Batten Disease: A Typical Neuronal Storage Disease or a Genetic Neurodegenerative Disorder Characterized by Excitotoxicity?

Abstract

Batten disease (neuronal ceroid lipofuscinosis) is an inherited neurological disorder of humans and a variety of animal species including dogs, mice, and sheep. Affected individuals appear normal at birth but later exhibit progressive neurological deterioration and death. The spectrum of clinical disease includes retarded mental development and/or dementia, blindness, motor system dysfunction, and seizures, and in late disease the latter can be intractable. The age at which clinical symptoms appear varies and infantile, late infantile, juvenile and adult-onset disease subtypes are recognized. Disease course in individuals with early-onset disease generally is rapid, whereas late-onset disorders exhibit a more protracted course. On postmortem exam, atrophy of cerebral cortex and ballooning of surviving neurons are characteristic features. The latter finding has led to classification of Batten disease as a neuronal storage disorder along with Tay-Sachs, Hurler, and related lysosomal diseases. Although the primary metabolic defect(s) in Batten disease remain unknown, recent research has established that, with the exception of infantile disease variants, a substantial portion of the intracellular storage material is a single protein, subunit c of mitochondrial ATP synthase.1 Current findings suggest that this subunit, which is encoded by nuclear DNA, is synthesized correctly and undergoes normal trafficking to mitochondria; however, its subsequent removal from mitochondria and degradation appear to be delayed.2 Why this particular mitochondrial component accumulates in cells, and whether its accumulation signals the primary metabolic defect in Batten disease, are unknown.