Neuronopathic juvenile glucosylceramidosis due to sap-C deficiency: clinical course, neuropathology and brain lipid composition in this Gaucher disease variant.

Glucosylceramide lipidosis results from a defective lysosomal degradation of this glycolipid. Lipid degradation is controlled by two components, the enzyme beta-glucocerebrosidase and a sphingolipid activator protein. While most Gaucher cases are due to mutations within the gene that codes for the lysosomal enzyme, only two patients have been described with normal enzyme levels and mutations in the gene for the sphingolipid activator protein C (sap-C). Here we present the detailed neurological manifestations, neuropathological findings and brain lipid composition in one sap-C-deficient patient. The patient was an 8-year-old boy who presented with transient losses of consciousness, myoclonic jerks and generalized seizures resistant to all antiepileptic drugs. He developed progressive horizontal ophthalmoplegia, pyramidal and cerebellar signs, and died at the age of 15.5 years. Neuropathological studies demonstrated neuronal cell loss and neuronophagia, massive intraneuronal lipid storage and lack of perivascular Gaucher cells. Electron microscopy examination showed different types of storage including lipofuscin granules as well as the cytosomes with parallel arrays of bilayers that are assumed to be formed by stored lipids. General brain lipid composition did not show a remarkable increase or loss of any of the major lipid fractions but the glucosylceramide concentration in the cortex of several anatomical regions showed a striking increase. Fatty acid composition of the ceramide moiety clearly suggests that gangliosides are the main precursors in the cerebral cortex, while it implies an additional and distinct source in the cerebellum. Studying the phenotypic consequences of mutant sphingolipid activator proteins is critical to a better understanding of the physiological significance of these proteins.

Low beta-glucuronidase activity in a healthy member of a family with mucopolysaccharidosis VII.

A phenotypically normal mother of a mucopolysaccharidosis VII child, is reported with an unusually low beta-glucuronidase activity. Low enzyme activity was systemic (6-10% of controls) and residual beta-glucuronidase in leukocytes had an apparently normal Km value. [35S]sulphate incorporation and chase assays in fibroblasts gave values similar to control cells. A normal excretion pattern of glycosaminoglycan was found in this woman's urine. Low enzymatic activity can be related to a non-pathological 'pseudodeficiency' allele for beta-glucuronidase; this woman appears to be an apparent compound heterozygote for this allele and mucopolysaccharidosis VII. Her next pregnancy was monitored by chorionic villus sampling and a heterozygous fetus was suspected. These studies stress the need for complete enzyme investigations of obligate carriers for mucopolysaccharidoses in order to prevent difficulties at prenatal analysis.

[Sandhoff's disease (GM2 gangliosidosis, type II). Presentation of a case with a clinical and biochemical study. Carrier detection]. / Enfermedad de Sandhoff (gangliosidosis GM2 tipo II). Presentación de un caso con estudio clínico y bioquímico. Investigación de portadores.

A case affected by Sandhoff's disease is reported, with clinical and biochemical studies. In the propositus, total absence of hexosaminidases is reported. In parents hexosaminidase A is present, but hexosaminidase B is decreased. In the carriers there is a total low activity of hexosaminidase and a lower proportion 20% of hexosaminidase is confirmed.

[GM2 gangliosidosis diagnosis and carriers detection by fractionation of N-acetyl-beta-D-hexosaminidase by electrophoresis on cellulose acetate gel (author's transl)]. / Diagnóstico de las gangliosidosis GM2 y detección de portadores mediante la determinación de los isoenzimas de la N-acetil-beta-D-hexosaminidasa sérica por electroforesis en celogel.

A method is described for the fractionation of GM2 gangliosidosis diagnosis and carriers detection by fractionation of N-acetyl-beta-D-Hexosaminidase by electrophoresis on cellulose acetate gel. The hexosaminidase activity is resolved into three bands that are quantified by a densitometric procedure. The methods is applied to normal controls, normal pregnant women, patients of Tay-Sachs disease, heterozigous carriers of Tay-Sachs disease, amniotic fluid, uncultured amniotic cells. The results are compared with those obtained by the "heat inactivation method".