1. Genetic testing for Mucopolysaccharidosis type IVA

Mucopolysaccharidosis type IVA

December 22, 2017

Disease synonyms

Mucopolysaccharidosis type 4A (MPS IVA), Morquio syndrome A, MPS4A, Morquio A disease, Galactosamine-6-sulfatase deficiency, GALNS deficiency

Inheritance pattern

Autosomal recessive

Clinical features

Mucopolysaccharidosis type IVA (MPS IVA), also known as Morquio syndrome A, is an autosomal recessive lysosomal storage disease characterized by intracellular accumulation of keratan sulfate and chondroitin-6-sulfate. The absence of the enzyme GALNS leads to intracellular accumulation of the glycosaminoglycans in the lysosomes of multiple tissues, resulting in the symptoms of Morquio disease. For example, the accumulation mainly in cornea and bone leads to the pathognomonic findings of corneal clouding and skeletal dysplasia.

MPS IVA is very rare disease, with a birth prevalence ranging from 1:71,000 to 1:179,000 across multiple countries 1.

MPS IV is a continuum of associated conditions which ranges from a severe and rapidly progressive early-onset form to a slowly progressive later-onset form. MPS IV included two major types of condition, with overlapping clinical features but with different genetic cause:

  • Mucopolysaccharidosis type IVA (MPS4A; Morquio syndrome A) is caused by homozygous or compound heterozygous variants in the GALNS gene encoding galactosamine-6-sulfate sulfatase
  • Mucopolysaccharidosis type IVB (Morquio syndrome B) is caused by variants in the gene encoding beta-galactosidase (GLB1)

MPS IVA accounts for >95% of affected individuals, while MPS IVB is less frequent and accounts for less than 5% of affected individuals 2, 3, 4.

Although most individuals with Morquio syndrome appear normal at birth, skeletal abnormalities often develop within the first year of life. The severe form is usually apparent between ages one and three years, often first manifesting as kyphoscoliosis, genu valgum and pectus carinatum2, 3.

The slowly progressive form of Morquio syndrome may not become evident until late childhood or adolescence, often first manifesting as hip problems. Progressive bone and joint involvement leads to short stature, disabling pain and arthritis. Involvement of other organ systems can lead to respiratory complications, valvular heart disease, hearing impairment, visual impairment from corneal clouding, dental abnormalities, and hepatomegaly. Compression of the spinal cord is a common complication which results in neurologic impairment. Children with MPS IVA have normal intellectual abilities at the outset of the disease 2, 3.

Mucopolysaccharidosis IVA (MPS IVA) should be suspected in an individual with the following clinical and suggestive laboratory findings 4:

  • No distinctive clinical findings at birth
  • History of adenoidectomy, tonsillectomy, hernia repair, ear ventilation, cervical spine decompression
  • Respiratory abnormalities including sleep apnea, endurance limitations, snoring
  • Cardiac valve abnormalities
  • Dental abnormalities
  • Marked disproportionate short stature with short trunk and normal limbs
  • Skeletal abnormalities including ulnar deviation of the wrists, pectus carinatum, kyphosis, scoliosis
  • Hypermobile joints and waddling gait with frequent falls
  • Visual impairment secondary to corneal clouding, astigmatism, and/or retinopathy

Frequent findings on skeletal radiographs in MPS IV-affected children include the following 2, 4:

  • Kyphosis and gibbus (structural kyphosis)
  • Odontoid hypoplasia
  • Abnormalities of the lumbar spine
  • Scoliosis
  • Pectus carinatum or (less frequently) excavatum
  • Short ulnas, short metacarpals, flared iliac wings, flattening of femoral epiphyses and coxa valga

Qualitative urine glycosaminoglycan (GAG) analysis, which uses thin layer chromatography or electrophoresis to identify specific types of GAG, was commonly used for MPS IVA diagnostics 4. Now, the diagnosis of MPS IVA is established with the identification of the low GALNS enzyme activity in cultured fibroblasts or leukocytes. Finally, molecular genetic testing to identify GALNS gene pathogenic variants has become the most specific diagnostic tool.

Mucopolysaccharidosis type IVA is caused by homozygous or compound heterozygous pathogenic variants in the GALNS gene on chromosome 16q24. Missense, nonsense, and splicing variants, as well as small deletions, small insertions, gross insertions/duplications, and gross deletions have been identified in GALNS.

At CENTOGENE we have analyzed a large number of individuals clinically suspected for mucopolysaccharidosis type 4A (Morquio syndrome A) and 43% of affected and gene-tested individuals had pathogenic variant in GALNS gene, while 18% were identified as carriers 7.

Out of all GALNS identified pathogenic variants 84% were identified as substitution, 7% as gross/complex rearrangements, 6% as deletions and 3% as duplications (Figure 1) 7. GALNS classification of variants on protein level identified 67% missense variants, 11% splicing, 8% nonsense, 8% frameshift, 3% in-frame, and 2% of variants of unknown effect (Figure 2) (CentoMD® 4.1) 7.

Types of GALNS clinically relevant variants on DNA level CentoMD

Figure 1. Types of GALNS clinically relevant variants on DNA level (CentoMD® 4.1) 7.

Types of GALNS clinically relevant variants on protein level CentoMD

Figure 2. Types of GALNS clinically relevant variants on protein level (CentoMD® 4.1) 7.

Management of individuals with MPS IVA is best undertaken by multiple specialists, including psychiatrists, physical therapists, occupational therapists, and others. Enzyme replacement therapy (ERT) using elosulfase alfa, or Vimizim™, is still being investigated, but recent studies have confirmed the beneficial effects of the long-term ERT in adult patients with Morquio disease type A 5, 6.

CENTOGENE offers detection of enzymatic activity of the lysosomal enzyme N-acetylgalactosamine-sulfate sulfatase,  full GALNS gene sequencing and deletion/duplication testing of the GALNS gene. GALNS is also part of certain gene panels:

  • Mucopolysaccharidosis panel
  • AllNeuro panel
  • CentoDetect
  • CentoICU™ platinum plus
  • CentoICU™ platinum

Differential diagnosis

The differential diagnosis of GALNS-related disorders – depending on the major symptoms in the initial case – includes the following diseases:

  • Hunter Syndrome (Mucopolysaccharidosis Type II) caused by pathogenic variants in IDS
  • Sanfilippo Syndrome (Mucopolysaccharidosis Type III) caused by pathogenic variants in GNS
  • Maroteaux-Lamy Syndrome (Mucopolysaccharidosis Type VI) caused by pathogenic variants in ARSB
  • Sly Syndrome (Mucopolysaccharidosis Type VII) caused by pathogenic variants in GUSB
  • GM1 Gangliosidosis caused by pathogenic variant in GLB1
  • Mucolipidosis II/III caused by pathogenic variant in GNPTAB
  • Mucopolysaccharidosis Type I H/S; H; S, caused by pathogenic variants in IDUA
  • Spondyloepiphyseal dysplasias (SED) caused by pathogenic variants in COL2A1, TRAPPC2
  • Spondylometaphyseal dysplasia (SMD) caused by pathogenic variants in TRPV4, GPX4

Diagnostic strategy

To confirm/establish the diagnosis, we offer N-acetylgalactosamine-sulfate sulfatase enzymatic activity testing, full GALNS gene sequencing and deletion/duplication gene testing. We also offer a broad selection of NGS panels which are designed for the molecular genetic diagnosis of Mucopolysaccharidosis type IVA (Morquio syndrome A) and related conditions/phenotypes.

Thus, CENTOGENE offers the following testing strategy for GALNS gene testing:

Step 1:    Tandem-MS-based determination of enzymatic activity of the lysosomal enzyme N-acetylgalactosamine-sulfate sulfatase.

Step 2:   GALNS full gene sequencing – covers the entire coding region, exon/intron boundaries and 200 bp of the gene promoter.

Step 3:    Deletion/duplication analysis/pathogenic variant scanning of GALNS

Step 4:   If no pathogenic variant is identified after analysis of the GALNS gene, panel testing with related genes or further genetic testing of related genes can be performed.

Step 5:    If no pathogenic variant is identified in any of the panel genes listed, we can offer whole exome sequencing, based on NGS technology.

Referral reasons

The following individuals are candidates for GALNS gene testing:

  • Individuals with a family history Mucopolysaccharidosis type IVA (Morquio syndrome A)  and presentation of the most common symptom
  • Individuals without a positive family history of Mucopolysaccharidosis type IVA (Morquio syndrome A), but with symptoms resembling the disease 
  • Individuals with a negative but suspected family history of Mucopolysaccharidosis type IVA (Morquio syndrome A), in order to perform proper genetic counseling (prenatal analyses are recommended in families with affected individuals).

Test utility

Tandem-MS-based assessment of N-acetylgalactosamine-sulfate sulfatase enzyme activity, sequencing and deletion/duplication of GALNS and related genes should be performed in all individuals suspected of having Mucopolysaccharidosis type IVA (Morquio syndrome A). In parallel, other genes reported to be related with this clinical phenotype should also be analyzed for the presence of reduced/abnormal enzymatic activity and/or GALNS pathogenic variants, due to the overlap in many clinical features caused by genes associated with various clinically overlapping forms of Mucopolysaccharidosis type IVA (Morquio syndrome A). Confirmation of a clinical diagnosis through genetic testing can allow for genetic counseling and may direct management.

Genetic counseling can provide a patient and/or family with the natural history of Mucopolysaccharidosis type IVA (Morquio syndrome A) to identify at-risk family members, provide information about reproductive risks as well as preconception/prenatal options, and allow for appropriate referral for patient support and/or resources.

More information on CENTOGENE´s genetic tests for Mucopolysaccharidosis diseases can be found in our genetic test catalogue.