IntroductionMucopolysaccharidosis 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.
- Autosomal recessive (AR) inheritance: α1-iduronidase (IUDA) enzyme gene (chromosome 4)
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.
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
Hurler syndrome (MPS I H): M/C and M/severe formPatients 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-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
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
- 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).
- Macroglossia (due to GAG deposition in tongue muscle) leading to dysphagia and impaired speech
- Umbilical and inguinal hernias (early clinical sign)
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)
- Clouding of cornea (due to structural alteration of corneal stroma and derangement of collagen fibrils) leading to blindness
- Retinal degeneration and optic nerve compression
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
- Abundant coarse hair (more than normal)
- Mongolian spots (bluish birthmarks)
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.
- Mucopolysaccharidosis Type III (Sanfilippo syndrome)
- Mucopolysaccharidosis Type II (Hunter syndrome)
- Mucopolysaccharidosis Type VII (Sly syndrome)
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.
- 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)