Introduction to Morbus Morquio

• Mucopolysaccharidosis (MPS) are lysosomal storage diseases (LSDs)‏
• LSDs are a group of at least 41 rare distinct genetic disorders
• Deficiency of lysosomal enzyme results in the accumulation of substrate in cells
• Deposition of mucopolysaccharides in tissues damages and distorts them, stunts growth and development, affects joint movement and, in some types of MPS, causes mental retardation
• Morbus Morquio (MPS IVA), is a MPS with distinctive clinical phenotype

Introduction to Lysosomal Storage Diseases (LSD)

LSDs are inherited disorders caused by a deficiency of specific enzymes that are normally required for the breakdown of certain complex carbohydrates.

If a specific lysosomal enzyme is not present in sufficient quantities, the normal breakdown of these complex carbohydrates is incomplete or blocked. The cell is then unable to excrete the carbohydrate residues and they accumulate in the lysosomes of the cell. This accumulation disrupts the cell's normal functioning and gives rise to the clinical manifestations of LSDs.

Mucopolysaccharidoses (MPS)

The mucopolysaccharidoses (MPS) are a set of lysosomal storage diseases caused by deficiencies of enzymes required to catabolize glycosaminoglycans (GAGs).

As a result, GAGs accumulate in the lysosomes of affected tissues. The clinical consequences can vary for each individual patient, but the common pathophysiology is lysosomal accumulation of GAG molecules leading to cellular engorgement, organomegaly, tissue damage, and organ system dysfunction. The storage of GAGs is progressive; thus, the clinical syndromes are all chronic and progressive. These diseases are associated with profound and disabling morbidity as well as early mortality. Many of these diseases are associated with death in infancy or early childhood. MPS is classified into 11 subtypes (MPS I, II, IIIA, IIIB, IIIC, IIID, IVA, IVB, VI, VII, and IX).

MPS IVA (Morbus Morquio)

Mucopolysaccharidosis Type IVA (MPS IVA or Morquio A Syndrome) is an autosomal recessive disease caused by the deficiency of the lysosomal enzyme N-acetylgalactosamine-6-sulfate sulfatase (GALNS). It represents approximately 5% of the lysosomal storage diseases. GALNS functions to cleave O-linked sulfate moieties from both keratan sulfate and chondroitin-6-sulfate; therefore, due to the deficiency of GALNS, these molecules progressively accumulate in MPS IVA.

MPS IVA is a rare disease. The clinical phenotype of MPS IVA is due to the chronic and progressive accumulation of GAGs in nearly all cell types, tissues, and organs of the body. MPS IVA is characterized by GAG accumulation in the respiratory tract, heart, liver, spleen, bones, joints, oropharynx, head, neck, and ligament. MPS IVA causes skeletal dysplasia through excessive storage of keratan sulfate (KS). Patients with MPS IVA appear healthy at birth.

MPS IVA patients are usually evaluated during the second or third year of life for unusual skeletal features. These include striking short trunk dwarfism, odontoid hypoplasia, pectus carinatum, kyphosis, gibbus, scoliosis, genu valgus, coxa valga, flaring of the lower ribs, hypermobile joints, and abnormal gait with a tendency to fall. Patients with MPS IVA can usually be clinically distinguished from patients with other MPSs because they preserve intelligence and have additional skeletal manifestations derived from a unique spondyloepiphyseal dysplasia and ligamentous laxity.

History of Morbus Morquio

1929

First description of Morquio patients in Uruguay (Morquio L)‏

1974

Identification of defective enzyme in Morquio syndrome (Matalon et al.)‏

1976

Assay of N-acetyl galactosamine 6-sulfate sulfatase (GALNS) in Morquio syndrome (Singh et al)‏

1991

Purification of enzyme (Masue et al., Bielicki et al.)‏

1991

cDNA cloning of GALNS (Tomatsu et al.)‏

2003

Establishment of mouse model with Morquio A disease (Tomatsu et al.)‏

2004

Development of keratan sulfate assay for Morquio (Tomatsu et al.)