P-Galactosidase deficiency

In p-galactosidase II deficiency, GL-2a (Gaipi,4Glcpi,lCer) is the storage product. Unlike Krabbe s disease, it is the grey matter, rather than the white matter, which is affected. The liver, spleen, bone marrow and lymph nodes are all involved. It is by no means certain that this disease is a simple P galactosidase deficiency or that all cases are alike. 

In fact, all of the patients classified by Lowden and O Brien (1979) as sialidosis type 2, juvenile onset form, exhibited a p-galactosidase deficiency when it was looked for. 

Yamada, T., Tsuji, S., and Miyatake, T., 1983, Lysosomal sialidase deficiency in sialidosis with partial P-galactosidase deficiency, Biochim. Biophys. Acta 755 106-111. 

Nishimoto, J., Nanba, E., Inui, K., Okada, S., and Suzuki, K., 1991, GMl-gangliosidosis (genetic P-galactosidase deficiency) Identification of mutations in different clinical phenotypes among Japanese patients. Am. J. Hum. Genet. 49 566-574. 

Suzuki, Y, Nakamura, N., Fukuoka, K., Shimada, Y., and Uono, M., 1977, p-Galactosidase deficiency in juvenile and adult patients. Report of six Japanese cases and review of literature. Hum. Genet. 36 219-229. 

Suzuki, Y, Sakuraba, H., Oshima, A., Yoshida, K., Shimmoto, M., Takano, T., and Fukuhara, Y., 1991, Clinical and molecular heterogeneity in hereditary p-galactosidase deficiency, Dev. Neurosci. 13 299-303. 

Wenger, D. A., Tarby, T. J., and Wharton, C., 1978, Macular cherry-red spots and myoclonus with dementia Coexistent neuraminidase and P-galactosidase deficiencies, Biochem. Biophys. Res. Commun. 82 589-595. 

Galactosialidosis is characterized by the simultaneous deficiencies of P-galactosidase and a-neuroaminidase. Clinical and pathological manifestations resemble those in GM1 gangliosidosis and like it show a range of severity. The underlying defect involves a protective protein, which stabilizes these two enzymes by a mechanism that is not understood. Curiously, the protective protein is itself a peptidase. The disorder is most common in Japan. The defective gene has been cloned and mutations have been identified. 

Eyer, J. and Peterson, A. Neurofilament-deficient axons and perikaryal aggregates in viable transgenic mice expressing a neurofilament-P-galactosidase fusion protein. Neuron 12 389-405,1994. 

Kint, J. A., In vitro restoration of deficient p-galactosidase activity in liver of patients with Hurler and Hunter disease. Nature (London) 250, 424-425 (1974). 

The key feature of a plasmid capable of blue/white screening is the gene for the a-subunit of the enzyme p-galactosidase. These plasmids are used with a strain of E. coli that are deficient in the a-subunit of this enzyme. Galactosidase can convert a colorless sugar derivative, called X-gal, to a... 

In addition to these two types of sialidosis, there are patients with a combined defect of neuraminidase and p-galactosidase (Wenger etal. 1978, Andria etal. 1978, OK.ADAetal. 1979), possibly caused by a common defect in the biosynthetic processing of the two enzymes (Hoogeveen etal. 1980). A neuraminidase deficiency has also been observed in patients with mucolipidosis II (I-cell disease) and mucolipidosis III (Strecker etal. 1976, Thomas etal. 1976). In these disorders, however, the neuraminidase deficiency is but one of many lysosomal hydrolase deficiencies, presumably due to a defect in the proper compart-mentalization of these enzymes (Neufeld 1974). 

As neuraminidase activity is readily detectable in amniotic cells, a prenatal diagnosis should be possible in a fetus at risk for sialidosis. Indeed, prenatal diagnosis has been performed in a pregnancy at risk for combined p-galactosidase/neuraminidase deficiency, and the diagnosis of an affected fetus was confirmed by assays of neuraminidase and p-galactosidase in tissues from the aborted fetus Kleuer etal. 1979). 

The combined p-galactosidase/neuraminidase deficiency, on the other hand, presents a clinical picture which seems intermediate in severity between the mild and severe forms of isolated neuraminidase deficiency. Whereas it is not yet clear whether the neuraminidase deficiency in this disorder is secondary to an unknown processing defect, a defect in such a mechanism has been shown to be responsible for the deficiency of numerous lysosomal hydrolases, including neuraminidase, in patients with mucolipidoses II and III. 

Not only the deficiency of a hydrolytic enzyme, but also of other proteins required for sphingolipid degradation can cause a sphingolipid storage disease. Besides deficiencies of activator proteins, this is the case in galactosialidosis. This disease is characterized by the secondary deficiency of P-galactosidase and sialidase activity. The primary defect is due to mutations within the protective protein, which forms a stable complex with the GMl-p-galactosidase and the lysosomal sialidase [47]. 

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