Clinical Information

N-acetylglucosamine-1-phosphate transferase, alpha and beta subunits (GNPTAB)-related mucolipidoses are progressive lysosomal storage diseases traditionally classified as mucolipidosis II and mucolipidosis III based upon their severity and disease onset. These conditions have substantial clinical overlap and mutation testing can aid the diagnosis.

Mucolipidosis II alpha/beta (ML II alpha/beta or I-cell disease) is a progressive inborn error of metabolism with clinical onset at birth and fatal outcome most often in early childhood. Postnatal growth is limited and often ceases in the second year of life; contractures develop in all large joints. The skin is thickened, facial features are coarse, and gingiva are hypertrophic. Orthopedic abnormalities present at birth may include thoracic deformity, kyphosis, clubfeet, deformed long bones, and hip dislocation. There is often cardiac involvement, most commonly thickening and insufficiency of the mitral valve and, less frequently, the aortic valve. Progressive mucosal thickening narrows the airways and gradual stiffening of the thoracic cage contributes to respiratory insufficiency, the most common cause of death.

Mucolipidosis III alpha/beta (ML III alpha/beta or pseudo-Hurler polydystrophy) is a slowly progressive disorder with clinical onset at approximately 3 years of age. It is characterized by a 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.

ML II/ML III alpha/beta are inherited in an autosomal recessive manner. Both disorders have been reported from nearly all parts of the world and the overall carrier rate ranges between 1 in 158 and 1 in 316.

GNPTAB is the gene in which mutations are most often known to cause ML II/ML III alpha/beta. Bidirectional sequencing of the entire GNPTAB coding region detects 2 disease-causing mutations in more than 95% of individuals with ML II/MLIII alpha/beta. This gene encodes 2 of 3 subunits (alpha/beta) of the heterohexameric enzyme, N-acetylglucosamine-1-phosphotransferase. In the absence of this enzyme, a mannose 6-phosphate (M6P) recognition marker is not added to lysosomal hydrolases and other glycoproteins. This leads to disruption of acid hydrolases transport to the lysosome. Formation of the M6P recognition marker on lysosomal hydrolases is significantly reduced in ML III alpha/beta, and nearly or totally absent in ML II alpha/beta. 

To confirm or establish the diagnosis in a proband requires a combination of clinical evaluation and laboratory testing. The use of the following diagnostic testing is recommended: Identification of characteristic clinical and radiographic findings, assay of oligosaccharides in urine, assay of several acid hydrolases in plasma, sequence analysis of GNPTAB. The activity of nearly all lysosomal hydrolases in plasma and other body fluids is higher in individuals affected with ML II alpha/beta (5- to 20-fold) and ML III alpha/beta (up to 10-fold) than in normal controls. ML II/ML III alpha/beta is diagnosed by assay of N-acetylglucosamine-1-phosphotransferase in skin fibroblasts. Demonstration of nearly complete inactivity (<1%) of the enzyme confirms the diagnosis of ML II alpha/beta, whereas significant deficiency (1%-10% of normal) of this enzyme is suggestive of the diagnosis of ML III alpha/beta. Urinary excretion of oligosaccharides is often excessive. Prior to molecular analysis, the delineation of ML II alpha/beta from ML III alpha/beta depended solely on clinical criteria including age of onset, rate of progression, and overall severity.

Molecular genetic studies reveal a genotype-phenotype correlation supporting the clinical distinction between ML II alpha/beta and ML III alpha/beta. Mutations that completely inactivate the phosphotransferase consistently result in ML II alpha/beta, irrespective of their location within the gene. Mutations with less adverse effect on this enzyme activity usually result in ML III alpha/beta or occasionally in intermediate phenotypes.(1,2)