Inclusion cell disease

Disorders caused by mislocalization of lysosomal proteins (e.g., mutations in the N-acetylglucosamine 1-phosphotransferase leading to inclusion cell disease). 

As indicated above, Man 6-P serves as a chemical marker to target certain lysosomal enzymes to that organelle. Analysis of cultured fibroblasts derived from patients with I-cell (inclusion cell) disease played a large part in revealing the above role of Man 6-P. I-cell disease is an uncommon condition characterized by severe progressive psychomotor retardation and a variety of physical signs, with death often occurring in the first decade. Cultured cells from patients with I-cell disease were found to lack almost all of the normal lysosomal enzymes the lysosomes thus accumulate many different... 

Terman A, Neuzil J, Kagedal K, et al. Decreased apoptotic response of inclusion-cell disease fibroblasts a consequence of lysosomal enzyme missorting Exp Cell Res 274 9-15,2002. Verkruyse LA, Natowicz MR, Hofmann SL Palmitoyl-protein thioesterase deficiency in fibroblasts of individuals with infantile neuronal ceroid lipofuscinosis and I-cell disease. Biochim Blophys Acta 1361 1-5,1997. von Figura K, Hasilik A Lysosomal enzymes mind their receptors. Anna Rev Biochem 55 167-193, 1986. 

Mucolipidoses are characterized by a combined metabolic disorder of mucopolysaccharides, lipids, and glycoproteins. Lysosomal storage and foamy swollen Kupffer cells with hepatomegaly may be seen. In some of the numerous types, the underlying enzymatic defects have not yet been detected. Type II is also called Leroy syndrome (J.G. Leroy et al., 1967). Due to distinctive cytoplasmic inclusions in fibroblast cultures, this disorder is also known as inclusion cell disease (J.G. Leroy et al., 1971). Foamy altered stellate cells, macrophages and also epithelioid foam cell granulomas are found. 

The new work has established that a neurodegenerative pathway leading from soluble to insoluble, filamentous a-synuclein is central to Lewy body diseases and multiple system atrophy. The development of experimental models of a-synucleinopathies has opened the way to the identification of the detailed mechanisms by which the formation of inclusions causes disease. These model systems have also made it possible to identify disease modifiers that may well lead to the development of the first mechanism-based therapies for these diseases. At a conceptual level, it will be important to understand whether a-synuclein has a role to play in disorders, such as autosomal-recessive juvenile forms of parkinsonism caused by mutations in the Parkin, DJ-1 and PINK-1 genes, or whether there are entirely separate mechanisms by which the dopaminergic nerve cells of the substantia nigra degenerate in Parkinson s disease and in inherited disorders with parkinsonism. 

The answer is D. As this patient ages, a variety of skeletal defects and short stature that are consistent with a lysosomal storage disease (mucolipidosis), either I-cell disease or pseudo-Hurler polydystrophy, are developing. Both diseases arise from a deficiency of an enzyme involved in synthesis of the Man-6-P marker on lysosomal enzymes. Such misaddressed proteins are secreted rather than trafficked to the lysosomes. The degradative function of lysosomes is impaired as a result and the organelles tend to accumulate waste products (hence, the term storage disease ). It is these inclusion bodies or dense structures that would be visible by microscopic examination of the patient s cells in a biopsy specimen. 

By 6 months of age, psychomotor retardation is usually obvious. Joint immobility progresses with development of claw-hand deformities and kyphoscoliosis. Hepatomegaly is prominent, but splenomegaly is minimal. Corneal haziness may be present but is subtle, and corneal opacities due to the accumulation of storage material are not as striking as in Hurler syndrome. Examination of peripheral blood smears reveals the presence of abnormal inclusions in cells such as lymphocytes, and increased lysosomal enzyme activity in whole blood as well as cultured fibroblasts is confirmatory of I-cell disease. 

Within the past few years, several patients have been described who have a hereditary defect characterized by severe psychomotor retardation, shortness of stature, intermittent respiratory infections, and slowly progressive Hurler-like changes of facies and bony configuration. Fibroblasts grown from a skin biopsy have inclusion bodies and, hence, have been considered to display the I (for inclusion) cell phenomenon. The disease has also been referred to as I-cell disease. ... 

Hepatocytes from patients with I-cell disease contain a normal complement of lysosomal enzymes and no Inclusions, even though these cells are defective In mannose phosphorylation. This finding Implies that hepatocytes (the most abundant type of liver cell) employ a MGP-Independent pathway for sorting lysosomal enzymes. The nature of this pathway, which also may operate In other cells types, Is unknown. I... 

Goedert M. Filamentous nerve cell inclusions in neurodegenerative diseases tauopathies and a-synucleinopathies. Philos Trans R Soc Lond B 1999 354 1101-1118. 

The pathological hallmark of the disease is the presence in the brain of Lafora bodies round, basophilic, PAS-positive intracellular inclusions varying in size from small, dust-like bodies less than 3 nm in diameter to large bodies up to 30 nm in diameter. Lafora bodies are typically seen in neuronal perikarya and processes, not in glial cells, and are more abundant in cerebral cortex, substantia nigra, thalamus, globus pallidus and dentate nucleus. Ultrastructural studies have shown that Lafora bodies consist of two components amorphous electron-dense... 

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