Mucolipidosis III Alpha/Beta – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY

Excerpt

NOTE: THIS PUBLICATION HAS BEEN RETIRED. THIS ARCHIVAL VERSION IS FOR HISTORICAL REFERENCE ONLY, AND THE INFORMATION MAY BE OUT OF DATE.

Clinical characteristics: Mucolipidosis alpha/beta (ML III alpha/beta; pseudo-Hurler polydystrophy), a slowly progressive disorder with clinical onset at approximately age three years, is characterized by slow growth rate and subnormal stature; radiographic evidence of mild to moderate dysostosis multiplex; joint stiffness and pain initially in the shoulders, hips, and fingers; gradual mild coarsening of facial features; and normal to mildly impaired cognitive development. If present, organomegaly is mild. Pain from osteoporosis that is clinically and radiologically apparent in childhood becomes more severe from adolescence. Cardiorespiratory complications (restrictive lung disease, thickening and insufficiency of the mitral and aortic valves, left and/or right ventricular hypertrophy) are common causes of death, typically in early to middle adulthood.

Diagnosis/testing: In ML III alpha/beta the activity of nearly all lysosomal hydrolases is up to tenfold higher in plasma and other body fluids than in normal controls because of inadequate targeting to lysosomes. Urinary excretion of oligosaccharides (OSs), a nonspecific finding, is often excessive. Significant deficiency (1%-10% of normal) of the activity of the enzyme UDP-N-acetylglucosamine: lysosomal hydrolase N-acetylglucosamine-1-phosphotransferase (GNPTA), encoded by GNPTAB, confirms the diagnosis. Bidirectional sequencing of the entire GNPTAB coding region detects two pathogenic variants in more than 95% of individuals with ML III alpha/beta.

Management: Treatment of manifestations: Low-impact physical therapy is usually well tolerated. Myringotomy tube placement may be indicated in the treatment of recurrent otitis media. Carpal tunnel signs may require tendon release. In late childhood or early adolescence symptomatic relief of hip pain may be initially accomplished with over-the-counter analgesics; in some older adolescents and adults with milder phenotypic variants, bilateral hip replacement has been successful. Later in the disease course management focuses on relief of general bone pain associated with osteoporosis, which has responded in a few individuals to scheduled intermittent IV administration of the bisphosphonate pamidronate.

Prevention of secondary complications: Because of concerns about airway management, surgical intervention should be undertaken only in tertiary care settings with pediatric anesthesiologists and intensivists.

Surveillance: Twice-yearly outpatient clinic visits for young children; annual routine follow-up visits after age six years unless bone pain, deteriorating ambulation, and/or cardiac and respiratory monitoring need more frequent attention.

Genetic counseling: ML III alpha/beta 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. Carrier testing for at-risk relatives and prenatal diagnosis for pregnancies at increased risk are possible if the pathogenic variants in the family are known.