Neuropathology of the Norrbottnian type of Gaucher disease

Abstract

The Norrbottnian type of Gaucher disease is characterized by infantile or juvenile onset and variable degrees of neurological symptoms, some of which develop only after splenectomy. A full neuropathological description of this type of Gaucher disease has not been reported previously. The brains of five patients were examined morphologically and biochemically. All presented typical accumulations of glucosylceramide storing cells in the adventitia of vessels in the cerebral and cerebellar sub-cortical white matter (s.c.w.m.). There were differences between the five cases with regard to the accumulation of adventitial storage cells and to the fatty acid pattern of the glucosylceramide isolated from the s.c.w.m., which implicate that the accumulation of glucosylceramide in adventitial cells in the brain is dependent on the generalized lipid storage process and enhanced by splenectomy. Loss of neurones and myelin was noted in the vicinity of accumulations of storage cells in two cases. The five cases showed varying degrees of nerve cell loss, satellitosis and neuronophagia. Lipofuscin with simple and complex lipids but no glycolipids could be demonstrated in neurones light-microscopically. Ultrastructural examination revealed inclusion bodies with bilayers in neurones of the cerebral and cerebellar cortex, dentate nucleus and pons. Because of the bilayered structure of Gaucher cell inclusions the bilayers in neurones are assumed to be formed by glucosylceramide. The fatty acid composition of glucosylceramide isolated from cerebral cortex in all cases suggested that cerebral gangliosides were its main precursor. The highest levels of psychosine (glucosylsphingosine) were seen in the cases with the most advanced nerve cell loss. The morphological and biochemical findings indicate that the neuronopathic process is associated with accumulation of glucosylceramide and psychosine in neurones.

Dependence of reversibility and progression of mouse neuronopathic Gaucher disease on acid β-glucosidase residual activity levels

“…For the above mouse as well as the human neuronopathic variants of Gaucher disease the primary pathological process is neuronal cell death [6,12]. These are clearly not recoverable without additional influx of new neurons from stem cells that have adequate enzyme levels to prevent disease initiation.…”

“…Few studies are available from human tissues that correlate neuronopathic progression, pathologic involvement, and the clinical manifestations [11,12]. To fill this void, several mouse models with GCase null or point mutations or chemical inhibition were developed [13][14][15][16].…”

Multi-system disorders of glycosphingolipid and ganglioside metabolism

“…5 ). CNS neuronal cell loss and gliosis in Gaucher disease types 2 and 3 correlate with GlcCer and, particularly, glucosylsphingosine levels ( 252,253 ). Neurological deterioration in human GM1 gangliosidosis can span a period from birth up to 30 years; apoptosis is the major mechanism of neuronal death, but this is not universal, because several other cell death mechanisms have been implicated in different LSDs.…”

Downregulation of neurotrophic factors in the brain of a mouse model of Gaucher disease: implications for neuronal loss in Gaucher disease

“…Patients with Gaucher disease type I usually present with hepatosplenomegaly and bone disease, but do not have central nervous system symptoms. Patients with Gaucher disease type II or type III have additional neurological symptoms, which may lead to neurodegeneration in infancy or take an intermediate course (Conradi et al, 1984;Brady et al, 1993). The characteristics of the neuronopathic forms include extensive neuronal loss in the anterior horn, basal ganglia, pons, medulla, cerebellum, and hypothalamus, and an increased concentration of glucosylceramide and glucosylsphingosine in the cerebral cortex and cerebellum (Grafe et al, 1988;Orvisky et al, 2000;Wong et al, 2004).…”