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Mucopolysaccharidosis type I (MPS I)

Rare lysosomal storage disorder due to deficiency of lysosomal enzyme α1-iduronidase resulting in progressive accumulation of glycosaminoglycans (GAG) within lysosomes, leading to multiorgan dysfunction and damage.

Introduction

Mucopolysaccharidosis type I, or MPS I, is a rare genetic metabolic disorder caused by deficiency of a lysosomal enzyme required to break down mucopolysaccharides. The disorder presents as a spectrum ranging from severe forms, classically known as Hurler syndrome, which are associated with life-threatening complications, to attenuated forms, classically known as Scheie syndrome or Hurler-Scheie syndrome.

Rare lysosomal storage disorder due to deficiency of lysosomal enzyme α1-iduronidase resulting in progressive accumulation of glycosaminoglycans (GAG) within lysosomes, leading to multiorgan dysfunction and damage.

  • Autosomal recessive (AR) inheritance: α1-iduronidase (IUDA) enzyme gene (chromosome 4)

History:

Hurler syndrome was first described by German pediatrician, Gertrud Hurler in 1919. It is one of the 11 disorders of the mucopolysaccharidoses (MPS). Hurler syndrome is considered as mucopolysaccharidosis type I (MPH I) and formerly known as gargoylism. In 1962, a milder form of MPS I was identified and named as Scheie syndrome.

Classification

Hurler syndrome is caused by a deficiency of a lysosomal enzyme, IUDA, which aids in the breakdown of dermatan sulfate and heparin sulfate (GAG). This finally results in the accumulation of large amounts of GAG in the body, eventually causing the cells to become severely dysfunctional leading to death. The deposition of GAG causes enlargement and thickening of various organs like the heart, spleen, liver, muscles, connective tissues, joints, and the central nervous system causing severe functional impairment.

  • Severe MPS I: Hurler Syndrome
  • Attenuated MPS I: Hurler-Scheie and Scheie syndromes
Spectrum of MPS I patients. Manifestations written to the left are more commonly found as presenting signs and symptoms in patients with the severe phenotypes, while those to the right are also frequently seen as presenting signs and symptoms in patients with attenuated phenotypes. Informed consent was obtained for image use. | Kubaski, F., de Oliveira Poswar, F., Michelin-Tirelli, K., Matte, U., Horovitz, D. D., Barth, A. L., Baldo, G., Vairo, F., & Giugliani, R. (2020). Mucopolysaccharidosis Type I. Diagnostics (Basel, Switzerland), 10(3), 161. https://doi.org/10.3390/diagnostics10030161

Hurler syndrome (MPS I H): M/C and M/severe form

Patients develop symptoms shortly after birth and progress rapidly. Patients usually die within the first year of life.
  • Developmental delay, cognitive decline
  • Characteristic coarse facial features
  • Joint stiffness and contractures
  • Short stature
  • Cardiac and hepatic disease
Hurler syndrome features. (a). Coarse facial features. Note the large forehead, short neck, broad nasal tip, coarse facial features, and corneal clouding. (b). Claw hands due to camptodactyly of the fingers. (c). umbilical hernia. (d). lateral view of the spine. Note the thoracolumbar kyphosis and the broad ribs. Informed consent was obtained for image use. | Kubaski, F., de Oliveira Poswar, F., Michelin-Tirelli, K., Matte, U., Horovitz, D. D., Barth, A. L., Baldo, G., Vairo, F., & Giugliani, R. (2020). Mucopolysaccharidosis Type I. Diagnostics (Basel, Switzerland), 10(3), 161. https://doi.org/10.3390/diagnostics10030161

Hurler-Scheie syndrome (MPS I H-S):

Intermediate phenotype, typically diagnosed at 2-6 years. Life expectancy usually extends into the late teens or early twenties. Death is usually due to respiratory failure.
  • Facial features (less coarse)
  • Achilles tendon contractures lead to toe walking
  • Hepatosplenomegaly causes respiratory compromise
  • Spondylolisthesis and kyphoscoliosis
  • The meninges are thickened and cause
  • Pachymeningitis cervicalis (cervical spinal cord compression due to thickened meninges), leading to weakness or paralysis
  • Mild cognitive impairment

Sheie syndrome (MPS IS):

Rare and mild phenotype. The physical symptoms of Sheie syndrome are similar to Hurler and Hurler-Sheie syndromes, but patients have normal intelligence. Most patients die before the age of 25 to 30 years.
  • Normal intelligence

Clinical features

Characteristic appearance “gargoylism”:

  • Coarse facies, enlarged head with prominent frontal bones, widely placed eye sockets with protruding eyes, flat appearance of the nasal bridge, enlarged lips, and wide-open eyes
  • Short and stiff neck
Patient with stunted growth and coarse facial features | Tatapudi, R., Gunashekhar, M., & Raju, P. S. (2011). Mucopolysaccharidosis type I Hurler-Scheie syndrome: A rare case report. Contemporary clinical dentistry, 2(1), 66–68. https://doi.org/10.4103/0976-237X.79287

Neurological manifestations:

  • Progressive developmental delay: Before 2 years of age and lose previously acquired skills.
  • High pressure communicating hydrocephalus and convulsions (due to obstruction of CSF from GAGs deposition in meninges and spinal cord).
Developmental charts. The figures plot individual age-equivalent scores (y-axis) against the actual age of the patient (x-axis) for each of the developmental domains. The red line represents the estimated group mean. a Cognitive development, b adaptive behavior, c gross motor, d fine motor, e receptive language and f expressive language |

Gastrointestinal manifestations:

  • Macroglossia (due to GAG deposition in tongue muscle) leading to dysphagia and impaired speech
  • Umbilical and inguinal hernias (early clinical sign)
  • Hepatosplenomegaly

Musculoskeletal system:

Skeletal abnormalities occur by about 6 months but become more clinically obvious by 10-14 months.
  • Stunting of growth: Patients may be of normal height during infancy but stop growing by the age of 2 years. They may not reach a height of greater than 4 feet.
  • Rapidly enlarging head size: Due to craniosynostosis and hyperostosis of skull
  • Debilitating spine and hip deformities:
    • Gibbus (dorsal kyphosis) deformity: Abnormal curvature of the lower spine, giving a hunchback appearance
    • Cervical myelopathy: Due to hypoplastic vertebral bodies (anteroinferior beaking on radiological examination) and atlantoaxial subluxation
  • Carpal tunnel syndrome
  • Progressive joint stiffness and contractures: Painful and limit mobility
  • Dysostosis multiplex (typical skeletal abnormalities)
Lateral radiograph (A) and sagittal CT (B) show hypoplastic cervical vertebrae with pathognomonic ‘inferior beaking’ (arrows). Previous posterior cervical decompression and characteristic hypoplasia of the odontoid process (arrowhead) is seen. | Grech, R., Galvin, L., O’Hare, A., & Looby, S. (2013). Hurler syndrome (Mucopolysaccharidosis type I). BMJ case reports, 2013, bcr2012008148. https://doi.org/10.1136/bcr-2012-008148

Ocular manifestations:

  • Clouding of cornea (due to structural alteration of corneal stroma and derangement of collagen fibrils) leading to blindness
  • Retinal degeneration and optic nerve compression
Picture showing cloudy corneas | Tatapudi, R., Gunashekhar, M., & Raju, P. S. (2011). Mucopolysaccharidosis type I Hurler-Scheie syndrome: A rare case report. Contemporary clinical dentistry, 2(1), 66–68. https://doi.org/10.4103/0976-237X.79287

Hearing manifestations:

GAGs build up in tubes of the middle ear and further prevent them from draining properly
  • Recurrent ear infections
  • Combined conductive and sensorineural hearing loss

Integumentary manifestations:

  • Abundant coarse hair (more than normal)
  • Mongolian spots (bluish birthmarks)
Median age of symptom onset with minimum to 9th decile range | Kiely, B. T., Kohler, J. L., Coletti, H. Y., Poe, M. D., & Escolar, M. L. (2017). Early disease progression of Hurler syndrome. Orphanet journal of rare diseases, 12(1), 32. https://doi.org/10.1186/s13023-017-0583-7

Diagnosis

Diagnosis of this condition is based on a thorough clinical examination and measurement of urinary GAG levels which is a useful screening test. A positive test is suggestive of an MPS, but false-negative results are common. Positive family history is often present.

Flowchart for the newborn screening of MPS I (this flowchart could be used to investigate symptomatic subjects, although in these cases the investigation usually starts with the quantitative and/or qualitative evaluation of urinary GAGs, positive cases being referred for the blood testing). * Reference ranges for alfa-l-iduronidase (IDUA) and glycosaminoglycans may vary according to the methodology used and must be established in each laboratory. # Pseudodeficiency leading to low IDUA levels with normal GAG levels. † Careful examination should be performed with variants of unknown significance (VUS). If no variant is found with Sanger or next-generation sequencing, other techniques such as multiplex ligation-dependent probe (MLPA) should be performed. It is also always recommend to analyze the trio (proband and parents). The dashed line for MPS I diagnosis represents the choice of some laboratories to report a diagnosis solely based on enzyme levels and GAG analysis without molecular analysis of the IDUA gene; this approach has been used in NBS at some centers. | Kubaski, F., de Oliveira Poswar, F., Michelin-Tirelli, K., Matte, U., Horovitz, D. D., Barth, A. L., Baldo, G., Vairo, F., & Giugliani, R. (2020). Mucopolysaccharidosis Type I. Diagnostics (Basel, Switzerland), 10(3), 161. https://doi.org/10.3390/diagnostics10030161

Differential diagnosis:

  • Mucopolysaccharidosis Type III (Sanfilippo syndrome)
  • Mucopolysaccharidosis Type II (Hunter syndrome)
  • Mucopolysaccharidosis Type VII (Sly syndrome)

Management

Most therapies for Hurler syndrome are directed towards treatment of complications and are not specific for an underlying abnormality.

Enzyme replacement therapy:

Used for Hurler and Hurler-Scheie forms of MPS I and moderate-to-severe symptoms in patients with Scheie form.
  • Recombinant human alpha L- iduronidase (Aldurazyme) (weekly IV injection)

Hematopoietic stem cell transplant (HSCT):

Progressive replacement of enzyme-deficient hematopoietic cells with donor-derived enzyme competent cells. It is the ideal treatment for patients who are under 2 years of age and in selected patients over this age limit as it can prolong the survival. HSCT is more effective at preventing disease progression than reversing the established disease.

Supportive management:

  • Surgical interventions: Adenotonsillectomy; hernia repair; ventriculoperitoneal shunt; cardiac valve replacement; carpal tunnel release; spinal decompression
  • Physical, occupational, and speech therapies
  • Respiratory support: Continuous positive pressure ventilation with oxygen supplementation (CPAP)
  • Hearing aids
  • Medications for pain and gastrointestinal disturbances
  • Corneal transplants (for vision problems)

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