Progressive epilepsy with mental retardation

C P Panayiotopoulos MD PhD (Dr. Panayiotopoulos of St. Thomas' Hospital has no relevant financial relationships to disclose.)
Originally released November 11, 2003; last updated November 29, 2016; expires November 29, 2019

This article includes discussion of progressive epilepsy with mental retardation, CLN8 disease, EPMR, neuronal ceroid lipofuscinosis subtype 8, NCL8, Northern epilepsy, Northern epilepsy syndrome, Northern epilepsy variant, and progressive epilepsy with mental retardation. The foregoing terms may include synonyms, similar disorders, variations in usage, and abbreviations.

Overview

Progressive epilepsy with mental retardation (Northern epilepsy syndrome) is a subtype 8 of neuronal ceroid lipofuscinosis described in families in Northern Finland. It is an autosomal recessive disease characterized by generalized tonic-clonic seizures that first appear between 5 and 10 years of age, prior to slowly progressive intellectual and neurologic deterioration that continues during late adulthood. All patients show mental retardation by 30 years of age, when the first signs of motor clumsiness and marked ataxia also appear. One third of patients suffer from diminished visual acuity without ocular abnormality. The responsible gene (CLN8) on chromosome 8p23, encoding an endoplasmic reticulum transmembrane protein of unknown function, also causes other phenotypes more typical of neuronal ceroid lipofuscinosis in humans and animals. In this update, the author details recent developments in molecular genetics and modern diagnostic procedures for the identification of this mild and protracted form of neuronal ceroid lipofuscinosis.

Key points

 

• Progressive epilepsy with mental retardation (Northern epilepsy syndrome) is a rare autosomal recessive disorder occurring in an isolated region in Finland.

 

• It is a relatively mild form of neuronal ceroid lipofuscinosis caused by mutations in a novel gene (CLN8) on chromosome 8p23.

 

• Mutations in the same CLN8 gene may cause other more serious clinical phenotypes.

 

• Mutation analysis that identifies a mutation in both copies of a CLN8 gene is definitive for diagnosis of NCL8 type and also accurate for carrier detection and prenatal testing.

Historical note and terminology

Progressive epilepsy with mental retardation is an autosomal recessive disorder of neuronal ceroid lipofuscinosis identified by Hirvasniemi and colleagues in Northern Finland (Hirvasniemi et al 1994; Hirvasniemi et al 1995). It is now recognized as type 8 of neuronal ceroid lipofuscinosis with the responsible gene (CLN8) on chromosome 8p23 (MIM 600143) also causing other phenotypes more typical of neuronal ceroid lipofuscinosis in humans and animals.

Initially named “Northern epilepsy syndrome,” it is now more often referred to as “progressive epilepsy with mental retardation.” For new neuronal ceroid lipofuscinoses nomenclature proposals, see the University College London site (Williams and Mole 2012; Mole 2016). This takes into account recent genetic and biochemical advances. The aim is to provide young people, carers, and professionals with a diagnostic label that is informative and that leads to effective clinical management of symptoms and in the future perhaps a cure, as well as aiding basic scientific and clinical research. Clinicians should aim to provide every child and family with detailed diagnostic information at clinical, biochemical, and genetic levels where possible, which the new classification allows in a gene-led hierarchical manner.

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