Myoclonus epilepsy with ragged-red fibers
Jun. 10, 2021
At vero eos et accusamus et iusto odio dignissimos ducimus qui blanditiis praesentium voluptatum deleniti atque corrupti quos dolores et quas.
This article includes discussion of epilepsy with progressive 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.
Epilepsy with progressive mental retardation (Northern epilepsy syndrome) is a subtype 8 of neuronal ceroid lipofuscinosis (CLN8 disease) described in families in northern Finland. It is an autosomal recessive disease characterized by generalized tonic-clonic seizures that first appear between five and 10 years of age, followed by 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 ataxia also appear. One third of patients suffer from diminished visual acuity without ocular abnormality. Mutations of the responsible CLN8 gene on chromosome 8p23.3 (encoding an endoplasmic reticulum transmembrane protein of unknown function), also cause other more severe phenotypes of neuronal ceroid lipofuscinosis in humans (late infantile variant) and animals. In this update, the author details developments in molecular genetics and modern diagnostic procedures for the identification of this mild and protracted form of neuronal ceroid lipofuscinosis.
• Epilepsy with progressive 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 of the CLN8 gene on chromosome 8p23.3.
• Mutations in the same CLN8 gene may cause other more serious clinical phenotypes of late infantile variant.
• Mutation analysis that identifies a mutation in both copies of a CLN8 gene is definitive for diagnosis of CLN8 disease and also accurate for carrier detection and prenatal testing.
Epilepsy with progressive mental retardation was first described as “Northern epilepsy” by Hirvasniemi and colleagues (10; 08). The authors identified 23 patients (11 males and 12 females) belonging to 11 families from northern Finland. A common ancestor has been found for nine families. The mean age of onset of epilepsy was 6.7 years (range 5-10 years) and the epilepsy was characterized by generalized tonic-clonic seizures increasing in frequency up to puberty. One third of the patients also had complex focal seizures during childhood. During young adulthood the epileptic seizures began to decrease, but complete remission did not occur. Electroencephalography showed progressive slowing of the background activity with relatively scanty epileptiform activity. Out of four ictal recordings the paroxysmal activity was initiated focally in two cases. Mental development, which was originally normal, began to deteriorate two to five years after the onset of epilepsy, and the deterioration continued during adulthood in spite of good epilepsy control, leading to mental retardation by middle age (10; 08).
A mutation responsible for the disease has been identified in a novel gene (CLN8) on chromosome 8p23.3 (33; 26; 25; 28; 24; 29). Haltia and colleagues and Herva and associates recognized Northern epilepsy as a subtype of neuronal ceroid lipofuscinosis (05; 07). Herva and associates reported neuropathologic findings of three patients with Northern epilepsy (07). There was intraneuronal accumulation of cytoplasmic autofluorescent granules that were immunoreactive to subunit C of mitochondrial ATP synthase. Membrane-bound storage cytosomes showed a curvilinear ultrastructure with admixture of some granular components. The findings confirmed Northern epilepsy as a form of neuronal ceroid lipofuscinosis with an exceptionally protracted course. Mutations of the same gene are known to cause other very severe phenotypes of neuronal ceroid lipofuscinosis in humans (late infantile variant) and animals (17).
Initially named “Northern epilepsy syndrome,” it is now more often referred to as “epilepsy with progressive mental retardation.” According to the new neuronal ceroid lipofuscinoses nomenclature proposals:
Epilepsy with progressive mental retardation (EPMR)
Short form: CLN8 disease, EPMR (alternatively: EPMR CLN8 disease)
Axis 1 (affected gene):CLN8
Axis 2 (mutation diagnosis): p.[Arg24Gly]+[Arg24Gly]
Axis 4 (clinical phenotype); EPMR
For new neuronal ceroid lipofuscinoses nomenclature proposals, see the University College London site (36; 17). This new nomenclature 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.
Nearly 3,000 illustrations, including video clips of neurologic disorders.
Every article is reviewed by our esteemed Editorial Board for accuracy and currency.
Full spectrum of neurology in 1,200 comprehensive articles.