Clinical characteristics: Mucopolysaccharidosis type III (MPS III) is a multisystem lysosomal storage disease characterized by progressive central nervous system degeneration manifest as severe intellectual disability (ID), developmental regression, and other neurologic manifestations including autism spectrum disorder (ASD), behavioral problems, and sleep disturbances. Disease onset is typically before age ten years. Disease course may be rapidly or slowly progressive; some individuals with an extremely attenuated disease course present in mid-to-late adulthood with early-onset dementia with or without a history of ID. Systemic manifestations can include musculoskeletal problems (joint stiffness, contractures, scoliosis, and hip dysplasia), hearing loss, respiratory tract and sinopulmonary infections, and cardiac disease (valvular thickening, defects in the cardiac conduction system). Neurologic decline is seen in all affected individuals; however, clinical severity varies within and among the four MPS III subtypes (defined by the enzyme involved) and even among members of the same family. Death usually occurs in the second or third decade of life secondary to neurologic regression or respiratory tract infections.
Diagnosis/testing: The diagnosis of MPS III is established in a proband with suggestive clinical and laboratory findings in whom either biallelic pathogenic variants in one of four genes (GNS, HGSNAT, NAGLU, and SGSH) or deficiency of the respective lysosomal enzyme has been identified.
Management: Treatment of manifestations: Supportive therapies for neurodevelopmental delays, hearing loss, and visual impairment; medications (rather than behavioral therapy) for psychiatric/behavioral issues; physical therapy and/or orthopedic management of musculoskeletal manifestations; and management as prescribed by consulting specialists for seizures, cardiac involvement, sleep disorders, feeding difficulties.
Surveillance: Routine monitoring of: developmental capabilities and educational needs, destructive or disruptive behaviors; musculoskeletal involvement; hearing; cardiac involvement.
Agents/circumstances to avoid: Procedures requiring anesthesia in centers ill-equipped or inexperienced in caring for patients with complex airway-management issues; hip surgery (due to high risk of osteonecrosis of the femoral head); environments not adapted to minimize risk from unpredictable behaviors.
Therapies under investigation: Despite ongoing research for a variety of therapeutic options, no treatments are currently clinically available for treatment of the primary manifestations of MPS III.
Genetic counseling: MPS III is inherited in an autosomal recessive manner. At conception, each sib of an affected individual 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. Once the MPS III-causing pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives, prenatal testing for a pregnancy at increased risk, and preimplantation genetic testing are possible.
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