Clinical characteristics: Mucopolysaccharidosis type I (MPS I) is a progressive multisystem disorder with features ranging over a continuum of severity. While affected individuals have traditionally been classified as having one of three MPS I syndromes (Hurler syndrome, Hurler-Scheie syndrome, or Scheie syndrome), no easily measurable biochemical differences have been identified and the clinical findings overlap. Affected individuals are best described as having either a phenotype consistent with either severe (Hurler syndrome) or attenuated MPS I, a distinction that influences therapeutic options.
Severe MPS I. Infants appear normal at birth. Typical early manifestations are nonspecific (e.g., umbilical or inguinal hernia, frequent upper respiratory tract infections before age 1 year). Coarsening of the facial features may not become apparent until after age one year. Gibbus deformity of the lower spine is common and often noted within the first year. Progressive skeletal dysplasia (dysostosis multiplex) involving all bones is universal, as is progressive arthropathy involving most joints. By age three years, linear growth decreases. Intellectual disability is progressive and profound but may not be readily apparent in the first year of life. Progressive cardiorespiratory involvement, hearing loss, and corneal clouding are common. Without treatment, death (typically from cardiorespiratory failure) usually occurs within the first ten years of life.
Attenuated MPS I. Clinical onset is usually between ages three and ten years. The severity and rate of disease progression range from serious life-threatening complications leading to death in the second to third decade, to a normal life span complicated by significant disability from progressive joint manifestations and cardiorespiratory disease. While some individuals have no neurologic involvement and psychomotor development may be normal in early childhood, learning disabilities and psychiatric manifestations can be present later in life. Hearing loss, cardiac valvular disease, respiratory involvement, and corneal clouding are common.
Diagnosis/testing: The diagnosis of MPS I is established in a proband with suggestive clinical and laboratory findings by: detection of deficient activity of the lysosomal enzyme α-L-iduronidase (IDUA) in combination with elevation of glycosaminoglycan levels; and/or identification of biallelic pathogenic variants in IDUA on molecular genetic testing. Identification of the causative IDUA variants plays an important role in the determination of phenotype.
Management: An essential component of management is the determination of whether the proband has severe or attenuated MPS I. This requires detailed clinical and laboratory assessment and can be challenging in very young individuals.
Treatment of manifestations: Infant learning programs/special education for developmental delay; physical therapy, orthopedic surgery as needed, joint replacement for progressive arthropathy, atlanto-occipital stabilization; spinal cord decompression for cervical myelopathy; cerebrospinal fluid shunting for hydrocephalus; early median nerve decompression for carpal tunnel syndrome based on nerve conduction studies before clinical manifestations develop; special attention to anesthetic risks; hats with visors/sunglasses to reduce glare, corneal transplantation for ophthalmologic involvement; cardiac valve replacement as needed and bacterial endocarditis prophylaxis for those with cardiac involvement; tonsillectomy and adenoidectomy for eustachian tube dysfunction and/or upper airway obstruction; ventilating tubes; hearing aids as needed; CPAP for sleep apnea; gastrointestinal management for diarrhea and constipation.
Prevention of primary manifestations
Hematopoietic stem cell transplantation (HSCT) for children with severe MPS I. Outcome is significantly influenced by disease burden at the time of diagnosis (and thus, by the age of the individual). HSCT can improve cognitive outcomes, increase survival, improve growth, reduce facial coarseness and hepatosplenomegaly, improve hearing, prevent hydrocephalus, and alter the natural history of cardiac and respiratory symptomatology. HSCT has lesser effects on the skeletal and joint manifestations, corneal clouding, and cardiac involvement. HSCT alters the course of cognitive decline in children with severe MPS I; cognitive outcome is greatly influenced by the degree of cognitive impairment at the time of transplantation. Due to the morbidity and mortality associated with HSCT, it is currently recommended primarily for children with severe MPS I.
Enzyme replacement therapy (ERT) with laronidase (Aldurazyme®), licensed for treatment of the non-CNS manifestations of MPS I, improves liver size, linear growth, and mobility and joint range of motion; slows progression of respiratory disease; and improves sleep apnea in persons with attenuated disease. The age of initiation of ERT influences the outcome.
Surveillance: Annual assessment by a team of physicians with knowledge of the multisystem nature of MPS I. Specialists and assessments: orthopedic surgery including annual assessment of median nerve conduction velocity; ophthalmology, cardiology (including echocardiography), respiratory with assessment of pulmonary function and sleep studies, audiology, and otolaryngology. Assessment for constipation and/or hernias as needed. Early and continuous monitoring of head growth in infants and children with imaging as needed; assessment for evidence of spinal cord compression by neurologic examination; developmental assessment annually; and psycho-educational assessment of children with attenuated disease prior to primary school entry.
Evaluation of relatives at risk: Early diagnosis prior to significant disease manifestations is warranted in relatives at risk in order to initiate therapy as early in the course of disease as possible.
Genetic counseling: MPS I is inherited in an autosomal recessive manner. At conception, each child of a couple in which both parents are heterozygous for a IDUA pathogenic variant has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk relatives and prenatal testing for pregnancies at increased risk are possible if both disease-causing IDUA variants have been identified in the family.
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