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morquio a: multisystemic.
progressive. Life threatening.

Mucopolysaccharidosis IVA (MPS IVA), or Morquio A, is an autosomal recessive lysosomal storage disorder that, while commonly perceived as a musculoskeletal condition, is in fact a progressive, multisystemic disease. The root cause of Morquio A is an inherited deficiency in the N-acetylgalactosamine-6-sulfatase (GALNS) enzyme, which has been shown to lead to systemic morbidities and a shortened life span.1-3 GALNS is a critical lysosomal enzyme that, when inactive or deficient, drives a cascade of progressive metabolic pathologies that affect major organ systems.2,4-8

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Deficient GALNS activity leads to potentially life-threatening,
systemic organ involvement

The signs and symptoms of Morquio A may initially present as musculoskeletal complications but progressively manifest throughout the body, with potentially severe cardiovascular, pulmonary, neurological, skeletal, rheumatologic, ophthalmologic, ENT, hepatic, and dental consequences.1,4,9-23

In addition to systemic organ involvement, patients with Morquio A suffer from dramatically impaired functional capacity, severely limiting their potential.9


PATHOLOGY

Morquio A syndrome (MPS IVA) is a lysosomal storage disorder caused by a mutation in the gene encoding the enzyme N-acetylgalactosamine-6-sulfatase (or GALNS). In Morquio A syndrome, defective GALNS enzyme activity impairs lysosomal degradation of the glycosaminoglycans keratan sulfate and chondroitin-6-sulfate.1,7,22,24

As lysosomes accumulate, they occupy an increasingly greater area of the cytoplasm, obscuring other organelles and disrupting function. The defective enzyme activity in Morquio A syndrome leads to cell, tissue, and organ system dysfunction that results in the progressive multisystemic morbidities that are the hallmark of this disorder.22,24,25

collagen-fibrils articular-cartilage
Articular cartilage chondrocyte in
(A) control, (B) Morquio A patient

Chondroitin-6-sulfate is found in the extracellular matrix surrounding chondrocytes, skin, blood vessels, ligaments, and tendons. 24,26

Collagen fibrils in articular cartilage
of (A) control, (B) Morquio A patient

Keratan sulfate is found in cartilage, bone, connective tissue, epithelial and neural tissues, and the cornea.24,26

Bank et al, Mol Genet Metab, 2009 Bank et al, Mol Genet Metab, 2009

Consequences

Deficient GALNS enzyme activity can lead to progressive organ damage resulting in complex manifestations with life-altering consequences across multiple organ systems.1-3

overview-2

Together, multisystemic consequences severely impact functional outcomes for Morquio A patients and their families, affecting almost every aspect of life.9 These outcomes may be measured clinically through endurance functional tests such as the 6-minute walk test (6MWT) and the 3- minute stair climb (3MSC), as well as by respiratory function tests such as forced vital capacity (FVC) and maximum voluntary ventilation (MVV).9 Learn more about the natural history of Morquio A.

overview-3

6MWT is a commonly used measure of the integrative functional capacity of multiple organ systems, such as cardiopulmonary competence and musculoskeletal function. 6MWT is routinely used across multiple disease states to assess endurance as a measure of integrative functional capacity in disorders as widely varying as cystic fibrosis, cardiovascular disease, and Morquio A.27


Systemic effects

Explore the systemic effects of Morquio A

Place your cursor over each of the patient images below to see more detailed information.


NATURAL HISTORY

MorCAP: The largest longitudinal study involving direct assessments of Morquio A patients

The Morquio Clinical Assessment Program (MorCAP) is an ongoing longitudinal study of over 325 Morquio A patients from 15 sites in 10 countries, initiated in 2008. The baseline analysis reveals a spectrum of disease complications, with wide-ranging clinical effects.9

Growth

Growth retardation is evident in the MorCAP population9

Majority of adults are <120 cm in height

Growth retardation is evident in the MorCAP population9

71% of Morquio A patients =18 years of age are below 3rd percentile in height

Endurance

Endurance is impared in MorCAP patients9

The 6MWT measures how far a person can walk on a hard, flat surface in 6 minutes

Submaximal intensity tests are sensitive indicators of endurance9

The 3MSC measures how many steps a person can climb in 3 minutes, using railings and resting if needed

Respiratory function

Respiratory function is severely limited in MorCAP patients9

Respiratory function is severely limited in MorCAP patients9

Cardiac Function

Cardiac involvement is common in MorCAP patients9

Natural-history-Cardiac-function

Other Non-skeletal Complications

Nonskeletal involvement is common9

Natuaral-history-other-non-skeletal-complications

Medical and surgical History

Spinal involvement is common in Morquio A9

Natural-history-Medical-and-surgical-history

Biochemical abnormalities

Higher uKS levels correlate with greater endurance impairments9

overview-biochemic-6mwt

Higher uKS levels correlate with greater endurance impairments9

overview-biochemic-3msct

Download the Morquio Clinical Assessment Program (MorCAP): Baseline Results slide deck.


Genetics

Morquio A is an autosomal recessive, monogenic disorder resulting from mutations in the gene encoding N-acetylgalactosamine-6-sulfatase (GALNS).28

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Morquio A is a genetically heterogeneous disorder with a high frequency of novel mutations reported.

  • Mutation analysis has identified over 150 unique mutations in the GALNS gene to date.29
  • The 3 most common mutations in Morquio A comprise only 8.9%, 6.8%, and 5.7% of the population.28
  • In a survey of 3 laboratories regularly assessing for GALNS mutations, the frequency of identified alleles with novel mutations ranged from 26% to 42%.29

As in other autosomal recessive disorders, molecular analysis, genetic counseling, and family screening are important components of familial risk assessment.

Genetic determination of Morquio A in a family can identify carriers and undiagnosed patients.

FamilyTree-forever