Mucopolysaccharidosis Type IVA / Morquio Type A Disease via the GALNS Gene

The mucopolysaccharidoses (MPS) are a group of inherited disorders caused by defects in lysosomal enzymes responsible for the degradation of glycosaminoglycans (GAGs). Each enzyme deficiency results in progressive storage of distinct GAGs in multiple organ systems and subsequent abnormalities. Although MPS share several symptoms, including physical and mental developmental abnormalities, they may differ even within the same enzyme deficiency. Seven clinically distinct types can be recognized (Types I, II, III, IV, VI, VII, and IX). Based on the biochemical and genetic defects, MPS III and IV are further divided in four and two subtypes, respectively (MPSIII-A to MPSIII-D; MPS IV-A and MPSIV-B).

To date, defects in eleven different enzymes have been associated with the various MPS. MPSIVA, also known as Morquio A disease, is caused by deficiency in N-acetylgalactosamine-6-sulfatase, while MPSIVB (Morquio B disease) is caused by deficiency in beta-galactosidase. Both enzymes are required for the degradation of the glycosaminoglycan keratan sulfate. Deficiency of either enzyme results in the abnormal accumulation of keratan sulfate mainly in the corneas and cartilage (Neufeld and Muenzer 2001).

The clinical manifestations of MPS IVA and B are identical. They are distinguished from other MPS by normal intelligence and skeletal dysplasia that results in short stature and skeletal abnormalities with secondary effects on the central nervous system. Various parts of the body may be affected including the wrists, knees, hips, ribs, chest and spine. Odontoid hypoplasia is a characteristic feature. Additional features include osteoporosis; coarse traits; corneal clouding leading eventually to loss of vision; widely spaced teeth with multiple cavities; repeated upper respiratory and ear infections that result in apnea and hearing loss; hernia; and hepatomegaly (Hughes et al. 1997; O’Brien et al. 1976).

In the classical and most severe form, symptoms begin during early childhood. If not treated, death occurs by the third decade of life, usually from complications as the result of spinal cord compression and airway obstruction. A milder form of MPS IV is characterized by a later age of onset; slow progression; mild bone and somatic involvement; and survival into late adulthood (Montaño et al. 2007; Solanki et al. 2013; Nelson et al. 1988).

MPSIV affects people worldwide with various incidences, ranging from 1:76,000 in Northern Ireland to 1:640,000 in Western Australia (Tomatsu et al. 2005). An incidence of 0.38:100,000 was reported in Germany (Baehner et al. 2005).

MPS IVA is an autosomal recessive disease that results from defects in the GALNS gene (Fukuda et al. 1992). Over 200 pathogenic variants have been reported in patients from various ethnic populations. All types of variants have been reported. However, the vast majority were missense and nonsense mutations. Of note, a substantial number of missense pathogenic variants occurred in moderately conserved amino acids. Large pathogenic deletions account for about 1% of alleles in patients (Tomatsu et al. 2005; Dung et al. 2013).

The GALNS gene encodes the N-acetylgalactosamine-6-sulfatase enzyme, which catalyzes the hydrolysis of keratan and chondroitin 6-sulfates.

Using Sanger sequencing, a recent study identified pathogenic variants in 93.6% of the analyzed mutant alleles. Identified pathogenic variants included missense, nonsense, small deletions or insertions, and splice-site mutations (Dung et al. 2013).

Large pathogenic deletions account for about 1% of alleles in patients with identified pathogenic variants (Tomatsu et al. 2005).

This test provides full coverage of all coding exons of the GALNS gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).