliosis and thoracic deformity within the first year of life. Within the first few years of life, more than 70% of individuals with severe Morquio A syndrome have skeletal abnormalities such as pectus carinatum, kyphoscoliosis, joint laxity, and genu valgum.[30, 31]

Progressive coxa valga, genu valgum, and ankle valgus are the main lower-extremity features of Morquio A syndrome (see image below),[32] and these develop during childhood. Hips appear either normal or partially dislocated as early as the second year of life in the severe form of Morquio A syndrome. Children with Morquio A syndrome have small capital femoral epiphyses. Epiphyses are progressively flattened and fragmented with growth and are finally lost in adulthood. Hip subluxation and associated pain often force individuals with Morquio A syndrome to become wheelchair bound as teenagers in the absence of surgical treatment.[33] Knee deformity is most commonly observed in children with Morquio A syndrome by age 3 years.

Without appropriate treatment, most patients with severe Morquio A syndrome become completely wheelchair bound by their teenaged years and rarely survive beyond a few decades of life owing to spinal cord compression, airway compromise, or valvular heart disease. Airway obstruction progresses with age and contributes to increased morbidity and mortality. The most significant component of the airway obstruction occurs in the trachea itself, whereby deviation, folding and buckling of trachea, and vascular and bony compression result in unique obstructive pathology.[34, 35, 31]

Morquio B Syndrome

Morquio A syndrome and Morquio B syndrome cannot be distinguished clearly based on clinical features. In general, individuals with Morquio B syndrome have mild skeletal dysplasia, and the symptoms progress more slowly than those of Morquio A syndrome.

Morquio syndrome is characterized by unique skeletal and nonskeletal manifestations.

Skeletal Problems

Skeletal manifestations caused by incomplete ossification include short neck, short stature, spinal cord compression, pectus carinatum, joint laxity, kyphoscoliosis, coxa valga, and genu valgum, leading to many physical disabilities, including floppy hands and poor fine motor skills, frequent tendency to fall, abnormal gait, hip dislocation, reliance on a wheelchair, joint pain, and restriction of joint mobility. See the images below.

Odontoid hypoplasia is the most critical skeletal feature to be recognized in any patient with Morquio syndrome. This condition, in combination with ligamentous laxity and extradural mucopolysaccharide deposition, results in atlantoaxial subluxation, leading to consequential quadriparesis or even death (see image below).

Another potential complication is cervical myelopathy. A history of exercise intolerance in patients with Morquio syndrome often precedes occult cervical myelopathy, which can also cause bowel and bladder dysfunction and compression of the spinal cord, leading to weakness or paralysis. Mortality and morbidity are primarily related to the atlantoaxial instability and subsequent cervical myelopathy, and patients with a severe form, primarily related to cervical instability, often do not survive beyond the second or third decade of life, if untreated. A minor fall or extension of the neck can result in cord transection and subsequent quadriparesis or sudden death.

Airway Problems

Earlier in the disease process, obstructive sleep apnea (also known as sleep disordered breathing) results mainly from upper airway pathology (small nostrils, large tongue, and short neck).[36, 37] Noisy breathing, snoring, intolerance of effort-dependent motion, and a ”look-up” position of the head and neck (occurs with aging) starts to develop, which often indicates significant tracheal (level) breathing obstruction.[35]

The pathophysiology of airway problems in Morquio A syndrome is progressive and cyclical, consisting of restrictive and obstructive sequences. The restrictive defect results from thoracic cage deformity. The obstructive defect results from tracheobronchial abnormalities, large tongue, and adenoidal, tonsillar, and vocal cord hypertrophy due to the accumulation of storage materials.[38, 39] Obstructive airway disease is common at the severe end of the Morquio A syndrome spectrum and results from narrowed trachea, which folds and buckles on itself, as well as from external compression from major vessels (brachiocephalic artery) and/or bony components of the thoracic cage (eg, manubrium and sternal heads of the clavicles). Common abnormalities also include thickened vocal cords, redundant tissue in the upper airway, and an enlarged tongue. Individuals with obstructive airway disease may exhibit loud snoring, daytime hypersomnolence, and alveolar hypoventilation. Noisy breathing is a general consequence of upper airway obstruction.

Moreover, individuals with Morquio A syndrome may have small nasal passages due to thickened mucous membranes with thick and copious secretions. Chronic upper respiratory tract infection further decreases the already diminished airway lumen.

Thus, the most important and challenging aspect is the management of the problematic airway.

Intermittent obstruction may lead to sleep apnea. Tracheal problems result mainly from an imbalance of growth between the trachea, innominate artery, spine, rib, and thoracic inlets (see image below). In many cases, tracheostomy has been required to maintain the airway and to control pulmonary hypertension and heart failure; however, tracheostomies are difficult to maintain, and loss of airway has occurred during routine changing of tracheostomy tubes. Tracheal reconstructive surgery has been performed successfully in a few patients, and one such case has been published.[40]

Cardiovascular Disease

Cardiovascular manifestations of Morquio syndrome include coronary heart disease and valve thickening manifesting as cardiac dysfunction. Heart disease is clinically evident in adults with Morquio syndrome. Mild mitral or aortic valvular disease is common, and myocardial thickening, systemic and pulmonary hypertension, and narrowing of the coronary arteries with ischemia are rare. The aortic valvular disease is more likely to occur in Morquio A syndrome.[26] Cardiac evaluation at regular intervals with echocardiography is useful in the treatment of patients via serial monitoring of ventricular function and size. Bacterial endocarditis prophylaxis is advised in patients with Morquio syndrome who have cardiac abnormalities.

Hearing Problems

Audiological manifestations of Morquio syndrome include frequent middle ear infections, deformed ossicles, and abnormalities of the inner ear, leading to hearing loss. Mild to moderate hearing loss is common in individuals with Morquio A syndrome and may correlate with the severity and duration of skeletal disease. Hearing problems can become apparent by the end of the first decade of life.[41]

Deafness, usually due to combined conductive and neurosensory etiologies, is common in Morquio syndrome. The deafness has been attributed to three causes: frequent middle ear infections, deformity of the ossicles, and probable abnormalities of the inner ear. The auditory brainstem response is nonspecifically abnormal, probably reflecting a mixture of middle-ear, cochlear, eighth-nerve, and lower-brainstem anomalies. Ventilating tubes can minimize the long-term sequelae of the frequent episodes of acute otitis media and chronic middle-ear effusions. Most individuals with Morquio syndrome would benefit from hearing aids.

Eye Problems

Ophthalmological manifestations of Morquio syndrome include visual disturbance and photophobia, as well as corneal clouding. Fine stromal corneal clouding due to GAGs storage is common in Morquio A syndrome, and photophobia is the main symptom associated with this abnormality. Corneal transplantation has been performed as treatment, although the long-term outcome is not always successful with a recurrence of corneal clouding.

Other rare ocular problems include retinal degeneration, resulting in decreased peripheral vision and night blindness, glaucoma,[42] and optic nerve disease. Ultimately, these abnormalities affect vision and may all lead to blindness.

Dental Problems

Dental abnormalities associated with Morquio syndrome include dental caries, tooth fractures, and abnormally thin enamel. Individuals with Morquio A syndrome have small and widely spaced teeth with abnormally thin enamel and frequent formation of caries. The enamel is structurally weak, showing a tendency to fracture and flake off. Thin enamel with small sharp pointed cusps is unique to patients with Morquio A syndrome, but the enamel is of normal radiodensity. Other features include spade-shaped incisors, concave buccal and occlusal surfaces, and pitted buccal surfaces. The dentin, pulp chambers, and root canal systems of all the teeth are usually normal.

Patients with Morquio A syndrome require good dental hygiene. Treatment should be confined to preventive regimes involving dietary analysis and advice, toothbrush instruction, systematic topical fluorides, and fissure sealants. Teeth should be cleaned regularly, and patients should take fluoride tablets or drops daily if their water supply is not treated with fluoride. Bacterial endocarditis prophylaxis should be administered before and after any dental treatment. If teeth need to be removed under an anesthetic, the procedure should be performed in a hospital with an experienced anesthesiologist trained in the management of obstructive airway disease.

Summary

Obstructive airway and heart valve disease are life-threatening in severe Morquio syndrome, and affected individuals who are untreated or physically handicapped typically die in their second or third decade of life. Compared with individuals with Morquio A syndrome, those with Morquio B syndrome usually results in normal or near-normal stature with normal neck development and an absence of hearing loss and hepatomegaly.[10, 11]

Morquio A syndrome is caused by a deficiency of the lysosomal enzyme GALNS, while Morquio B syndrome is caused by a deficiency of the lysosomal enzyme β-galactosidase. KS and C6S accumulate in systemic tissues, including bone and cartilage, among individuals with Morquio A syndrome; in persons with Morquio B syndrome, KS accumulates in these tissues. KS and/or C6S accumulation in both types of Morquio syndrome leads to unique skeletal dysplasia. The gene mutations in Morquio syndrome have been mapped on the human genome. Their chromosomal locations are 16q24.3 for GALNS and 3p21.33 for β-galactosidase.

Clinical recognition of unique skeletal abnormalities, combined with radiographic and biochemical analyses, is important in the diagnosis of Morquio syndrome (mucopolysaccharidosis type IV [MPS IV]). Although radiographic findings provide substantial insight, they need to be combined with biochemical analysis (enzyme activity), substrate analysis (KS and C6S), and molecular analysis to diagnose Morquio syndrome.

Biochemical Analysis

Morquio A syndrome

GALNS enzyme activity in fibroblasts and leukocytes is assessed when Morquio syndrome is suspected. However, GALNS activity in fibroblasts and leukocytes is sensitive to temperature changes, so strict adherence to guidelines for shipping specimens and interpretation of results is required. Dried blood spots (DBS) have been used as an alternative sample source when there are difficulties in shipping of viable cells.[44, 45] However, enzyme activity in DBS samples is also affected by temperature changes. Therefore, the delay between collection and assay can provide false-positive results.[45]

Currently, many laboratories use an assay based on the fluorogenic substrate.[46] The fluorometric assay needs 4-methylumbelliferyl-ß-D-galactopyranoside-6-sulfate (4MU-Gal6S) as a substrate. GALNS and exogenous ß-galactosidase in samples remove 6-sulfate and galactoside, respectively. The released methylumbelliferone fluoresces at a high pH.[47]

A quantitative GALNS assay method has been established by measuring processing of a novel substrate via tandem mass spectrometry.[44, 48, 49, 50] A careful interpretation of enzyme activity results is required since the reference range of GALNS activity is affected by the sample type, laboratory techniques, and specific methodologies.[51]

Morquio B syndrome

β-galactosidase activity is tested in fibroblasts or leukocytes. The fluorometric assay often uses p-nitrophenyl β-galactopyranoside or 4-methylumbelliferyl-ß-galactopyranoside as a substrate.

Substrate Analysis

Morquio A syndrome

Serum and urinary KS levels show a positive correlation with clinical severity in Morquio A syndrome (mucopolysaccharidosis type IVA [MPS IVA]).[52, 53, 54, 55, 56] Results of these studies indicate that serum and urinary KS levels may be used as a potential biomarker for evaluating the clinical severity of Morquio A syndrome at an early stage and may be valuable for monitoring therapeutic effects.

A range of assay methods have been developed to measure serum and urinary KS, both experimentally and clinically, including an inhibition enzyme-linked immunoassay (ELISA),[57] a sandwich ELISA,[57, 58] and liquid chromatography–tandem mass spectrometry (LC-MS/MS).[55, 59, 60, 61, 62] Oguma et al first reported a detection method to specifically measure abnormal GAG levels including KS by using LC-MS/MS.[59, 60] These methods have been revised and refined by other groups.[54, 55, 61, 62, 63, 64, 65, 66, 67] Therefore, LC-MS/MS has become a highly specific, sensitive, and cost-effective quantitative method for measuring KS and C6S levels in the blood, urine, and DBS specimens.[66, 67]

Mono-sulfated and di-sulfated KS levels in blood and urine were significantly higher in young patients with Morquio A syndrome compared with age-matched controls. The elevation of di-sulfated KS levels was more significant compared with that of mono-sulfated KS. The proportion of di-sulfated KS in total KS level increases with age in control patients but is age-independent among patients with Morquio A syndrome, suggesting that the proportion of di-sulfated KS in total KS is more discriminating for younger patients with Morquio A syndrome than for older patients.

A quantitative method to measure C6S was also established by using LC-MS/MS.[67] This assay method separates C6S disaccharides from other CS disaccharides in blood and urine. Levels in both tissues were significantly higher in patients with Morquio A syndrome than in age-matched controls. Combining KS and C6S data is better than either C6S or KS alone at differentiating patients with Morquio A syndrome from age-matched controls.

Overall, KS and C6S levels are potential biomarkers not only for screening and diagnosing Morquio A syndrome but also for assessing the clinical severity and therapeutic efficacy.

Morquio B syndrome

Patients with Morquio B syndrome have increased excretion and defective degradation of KS.[68] Urinary specimens in patients with Morquio B syndrome also contain much smaller chondroitin sulfate amounts than in patients with Morquio A syndrome.

Molecular Analysis

Morquio A syndrome

The human GALNS gene is localized at 16q24.3,[69, 70] and the entire gene is approximately 50 kb long, containing 13 introns and 14 exons.[71] The spliced mRNA is 1566-bp, encoding a protein of 522 amino acid residues. After a 21–amino acid signal peptide and N-glycosylation are removed by cleavage, the protein is processed, yielding the mature active GALNS enzyme, which consists of 40- and 15-kDa subunits.[71, 72, 73] GALNS is one of 13 evolutionary related sulfatases in the human genome. All sulfatases show 20%-35% similarity at the amino acid level, and the C79 residue in exon 2 of human GALNS is conserved in all sulfatase proteins from many species. This cysteine is post-translationally modified to a formylglycine residue by sulfatase modifying factor 1,[74] and structural and homology analysis shows that it is a vital part of the active GALNS site.

More than 400 mutant GALNS alleles have been identified from 250 patients with Morquio A syndrome. Of these mutant alleles, 328 different mutations have been shown to cause the disease phenotype as of October 2016;[52, 56, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85] missense/nonsense mutations account for 243 mutations (74.1%), while the rest consist of deletions (32 [9.8%]), splicing site mutations (32 [9.8%]), and insertions (5 [1.5%]).[6] The most common mutations are reported to be missense mutations: C1156>T (p.R386C), G901>T (p.G301C), and A337>T (p.l113F). These mutations have been detected in various ethnic groups.[80, 86, 87, 88, 89] The 10 most prevalent GALNS mutations account for 35% of all known Morquio A syndrome cases. Molecular analysis is commonly performed using a blood or DBS sample.

Morquio B syndrome

The human β-galactosidase gene is localized on chromosome 3 at 3p21.33, and the entire gene is approximately 60 kb long, containing 16 exons. The cDNA encodes 677 amino acid residues. Paschke et al reported that 14 of 15 European patients with Morquio B syndrome had a missense mutation, p.W273L.[90]

Morquio A syndrome

Imaging techniques such as radiography, computed tomography (CT), and magnetic resonance imaging (MRI) are often used to help management of Morquio A syndrome. Radiography, CT, and MRI are used to evaluate compression and instability in the upper cervical spine and spinal stenosis. These imaging studies commonly reveal anterior beaking, kyphoscoliosis, platyspondyly, and vertebrae irregularity. Imaging before age 2 years is important. Patients should be monitored annually to determine whether orthopedic surgery is required.

Regular follow-up of tracheal obstruction is also necessary, as tracheal obstruction in individuals with Morquio A syndrome is life-threatening and places them at high risk of mortality and extubation failure in the anesthetic procedure owing to sleep apnea and airway complications.[34, 91] CT angiography is required to observe anatomy of the trachea, artery, cervicothoracic spine, manubrium, and thoracic inlet. CT angiography has identified multiple factors that cause tracheal obstruction in Morquio A syndrome, including (1) disproportionate development of the trachea, brachiocephalic artery, cervicothoracic spine, and chest cavity and (2) a severe pectus carinatum and crowding of thoracic inlet (see image below).[91]

Morquio B syndrome

Gucev et al reported on a 24-year-old female with Morquio B syndrome in whom bone radiography showed platyspondyly with ovoid vertebrae and anterior projection. Her hip joint had coxa valga. The femoral head was flattened, and acetabulum was dysplastic and wavelike. Her hand had a deformity of radiocarpal articulation, and her metacarpals had conical bases.[92]

Morquio A syndrome

An autopsy case study in a patient with Morquio A syndrome showed systemic storage materials in multiple tissues (trachea, lung, thyroid, humerus, aorta, heart, liver, spleen, kidney, testes, bone marrow, and lumbar vertebrae) beyond cartilage.[93] Severely vacuolated and ballooned chondrocytes are found in the trachea, humerus, vertebrae, and thyroid cartilage with disorganized extracellular matrix and poor ossification. The appearance of foam cells and macrophages is shown in the lung, aorta, heart valves, heart muscle, trachea, visceral organs, and bone marrow.

Morquio B syndrome

Bulbar conjunctival biopsies showed intracytoplasmic vacuoles.[11]

To fully understand and treat rare genetic diseases in humans, animal models are typically developed.[94, 95] Molecular biology techniques and homologous recombination have been used to engineer animal models for Morquio A syndrome.[96]

In 2000, Montaño et al reported on the isolation and expression of mouse Galns cDNA, its chromosomal localization, genomic organization, and promoter analysis of the mouse Galns gene.[97] The full-length mouse Galns cDNA encodes 520 amino acids, two residues shorter than the human protein. The mouse and human nucleotide and amino acid sequences are 83% and 84% identical, respectively. The mouse Galns gene was mapped to the distal region of mouse chromosome 8, which is in a syntenic group on 16q24.3 that contains human GALNS. Both the mouse Galns gene and human GALNS gene have 14 exons and 13 introns, and both are approximately 50 kb in length, indicating high conservation of gene structure between these two species.[97]

After the elucidation of the mouse Galns gene structure, the first mouse model of Morquio A syndrome was produced via homologous recombination in 2003. This mouse model is a classic knock-out type mouse (Galns-/-), which produces no Galns mRNA because of a gene deletion in part of intron 1 and exon 2.[98] Lysosomal storage was present primarily within reticuloendothelial cells such as Kupffer cells and cells of the sinusoidal lining of the spleen at age 2 months. In addition, by age 12 months, vacuolar changes were observed in the visceral epithelial cells of glomeruli and cells at the base of heart valves, but not in parenchymal cells such as hepatocytes and renal tubular epithelial cells. In the brain, hippocampal and neocortical neurons and meningeal cells had lysosomal storage. Immunohistochemistry showed that KS and C6S were more abundant in the cytoplasm of corneal epithelial cells of Galns-/- mice compared with wild-type mice. Radiographs revealed no change in the bones of mice up to age 12 months.[98] After 50 mouse generations, the phenotype of the Galns-/- mouse model became more severe, with GAG accumulation in chondrocytes and other tissues. The genetic characteristics of this mouse model correspond to patients who have a large deletion in the GALNS gene and either no functional protein or no protein at all (unpublished).

In 2005, a mouse model tolerant to human GALNS (Galns tm (hC79S.mC76S) slu) was engineered.[99] This mouse model contains a point mutation in the active site (C76S) and a transgene (cDNA) expressing inactive human GALNS in intron 1 in which the active site cysteine is substituted with serine (C79S). This tolerant mouse model contains the inactive human cDNA and the C76S mouse mutation by targeted mutagenesis. This model showed an irregular growth plate region, with ballooned vacuolated chondrocytes in histopathological studies. The cartilage layer, especially the proliferative layer, was narrower than that in wild-type mice. The hypertrophic zone was thicker, and cells were disarrayed.[99] In addition, this tolerant mouse model had a ubiquitous expression of the inactive human GALNS, which resulted in tolerance to the immune response to human GALNS enzyme. This model has been very useful in the evaluation of enzyme replacement therapy or gene therapy in adult mice[100, 101] without the adverse effects of an immune response.

In 2007, a knock-in mouse model was developed (Galnstm (C76S) slu) in which the active site Cys was replaced with Ser (C76S) in the endogenous murine Galns by targeted mutagenesis.[102] The Galnstm(C76S)slu mouse model had lysosomal storage in Kupffer and spleen sinus-lining cells, heart valve stoma cells, glomerular visceral epithelial kidney cells, chondrocytes, and neocortical and hippocampal neurons.[102] Overall, the lysosomal accumulation in this mouse model was milder than that observed in the tolerant mouse model. The genetic characteristics of this mouse model correspond to patients with a point mutation in the GALNS gene who cannot produce a functional protein.

The bone phenotype of these mouse models is milder than that in patients with Morquio A syndrome. This can be explained by the lack of di-sulfated KS in mice and rats.[103] However, these mouse models still have mono-sulfated KS, which is present in proteoglycans that are found in cartilage, tendons, ligaments, and bone.[104] The phenotype of Morquio A syndrome mouse models has been questioned for several years owing to the milder appearance compared with patients who have Morquio A syndrome. The authors of this article have found that (1) the phenotype appears to be more severe after more than 50 generations of mice have been produced, (2) disease phenotype appears to progress with age, and (3) histological analysis of Morquio A mouse skeletal system has shown GAG accumulation and disarray in growth plate and chondrocytes.

Overall, the mouse models for Morquio A syndrome disease have helped significantly in the evaluation of therapies, including enzyme replacement therapy (ERT), hematopoietic stem cell transplantation (HSCT), and gene therapy. They remain essential tools in the development and evaluation of novel treatments for this devastating disease.

Enzyme replacement therapy (ERT; elosulfase alfa [Vimizim]) may improve the activity of daily living (ADL) in patients with Morquio syndrome, although no evidence has shown that ERT can penetrate the avascular cartilage region to improve the bone pathology, which suggest limited benefit for skeletal dysplasia. Long-term investigation is still required.

Hematopoietic stem cell transplantation (HSCT) has improved ADL and mobility after over 10 years of follow-up in several cases; however, careful consideration is required because of a risk.

Surgical interventions must be performed with appropriate timing by a well-trained team in an appropriate facility. Cervical decompression and fusion and tracheal reconstructive surgeries should markedly improve the morbidity and mortality risk.

Overall, the cost/benefit profile and availability of each treatment option should be carefully evaluated.

Enzyme Replacement Therapy (ERT)

Enzyme replacement therapy (ERT) consists of administration of an enzyme to patients who lack it. ERT for lysosomal storage diseases takes advantage of the fact that the enzyme can be taken up by the cell and targeted to the lysosome via receptor-mediated endocytosis.[104]

Although the concept of ERT was introduced by Christian de Duve in the 1970s,[105] it was not until 2008 that the first preclinical results of ERT for Morquio A syndrome (mucopolysaccharidosis type IVA [MPS IVA]) in an animal model were published.[100] The progress of ERT for Morquio A syndrome was hindered by the difficulty in purifying a stable GALNS enzyme to a large scale and the absence of a spontaneous mouse model for treatment and evaluation. After achieving large-scale purification of phosphorylated GALNS in the laboratory using Chinese hamster ovary cells, pharmacokinetics and pharmacodynamics were evaluated, showing that GALNS enzyme was indeed taken up by cells via the mannose 6 phosphate receptor and distributed systemically in mice after a single injection.[106]

After mouse Galns gene was isolated and its structure elucidated,[97] the three mouse models described above were used in preclinical studies.[83, 98, 99] The first preclinical trial results for Morquio A syndrome mice were published in 2008. The results indicated that Morquio A syndrome mice treated with human recombinant GALNS enzyme weekly for 12 weeks with 250 U/g, 500 U/g, or 1,000 U/g of body weight had normal serum KS levels.[100] In addition, storage material was cleared in liver, bone marrow, and connective tissue in articular cartilage. A limited response was observed in the growth plate and the articular cartilage, since that region is avascular, making enzyme delivery difficult. The limited effectiveness in bone and cartilage suggested that a bone-targeting system could be more effective.

Based on efficacious modifications of other enzymes with acidic tags to target proteins to the bone, the author of this article applied similar technology to target GALNS.[101, 107, 108] An acidic amino acid sequence (aspartic or glutamic acid) has a high affinity for hydroxyapatite;[109] consequently, a similar tag should concentrate GALNS enzyme near bone cells and improve its uptake into such cells.

The recombinant E6-GALNS enzyme had a longer half-life than native enzyme (30 minutes vs 3 minutes), decreasing its plasma clearance.[101] Adult Morquio A syndrome mice treated for 24 weeks with the tagged enzyme or E6-GALNS showed (1) improvement in biodistribution, since bone and bone marrow contained more enzyme than native GALNS and (2) improved clearance of storage materials in bone, ligaments, connective tissues, and heart valves when compared to mice treated with the native enzyme. Mice treated at birth with the tagged enzyme for eight weeks showed better clearance than adult mice treated with the tagged enzyme.[101]

To confirm these observations, the authors treated mice at birth for 15 weeks with the native enzyme and found that the growth plate was more organized with an overall reduction of substrate accumulation in bone compared to that of untreated mice. However, there was less clearance of storage material in fibrous cartilage cells of the articular disc, ligaments, periosteum, and synovium surrounding the femur of Morquio A syndrome mice. In addition, there was a limited response in heart valves.[110] Overall, the preclinical trial with native GALNS on Morquio A syndrome mouse models provided little impact to bone lesions. Native GALNS used in clinical trials had not been tested in Morquio A syndrome mouse models.

Clinical trials in humans consisted of phase I/II (MOR-002), phase II (MOR-008), and phase III (MOR-004). In 2009, the phase I/II started as an open-label, multicenter, dose-escalation study, which enrolled 20 patients aged 5 to 18 years with Morquio A syndrome disease to evaluate safety and tolerability of the drug (GALNS enzyme or elosulfase alfa). Two patients abandoned the trial (one subject had an adverse event, and the other subject withdrew from the study), which continued with 18 subjects.[111]

The study patients received elosulfase alfa over a 36-week dose-escalation period of 12 weeks each (0.1, 1.0, and 2.0 mg/kg/w), followed by 36-48 weeks of additional treatment at 1 mg/kg per week.[112] All patients showed reduced urinary KS levels, and a dose of 2 mg/kg per week was chosen for subsequent studies.[113]

Phase III consisted of a double-blind, randomized, placebo-controlled, multicenter, multinational, 24-week study to compare two dose regimens (2 mg/kg per week vs 2 mg/kg every other week), and 175 patients completed the study. Subjects were divided into three groups, receiving 2 mg/kg per week, 2 mg/kg every other week, or placebo. A modest improvement was found in the 6-minute walk test (6MWT), and a significant reduction in urinary KS was reported among subjects who received a weekly dose of elosulfase alfa. There was no improvement in subjects who received the enzyme every other week. Both elosulfase alfa regimens did not improve endurance in the 3-minute stair climb test (3MSCT).[113]

Owing to the heterogeneous presentation of the disease, it was challenging to evaluate efficacy in a heterogeneous group of patients. Composite analyses of tertiary data points (eg, forced volume vital capacity [FVC], maximum voluntary ventilation [MVV], standing height, growth rate) demonstrated that the group receiving 2 mg/kg per week had benefitted from treatment when changes from baseline 6MWT, 3MSCT, and MVV were combined.[114, 115]

Based on long-term data from an extension study, patients who continued to receive 2 mg/kg per week for another 48 weeks (a total of 72 weeks of treatment) did not show further improvement on 6MWT beyond what was demonstrated during the first 24-week placebo-controlled trial.[116] There was no comparable placebo group in this extension trial.[117] Notably, patients who received placebo during the initial 24-week controlled trial and were subsequently randomized to receive 2 mg/kg per week in the extension study did not show any improvement in 6MWT compared to baseline.[118, 119]

Although data on treatment efficacy are somewhat limited, elosulfase alfa was approved in February 2014 by the US Food and Drug Administration (FDA) and the European Medicines Agency Committee for Medicinal Products for Human Use (CHMP).[120]

The authors have evaluated the effect of ERT on the activity of daily living (ADL) and surgical intervention in patients with Morquio A syndrome.[121] ADL scores among patients younger than 10 years who received ERT (an average of 2.5 years of follow-up) were similar to those of age-matched controls but declined in older patients. Surgical frequency did not decrease after ERT treatment and was not decreased compared to untreated patients.[116, 121] These pathological findings are consistent with the fact that frequency of need for orthopedic surgical interventions has not been reduced by ERT (average duration of ERT, 2.5 ± 1 years).[116, 25, 122] Early ERT treatment at age 21 months did not improve the bone outcome in a patient with severe Morquio A syndrome after 30 months of treatment.[123]

In the United Kingdom, a ”managed access” program was formulated in December 2015[124] in which a drug is made available for a limited period (eg, 5 years), often at a discounted price, to allow further evidence to be gathered on its effectiveness while ensuring that patients receive access to the drug. Through this study, how well the medicine works in practice can be monitored before future funding decisions are made.

In the Netherlands, costs were initially reimbursed, but reimbursement was stopped when the authorities decided that the data provided were limited to a suboptimal short-term outcome in a heterogeneous population, showing a small effect that was not clinically relevant,[122, 125] as several other EU countries (Sweden, Belgium, Spain) made the same decision. This is agreeable with the statement of Australia’s PBAC, which recently rejected reimbursement for elosulfase alfa.[126]

The statements by these authorities emphasize the importance of cost/benefit in assessing ERT. The cost of ERT is one of the major disadvantages of the treatment. In the United States, the enzyme costs around $1,068 per vial, meaning that, for the typical 22.5-kg patient who needs nine vials per weekly infusion, the annual cost of ERT would be nearly $380,000.

Careful long-term observations will be required to determine whether limited enzyme delivery to bone and cartilage will be sufficient to improve outcomes in these patients. The response to ERT is likely to depend on the age of the patient when treatment is initiated and the severity of the clinical condition. Patients who respond to ERT are likely to have more storage materials through the airway (mucosa membrane).

ERT may have a clinical effect in terms reducing the proinflammatory factors that are induced when excessive KS levels result in an abnormal structure of the extracellular matrix, leading to relieved arthritis and joint pain, thereby enabling increased physical activity, as described in other types of MPS.[127]

ERT with native enzyme could also improve hearing, reduce recurrent infection, and reduce airway narrowing (if the stor­age materials are released from the airway). Thus, while ERT may benefit some patients with Morquio A syndrome by arresting some aspects of disease progression, the fundamental problems associated with advanced skeletal deformity and joint laxity are unlikely to be solved by current ERT.

The limitations of ERT for Morquio A syndrome open new challenges and opportunities to researchers to improve it and deliver a better product to patients.

Hematopoietic Stem Cell Transplantation (HSCT)

Overview

Hematopoietic stem cell transplantation (HSCT) is a treatment method in which multipotent hematopoietic (blood-forming) stem cells are used to reestablish hematopoietic function that has been present at low levels or has been lost entirely owing to severe illness. These cells (preferably from autologous or allogenic donors) are usually gathered from umbilical cord blood, bone marrow, or peripheral blood and are intravenously injected into a patient whose immune system or bone marrow is not adequate to function as it should.

The immune response of HSCT comprises early and late effects. The potential early adverse effects consist of acute graft versus host disease (GVHD), bacteremia/sepsis, hemorrhagic cystitis, veno-occlusive disease, and mucositis. The potential late effects include chronic GVHD, congestive heart failure, endocrine effects, ocular effects, late-onset infections, and an increased risk of malignancy.[128] HSCT once carried a high mortality risk due to immunological reactions; however, owing to the greatly improved supportive care, donor type, HLA typing, conditioning regimens, and prevention and treatment of serious infections, the mortality and morbidity rates have significantly decreased.[129, 130]

It is preferable that the donation used in HSCT is autologous owing to the low risk of malignancy and low associated morbidity and mortality rates. However, if autologous is not feasible, allogenic transplantation is another option.[130] The HLA typing should be matched as close as possible to avoid GVHD and other immune complications.[129]

Hematopoietic Stem Cell Transplantation for Mucopolysaccharidosis

HSCT for MPS I was used for the first time in 1980.[131] Subsequently, HSCT was used for MPS II in 1981,[132] for MPS VI in 1982,[133] and for MPS VII in 1998.[134] Currently, HSCT has been proven effective for MPS I, II, VI, and VII.[135, 136, 137]

HSCT improves ADL, respiratory function, and biochemical findings and prevents bone deformities if performed early enough (before age 2 years) and before neurologic symptoms appear (if relevant). If instituted after age 2 years, the deformities cannot be reversed, but growth does improve.[24, 25]

HSCT performed in patients with these MPSs demonstrate an improvement in hearing and heart function and a reversal in visceral organ involvement; however, HSCT does not reduce corneal clouding. There is a high risk of mortality if patients are already expressing advanced symptoms of MPS or progressive stage before HSCT is initiated. These patients usually cannot endure the rigorous regimen that HSCT requires; therefore, it is better to perform HSCT in patients who are young and/or otherwise healthy.

Early diagnosis is valuable in the treatment of MPS. HSCT candidates are generally young, otherwise healthy, and strong enough to endure rigorous treatment and in whom ERT is not expected to provide improvement.[25]

Hematopoietic Stem Cell Transplantation for Morquio A Syndrome

HSCT for Morquio A syndrome is an ever-evolving treatment option. Although the number of patients with Morquio A syndrome who have undergone HSCT is limited, beneficial effects have been documented.

In a study by Chinen et al in 2014, the goal was to observe the long-term efficacy of allogenic HSCT.[138] HSCT was performed in a Japanese patient when he was aged 15 years, 8 months. Loud snoring and orthopnea were resolved following HSCT, and the patients ADL score improved following treatment. The patient’s age did not allow for HSCT to reverse existing bone deformity since it was too late for the treatment to be effective. However, over 10 years post-HSCT, the patient could walk over 400 m in parallel despite bilateral leg surgery performed one year later post-HSCT and was kept stable. No further surgical intervention was required. Since 70% of patients with Morquio A syndrome become wheelchair-dependent as they reach their teenaged years and most need multiple surgical interventions, this patient had the benefit of receiving HSCT for a long period of time.

In 2016, Yabe et al reported 4 cases involving HSCT in Japanese patients, including the case described above.[139] The patient age at HSCT initiation ranged from 4-15 years (average, 10.5 years). Serious GVHD was not reported as a result of successful administration of allogenic HSCT.

Compared with patients who did not undergo HSCT, the four study patients who underwent HSCT had a higher ADL score, and only one patient underwent a surgical procedure (osteotomy in both legs performed one year post-HSCT), with the follow-up being over 10 years (range: 11 to 28 years, mean: 19 years). The ADL scores among patients who underwent HSCT or ERT were similar to those of age-matched controls younger than 10 years. Among older patients who had undergone ERT, the ADL score decreased with age. This was in contrast to patients who had undergone HSCT, suggesting that HSCT provides a better outcome in terms of ADL, biochemical findings, and respiratory function, although careful long-term observation is required. All four patients who underwent HSCT were able to remain ambulatory, with three being able to walk more than 400 meters. The regular GALNS function of the lymphocytes was found to be at a similar level of the donors 10 years post-HSCT.

A study of 82 patients with Morquio A syndrome found that lower ADL scores resulted from reduced movement and movement with cognition, despite having a high ADL score on the cognitive function portion.[121] ADL scores were shown to decrease, especially in categories that involved movement. The study confirmed that, the earlier HSCT is performed, the more beneficial the outcome in terms of ADL scores later in life.[121, 139] The best ADL score among a patient older than 20 years with a severe Morquio A syndrome phenotype was recorded in a patient who underwent HSCT at age 4 years.

A Chinese study of 4 children with Morquio A syndrome who underwent HSCT[140] found that the average age at the time of transplantation was 2.9 years (range, 1-7 years). The average follow-up time for these patients was 24 months, with the median being 14 months (ranging, 2-119 months). The evaluation given after HSCT showed tremendous improvement in the patients’ joint hypermobility and ligamentous laxity. The reported hepatosplenomegaly, recurrent otitis media, and upper airway obstruction had signs of being in remission, and there was little improvement in thoracic deformity and height. One of the four patients underwent surgery for genu valgus one year after HSCT. The same patient also had spinal cord compression syndrome that remained stable after HSCT. A long-term follow-up of the patients who underwent HSCT showed that an integration of both surgical intervention and HSCT was advantageous in maintaining mobility, respiratory function, and gait.

HSCT is a one-time permanent treatment, is less expensive than ERT ($100,000-$250,000 per HSCT versus $380,000 per year for ERT[24] ), and provides constant enzyme expression. The secretion of the active enzyme reaches various storage tissues and improves skeletal deformities, restrictive and obstructive airway, and abnormal growth development if performed early.[25] The reversal of visceral organ involvement and improved heart function and hearing have also been reported among patients who underwent HSCT. The criteria for HSCT to treat patients with Morquio A syndrome are similar to that used for patients with other MPSs (eg, donor type, age, clinical condition).

Gene Therapy

Gene therapy is based on the administration of autologous cells that contain cDNA, which codes for the normal enzyme so that the protein can be produced and secreted for cell uptake.[94] The main challenges of gene therapy relate to the use of a strong promoter and a stable vector.

In 2004, Toietta et al performed the first ex vivo gene therapy experiment by using the retroviral vector LGSN containing the full-length human GALNS cDNA. GALNS activity in Morquio A syndrome transduced cells were several folds higher than nontransduced cells. The uptake was shown to be mannose-6-phosphate–dependent, and GALNS enzyme activity was shown to reach normal levels for up to six days.[141]

To explore the effect of different promoters in vitro, the elongation factor 1α (EF1) and the cytomegalovirus immediate early enhancer/promoter (CMV) were analyzed in HEK 293 cells. Results showed that cells transfected with EF1apIRES- GALNS continued to have normal GALNS enzyme activity levels for 8 days.[142]

In 2010, adenoassociated viral vector (AAV) and CMV, EF1, and α1-antitrypsin (AAT) promoters in vitro were evaluated.[143] The eukaryotic AAT promoter resulted in equal or higher enzyme activity levels compared with the CMV promoter, and co-transduction with SUMF1, the enzyme required to activate GALNS, led to a substantial elevation of the enzyme activity (50%-70%) of normal control levels in deficient cells.[143]

The Morquio A syndrome mouse models were used to evaluate gene therapy in vivo. Using AAV2 viral vector and the CMV promoter, the authors of this article have evaluated in vitro and in vivo the affinity of an AAV2 vector to bone matrix, hydroxyapatite (HA) (unpublished). By inserting an aspartic acid octapeptide (D8) immediately after the N-terminal region of the VP2 capsid protein, the authors showed that this bone-targeting vector had significantly higher HA affinity and vector genome copies in bone compared with the unmodified vector. Using the same mouse model, the authors found that D8/CBA-GALNS increased activity levels in bone three months postinjection, reaching therapeutic levels of an enzyme (unpublished). Variations in gene therapy could maximize the efficiency of the transduction to deficient cells, as well as to hard-to-reach tissues.

Summary

ERT and HSCT are clinically available for patients with Morquio A syndrome. Gene therapy remains under investigation.

ERT has been shown to improve the endurance of patients in clinical trials when administered weekly via intravenous infusion (2 mg/kg of body weight) but only moderately improves 6-minute walk test (6MWT) results, since the extension clinical trial did not show a significant improvement over the placebo control group. ERT has a limited effect on bone lesions in these patients.[113]

Because of its limited clinical benefit and high cost, ERT remains unapproved or unreimbursed as a form of treatment in several countries.[24] Precise long-term observations are needed to ascertain whether limited enzyme delivery to the cartilage and bone will result in adequate benefit.

HSCT should provide more clinical benefit than ERT, although careful assessment is required before HSCT is performed.

To correct cervical cord compression, decompression/fusion surgery is needed to stabilize the upper cervical spine.[144, 145, 146] This is recommended for patients with atlantoaxial instability who express signs of myelopathy, significant instability of greater than 8 mm, or cord signal change on a T2-weighted MRI. This surgery is challenging owing to the hypoplastic spine and anesthesia troubles due to the difficult airway. A halo vest support may be needed following surgery, and the acquisition of a postoperative critical care bed and neuromonitoring for possible spinal cord injury for all surgeries longer than 45 minutes are recommended.[24, 144, 145, 146] Prophylactic treatment of atlantoaxial instability is not recommended, and a clinical and imaging evaluation is necessary to determine whether surgical stabilization of the occipital-cervical junction is required.[24, 147]

Gibbus deformity (thoracolumbar kyphosis) is corrected with surgical stabilization if the patient shows signs of continued progression (curves up to 70° below the level of the conus) or myelopathy.[24] For advanced curves, anterior and posterior fusion or three-column correction is recommended,[24] followed by 3 months of postoperative bracing.[24]

In patients with hip dysplasia and osteonecrosis, surgical intervention should correct the global acetabular deficiency and prevent progressive subluxation and attenuating arthrosis.[24] Surgical intervention for hip dysplasia is controversial because of corresponding femoral head necrosis but is needed if the subluxation is painful.[24] Surgical reconstruction of the hip that devotes particular attention to both the femoral and acetabular sided pathology provides the best radiographic outcomes. Other recommended surgeries include San Diego (Dega) innominate osteotomy, shelf arthroplasty for the pelvic side of the hip with a femoral varus osteotomy, augmentation with an acetabular shelf (in patients that are prone to subluxation), and total hip arthroplasty (in young adult patients who have pain and cannot be treated with reconstruction).[24, 148]

Lower-extremity valgus such as genu valgum makes walking painful, leading to corrective knee surgery. Two-hole growth modulation plates are recommended, especially for small children, with growth guidance techniques.[24, 149, 150] Osteotomy of the proximal tibia or distal femur is recommended instead among patients with limited growth.[24] In patients with arthritis in addition to genu valgum, total knee arthroplasty or significant lateral release and allograft augmentation may be needed.[151, 152] Ankle valgus is treated with screw hemiepiphysiodesis through the medial malleolus to correct the valgus deformity found in the lower extremities and to augment overall extremity alignment.[24] Flat foot, or pes valgus, is treated with custom orthotics and rarely with surgery if the pain does not respond to the orthotics.[24]

To improve tracheal obstruction, new tracheal reconstructive surgery has been developed.[35, 40] The procedure comprises reimplantation of the innominate artery and excision of the redundant trachea with end-to-end anastomosis.[35, 40] As of late 2016, surgery has been successful in five patients with severe tracheal obstruction and declining respiratory status, three of whom had been receiving ERT (1-5 years). Postsurgery, each patient has substantially improved respiratory function and ADL scores, although long-term follow-up is still needed. This surgical intervention should be performed in a well-trained facility familiar with Morquio syndrome, if possible.

Tracheostomy, which has been used to improve airway obstruction, is a notoriously challenging procedure to perform in patients with Morquio A syndrome because of inherent respiratory and anatomic problems, such as a tortuous and redundant trachea, an exceptionally short neck, and the inability to hyperextend the neck because of fixed cervical vertebrae. Maintaining the tracheostomy in good shape is also a challenge. These complications, along with the availability of a novel tracheal intervention, may reduce the need for tracheostomy in the future.

In patients with corneal clouding, corneal transplantation may be an option. However, this procedure is not always successful.

To help alleviate deafness, ventilating tubes may be placed to minimize episodes of acute otitis media and chronic middle ear effusions.[153]

Sleep apnea is resolved with tonsillectomy and adenoidectomy or high-pressure nasal continuous positive airway pressure (CPAP) and supplemental oxygen.[24] Bilevel positive airway pressure (BiPAP) may also be used in place of CPAP if the patient opts for the noninvasive management of sleep apnea. However, without proper treatment, patients with severe tracheal obstruction are highly susceptible to dying of sleep apnea and other related complications.

Patients with Morquio syndrome have major anesthesia risks owing to a difficult airway and major tracheal obstruction. Death or severe handicaps during the anesthetic procedure have been reported as a result of an anesthesia complication.[24]

It is critical that any surgical intervention is performed by a well-trained team familiar with Morquio syndrome.

Genetic counseling is needed to discuss the genetic risks in patients with Morquio syndrome or who are at risk of Morquio syndrome. Depending on the counseling outcome, genetic testing may be used as a follow-up.

Consultations with an anesthesiologist, cardiothoracic surgeon, geneticist, ophthalmologist, orthopedist, otolaryngologist, and hematologist are vital to the patient’s well-being.

Consultation with a dietician is required to maintain proportional body weight and height. Obesity diminishes the patient’s activity of daily living (ADL).

Patients with Morquio syndrome require a balanced diet to maintain a proportional stature. 

A person with Morquio syndrome (mucopolysaccharidosis type IV) can participate in activities as tolerated with a few important restrictions.

Contact sports could damage the cervical spine and should be avoided.

Repetitive motions at work or with sports could strain abnormal joints and should also be avoided.

Morquio syndrome is associated with many complications, including skeletal abnormalities, corneal clouding, hearing problems, dental cavities, narrowing airway, cervical myelopathy, atlantoaxial instability, laxity of joints (floppy wrists, knock-knee), and valvular and coronary heart disease.[24] Patients with Morquio syndrome typically do not have carpal tunnel syndrome, although their wrists are typically enlarged and curved.

Although individuals with Morquio syndrome have tachycardia, cardiac and hemodynamic alterations (eg, arterial hypertension) have not been described or documented in younger patients.[26] However, there does seem to be an age-progressive disproportion of the intrathoracic organs of patients with Morquio syndrome, followed by aortic root extension and thickened left ventricles, with reduced stroke volumes, impaired diastolic filling patterns, and increased heart rate.

Many tests should be performed annually or bi-annually to monitor the health of patients with Morquio syndrome, as follows:[153]

• Urinary and serum KS and C6S assessment
• Health assessment questionnaire
• ENT examination
• Hearing test
• Skeletal survey of the hips, spine, and knees in pediatric patients
• MRI of the neck
• Pulmonary function testing
• Sleep study
• Vision tests, including pressure, split lamp, and funduscopy
• CT for tracheal obstruction
• Ultrasonography of the heart and electrocardiography (every other year) ^{[24, 26]}