New Subform of the Late Infantile Form of Neuronal Ceroid Lipofuscinosis

Abstract

Clinicopathological studies of a series of nine children with a new subform of Jansky-Bielschowsky disease or late infantile neuronal ceroid lipofuscinosis (LINCL) is presented. The onset of this subform is between 2.5-3.5 years of age with initial neurological symptoms of abnormal motor skills caused by cerebellar and extrapyramidal signs. Soon after dementia, myoclonic seizures are followed. Visual impairment is more clearly seen after the age of 5 or 6 years. The ultrastructural studies of the skin and/or buffy coat showed abundant lysosomal storage of curvilinear profiles, rarely intermixed with fingerprint profiles. The MRI of the head performed in seven cases, showed initially enlargement of the ventricles that is secondary to basal ganglia atrophy and presence of cerebellar and cerebral atrophy. In 4 of 7 cases (Cases 1,5,6,8) abnormalities in the deep white matter showing increased signals of T2-weighted imaging in the periventricular areas of the fronto-parietal region, internal capsule, tracks of the brainstem, and white matter of cerebellum were seen. These abnormalities were also observed by post-mortem neuropathological studies in three cases (nos. 7-9). The MRI in Cases 7 and 9 was not performed. The electrophysiological abnormalities (EEG, ERG, VER) are similar as described in the classical LINCL. Neuropathological studies done in 3 of 9 cases showed generalized brain atrophy and unique type of neuronal cytoplasmic inclusion body in the basal ganglia, brainstem, dentate nuclei, and rarely, cerebral cortex. These large, round neuronal cytoplasmic inclusions were pink in hematoxylin (HE), violet in cresyl violet, and dark blue with Klüver-Barrera method. They were unstained with ConA and distinctly varied ranging from negative to strong positive with Sudan BB. These lysosomal inclusions correspond to unusually densely packed curvilinear profiles which in some cells formed large aggregates almost entirely filling the neuronal cytoplasm. Neurons of other grey matter regions, however, showed loosely arranged curvilinear profiles that were surrounded by single membranes and sometimes intermixed with fingerprint profiles, similar as described in the classical LINCL cases. The cerebellum showed unusually severe atrophy. This new variant of Jansky-Bielschowsky disease stresses the heterogeneity within this particular subform of LINCL. Further biochemical and genetic studies are needed to better define these different subforms of NCL cases.

Key words

Neuronal ceroid lipofuscinosis - Jansky-Bielschowsky disease - Neuropathology