Sialidosis type I carrying V217M/G243R mutations in lysosomal sialidase: an autopsy study demonstrating terminal sialic acid in lysosomal lamellar inclusions and cerebellar dysplasia.

Autopsy findings of a patient, with sialidosis type I phenotype carrying V217M/G243R mutations in the lysosomal sialidase gene and biochemically defined isolated sialidase deficiency, who died of intractable lymphoma at the age of 32 years, are described. Perikaryal expansion of cytoplasm was evident, mostly in motor neurons (in the anterior horn and the brain stem), dorsal root ganglia, cerebellar dentate neurons and some neurons in the thalamus and nucleus basalis of Meynert. The stored material was lamellar in lysosomes and exhibited a specific affinity to wheat germ agglutinin at light and electron microscopy, which indicates the accumulation of terminal sialic acid at the non-reducing end of the sugar chain in this pathological structure. Neuronal loss in these nuclei, however, was not frequent in spite of frequent and massive cytoplasmic expansion. Neocortex exhibited a mild spongiosis with some swelling of neurons, which contained lipofuscin-like granules and small amount of lamellar structures in lysosomes. This contrast suggests a discrepancy between the storage process and vulnerability of neurons, both variable according to areas examined. In the cerebellar vermis, dysplastic features, such as abnormal layering of Purkinje cells, thinning and rarefaction of the granule cell layer, incomplete formation of synapse and disordered proliferation of Bergmann's glia, were focally accentuated, suggesting some developmental abnormality not secondary to the storage process. This is the first autopsy demonstration of sialic acid in the lamellar materials and of a developmental abnormality in isolated sialidase deficiency. Additional studies are needed to clarify how this molecular abnormality leads to these morphological and clinical manifestations.