Variability in the clinical and pathological findings in the neuronal ceroid lipofuscinoses: Review of data and observations

Abstract

We reviewed the clinical and pathological data on 319 neuronal ceroid lipofuscinosis (NCL) cases to determine the degree of variability within the different forms and among and within families. Thirty‐six cases (11.3%) were the infantile form; 116 cases (36.3%), late infantile, 163 cases (51.1%), juvenile; and four cases (1.3%), the adult form (Kufs disease). Clinical variability was found in all forms studied, but was most striking in the juvenile and late infantile forms of NCL. The expected initial findings of seizures, dementia, blindness, or motor impairment were evident in 255 cases (80%), and rarer, less typical initial neurological symptoms were seen mainly in the 64 cases (20%) of the juvenile form: behavior abnormalities (18/64), psychoses (12/64), neuropathy (2/64), involuntary movements (15/64), ataxia (9/64), Six juvenile and two adult cases had no detectable impairment of vision. All 319 NCL cases had skin or conjunctiva biopsies or buffy that showed the characteristic ultrastructural abnormalities of NCL. Variability was evident in 16.7% in that a combination of fingerprint, curvilinear, and membranous profile inclusion bodies was observed in storage lysosomes, although one type of inclusion was distinctly predominant for each form. Postmortem examination of brains of 19 NCL cases (three with the infantile form, six with the late infantile form, nine with the juvenile form, and one with the adult form) revealed characteristic changes, Sixteen of the 19 NCL brains (84%) showed pathological variability in that they contained more than one kind of characteristic inclusion body in the neuronal lysosomal storage compartment. In all 19 NCL brains, small amounts of aging lipofuscin were also found. In three late infantile cases, neuronal cytoplasmic inclusion bodies were found mainly in the basal ganglia, midbrain, and cerebellar (BG), At the ultrastructural level, theses inclusions were found to be large lysosomes filled with very densely packed curvilinear profiles. Histological and immunocytochemical staining properties of these basal ganglial, midbrain, and cerebellar neurons were found to be different from those storage neurons of other brain regions in this subform and other NCL forms. Therefore, we conclude that these cases represent a distinct NCL subtype. More confounding was the discovery of several neuritic plaques in the fronto‐temporal lobes of a 53‐year‐old female with the adult form. Our present results reveal theat not all epitopes of amyloid β‐precursor protein (APP) can be detected in the NCL brain, and moreover, their distribution and intensity of immunostaining vary, not only among different NCL forms but in some instances with the same forms. The significance of high levels of epitope expression of certain APP domains in NCL brains is still unknown and needs further biochemical studies.