Mucopolysaccharidosis type ICH (MPS1-H)
Hurler syndrome, Mucopolysaccharidosis type ICH (MPS1-H), Hurler-Scheie syndrome, Mucopolysaccharidosis type IH/S (MPS1-HS), Mucopolysaccharidosis type IH, Mucopolysaccharidosis IS (MPS1-HS)
Mucopolysaccharidoses (MPSs) are a group of lysosomal storage diseases, each of which is produced by an inherited deficiency of an enzyme involved in the degradation of acid mucopolysaccharides, called glycosaminoglycans (GAGs) 1. The mucopolysaccharidoses share many clinical features but have varying degrees of severity. These features may not be apparent at birth but progress as storage of glycosaminoglycans affects bone, skeletal structure, connective tissues, and organs. Neurological complications may include damage to neurons as well as pain and impaired motor function.
Depending on the mucopolysaccharidoses subtype, affected individuals may have normal intellect or may be profoundly retarded, may experience developmental delay, or may have severe behavioral problems. Many patients have hearing loss, conductive and/or neurosensitive, communicating hydrocephalus, cloudy cornea and degeneration of the retina and glaucoma, and many other symptoms.
MPS I has been divided into three broad groups based on severity of symptoms: Hurler, Hurler-Scheie, and Scheie syndromes. Hurler and Scheie syndromes represent phenotypes at the severe and mild ends of the MPS I clinical spectrum, respectively; and the Hurler-Scheie syndrome is intermediate in phenotypic expression. MPS I is increasingly regarded as a continuous spectrum of disease, with the following major clinical findings 1:
- Coarse facial features
- Characteristic skeletal and joint findings (gibbus deformity; limitation of joint range of motion)
- Marked disproportionate short stature with short trunk and normal limbs
- Visual impairment secondary to corneal clouding, astigmatism, and/or retinopathy
Severe MPS I, also known as Hurler syndrome, is characterized by a chronic and progressive disease course involving multiple organs and tissues 1. Infants with severe MPS I appear normal at birth. Most affected children are diagnosed before age 18 months. The only finding at birth may be an inguinal or umbilical hernia.
Coarsening of facial features, caused by storage of GAGs in the soft tissues of the orofacial region and facial bone dysostosis, becomes apparent within the first two years. Hepatosplenomegaly is very common. Progressive skeletal dysplasia (dysostosis multiplex) involving all bones is seen in all individuals with severe MPS I. Defective ossification centers of the vertebral bodies lead to flattened and beaked vertebrae and subsequent spinal deformity. Complications may include spinal nerve entrapment, acute spinal injury, and atlanto-occipital instability.
All affected infants show corneal clouding and progressive visual impairment which inevitably leads to blindness. Hearing loss is also observed as a common finding. However, the most life-threatening clinical features of MPS I are cardiovascular complications of the disease. Cardiac involvement presents with mitral and aortic regurgitation. As lysosomal storage continues in the heart, cardiomyopathy, sudden death from arrhythmia, coronary artery disease, and cardiovascular collapse may occur, and most commonly these cardiac features lead to premature death.
The attenuated form of MPS I, also known as Hurler-Scheie Syndrome or Scheie Syndrome, is characterized by slower progression and milder symptoms compared to the severe MPS I form (Hurler syndrome). Onset of attenuated MPS I is between ages three and ten years. The rate of disease progression can range from serious life-threatening complications to a normal life span. Affected children with attenuated MPS I may have detectable learning disabilities. Coarseness of facial features is less obvious than in the severe MPS I, but skeletal and joint manifestations are the most significant signs of the disease. Cardiac involvement is estimated to occur in approximately 88% of children with attenuated MPS I at a median age of 11.7 years 8. Many affected patients show regurgitation and/or stenosis of mitral and aortic valves and resulting cardiovascular abnormalities. Optical and hearing abilities could be significantly affected. Hernias are present in 65% of affected children 1, 8.
MPS I is observed in all populations worldwide at a frequency of approximately 1:100,000 for the severe form and 1:500,000 for the attenuated form 1, 4, 5, 6.
All individuals with MPS I have an absence or insufficient levels of the enzyme α-L-iduronidase (IDUA enzyme), encoded by the gene IDUA. The diagnosis of MPS I relies on the demonstration of deficient activity of the lysosomal enzyme α-L-iduronidase in peripheral blood leukocytes, cultured fibroblasts, or plasma, and on genetic testing of the IDUA gene. Complete loss of IDUA enzyme activity, often due to homozygosity or compound heterozygosity of the common p.Glu70* or p.Typ402* pathogenic variants, is associated with severe MPS I. Any combination of two “severe” variants leads to severe MPS I 1, 2, 3.
Analysis of urinary glycosaminoglycans (GAG) may be helpful and supportive in the diagnosis of MPS I 1. Also, GAG electrophoresis can exclude and include certain MPS disorders. However, a definitive diagnosis requires additional genetic testing.
The Human Gene Mutation database currently lists more than 110 IDUA pathogenic variants. Known pathogenic variants include nonsense, missense, and splice site variants, small deletions, and insertions. Most common variants in this gene are p.Gln70* and p.Trp402*. Pathogenic variant p.Gln70* is present in 35% of affected persons in Europe and 62% of affected persons in Scandinavia 7. Furthermore, variant p.Trp402* is identified in 48% of MPS I patients in Netherlands and Germany 7.
At CENTOGENE we have analyzed number of individuals (460) clinically suspected for mucopolysaccharidosis type I and 29% of mucopolysaccharidosis type I-suspected individuals had pathogenic variant in IDUA gene, while 18% were identified as carriers 9.
Out of all IDUA identified pathogenic variants 73% were identified as substitution, 17% as deletions, 5% as gross/complex rearrangements and 2% as duplications and other type of variants each (Figure 1) 9. IDUA classification of variants on protein level identified 42% missense variants, 18% nonsense, 12% splicing, 10% in-frame, 4% variants of unknown effect and 2% of start loss variants (Figure 2) (CentoMD® 4.1) 9.
Figure 1. Types of IDUA clinically relevant variants types on DNA level (CentoMD® 4.1) 9.
Figure 2. Types of IDUA clinically relevant variants on protein level (CentoMD® 4.1) 9.
Treatment and management of MPS includes special education for developmental delays, correction of hearing and vision, physical therapy, orthopedic surgery as needed, cerebrospinal fluid shunting for hydrocephalus, and many other treatments. Various enzyme replacement therapies (ERT) with different enzymes are in the process of development, and many drugs are already licensed for treatment of the non-CNS manifestations of MPS I, MPS II, MPS IV and other forms of MPS.
CENTOGENE offers detection of enzymatic activity of the lysosomal enzyme α-L-iduronidase, full IDUA gene sequencing and deletion/duplication testing of the IDUA gene. IDUA is also part of these gene panels:
- Mucopolysaccharidosis panel
- AllNeuro panel
- CentoICU™ platinum plus
- CentoICU™ platinum
The differential diagnosis of IDUA-related disorders – depending on the major symptoms in the initial case – includes the following diseases:
- Hunter Syndrome (Mucopolysaccharidosis Type II)
- Sanfilippo Syndrome (Mucopolysaccharidosis Type III)
- Morquio Syndrome (Mucopolysaccharidosis Type IV)
- Maroteaux-Lamy Syndrome (Mucopolysaccharidosis Type VI)
- Sly Syndrome (Mucopolysaccharidosis Type VII)
To confirm/establish the diagnosis, we offer enzymatic activity testing, full IDUA 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 related conditions/phenotypes.
Thus, CENTOGENE offers the following testing strategy for IDUA gene testing:
Step 1: Enzymatic activity of the lysosomal enzyme α-L-iduronidase.
Step 2: IDUA full gene sequencing – covers the entire coding region, exon/intron boundaries and 200 bp of the gene promoter.
Step 3: Deletion/duplication analysis/variant scanning of IDUA
Step 4: If no pathogenic variant is identified after analysis of the IDUA gene, panel testing with related genes or further genetic testing of related genes can be done.
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.
The following individuals are candidates for IDUA gene testing:
- Individuals with a family history of mucopolysaccharidosis type I and presentation of the most common symptoms
- Individuals without a positive family history of mucopolysaccharidosis type I, but with symptoms resembling mucopolysaccharidosis type I
- Individuals with a negative but suspected family history, in order to perform proper genetic counseling (prenatal analyses are recommended in families with affected individuals).
Sequencing, deletion/duplication of IDUA and related genes should be performed in all individuals suspected of having mucopolysaccharidosis type I. In parallel, other genes reported to be related with this clinical phenotype should also be analyzed for the presence of variants, due to the overlap in many clinical features caused by those particular genes. Confirmation of a clinical diagnosis through genetic testing can allow for genetic counseling and may direct medical management.
Genetic counseling can provide a patient and/or family with the natural history of mucopolysaccharidosis type I, 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.