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  • Updated 03.30.2023
  • Released 02.01.1994
  • Expires For CME 03.30.2026

Mucolipidosis II alpha/beta and mucolipidosis III alpha/beta



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 more prolonged survival.

Key points

• Mucolipidosis II and III can be mild with little or no dysmorphic features, or severe with prominent dysmorphic features.

• Mucolipidosis II and III are caused by a deficiency of multiple lysosomal enzymes and the accumulation of their respective substrates.

• 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 was described. Because of the overlapping phenotypes and evidence of visceral storage of mucopolysaccharides, sphingolipids, and glycolipids, these patients were grouped under the generic term "genetic mucolipidosis" (76).

Among the eight 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 disorders can 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 who had many of the clinical features of the Hurler syndrome but lacked the excessive mucopolysacchariduria expected in that disorder (40). Because of the striking cytoplasmic inclusions in their cultured fibroblasts, the disorder was given the designation "inclusion cell disease" (40), subsequently abbreviated to "I-cell disease" (41). Peripheral blood lymphocytes also show abnormal vacuoles in patients with I-cell disease (33).

Peripheral blood lymphocyte of a patient with I-cell disease (mucolipidosis II)

May-Giemsa staining; x40 magnification. (Source: Khan SA, Tomatsu SC. Mucolipidoses overview: past, present, and future. Int J Mol Sci 2020;21(18):6812. Enlarged and edited by Douglas J Lanska MD MS MSPH to improve sharpness an...

Spranger and Wiedemann included this disorder in the group of diseases they called the mucolipidoses and designated it mucolipidosis II (76). This has been renamed mucolipidosis II alpha/beta (08).

In 1966, Maroteaux and Lamy described four patients with mild Hurler-like features that they classified "la pseudo-polydystrophie de Hurler" (48). They considered these patients to have the same disorder previously described as "a mucopolysaccharidosis defying classification" (50). Subsequently, this disorder was also placed in the mucolipidosis group and was given the designation mucolipidosis III alpha/beta (08). 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 (78).

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