Mucolipidosis II alpha/beta and mucolipidosis III alpha/beta

Raphael Schiffmann MD (

Dr. Schiffmann of Baylor Scott & White Research Institute received research grants from Amicus Therapeutics, Takeda Pharmaceutical Company, Protalix Biotherapeutics, and Sanofi Genzyme.

Originally released February 1, 1994; last updated January 14, 2020; expires January 14, 2023

This article includes discussion of mucolipidosis II alpha/beta and mucolipidosis III alpha/beta, ML II, ML II alpha/beta, inclusion cell disease, ML III, ML III alpha/beta, mucolipidosis II alpha/beta, mucolipidosis III alpha/beta, I-cell disease, and pseudo-Hurler polydystrophy. The foregoing terms may include synonyms, similar disorders, variations in usage, and abbreviations.


Mucolipidosis II alpha/beta (I-cell disease) and mucolipidosis III alpha/beta (pseudo-Hurler polydystrophy) are caused by abnormal cellular lysosomal enzyme transport resulting from mutations in the GNPTAB gene, which encodes the alpha and beta subunits of N-acetylglucosamine-1-phosphotransferase. Mucolipidosis III can also be caused by mutations affecting the GNPTG gene.

N-acetylglucosamine-1-phosphotransferase is necessary for the synthesis of mannose-6-phosphate, which is essential for proper targeting of lysosomal enzymes to lysosomes. Mucolipidosis II alpha/beta has many features of Hurler syndrome, but presents earlier and does not show mucopolysacchariduria. There is severe progressive psychomotor retardation, and death usually occurs in the first decade. Craniosynostosis and moyamoya syndrome have been observed in mucolipidosis II patients. Pseudo-Hurler polydystrophy is milder with longer survival.

Key points


• Mucolipidosis can be severe or mild, with little or no dysmorphic features.


• The activity of multiple lysosomal enzyme is elevated in the plasma.


• The disease is caused by a deficiency of multiple lysosomal enzymes and the accumulation of their respective substrates.


• The phenotype is in fact a continuum and can even present with parkinsonism or masquerade as rickets.


• Hematopoietic stem cell transplantation is not recommended for mucolipidosis II.

Historical note and terminology

In the mid-1960s a group of patients with clinical features intermediate between those found in the mucopolysaccharidoses and those in the sphingolipidoses were described. Because of the overlapping phenotypes and evidence of visceral storage of mucopolysaccharides, sphingolipids, and glycolipids, these patients were grouped together under the general classification of "genetic mucolipidosis" (Spranger and Wiedemann 1970).

Among the 8 distinct diseases included in this group of disorders were mucolipidosis II alpha/beta and mucolipidosis III alpha/beta. The former is often referred to as I-cell disease, whereas the latter is also known as pseudo-Hurler polydystrophy. Because both of these disorders result from abnormalities affecting the same gene and also have many clinical, cellular, and biochemical features in common, they are considered together in this review.

Mucolipidosis II alpha/beta (I-cell disease) was first identified as a separate and distinct disorder in patients having many of the clinical features of the Hurler syndrome, but lacking the excessive mucopolysacchariduria expected in the disorder (Leroy and De Mars 1967). The conclusion that these patients suffered from a heretofore unknown disorder was based on the finding of striking cytoplasmic inclusions in their cultured fibroblasts. Because of this finding, the disorder was given the designation "inclusion cell disease" (Leroy and De Mars 1967), subsequently abbreviated to "I-cell disease" (Leroy et al 1971). Spranger and Wiedemann included this disorder in the group of diseases they called the mucolipidoses and designated it mucolipidosis II (Spranger and Wiedemann 1970). This has been renamed mucolipidosis II alpha/beta (Cathey et al 2008).

In 1966, Maroteaux and Lamy described 4 patients with mild Hurler-like features that they classified "la pseudo-polydystrophie de Hurler" (Maroteaux and Lamy 1966). They considered these patients to have the same disorder previously described as "a mucopolysaccharidosis defying classification" (McKusick et al 1965). Subsequently, this disorder was also placed in the mucolipidosis group and was given the designation mucolipidosis III alpha/beta (Cathey et al 2008). Support for this classification was provided by the discovery that cultured fibroblasts from these patients were characterized by the same "I-cell phenomenon" previously seen in mucolipidosis II patients (Taylor et al 1973).

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