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Mucolipidosis type III

Synonym(s) Pseudo-Hurler polydystrophy
Prevalence Unknown
Inheritance Autosomal recessive
Age of onset Childhood
  • E77.0
MeSH -
MedDRA -


Mucolipidosis III alpha/beta (MLIII alpha/beta) is a lysosomal disorder characterized by progressive slowing of the growth rate from early childhood, stiffness and pain in joints, gradual coarsening of facial features, moderate developmental delay and mild intellectual disability in most patients.

Prevalence has been estimated at 1/53,000 live births in Portugal and 1/1, 250,000 live births in the Netherlands.

Infants appear normal at birth. Onset is gradual and usually observed around the age of 3 years with slowing of growth rate and apparent shoulder, hip and knee contractures. Dysmorphic facial features (full cheeks, depressed nasal bridge, prominent mouth and inconsistently mild gingival hypertrophy) are mild but coarsen with age. Otitis media is common in the young. Functional changes in hard and soft connective tissues result in a slowly progressive reduction of motion range in shoulders, hips and knees. Gradual hardening of the cardiac valves from childhood onwards ultimately leads to cardiac insufficiency. Gait slows in childhood, becoming increasingly painful due to severe hip disease. Bone pain, even at rest, results from osteoporosis and osteolytic bone lesions. Moderate claw-like flexion deformity of the fingers and carpal tunnel syndrome are common complications. Bronchitis/bronchopneumonia is frequent in childhood and gradual restrictive lung disease becomes life-threatening in older patients. Mild intellectual disability has been reported in most patients. Death is often due to treatment-refractory cardiopulmonary failure.

ML III alpha/beta is due to mutations in the GNPTABgene (12q23.3), encoding the inactive alpha/beta precursor protein that generates the catalytically active alpha and beta subunits of N-acetylglucosamine-1-phosphotransferase (GNPT). The gamma subunit is encoded by the GNPTG gene (16p13.3) and mutations in this gene cause the milder MLIII gamma (see this term). In MLIII alpha/beta, at least one of the two mutations is hypomorphic, which results in the later onset and less severe phenotype than ML II.

Diagnosis is based on clinical and radiographic observations at the time of onset and is confirmed initially by assays of several lysosomal enzymes in plasma demonstrating increased activity (up to 10-fold) of almost all lysosomal hydrolases. In cultured fibroblasts, the activity of the same lysosomal enzymes is significantly decreased but not totally absent. Mutation screening of the GNPTAB gene provides the most formal and useful confirmation of the diagnosis.

Differential diagnoses include MLIII gamma; mucopolysaccharidosis type 1, 2, 4B, 6, and 7; free sialic acid storage disease, infantile form; multiple sulfatase deficiency; multiple epiphyseal dysplasia; progressive pseudorheumatoid arthropathy of childhood; chondrodysplasia punctata; and rheumatoid arthritis (see these terms).

Prenatal diagnosis is possible in families with a patient with known disease-causing mutant genotype.

ML 3 alpha/beta is inherited autosomal recessively and genetic counseling is offered accordingly.

There is no cure for ML III alpha/beta and treatment is only supportive. Myringotomy and tube placement may be recommended to those with recurrent otitis media. Low-impact physical therapy and tendon release procedures (for carpal tunnel features) can provide some relief. Analgesics and IV bisphosphonate can treat bone pain. Young children should be examined biannually. After the age of 6, yearly visits may suffice, but cardiac valve status must be monitored. Cognitive stimulation is of paramount importance in children with only minor intellectual disability. Careful weighing of risk and benefit is required when considering surgery.

Prognosis is generally poor, with the morbidity of late complications adversely affecting quality of life and limiting life expectancy. Occasionally patients may survive into mid-adulthood.

Expert reviewer(s)

  • Dr Jules LEROY

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Detailed information

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Clinical genetics review
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