Northern Epilepsy: A Novel Form of Neuronal Ceroid‐Lipofuscinosis

Abstract

Northern epilepsy is an autosomal recessive childhood onset epilepsy syndrome, clinically characterized by generalized tonic-clonic seizures with onset at 5 to 10 years of age and subsequent slowly progressive mental deterioration. The patients may reach 50 or 60 years of age. A mutation responsible for the disease has recently been identified in a novel gene on chromosome 8p23, encoding a putative membrane protein with an unknown function. The present study, based on three autopsied patients, is the first neuropathological analysis of the disease, and showed intraneuronal accumulation of cytoplasmic autofluorescent granules. The granules were strongly stained by the Luxol fast blue, periodic acid-Schiff, and Sudan black B methods in paraffin sections, and were immunoreactive for subunit c of the mitochondrial ATP synthase and sphingolipid activator proteins A and D. The intraneuronal storage was highly selective: the third layer of the isocortex and the hippocampal CA2, CA3, and CA4 sectors were severely affected, while other layers of the isocortex, the CA1 sector, and the cerebellar cortex were only minimally involved. The membrane-bound storage cytosomes showed a curvilinear ultrastructure with admixture of some granular components. Western blotting and N-terminal sequence analysis of purified storage material identified subunit c as the major component. These findings establish Northern epilepsy as a new form of neuronal ceroid-lipofuscinosis with an exceptionally protracted course.

Lysine 43 Is Trimethylated in Subunit c from Bovine Mitochondrial ATP Synthase and in Storage Bodies Associated with Batten Disease

“…A form in sheep is syntenic with the human CLN6 1 (early juvenile or late infantile variant) disease (11)(12)(13). Specific lysosomal storage of subunit c has been demonstrated by protein sequencing of bodies from these sheep and of human samples associated with the CLN2 (late infantile), CLN3 (juvenile), (14 -16), CLN5, and CLN8 human forms (17,18). They are not associated with the CLN1 (infantile) form (19).…”

Determination of the Substrate Specificity of Tripeptidyl-peptidase I Using Combinatorial Peptide Libraries and Development of Improved Fluorogenic Substrates

“…However, this extremely hydrophobic protein also accumulates in a number of different other NCLs (17)(18)(19)(20)(21)(22). Without detailed understanding of TPP I substrate specificity and the combined actions of other lysosomal proteinases, it remains difficult to distinguish whether subunit c accumulation in LINCL is a primary or secondary effect of TPP I deficiency.…”

Progression of early postnatal retinal pathology in a mouse model of neuronal ceroid lipofuscinosis

“…1,2 Electron microscopic observation revealed curvilinear-like profiles and granular storage material comprising mostly subunit c of mitochondrial ATP synthase. 1 The CLN8 gene underlying EPMR was identified by positional cloning, 2 and found to encode a novel protein of 286 amino acids and an estimated molecular weight of 30 kDa. Mutations in the CLN8 gene were found to be associated with not only EPMR patients but also the mnd mouse, a model of motor neuron degeneration.…”

“…The newest member of the NCL family is a Finnish variant associated with the CLN8 gene. 1,27 Progressive epilepsy with mental retardation (EPMR), also known as Northern epilepsy, was recently identified as one of the NCL family by accumulation of autofluorescent, intracytoplasmic storage material in CNS neurons. 1,2 Electron microscopic observation revealed curvilinear-like profiles and granular storage material comprising mostly subunit c of mitochondrial ATP synthase.…”

“…1,27 Progressive epilepsy with mental retardation (EPMR), also known as Northern epilepsy, was recently identified as one of the NCL family by accumulation of autofluorescent, intracytoplasmic storage material in CNS neurons. 1,2 Electron microscopic observation revealed curvilinear-like profiles and granular storage material comprising mostly subunit c of mitochondrial ATP synthase. 1 The CLN8 gene underlying EPMR was identified by positional cloning, 2 and found to encode a novel protein of 286 amino acids and an estimated molecular weight of 30 kDa.…”