Genetics of Mucopolysaccharidosis Type IV

Updated: Mar 24, 2014
  • Author: Nancy E Braverman, MS, MD; Chief Editor: Maria Descartes, MD  more...
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Overview

Background

Morquio syndrome (mucopolysaccharidosis type IV) is a member of a group of inherited metabolic disorders collectively termed mucopolysaccharidoses (MPSs). The MPSs are caused by a deficiency of lysosomal enzymes required for the degradation of mucopolysaccharides or glycosaminoglycans (GAGs). Eleven distinct single lysosomal enzyme deficiencies are known to cause 7 recognized phenotypes of MPS. All the MPSs are inherited in an autosomal recessive fashion except Hunter syndrome (MPS type II), which is X-linked.

In the early 1900s, Hunter and Hurler first described patients with MPS, whose diseases now bear their names; subsequent MPSs have been assigned numbers and eponyms loosely associated with the chronology and origin of their report.

In 1929, Morquio, a pediatrician in Uruguay, and Brailsford, a radiologist in England, simultaneously described cases of what is now believed to be Morquio syndrome. In the early 1930s, Husler coined the term dysostosis multiplex to describe the constellation of skeletal findings specific to patients with MPS and other lysosomal storage disorders. These included a large skull with a J-shaped sella, anterior hypoplasia of the thoracic and lumbar vertebral bodies, hypoplasia of the pelvis with small femoral heads and coxa valga, oar-shaped ribs (narrow at the vertebrae and widening anteriorly), diaphyseal and metaphyseal expansion of long bones with cortical thinning, and tapering of the proximal phalanges. However, this family of diseases was not described as the MPSs until 1952, when Brante isolated the stored mucopolysaccharides in these patients.

In 1957, Dorfman and Lorincz developed clinical assays to detect urinary mucopolysaccharides. The work of Neufeld et al from the late 1960s demonstrated that mucopolysaccharide accumulation in fibroblasts from patients with Hurler and Hunter syndromes could be corrected by co-culturing them with fibroblasts or tissue extracts from patients with a different MPS. This led to the purification and subsequent identification of each defective enzyme.

The MPSs share a chronic progressive course with multisystem involvement, several physical features, laboratory findings, and radiographic abnormalities; these include facial coarsening, hepatomegaly, excretion of urinary GAG fragments, and leukocyte inclusion bodies. Patients with Morquio syndrome (mucopolysaccharidosis type IV) can usually be clinically distinguished from patients with other MPSs because they do not have coarse facial features or mental retardation and they have additional skeletal manifestations derived from a unique spondyloepiphyseal dysplasia and ligamentous laxity. These skeletal manifestations include odontoid hypoplasia, a striking short trunk dwarfism, and genu valgus.

Compared with other patients who have MPS, those with Morquio syndrome (mucopolysaccharidosis type IV) tend to have greater spine involvement with scoliosis, kyphosis, and severe gibbus, as well as platyspondyly, rib flaring, pectus carinatum, and ligamentous laxity. Odontoid hypoplasia is the most critical skeletal feature to recognize in any patient with Morquio syndrome (mucopolysaccharidosis type IV). See the images below.

The individual on the front of the scooter is 19 y The individual on the front of the scooter is 19 years old and has Morquio syndrome. Her friend on the back is an average-stature 10 year old without Morquio syndrome. On the driver, note the enlargement at the knees and the wrist deformity. Also, note the successful adaptation of the scooter to ambulate.
Note the short trunk and protuberant rib structure Note the short trunk and protuberant rib structure in this child with Morquio syndrome. More importantly, notice that Morquio syndrome is not preventing this child from being active and fishing.

In 1976, the enzyme deficiency in Morquio syndrome type IVA (galactosamine-6-sulfatase deficiency [ie, N -acetyl-galactosamine-6-sulfate sulfatase deficiency]) was identified. Shortly thereafter, the enzyme deficiency in Morquio syndrome type IVB was described (β -galactosidase deficiency). Historically, type IVA was considered to have more severe manifestations than type IVB. However, with the ability to differentiate between types A and B by enzyme analysis, variability in clinical expression within both groups is apparent. No clear clinical differentiation between Morquio syndrome type IVA and IVB is recognized.

More recently, Montano et al collected natural histories on 354 patients with Morquio syndrome type IVA by questionnaire. [1] In addition, Morquio syndrome type IVA specific growth curves were generated.

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Pathophysiology

GAGs are oligosaccharide components of proteoglycans (macromolecules that provide structural integrity and function to connective tissues). The underlying defect in the MPSs is inability to degrade GAGs. The chronic progressive course is caused by the accumulation of partially degraded GAG, with resulting thickening of tissue and compromising of cell and organ function over time. Some of the clinical manifestations of GAG accumulation are coarse facial features, corneal clouding, thickened skin, and organomegaly. Some of the manifestations of abnormal cell function are mental retardation, growth failure, and skeletal dysplasia. GAGs accumulate in lysosomes and extracellular tissue and are excreted in the urine.

Dermatan sulfate, heparan sulfate, keratan sulfate (KS), and chondroitin sulfate are the main GAGs in tissues. They are composed of sulfated sugar and uronic acid residues (except for KS, which is mainly composed of galactose 6-sulfate alternating with sulfated N -acetylglucosamine residues) and are degraded in a stepwise fashion from the nonreducing end by a series of lysosomal enzymes. Depending on the specific enzyme deficiency, the catabolism of one or more GAGs may be blocked. Clinical features vary depending on the tissue distribution of the affected substrate and the degree of enzyme deficiency.

In Morquio syndrome (mucopolysaccharidosis type IV), the degradation of KS is defective because of deficiency of either N -acetyl-galactosamine-6-sulfate sulfatase (GALNS gene) in Morquio syndrome type IVA or β -galactosidase (GLB1 gene) in Morquio syndrome type IVB (see Media file 8). Defective GALNS also affects the catabolism of chondroitin 6-sulfate.

Defects in keratan sulfate (KS) degradation result Defects in keratan sulfate (KS) degradation resulting in Morquio syndrome.

KS is predominantly found in cartilage and cornea, the major organs affected in Morquio syndrome (mucopolysaccharidosis type IV). Heparan and dermatan sulfate have a more generalized tissue distribution. Their normal metabolism in patients with Morquio syndrome (mucopolysaccharidosis type IV) spares these patients from mental retardation and disease manifestations observed in other types of MPS.

The specific mechanism or mechanisms by which excess storage of KS results in the skeletal dysplasia unique to Morquio syndrome remains unknown. The biology of KS is currently under investigation. Numerous KS-containing proteins have been identified, and the elucidation of their functional roles will provide a better understanding of the pathophysiology of Morquio syndrome (mucopolysaccharidosis type IV). A few histological reports in patients are noted.

Three murine models for GALNS deficiency were recently generated and consist of a traditional null model and a more complex model engineered to achieve tolerance when challenged by the human enzyme in therapeutic applications. The latter expresses both the human and mouse GALNS proteins, containing an inactivating missense mutation in the highly conserved cysteine residue within the catalytic domain. The third expresses only the murine missense GALNS. These models accumulate GAGs in multiple tissues, including bone, and will be useful for study. Additional data on these mouse models, presented by Tomatsu et al, reveal that their skeletal phenotype is limited by expression of only KS type I, in contrast to humans who express KS types 1 and 2. [2]

The GALNS gene is located on chromosome arm 16q24.3 and encodes a 522–amino acid protein that is stabilized in a complex with 2 other lysosomal enzymes (β -galactosidase and α -neuraminidase) and the protective protein cathepsin A. The assembly of these 4 components is necessary for correct posttranslation processing and stability of the component enzymes and for the efficient catabolism of KS. More than 148 unique mutations have been reported in the GALNS gene. A few of these mutations represent founder alleles in certain population groups. Missense alleles represent the most prevalent type of mutations. Milder phenotypes may be explained, in part, by the residual activity of the mutant proteins.

The GLB1 gene is located on chromosome arm 3p21.33 and encodes a 677 catalytically active protein. A minor alternative transcript encodes S-GAL, an elastin-binding protein required for the orderly assembly of elastin and other cell-matrix interactions. β -galactosidase deficiency also causes GM1 gangliosidosis, a neurodegenerative disorder with minimal resemblance to Morquio syndrome (mucopolysaccharidosis type IV). The mutations that cause Morquio syndrome (mucopolysaccharidosis type IV) are proposed to affect the catabolism of KS but have little effect on GM1 gangliosides. Deficiency of cathepsin A also results in a secondary deficiency of GLB1; this disorder is galactosialidosis.

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Epidemiology

Frequency

United States

Incidence is unknown at present, but estimates may be available soon following the institution of newborn screening for lysosomal storage disorders. Development of newborn screening strategies is underway.

International

The estimated incidence of Morquio syndrome (mucopolysaccharidosis type IV) covers a wide range, including 1 case per 75,000 births in Northern Ireland, 1 case per 200,000 births in British Columbia, and 1 case per 263,157 births in Germany. One study also identified the first GALNS mutations in Tunisia in 6 affected individuals from 4 unrelated families.

Mortality/Morbidity

In Morquio syndrome (mucopolysaccharidosis type IV), mortality and morbidity rates are primarily related to the atlantoaxial instability and subsequent cervical myelopathy. A minor fall or extension of the neck can result in cord transection and subsequent quadriparesis or death. The cervical myelopathy can cause bowel and bladder dysfunction and apnea. Obstructive sleep apnea can cause prolonged periods of hypoxia, pulmonary hypertension, and even death. Airway obstruction also occurs secondary to thickening of tissue in the upper airway from mucopolysaccharide deposition.

Patients with Morquio syndrome (mucopolysaccharidosis type IV) have a predisposition to pulmonary infection because of progressive truncal deformity and immobility. Early onset coronary heart disease and valve thickening (aortic and mitral) with resultant cardiac dysfunction are described in these patients, and endocarditis prophylaxis is recommended. Corneal clouding can cause visual disturbance and photophobia. Enamel abnormalities in patients with Morquio syndrome (mucopolysaccharidosis type IV) predispose them to dental caries.

Based on a natural history study, patients with more severe short stature and those who underwent surgical procedures were reported to have more difficulties ambulating. The current clinical criteria establish that reduced growth and final height are associated with more severe clinical phenotypes. Increased relative weight in this population was also associated with increased morbidity. [3]

Race

No racial predilection is noted.

Sex

The male-to-female ratio is 1:1, and this is supported by the demographics of the cohort in a natural history study. [1]

Age

Patients with Morquio syndrome (mucopolysaccharidosis type IV) appear healthy at birth. The mean age of onset of the disease is 2.1 years, and 76% of children are diagnosed by age 6 years. Children are often evaluated for the first time for spinal deformity, growth retardation, and genu valgus in the second or third year of life. Morquio-specific radiographic changes occurring before phenotypic changes are obvious have been reported. 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, do not survive this long.

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