NLM Citation: Regier DS, Oetgen M, Tanpaiboon P.

Mucopolysaccharidosis Type IVA. 2013 Jul 11 [Updated 2016 Mar 24].

In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews®
[Internet]. Seattle (WA): University of Washington, Seattle; 1993-2020.
Bookshelf URL: https://www.ncbi.nlm.nih.gov/books/

Mucopolysaccharidosis Type IVA

Synonyms: MPS IVA, Morquio A Disease, Morquio Syndrome Type A
Debra S Regier, MD, PhD,1 Matthew Oetgen, MD,1 and Pranoot Tanpaiboon, MD1
Created: July 11, 2013; Updated: March 24, 2016.

Summary
Clinical characteristics
The phenotypic spectrum of mucopolysaccharidosis IVA (MPS IVA) is a continuum that ranges from a severe
and rapidly progressive early-onset form to a slowly progressive later-onset form. Children with MPS IVA have
no distinctive clinical findings at birth. The severe form is usually apparent between ages one and three years,
often first manifesting as kyphoscoliosis, knock-knee (genu valgum), and pectus carinatum; the slowly
progressive form may not become evident until late childhood or adolescence often first manifesting as hip
problems (pain, stiffness, and Legg Perthes disease). Progressive bone and joint involvement leads to short
stature, and eventually to disabling pain and arthritis. Involvement of other organ systems can lead to significant
morbidity, including respiratory compromise, obstructive sleep apnea, valvular heart disease, hearing
impairment, visual impairment from corneal clouding, dental abnormalities, and hepatomegaly. Compression of
the spinal cord is a common complication that results in neurologic impairment. Children with MPS IVA have
normal intellectual abilities at the outset of the disease.

Diagnosis/testing
The diagnosis of MPS IVA is established by analysis of N-acetylgalactosamine 6-sulfatase (GALNS) enzyme
activity or by the identification of biallelic pathogenic variants in GALNS on molecular genetic testing.

Management
Treatment of manifestations: Enzyme replacement therapy (elosulfase alfa, or Vimizim™) is available, although
the long-term effects of this treatment on the skeletal and non-skeletal features of MPS IVA are not yet known.
Evaluation and management of individuals with MPS IVA are best undertaken by multiple specialists,
coordinated by a physician specializing in the care of persons with complex medical problems. Physiatrists,
physical therapists, and occupational therapists help optimize mobility and autonomy. Psychological support can
optimize coping skills and quality of life; educational professionals can optimize the learning environment for a
medically fragile individual. Surgical intervention is often required for lower extremity malalignment, hip

Author Affiliation: 1 Children’s National Medical Center, Washington, DC; Email: dregier@childrensnational.org; Email:
moetgen@childrensnational.org; Email: ptanpaib@childrensnational.org.

Copyright © 1993-2020, University of Washington, Seattle. GeneReviews is a registered trademark of the University of
Washington, Seattle. All rights reserved.
2 GeneReviews®

subluxation and/or hip pain, upper cervical spine instability, and/or progressive thoracolumbar kyphosis. Upper
extremity management may include stabilizing external wrist splints or partial or complete wrist fusion. Cardiac
valve involvement may require placement of a bioprosthetic or prosthetic valve. Upper-airway obstruction and
obstructive sleep apnea are managed by removal of enlarged tonsils and adenoids; diffuse narrowing of the
airway may require positive airway pressure and/or tracheostomy. The outcome following keratoplasty for
corneal opacification varies. Hearing loss is often treated initially with ventilation tubes and later with hearing
aids.
Prevention of secondary complications: Potential pre- and postoperative anesthetic concerns secondary to spine
anomalies and difficult airway management need to be anticipated. All affected individuals should receive
influenza and pneumococcal immunizations as well as routine immunizations. Bacterial endocarditis
prophylaxis is recommended for those with a prosthetic cardiac valve, prosthetic material used for cardiac valve
repair, or previous infective endocarditis.
Surveillance: For those on ERT: physical examination at least every six months; annual assessment of quality of
life parameters and pulmonary function tests. For all individuals: annual endurance tests to evaluate functional
status of the cardiovascular, pulmonary, musculoskeletal, and nervous systems; annual assessment of upper and
lower extremities for functionality and malalignment, hips for dysplasia/subluxation and thoracolumbar spine
for kyphosis; neurologic examination and cervical spine radiographs every six months to assess for spinal cord
compression; yearly whole-spine MRI with flexion-extension views every one to three years. Perform annual
evaluation of heart rate with electrocardiogram and echocardiogram every one to three years depending on
disease course. Annual assessment for obstructive sleep apnea and pulmonary function; monitor nutritional
status using MPS IVA-specific growth charts. Perform vision and eye exam at every visit, dental evaluation every
six to 12 months, and annual audiogram.
Agents/circumstances to avoid: Excessive weight gain; beta blockers.

Genetic counseling
MPS IVA is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a
25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being
unaffected and not a carrier. Carrier testing for at-risk family members and prenatal testing for pregnancies at
increased risk are possible if the pathogenic variants in the family have been identified.

Diagnosis
Suggestive Findings
Mucopolysaccharidosis IVA (MPS IVA) should be suspected in an individual with the following findings on
medical history, physical examination, skeletal radiographs, and ophthalmologic examination; and suggestive
laboratory findings [Wood et al 2013].
Medical history
• No distinctive clinical findings at birth
• History of adenoidectomy, tonsillectomy, hernia repair, ear ventilation tubes (general findings for all MPS
disorders)
• History of cervical spine decompression and/or fusion or a history of surgery for limb alignments (unique
to MPS IVA among all MPS disorders)
• Respiratory compromise (sleep apnea, endurance limitations, snoring)
• Cardiac valve abnormalities
• Dental abnormalities
Mucopolysaccharidosis Type IVA 3

Physical examination. In severe MPS IVA the following findings are usually observed between ages one and
three years; in slowly progressive MPS IVA the following findings may not become evident until as late as the
second decade of life:
• Marked disproportionate short stature with short trunk and normal limbs (arm span exceeds height)
• Ulnar deviation of the wrists (Figure 1 and Figure 2)
• Pectus carinatum and flaring of the lower rib cage (Figure 3 and Figure 4)
• Gibbus (short-segment structural thoracolumbar kyphosis resulting in sharp angulation of the back),
kyphosis, and scoliosis
• Genu valgum (knock-knee) (Figure 5)
• Hypermobile joints
• Waddling gait with frequent falls
Skeletal radiographs
• Odontoid hypoplasia with subsequent cervical instability (Figure 6)
• Kyphosis (curving of the spine that causes a bowing or rounding of the back, which leads to a hunchback
or slouching posture) (Figure 7)
• Gibbus (structural kyphosis) with wedging of one or more adjacent vertebrae) (Figure 7)
Note: The radiographic abnormalities of the lumbar spine can be detected at birth in infants with rapidly
progressive disease [Tomatsu et al 2011].
• Scoliosis
• Pectus carinatum or (less frequently) excavatum
• Short ulnas, ulnar deviation of the radial epiphysis, and delayed bone maturation
• Short metacarpals with the proximal ends of the second to fifth metacarpals rounded or pointed [White et
al 2014]
• Flared iliac wings, flattening of femoral epiphyses (Figure 8), and coxa valga
Note: Skeletal abnormalities are observed before physical abnormalities [Montaño et al 2007, Tomatsu et al
2011].
Ophthalmologic examination. Visual impairment secondary to corneal clouding, astigmatism, and/or
retinopathy
Suggestive laboratory findings
• Qualitative urine glycosaminoglycan (GAG) analysis, which uses thin layer chromatography or
electrophoresis to identify specific types of GAG [Wood et al 2013], demonstrates keratan sulfate and
chondroitin 6-sulfate.
Note: The presence of keratan sulfate (on qualitative analysis) with or without abnormal quantitative urine
GAGs has been observed in some affected individuals.
• Quantitative urine GAG analysis, which measures the total amount of GAG, demonstrates:
⚬ Elevated keratan sulfate (KS), indicating deficiency of either the enzyme N-acetylgalactosamine 6-
sulfatase (in MPS IVA) or the enzyme B-galactosidase (in MPS IVB);
Note: Urine KS levels in younger individuals (≤18 years) is higher than in older individuals due to
the decrease in cartilage formation in older persons [Harmatz et al 2013].
4 GeneReviews®

⚬ Elevated chondroitin 6-sulfate (C6S), indicating deficiency of the enzyme N-acetylglactosamine 6-

sulfatase (MPS IVA).
• Urine keratan sulfate analysis is more sensitive than standard dye-based total GAG quantitative analysis
and may be used to replace urine total GAGs in the future.
• Both qualitative and quantitative urine GAGs can be normal in some affected individuals. Thus, further
enzymatic or molecular evaluation of a child with clinical evidence of MPS IV is warranted even when
GAG analysis is normal.

Establishing the Diagnosis

The diagnosis of MPS IVA is established in a proband with: (1) low N-acetylgalactosamine 6-sulfatase (GALNS)
enzyme activity in cultured fibroblasts or leukocytes OR (2) biallelic pathogenic variants in GALNS identified on
molecular genetic testing (see Table 1).
Molecular testing approaches can include single-gene testing or use of a multigene panel:
• Single-gene testing. Sequence analysis of GALNS is performed first followed by gene-targeted deletion/
duplication analysis if only one or no pathogenic variant is found.
• A multigene panel that includes GALNS and other genes of interest (see Differential Diagnosis) may also
be considered. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used
for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may
include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to
determine which multigene panel is most likely to identify the genetic cause of the condition at the most
reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants
in genes that do not explain the underlying phenotype. (3) In some laboratories, panel options may
include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that
includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis,
deletion/duplication analysis, and/or other non-sequencing-based tests.
For an introduction to multigene panels click here. More detailed information for clinicians ordering
genetic tests can be found here.
Mucopolysaccharidosis Type IVA 5

Figure 1. Ulnar deviation of both wrists and joint enlargement in a male age 15 years with MPS IVA
6 GeneReviews®

Figure 2. Shortened forearm and ulnar deviation of the wrist in a male age 15 years with MPS IVA

Figure 3. Pectus anomaly and short neck in a male age 15 years with MPS IVA
Mucopolysaccharidosis Type IVA 7

Figure 4. Lateral view of chest showing severe pectus carinatum in a male age 15 years with MPS IVA
8 GeneReviews®

Figure 5. Severe genu valgum (knock-knee) in a male age 15 years with MPS IVA
Mucopolysaccharidosis Type IVA 9

Figure 6. Lateral cervical spine x-ray of a female age six years with MPS IVA. Note hypoplastic odontoid (dashed line highlights that
the odontoid does not extend superiorly within the C1 ring); platyspondyly (vertebral flattening) (double arrows); and anterior
subluxation of C7 on T1 (lines indicate the posterior vertebral bodies of C7 and T1 and arrow indicates anterior translation of C7 on
T1).
10 GeneReviews®

Figure 7. Lateral spine x-ray of a female age eight years with MPS IVA. Note platyspondyly (flattened vertebrae) with anterior beaking
(arrow).
Mucopolysaccharidosis Type IVA 11

Figure 8. Hip x-ray of a female age eight years with MPS IVA. Note bilateral irregular flattening of the capital femoral epiphyses (thin
arrows), irregular dysplastic acetabuli with lateral joint subluxation (thick arrows).
12 GeneReviews®

Table 1. Molecular Genetic Testing Used in Mucopolysaccharidosis Type IVA

Proportion of Probands with Pathogenic
Gene 1 Method
Variants 2 Detectable by Method
Sequence analysis 3 94% 4
GALNS Gene-targeted deletion/duplication
2%-3% 6, 7
analysis 5
1. See Table A. Genes and Databases for chromosome locus and protein.
2. See Molecular Genetics for information on allelic variants detected in this gene.
3. Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic.
Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon
or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.
4. Caciotti et al [2015]. Intronic alterations account for 9% of gene alterations, the majority of which affect one of the -1,-2,+1, or +2
nucleotides [Morrone et al 2014].
5. Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative
PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect
single-exon deletions or duplications.
6. Approximately 2.7% of pathogenic variants are secondary to large deletions [Caciotti et al 2015].
7. One individual had maternal uniparental isodisomy of the telomeric end of chromosome 16, leading to disease [Catarzi et al 2012]
and two individuals had large deletions including GALNS exons 10-14 and exons 9-14 [Caciotti et al 2015]; this finding may be
detected by certain chromosomal microarray (CMA) methods.

N-acetylgalactosamine 6-sulfatase (GALNS) enzyme activity can be used when:

• Clinical findings strongly indicate MPS IVA and urine GAG analysis is normal; AND/OR
• Molecular genetic testing fails to identify biallelic pathogenic variants in GALNS.
In addition, establishing a diagnosis of MPS IVA by enzyme analysis may aid in interpretation of sequencing
variants of unknown significance. GALNS enzyme activity can be measured in cultured fibroblasts or leukocytes.
Because each laboratory has its own normal range of enzyme activity, results from different laboratories cannot
be directly compared. The level of residual enzyme activity may correlate with disease severity.
Note: (1) Low enzyme activity can be caused by other disorders including:
• Multiple sulfatase deficiency (MSD), i.e., deficient activity of several sulfatases (including GALNS). Thus,
when GALNS enzyme activity is abnormal, additional sulfatase enzymes need to be assayed to evaluate for
MSD.
• Mucolipidosis II and mucolipidosis III (see GNPTAB-Related Disorders, ML III Gamma). Mucolipidosis
II and mucolipidosis III impair mannose-6-phosphate lysosomal enzyme targeting, leading to low
lysosomal enzyme activities in fibroblasts, high lysosomal enzyme activities in plasma, and relatively
unchanged lysosomal enzyme activities in leukocytes.
(2) Because the clinical manifestations of MPS IVA and MPS IVB are indistinguishable, it is customary to
measure B-galactosidase enzyme activity at the same time.

Clinical Characteristics
Clinical Description
Mucopolysaccharidosis type IVA (MPS IVA) comprises a clinical continuum ranging from a severe and rapidly
progressive form to a slowly progressive form. In the past, the two forms were distinguished by height, the
subjective assessment of severity of bone deformity, and survival [Tomatsu et al 2011]; however, neither clinical
nor biochemical findings can provide clear distinctions between the two forms and, thus, the MPS IVA
phenotype should be considered a continuum from severe to slowly progressive.
Mucopolysaccharidosis Type IVA 13

Affected children have no distinctive clinical findings at birth. The severe form is usually apparent between ages
one and three years. The slowly progressive form may not become evident until late childhood or adolescence
[Montaño et al 2007].
In both forms, the initial presentations vary and may be a single finding or several findings. Kyphoscoliosis,
knock-knee (genu valgum) (Figure 5), and pectus carinatum (Figure 3 and Figure 4) are the most common
initial manifestations of the severe form [Montaño et al 2007]. In contrast, hip problems including pain and
stiffness (due to collapse and flattening of the proximal femoral epiphysis) are common initial manifestations of
the slowly progressive form [Hecht et al 1984, Wraith 1995, White et al 2014].
Because descriptions of the natural history of MPS IV published in the past may not have distinguished between
MPS IVA (Morquio syndrome type A; accounting for >95% of affected individuals) and MPS IVB (Morquio
syndrome type B; <5% of affected individuals), the following information is relevant to both MPS IVA and MPS
IVB.
While the skeletal findings of MPS IVA are the hallmark findings, involvement of other organ systems can lead
to significant morbidity, including respiratory compromise, obstructive sleep apnea, valvular heart disease,
hearing impairment, corneal clouding, dental abnormalities, and hepatomegaly. Compression of the spinal cord
results in neurologic involvement especially when disease is recognized later in life [reviewed in Neufeld &
Muenzer 2001, Tomatsu et al 2011, Solanki et al 2013].
Coarse facial features are also present but milder than in other mucopolysaccharidoses (see Differential
Diagnosis).
Children with MPS IVA typically have normal intellectual ability.
Ligamentous laxity and joint hypermobility are distinctive features of MPS IVA, and are rare among other
storage disorders.

Musculoskeletal
Skeletal findings worsen over time. The combination of bone and joint involvement leads to pain and arthritis
that result in subsequent disability.
Upper extremity involvement is also progressive and can impair hand-wrist strength and limit ability to perform
some activities of daily living, such as using a fork. Hypermobility and ulnar deviation of the wrist joint are
distinctive features of MPS IVA.
Lower extremity involvement, which is universal and progressive if untreated [Holzgreve et al 1981, Dhawale et
al 2012], generally consists of malalignment due to progressive hip subluxation and/or valgus deformity. It can
lead to significant gait alteration; hip, knee, and/or ankle pain with activity; and decreased endurance [Dhawale
et al 2012].
Knee and ankle valgus are the most common lower extremity deformities. Genu valgum (knock-knee) results
from distal femoral and proximal tibial involvement and joint laxity.
A longitudinal study using the Pediatric Evaluation of Disability Inventory and the Functional Independence
Measure found severely limited joint mobility in persons with MPS IVA, generally with loss of ambulation late in
the disease course. Aggressive and long-term intervention by a team of physical therapists and rehabilitative
specialists is often needed to optimize mobility (see Management) [Guarany et al 2012].
Hip dysplasia. Early in the disease course the capital femoral epiphyses are small and the acetabuli are shallow.
Subsequent progressive destructive changes in the femoral head and acetabuli result in hip dislocation, arthritis,
14 GeneReviews®

and severe joint restriction, causing affected individuals to become wheel-chair bound [reviewed in Tomatsu et
al 2011].
Spinal cord compression may occur in any spinal segment; cervical spinal compression is the most common
site. Spinal cord compression can be caused by cervical instability, unossified fibrocartilage associated with an
abnormal odontoid process, ligamentous laxity, cartilaginous and ligamentous hypertrophy at the atlantoaxial
joint, glycosaminoglycan (GAG) deposition in the extradural space, disc protrusion, thoracolumbar kyphosis,
and acquired central canal stenosis [Lipson 1977, Ransford et al 1996, Tomatsu et al 2011, McKay et al 2012,
Solanki et al 2013].
Odontoid hypoplasia leading to atlantoaxial instability, which later may result in upper cervical spinal cord
compression, occurs in 90% of affected individuals (Figure 6) [Hughes et al 1997].
Persons with untreated atlantoaxial instability often do not survive beyond the second or third decade because
minor falls and/or neck extension can result in quadriparesis or sudden death [reviewed in Tomatsu et al 2011].
Spinal canal stenosis may be diffuse or focal. The causes of spinal canal stenosis are similar to the causes of
spinal cord compression and include: kyphosis, disc protrusion, generalized thickening of posterior longitudinal
ligament, or localized thickening of intervertebral ligaments due to GAG deposition.
Lumbar spine misalignment (i.e., thoracolumbar kyphosis) in older individuals can result in focal spinal
stenosis, compressive myelopathy, and paraplegia [Dalvie et al 2001].
Ligamentous laxity resulting in hypermobile joints is common; however, decreased joint mobility can be
observed in the large joints including knees, hips, and elbows [Neufeld & Muenzer 2001].

Neurologic
At the time of diagnosis, individuals with MPS IV (i.e., MPS IVA and MPS IVB) typically have normal
developmental milestones and normal intellectual abilities. The neurologic findings of MPS IV are most often
secondary to spinal abnormalities in the neck and/or lumbar region. The increased risk for neurologic
compromise makes developmental delay and learning disabilities more common in children with MPS IVA than
in unaffected children [Montaño et al 2007].
Subtle abnormal brain MRI findings such as prominent perivascular space, enlarged lateral ventricles, and
prominent frontal CSF were reported in eight of 14 individuals with MPS IVA [Davison et al 2013]. From the
same study, neurocognitive evaluation revealed behavioral issues including anxiety, depression, decreased
attention span, and somatic complaints. Whether these findings are caused by disease-specific biochemical
abnormalities, chronic illness, or a combination of the two is unknown.

Cardiac
Cardiac complications include ventricular hypertrophy and early-onset, severe valvular involvement. Coronary
intimal sclerosis has also been reported [reviewed by Hendriksz et al 2013].
In a multicenter, multinational, cross-sectional study (MorCAP) involving 325 individuals with MPS IVA,
valvular regurgitation was more common than valvular stenosis. Among those with valvular regurgitation,
tricuspid regurgitation was the most common (35%). Mitral regurgitation, aortic regurgitation, and pulmonary
regurgitation were found in 25%, 19%, and 14% of affected individuals, respectively [Harmatz et al 2013].
Individuals with MPS IVA usually have an abnormally high heart rate and high myocardial index to compensate
for small left ventricular diameter and low stroke volume [Hendriksz et al 2015].
Mucopolysaccharidosis Type IVA 15

Respiratory
Respiratory complications are a major cause of morbidity/mortality. Airway obstruction, sleep-disordered
breathing, and restrictive lung disease have been described.
Glycosaminoglycan (GAG) accumulation in the adenoids, tonsils, pharynx, larynx, trachea, and bronchial tree
leads to adenotonsillar hypertrophy, tracheal distortion, trachea- and bronchomalacia, and obstructive sleep
apnea [Semenza & Pyeritz 1988, Walker et al 2003]. Deposition of GAG in the trachea and bronchi could cause
tortuosity of the airway leading to buckling and airway obstruction when the neck is flexed. If not recognized
(particularly during cervical spine fusion/stabilization surgery) and if the head and neck are fused in a flexed
position, acute obstruction may result on tracheal extubation [reviewed in Solanki et al 2013].
Restrictive lung disease results from a small thorax, chest wall anomalies, spine deformities, neuromuscular
compromise from cervical myelopathy, and hepatomegaly causing upward displacement of the diaphragm
[Walker et al 2003, Hendriksz et al 2013].
Because of atlantoaxial instability and upper-airway obstruction, persons with MPS IV prefer to sleep prone on a
flat surface without a pillow in order to keep the neck extended and minimize the tortuosity of the airway.
If respiratory complications are not recognized or are not treated, cor pulmonale and respiratory failure can
ensue, leading to early death [Semenza & Pyeritz 1988, Walker et al 2003, Montaño et al 2007, Hendriksz et al
2013].

Growth
Children with MPS IVA have a normal birth weight and a longer than normal birth length.
Between ages one and three years the growth velocity decreases compared to unaffected children.
By age 18 years, the average height in males is 123 cm and in females 117 cm, compared to 177 cm and 163 cm
in unaffected males and females, respectively.

Eye
Ophthalmologic findings are present in more than 50% of individuals with MPS IVA. Natural history studies
have not been performed; thus, it is not possible to predict the age of onset of ophthalmologic findings [reviewed
in Wood et al 2013].
Slowly progressive corneal clouding, found in 50% of affected individuals (ages 1-65 years), is the most common
ophthalmologic finding in MPS IVA.
Other less common ophthalmologic findings include: astigmatism, cataracts, punctate lens opacities, open-angle
glaucoma, optic disc swelling, optic atrophy, and retinopathy. While rare, these ophthalmologic findings can be
serious secondary complications [reviewed in Hendriksz et al 2013, Hendriksz et al 2015].
Pseudoexophthalmos, the appearance of a bulging eye secondary to a shallow orbit, can cause exposure keratitis
and also be of cosmetic concern.

Dental
Deciduous teeth erupt normally and are widely spaced and discolored with thin irregular (stippled) enamel and
small pointed cusps which flatten over time with normal wear.
Permanent teeth also have hypoplastic enamel [reviewed in Onçağ et al 2006].
16 GeneReviews®

Hearing
Mild to moderate hearing loss is common in MPS IVA. Hearing impairment is often noted toward the end of the
first decade.
Mixed (i.e., combined conductive and sensorineural) hearing loss is more common than conductive or
sensorineural hearing loss alone.
Conductive hearing loss is secondary to recurrent middle ear infections, serous otitis media, and deformity of
the ossicles [Hendriksz et al 2013].
Sensorineural hearing loss secondary to GAG accumulation in the inner ear and/or central nervous system has
been described [Ruckenstein et al 1991, Simmons et al 2005, Hendriksz et al 2013].

Genotype-Phenotype Correlations
Genetic alterations in GALNS that are predicted to severely affect protein function, such as deletions and
nonsense variants, are common in individuals with rapidly progressive growth failure [Montaño et al 2007,
Morrone et al 2014].
In contrast, affected individuals with more conservative genetic changes, such as p.Thr312Ser, are more likely to
have a milder phenotype, likely due to retained partial enzymatic activity [Yamada et al 1998].
Individuals homozygous for c.898+1G>C generally have a slowly progressive course [Tomatsu et al 2005].

Nomenclature
Much of the older literature and more complete natural history studies were performed prior to understanding
the basis of MPS IVA (N-acetylgalactosamine 6-sulfatase deficiency or biallelic GALNS pathogenic variants) and
MPS IVB (B-galactosidase deficiency or biallelic GLB1 pathogenic variants). Thus, the term MPS IV refers to
individuals with a clinical diagnosis without an enzymatic and/or molecular diagnosis, whereas the more specific
terms MPS IVA and MPS IVB refer to individuals with an enzymatic and/or molecular diagnosis.
Mucopolysaccharidosis type IVA (MPS IVA), also known as Morquio syndrome type A, was initially
characterized by Morquio [1929] and Brailsford [1929].
MPS IVA and MPS IVB are known as Morquio syndrome type A and type B, respectively.

Prevalence
MPS IVA is rare. The prevalence in Australia has been estimated at 1:926,000, whereas the prevalence in the UK
has been estimated at 1:599,000. The birth prevalence for MPS IVA ranged from 1:71,000 to 1:179,000 across
multiple countries [Leadley et al 2014]. In one German study, the incidence of MPS IVA was 1:270,000 and that
of MPS IVB less than 1:1,000,000 [Baehner et al 2005]. Similarly, the incidence of MPS IVA in Italy was
estimated at 1:300,000 live births [Caciotti et al 2015].

Genetically Related (Allelic) Disorders

No phenotypes other than those discussed in this GeneReview are associated with pathogenic variants in
GALNS.
Mucopolysaccharidosis Type IVA 17

Differential Diagnosis
Mucopolysaccharidosis type IVB (MPS IVB). The disorder that most closely resembles mucopolysaccharidosis
type IVA (MPS IVA) is MPS IVB, in which accumulation of keratan sulfate occurs due to biallelic pathogenic
variants in GLB1, the gene encoding the enzyme B-galactosidase. In most individuals with clinical findings of
MPS IV, MPS IVA can be distinguished from MPS IVB only by biochemical testing and/or molecular genetic
testing.
Biallelic pathogenic variants in GLB1 also cause GM1 gangliosidosis, a lysosomal storage disease with severe
neurologic outcomes and skeletal dysplasia. The spectrum of GM1 gangliosidosis comprises a continuum of
infantile, late infantile, juvenile, and adult forms. The infantile form often results in death by age two years, while
life span may not be shortened in the adult form.
Although novel GLB1 pathogenic variants identified in MPS IVB often map to the substrate binding regions of
the protein [reviewed in Ohto et al 2012], some pathogenic variants are associated with both GM1 gangliosidosis
and MPS IVB.
Other mucopolysaccharidoses. Signs and symptoms of MPS IVA overlap with those of other
mucopolysaccharidoses, all of which have a broad spectrum of clinical manifestations. See MPS I and MPS II.
Compared to other mucopolysaccharidoses, MPS IVA is characterized by normal intellectual abilities and less
coarsening of the facial features. In general, visual acuity in persons with MPS IVA is better than that of persons
with other types of MPS. In addition, joint hypermobility is unique to MPS IV. Atlanto-axial instability is more
common in individuals with MPS IV than in those with the other mucopolysaccharidoses.
See Mucopolysaccharidoses: OMIM Phenotypic Series to view genes associated with this phenotype in OMIM.
Spondyloepiphyseal dysplasia (SED) has similar radiographic findings. Clinical features, especially
extraskeletal features, could distinguish SED from MPS IVA. See Schimke Immunoosseous Dysplasia and X-
Linked Spondyloepiphyseal Dysplasia Tarda.
Legg-Calve-Perthes disease (OMIM 150600). In some instances mild MPS IVA can manifest only with hip pain
at the onset of disease, which can lead to an initial misdiagnosis of Legg-Calve-Perthes disease.

Management
Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with mucopolysaccharidosis type IVA
(MPS IVA), the following evaluations are recommended [Hendriksz et al 2013, Solanki et al 2013, Hendriksz et
al 2015]:
• Baseline neurologic examination to assess for signs of spinal cord compression
• Plain radiographs
⚬ Baseline radiographs of the cervical spine, including anterior-posterior (AP), neutral lateral, and
flexion-extension views
⚬ Baseline AP and lateral radiographs of the entire spine
⚬ Baseline AP and frog leg lateral radiographs of the pelvis
⚬ Baseline AP standing radiographs of the lower extremities; in individuals who are able to stand
independently and have signs of lower extremity misalignment, baseline standing lower extremity
alignment radiograph from hip to ankle
• MRI
18 GeneReviews®

⚬ Baseline MRI of the entire spine (neutral position) focusing on potential sites of cord compression
(occipitocervical, cervicothoracic, and thoracolumbar)
⚬ Flexion-extension MRI of the cervical spine when clinically indicated – for example, if cervical spine
instability is suspected on plain radiographs:
▪ Because MRI is usually performed under sedation or anesthesia, cervical spine radiographs
should be obtained prior to anesthesia to evaluate for upper cervical spine instability.
▪ In individuals with cervical spine instability suspected on plain film or those with
inconclusive radiographic findings, flexion-extension cervical spine MRI can be used to
evaluate for cord compression.
▪ Flexion-extension MRI can identify dynamic changes in canal diameter leading to cord
compression.
▪ Mackenzie et al [2013] demonstrated that cervical spine flexion-extension MRI under
sedation/anesthesia in children with skeletal dysplasia was safe under adequate supervision
and the result was useful for surgical decision making.
• Evaluation by:
⚬ A physiatrist (i.e., specialist in physical medicine and rehabilitation [PM&R]) to assess mobility and
autonomy. Endurance tests including six-minute walk test (6MWT) or timed 25-foot walk test
(T25FW) in patients with limited ambulation have been used to evaluate functional status of the
cardiovascular, pulmonary, musculoskeletal, and nervous systems. 6MWT and T25FW should be
performed at the time of diagnosis.
⚬ A physical therapist to assess joint range of motion and mobility
⚬ An occupational therapist to assess activities of daily living such as the functional dexterity test
(FDT). Baseline upper extremity strength assessments should be performed, including grip strength
assessed by dynamometer and pinch strength assessed by a pinch meter [White et al 2014].
• Consultation with a clinical geneticist and/or genetic counselor
• Electrocardiogram and echocardiogram. If coronary artery involvement is suspected, noninvasive stress
imaging should be performed [Braunlin et al 2011, Hendriksz et al 2013].
• Baseline pulmonary function and polysomnography, with evaluation by a pulmonologist
• Audiology evaluation
• Dental evaluation
• Ophthalmology evaluation to assess visual acuity and intraocular pressure; slit lamp examination and
posterior segment examination for retinopathy
• Plotting of height and weight on growth charts specific for MPS IVA [Montaño et al 2007, Montaño et al
2008]
• Pain assessment and quality of life questionnaires

Treatment of Manifestations
Management of individuals with MPS IVA is best undertaken by the following multiple specialists, coordinated
by a physician specializing in the care of individuals with complex medical problems:
• Physiatrist (specialist in physical medicine and rehabilitation [PM&R]) to optimize mobility and
autonomy
• Physical therapist to optimize mobility
• Occupational therapist to optimize autonomy
• Psychological support to optimize coping skills and quality of life
• Educational professions to optimize learning in a medically fragile individual
• Consideration of referral to family therapy to help normalize the experience for the affected individual,
parents, sibs, and extended family members
• Home care for affected individuals with multiple medical equipment needs
Mucopolysaccharidosis Type IVA 19

• Hospice for end-of-life care

Enzyme Replacement Therapy (ERT)

Recombinant human GALNS ERT (elosulfase alfa, or Vimizim™) was approved by the FDA in February 2014.
• The recommendation dose is 2 mg/kg/week intravenous. Although the treatment with ERT is not curative,
ERT could improve endurance and overall quality of life.
• Premedication (30-60 minutes prior to each enzyme infusion) with a non-sedating antihistamine (if
possible) with or without antipyretics is recommended to prevent infusion-associated reactions.
• A Phase III clinical trial demonstrated a statistically significant improvement in the 6MWT distance in the
2 mg/kg weekly dose group compared to the placebo group. The three-minute stair climb test (3MSCT)
and respiratory function were improved with the treatment but the differences were not statistically
significant.
• The long-term effects of this treatment on the skeletal features of MPSIVA are not yet known (see
Therapies Under Investigation). The efficacy of ERT in improving pathology in the musculoskeletal system
may be limited because of poor biodistribution of the enzyme in avascular tissue.

Musculoskeletal
For published orthopedic management guidelines, see White et al [2014]. The level of physical activity should be
monitored by specialists in orthopedic surgery, neurology, physiatry, and physical therapy to optimize mobility
while preventing joint injury, joint misalignments, and cervical cord damage.
Upper extremities. Non-operative interventions, such as external wrist splints, may be considered. Surgical
intervention, including partial or complete wrist fusion, may be necessary to stabilize wrist range of motion.
Knee and ankle valgus. Lower extremity malalignment associated with progressively poor mechanical
alignment and decreasing endurance requires intervention; however, no absolute indications for intervention
exist.
• Growth modulation, also called guided growth (temporary surgical tethering of the growth plate to allow
gradual correction of the deformity) or realignment osteotomies have been successful [Dhawale et al 2012,
White et al 2014].
• Early detection and evaluation may allow surgical tethering of the growth plate to treat mild-to-moderate
lower extremity angular deformities in children with open physes (growth plates). Typically this procedure
is less invasive and allows for easier recovery than realignment osteotomies.
• Once the growth plates close, distal femoral and proximal tibial osteotomies are needed to acutely or
gradually (with the use of external fixators) correct lower extremity malalignment.
• Ankle malalignment is often corrected by a distal tibial osteotomy with distal tibial screw
hemiepiphyseodesis [reviewed in Tomatsu et al 2011].
Hip dysplasia. Surgery can manage pain and alignment and permit optimal mobility.
• Hip reconstruction includes either femoral or acetabular osteotomy for mild cases or combined acetabular
and femoral osteotomy for severe cases. Augmentation of acetabular bone stock and customized implants
by using cortical grafts from the inner table of the ilium are usually required due to a shallow acetabulum
[White et al 2014].
• Total hip arthroplasty may be required in young adults experiencing significant hip pain which cannot be
corrected by reconstructive techniques.
20 GeneReviews®

Odontoid hypoplasia. When upper cervical spine instability is documented or when clinical findings of cervical
myelopathy are present, occipito-cervical or upper cervical decompression and fusion are required to stabilize
the upper cervical spine and relieve cervical cord compression.
• To minimize neurologic injury and maximize function, intervention in children is recommended when
radiographic signs of cervical compression are present, even in the absence of symptoms.
• Affected individuals undergoing surgical fusion typically do well; minor secondary complications can
include pin site infections, pressure sores, and long-term difficulty with endotracheal intubation.
• Note: It is important for clinicians to be aware that cervical myelopathy from upper cervical instability
may result in deteriorating endurance and worsening gait. If myelopathy is suspected, obtain cervical
spine radiographs and MRI (see Surveillance). The affected individual should be referred for evaluation by
a pediatric orthopedic surgeon or neurosurgeon at a tertiary care facility.
Lumbar spine malalignment. Thoracolumbar kyphosis (resulting from vertebral hypoplasia) may be
progressive and symptomatic.
• When kyphosis is less than 45 degrees, the risk of progressive deformity is less than with a greater curve,
but warrants clinical and radiographic monitoring.
• When kyphosis exceeds 45 degrees, progression is likely. Although extensive bracing with an orthosis or a
cast does not prevent progression of the thoracolumbar kyphosis, it may delay the need for surgical
intervention during a period of growth and development.
• Anterior and posterior circumferential spinal fusion are indicated if one or more of the following are
present:
⚬ Progressive thoracolumbar kyphosis greater than 70 degrees
⚬ Uncontrolled back pain
⚬ Neurologic changes related to spinal stenosis

Cardiac
Elevated heart rates could indicate a compensation mechanism, secondary to small left ventricular diameter and
small stroke volume; thus tachycardia treatment with beta blockers should be avoided. Valve replacement may be
considered for progressive valvular problems [Hendriksz et al 2015]. Risks need to be carefully weighed for valve
replacement, either mechanical (life-long use of anticoagulants) or bioprosthesis (increased risk of valve
dysplasia, degradation, and calcification).

Respiratory
Upper-airway obstruction and obstructive sleep apnea are managed by removal of enlarged tonsils and adenoids
(average age 7 years [Montaño et al 2007]). Note: Even with this intervention, the rate of obstructive sleep apnea
in children with a mucopolysaccharidosis is much higher than the general population; therefore, prompt clinical
evaluation and referral for polysomnography are appropriate [Nashed et al 2009].
In persons with diffuse narrowing of the airway in whom adenotonsillectomy only temporally relieves upper-
airway obstruction, other interventions to consider are: CPAP (continuous positive airway pressure), BiPAP
(bilevel positive airway pressure), and tracheostomy.
Lower-airway obstruction manifest as wheezing and recurrent infection is managed by inhaled and/or oral
bronchodilators and, in some instances, corticosteroids.
Restrictive lung disease is managed by supportive treatment.
Mucopolysaccharidosis Type IVA 21

Growth
Height of children with MPS IVA is best plotted on growth charts specific for MPS IVA [Montaño et al 2007,
Montaño et al 2008].
Nutrition should be optimized with a balanced diet and adequate vitamin D and calcium to assure bone health.

Learning Environment
Despite some physical limitation, individuals with MPS IVA have normal intellect and can thrive in an
environment with academic and social stimulation. Children routinely attend regular class/school with
assistance to prevent physical injury.

Eye
Corneal opacification often causes reduced vision in early childhood, necessitating penetrating keratoplasty, for
which the outcome can vary. Recurrence of opacities within the first year post keratoplasty has been reported,
making this a temporary measure for improving quality of life [reviewed by Bothun et al 2011]. In addition,
other ophthalmologic problems including glaucoma and retinopathy may limit the success of corneal
transplantation. Cataract surgery may benefit those with cataracts.

Dental
Daily oral hygiene care, fissure sealing, and adequate fluoride supplementation help prevent cavities.
Orthodontic management to correct malocclusion may be necessary.

Hearing
Because ventilation tube placement can minimize the long-term scarring associated with chronic middle-ear
effusions and recurrent acute otitis media, and improve hearing in the long term, most children have ventilation
tubes placed during the preschool years. At the first occasion, a long-lasting tympanostomy tube is
recommended due to high risk of recurrent middle-ear effusion and the risk associated with sedation in
individuals with MPS IVA [Hendriksz et al 2015].
The progressive hearing impairment observed in most individuals with MPS IVA benefits from hearing aids.

Prevention of Primary Manifestations

See Treatment of Manifestations for information regarding ERT.
The experience of hematopoietic stem cell therapy is very limited and has not been well studied.

Prevention of Secondary Complications

Anesthesia. Procedures requiring anesthesia require considerable planning and are best performed in a facility
in which anesthesiologists are experienced with the airway issues of MPS IVA, such as abnormal anatomy and
GAG accumulation, unstable cervical spine, and progressive pulmonary disease (both restrictive and
obstructive). Theroux et al [2012], who published the largest cohort of children with Morquio syndrome
undergoing anesthesia, made specific recommendations for care during anesthesia.
Preoperative assessment should include history of response to anesthesia and any evidence of airway
obstruction; cardiac evaluation, including electrocardiogram and echocardiography; evaluation of respiratory
function (spirometry and polysomnography); and airway fluoroscopy [Muhlebach et al 2011, Tomatsu et al
2011].
22 GeneReviews®

Endotracheal intubation likely includes use of a video laryngoscope, fiberoptic bronchoscope with or without a
laryngeal mask airway, and a smaller endotracheal tube than expected for age or size. Although nasal intubation
is an option, GAG deposits can lead to narrowing of the nasal passages and increased propensity to bleeding
[Aziz et al 2011, Muhlebach et al 2011, Walker et al 2013].
Postoperative narcotic management should be judicious; multimodal analgesics and non-narcotic medications
are preferable to avoid exacerbating preexisting respiratory issues, such as sleep apnea.
Postoperative complications including pulmonary edema have been described [Morgan et al 2002].
Surgery. Because subacute spinal stenosis and/or dynamic spinal stenosis could lead to spinal cord injury,
procedures involving cervical spine manipulation, prone positioning (including spinal surgery), and/or
prolonged time under anesthesia (e.g., exceeding 45 minutes), should be considered for intraoperative
neurophysiologic monitoring (IONM). IONM uses somatosensory and motor evoked potentials (SSEPs or
MEPs) to monitor spinal cord function [Solanki et al 2013, Walker et al 2013]. Note: While spinal infarct during
surgery was reported in a few individuals with skeletal dysplasia [Tong et al 2012, Pruszczynski et al 2015], data
demonstrating consistent improvement of outcome with this monitoring technology are limited [Solanki et al
2013].
Immunizations. Due to increased risk for pulmonary infection, all affected individuals should receive influenza
and pneumococcal immunizations as well as routine immunizations.
Bacterial endocarditis prophylaxis is recommended for those at high risk, including those with a prosthetic
cardiac valve, prosthetic material used for cardiac valve repair, or previous infective endocarditis [Wilson et al
2007].

Surveillance
Individuals on ERT
The following should be assessed before and after initiation of ERT to determine treatment efficacy:
• Physical and neurologic evaluation at least every six months
• Annual assessment of quality of life, disease burden, and endurance (see All Individuals)
• Annual pulmonary function tests, including maximum voluntary ventilation (MVV) and forced vital
capacity (FVC)
Note: (1) Changes in urine keratan sulfate (KS) levels do not correlate with efficacy of treatment; therefore, the
benefit of following urine KS (or urine GAG) levels during elosulfase alfa treatment is limited. (2) The benefit of
monitoring anti-elosulfase alfa antibodies is unknown.

All Individuals
Assessment of quality of life, disease burden, and endurance
• Every 6-12 months: track growth, pubertal stage, and progress; optimize ambulation
• Pain severity assessment every six months; age-appropriate quality of life questionnaires every year
• Yearly, before and after surgical procedures, or as clinically indicated: endurance tests including six-minute
walk test (6MWT) or timed 25-foot walk (T25FW) to evaluate functional status of the cardiovascular,
pulmonary, musculoskeletal, and nervous systems. Respiratory rate, pulse oximeter, and heart rate should
be measured before and after the annual testing.
Musculoskeletal. White et al [2014] recommended the following guidelines for monitoring musculoskeletal
involvement in those with MPS IVA (full text):
Mucopolysaccharidosis Type IVA 23

• Upper and lower extremities. Evaluate severity and progression of upper and lower extremity
involvement at least annually.
⚬ Evaluation of range of motion, grip and pinch strength, and functional assessments (e.g., functional
dexterity test) of the upper extremities
⚬ Assessment of lower extremity alignment, including standing AP radiographs (as clinically
indicated) and AP and frog leg lateral radiographs of the pelvis to assess hip dysplasia/subluxation
until skeletal maturity or when clinically indicated
• Spine. Neurologic examination every six months to assess for spinal cord compression [Solanki et al
2013]:
⚬ For children who are reliable historians, at each clinic visit obtain a history of exercise tolerance and
symptoms of myelopathy (e.g., extremity weakness; clumsiness; unsteady, changing gait; bowel or
bladder dysfunction or lower back/leg pain).
⚬ In those with multisegmental myelopathy, SSEPs and MEPs (if available) may provide detailed
information.
⚬ Perform plain radiography of the cervical spine (AP, lateral, neutral, and flexion-extension) every six
months.
⚬ Perform plain radiography of the spine (AP and lateral views for the thoracolumbar spine) every
one to three years.
⚬ Perform MRI whole spine (neutral position)* annually and flexion-extension MRI of the cervical
spine every one to three years.
* Neutral, flexion, and extension lateral radiographs of the cervical spine should be obtained prior to
cervical MRI to assess for atlanto-occipital instability.
Cardiac. Evaluate heart rate annually; perform electrocardiogram and echocardiogram every one to three years
depending on disease course [Braunlin et al 2011, Hendriksz et al 2013, Hendriksz et al 2015].
Respiratory
• For obstructive sleep apnea, yearly history focused on sleep patterns and sounds. Evaluation by an
otolaryngologist for adenotonsillectomy. Annual in home screening sleep studies (which monitor oxygen
saturation). Polysomnography every three years.
• To assess pulmonary function, annual MVV and FVC until children stop growing, then every two to three
years. The benefit of noninvasive pulmonary function tests, impulse oscillometry, and thoracoabdominal
motion analysis has been demonstrated in children with MPS IV [Rodriguez et al 2010].
Growth. Use MPS IVA-specific growth charts to monitor nutritional status [Montaño et al 2007, Montaño et al
2008]. Length/height and weight should be measured at every visit.
Eye
• Monitor for vision and ocular abnormalities at every visit; refer to an ophthalmologist as needed.
• For those with rod and cone retinal dystrophy, perform retinal examination and electroretinography
(ERG) under scotopic and photopic conditions every five years [Hendriksz et al 2013].
Dental. Evaluate every six to 12 months.
Hearing. Perform yearly audiogram.
24 GeneReviews®

Agents/Circumstances to Avoid
Because excessive weight gain causes undue stress on the axial skeleton and may decrease the duration of
independent ambulation, it is important to optimize nutrition for growth while maintaining a lean habitus.
Due to small ventricular diameter and stroke volume, beta blockers should be avoided in the treatment of
tachycardia.

Evaluation of Relatives at Risk

It is appropriate to evaluate apparently asymptomatic younger sibs of a proband in order to identify as early as
possible those who would benefit from initiation of ERT (see Treatment of Manifestations). Evaluations can
include:
• Molecular genetic testing if the pathogenic variants in the family are known;
• Analysis of N-acetylgalactosamine 6-sulfatase (GALNS) enzyme activity if the pathogenic variants in the
family are not known.
See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

ERT (elosulfase alfa, or Vimizim™) use in mildly affected individuals is still being investigated. As reported in the
MOR-008 Phase II clinical trial in which all participants were high functioning (defined as a mean baseline
walking distance of 70%-80% of the unaffected population), ERT made little change in endurance and
respiratory function tests but some positive change in exercise capacity, muscle strength, and pain.
Hypersensitivity reactions occurred in 18.7% of participants. Over all, the safety profile of elosulfase alfa appears
manageable and serious adverse reactions are uncommon, but further long-term safety data are being collected
[Tanpaiboon 2015].
Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on
clinical studies for a wide range of diseases and conditions.

Genetic Counseling
Genetic counseling is the process of providing individuals and families with information on the nature, inheritance,
and implications of genetic disorders to help them make informed medical and personal decisions. The following
section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for
family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may
face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance
Mucopolysaccharidosis type IVA (MPS IVA) is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband
• The parents of an affected child are obligate heterozygotes (i.e., carriers of one GALNS pathogenic
variant).
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
Sibs of a proband
Mucopolysaccharidosis Type IVA 25

• At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being
an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
Offspring of a proband. The offspring of an individual with MPS IVA are obligate heterozygotes (carriers) for a
GALNS pathogenic variant.
Other family members. Each sib of the proband’s parents is at a 50% risk of being a carrier of a GALNS
pathogenic variant.

Carrier (Heterozygote) Detection

Carrier testing for at-risk relatives requires prior identification of the GALNS pathogenic variants in the family.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose
of early diagnosis and treatment.
Family planning
• The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the
availability of prenatal testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and
reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because
it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in
the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Diagnosis

Once the GALNS pathogenic variants have been identified in an affected family member, prenatal testing for a
pregnancy at increased risk and preimplantation genetic diagnosis for MPS IVA are possible.
Differences in perspective may exist among medical professionals and within families regarding the use of
prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather
than early diagnosis. While most centers would consider decisions regarding prenatal testing to be the choice of
the parents, discussion of these issues is appropriate.

Resources
GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries
for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the
information provided by other organizations. For information on selection criteria, click here.
• Canadian Society for Mucopolysaccharide and Related Diseases, Inc.
PO Box 30034
North Vancouver British Columbia V7H 2Y8
Canada
Phone: 800-667-1846 (toll free); 604-924-5130
Fax: 604-924-5131
26 GeneReviews®

Email: info@mpssociety.ca
www.mpssociety.ca
• Medline Plus
Morquio syndrome
• Morquiosity
www.morquiosity.com
• My46 Trait Profile
Mucopolysaccharidosis Type 4
• National Library of Medicine Genetics Home Reference
Mucopolysaccharidosis type IV
• National MPS Society
PO Box 14686
Durham NC 27709-4686
Phone: 877-677-1001 (toll-free); 919-806-0101
Fax: 919-806-2055
Email: info@mpssociety.org
www.mpssociety.org
• Society for Mucopolysaccharide Diseases (MPS)
MPS House Repton Place
White Lion Road
Amersham Buckinghamshire HP7 9LP
United Kingdom
Phone: 0345 389 9901
Email: mps@mpssociety.co.uk
www.mpssociety.co.uk
• National Organization for Rare Disorders (NORD)
RareCareSM
Phone: 800-999-6673
Patient Assistance Programs

Molecular Genetics
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables
may contain more recent information. —ED.

Table A. Mucopolysaccharidosis Type IVA : Genes and Databases

Gene Chromosome Locus Protein Locus-Specific HGMD ClinVar
Databases
Mucopolysaccharidosis Type IVA 27

Table A. continued from previous page.

GALNS 16q24.3 N-acetylgalactosamine-6- GALNS database GALNS GALNS

sulfatase
Data are compiled from the following standard references: gene from HGNC; chromosome locus from OMIM; protein from UniProt.
For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click here.

Table B. OMIM Entries for Mucopolysaccharidosis Type IVA (View All in OMIM)
253000 MUCOPOLYSACCHARIDOSIS, TYPE IVA; MPS4A
612222 GALACTOSAMINE-6-SULFATE SULFATASE; GALNS

Pathophysiology
Mucopolysaccharidosis type IVA (MPS IVA) is caused by a deficiency of the lysosomal enzyme N-
acetylgalactosamine-6- sulfatase (GALNS), which cleaves the keratan sulfate at the O-linked sulfate moiety of
keratan sulfate (KS) and chondroitin-6-sulfate (C6S). The absence of the enzyme GALNS leads to intracellular
accumulation of the glycosaminoglycans KS and C6S in the lysosomes of multiple tissues. The accumulation
mainly in cornea and bone leads to the pathognomonic findings of corneal clouding and skeletal dysplasia
[reviewed in Neufeld & Muenzer 2001].

GALNS
Gene structure. GALNS comprises 14 exons. For a detailed summary of gene and protein information, see Table
A, Gene.
Pathogenic variants. Missense, nonsense, and splicing variants, as well as small deletions, small insertions, gross
insertions/duplications, and gross deletions have been found in GALNS.

Table 2. GALNS Pathogenic Variants Discussed in This GeneReview

DNA Nucleotide Change Protein Amino Acid Change Reference Sequences 1
c.337A>T 2 p.Ile113Phe
NM_000512.4
c.898+1G>C --
NP_000503.1
c.935C>G 3 p.Thr312Ser
Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of
variants.
GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen.hgvs.org). See Quick
Reference for an explanation of nomenclature.
1. Reviewed in Neufeld & Muenzer [2001]
2. British-Irish variant
3. British-Irish variant, mild phenotype

Normal gene product. The enzyme N-acetylgalactosamine-6-sulfatase (GALNS) removes the terminal sulfate
groups in mucopolysaccharides (e.g., KS and C6S). This 522-amino acid protein has a signal peptide of amino
acids 1 through 26. The protein has at least one bound calcium in the catalytic domain. Processing of cysteine 79
to 3-oxoalanine by formylglycine-generating enzyme is targeted by the specific sequence CXPXR. This 3-
oxoalanine is part of the catalytic site of all sulfatases.
Based on the finding that 26% of pathogenic missense variants were caused by transitional mutations at CpG
dinucleotides, the role of methylation in regulation of GALNS was identified: methylation was extensive within
exons 2 through 14 [Tomatsu et al 2005].
28 GeneReviews®

GALNS consists of an N-terminal domain including the active site, a second domain with antiparallel B-strands,
and a C-terminal domain region which loops back to form a region of the active site. The GALNS active site
contains a calcium bound to the catalytic nucleophile. Each GALNS molecule contains two glycosylation sites at
residues Asn204 and Asn 423. Within each monomer are three disulfide bonds and one unpaired cysteine, which
can pair with a second subunit to form the functional dimeric GALNS [Rivera-Colón et al 2012].
Abnormal gene product. The abnormal gene product demonstrates decreased enzymatic activity, leading to
accumulation of sulfated intermediates. A GALNS pathogenic variant can lead to misfolding (and subsequent
early degradation), mislocalization, or alterations in the catalytic domain either directly or through substrate
binding sites [Rivera-Colón et al 2012].

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Chapter Notes
Author Notes
Dr Oetgen, an attending surgeon in the Department of Orthopaedics and Sports Medicine at Children’s National
Medical Center, has a special interest in the orthopaedic manifestations of genetic conditions affecting pediatric
patients, including the mucopolysaccharidoses. He participates in the care of these patients in collaboration with
the Children’s National Medical Center Department of Genetics.
Dr Tanpaiboon is an attending physician in the Division of Genetics and Metabolism at Children’s National
Medical Center. Her main interest is the field of Inborn Errors of Metabolism, particularly the lysosomal storage
disorders (LSDs). She has been actively involved in international multicenter clinical trials of enzyme
replacement therapy for MPS IVA and other LSDs.

Revision History
• 24 March 2016 (ma) Comprehensive update posted live
• 13 March 2014 (pt) Revision: information on enzyme replacement therapy and MRI added
• 11 July 2013 (me) Review posted live
• 18 January 2013 (pt) Original Submission

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