The lysosomal storage disorders mucolipidosis type II, type III alpha/beta, and type III gamma: Update on GNPTAB and GNPTG mutations.

Mutations in the GNPTAB and GNPTG genes cause mucolipidosis (ML) type II, type III alpha/beta, and type III gamma, which are autosomal recessively inherited lysosomal storage disorders. GNPTAB and GNPTG encode the α/ß-precursor and the γ-subunit of N-acetylglucosamine (GlcNAc)-1-phosphotransferase, respectively, the key enzyme for the generation of mannose 6-phosphate targeting signals on lysosomal enzymes. Defective GlcNAc-1-phosphotransferase results in missorting of lysosomal enzymes and accumulation of non-degradable macromolecules in lysosomes, strongly impairing cellular function. MLII-affected patients have coarse facial features, cessation of statural growth and neuromotor development, severe skeletal abnormalities, organomegaly, and cardiorespiratory insufficiency leading to death in early childhood. MLIII alpha/beta and MLIII gamma are attenuated forms of the disease. Since the identification of the GNPTAB and GNPTG genes, 564 individuals affected by MLII or MLIII have been described in the literature. In this report, we provide an overview on 258 and 50 mutations in GNPTAB and GNPTG, respectively, including 58 novel GNPTAB and seven novel GNPTG variants. Comprehensive functional studies of GNPTAB missense mutations did not only gain insights into the composition and function of the GlcNAc-1-phosphotransferase, but also helped to define genotype-phenotype correlations to predict the clinical outcome in patients.

[Lysosomal disorders. Diagnostic role of extra-cerebral biopsy]. / Maladies lysosomales. Apport diagnostique de la biopsie extra-cérébrale.

Lysosomal disorders are related to dysfunctions of lysosomes which may affect enzymes, transporters or activators. Their clinical features are varied. This is due to several mechanisms, the metabolism of nervous tissue explaining its particular involvement in sphingolipidosis. The classifications are still changing and, recently, some ceroid-lipofuscinosis were included in this group. Biological diagnosis relies on biochemical study of accumulated substrate or on enzymatic assays. It remains sometimes difficult. The analysis of tissue is then a useful tool. Biopsies from extraneural tissues, essentially skin and conjunctival biopsies, are nowadays preferred to brain biopsies. However, the location of the biopsy varies according to the suspected disease. The specimen must be adequately prepared and electron microscopy is necessary. Results of this examination are summarized. The interest of the biopsy is not restricted to diagnosis, it is useful in follow-up of treated patients and for understanding the underlying pathophysiology.