The Child Neurology Knowledge Environment
Information
Last updated: 20 June 2024

Progressive myoclonus epilepsy

Information
Lafora disease, Progressive Myoclonus Epilepsies, Unverricht–Lundborg Disease

Introduction

  • Progressive Myoclonus Epilepsy (PME) with onset between late childhood and late adolescence includes several conditions:
    • Neuronal ceroid lipofuscinosis
    • Type I sialidosis
    • Myoclonic epilepsy with ragged red fibers
  • Most common forms of PME in this age group:
    • Lafora disease
    • Unverricht–Lundborg disease (ULD)

Unverricht–Lundborg Disease

Clinical Characteristics and Neurophysiology

  • ULD is an autosomal recessive PME.
  • Onset: Between ages 6 and 15 years, following a period of normal development.
  • Principal characteristics:
    • Stimulus-sensitive myoclonus: Sudden, brief, shocklike muscle contractions interfering with activities like writing, swallowing, speaking, and walking. Can be precipitated by simple intention to move (Harenko 1961, Koskiniemi 1974a, Koskiniemi 1974b, Koskiniemi 1974c).
    • Tonic-clonic and myoclonic seizures: Appear early, with other types of seizures potentially presenting later.
  • Disease progression: Slow, with ataxia, action tremor, and emotional lability. Patients experience a slow decline in intelligence.
  • Influence of antiepileptic medications:
    • Phenytoin: Exquisitely neurotoxic, previously contributing to severe progressive myoclonus and cerebellar ataxia.
    • Proper management: Can avert dementia, minimize myoclonus and seizures, and maintain a normal lifespan (Lehesjoki 2002).
    • Preferred anticonvulsants: Valproic acid, zonisamide, and levetiracetam. Piracetam helps against myoclonus.
    • N-Acetylcysteine (NAC): Improves tremor, gait, and myoclonus in some patients. Mechanism of action is poorly understood, possibly related to protection against oxidative stress and antiapoptotic effects in neurons deprived of nerve growth factor (Ferrari 1995, Hurd 1996).
  • Electroencephalographic (EEG) recordings: Abnormal even before symptom onset (Koskiniemi 1974).
    • Features: Disorganized and slow background activity, fast spike-waves or polyspike-waves with larger amplitudes in central regions, prominent photosensitivity.
    • Frequency of EEG paroxysms diminishes with rational antiepileptic treatment (Lehesjoki 1999).
    • Stimulus-sensitive myoclonus: Lacks a visible EEG correlate but shows time-locked cortical spikes preceding the myoclonic jerks in back-averaging analysis (Shibasaki 2000).
    • Giant somatosensory evoked potentials (SEPs) and enhanced long-loop (cortical) reflex (LLR) indicate cortical hyperexcitability in ULD myoclonus (Lehesjoki 1999).

EPM1, the ULD Gene

  • Identification: Using positional cloning. A genome-wide search in 12 families localized the gene to 21q22.3 (Shibasaki 2000).
  • Gene: Cystatin B (CSTB), previously known but unmapped. Identified through linkage disequilibrium analysis and systematic gene search.
  • Mutations:
    • Six different mutations identified in the coding region.
    • Three affect conserved splice-site sequences, predicting severe splicing defects (1926-1G→C, 2027G→A, 2355-2A→G).
    • Two mutations in exon 3 (R68X nonsense codon, 2400 delTC frameshift) predict truncated protein.
    • Transversion in exon 1 results in substitution of glycine by arginine at amino acid position 4 (G4R) (Pennacchio 1996, Lalioti 1997, Virtaneva 1997).
  • Additional findings:
    • Only 10% of EPM1 alleles contain mutations within the transcriptional unit.
    • Abnormally large EPM1-containing fragments in ULD patients due to a dodecamer repeat expansion upstream from the translation initiation codon.
    • Normal alleles: Two to three tandem copies of the dodecamer (rarely 12–17 repeats).
    • ULD patients: 30 to 150 copies, leading to reduced expression of EPM1 mRNA (Virtaneva 1997, Lafreniere 1997, Lalioti 1997, Lalioti 1997b, Virtaneva 1998).
    • Preliminary analysis: No correlation between the number of repeats and clinical severity or age of onset.

Cystatin B and the Cystatin B-Deficient Mouse

  • Cystatin superfamily: Encompasses proteins with multiple cystatin-like sequences, some of which are active cysteine protease inhibitors.
  • CSTB: A stefin functioning as an intracellular protease inhibitor, inhibiting papain and cathepsins B, H, L, and S in vitro (Ritonja 1985).
  • Histopathological studies in ULD patients:
    • Findings: Cerebellar granular and Purkinje cell loss, gliosis, neuronal degeneration in various brain regions (Koskiniemi 1974b, Haltia 1969, Eldridge 1983).
    • Genetic mutation or phenytoin neurotoxicity: Resolved by studying EPM1 knockout mice not treated with phenytoin (Pennacchio 1998).
    • Findings in mice: Myoclonic seizures, ataxia, apoptosis of cerebellar granular and Purkinje cells, cortical and striatal gliosis, and atrophy of cortical neurons (Shannon 2002).
  • Additional studies:
    • Differential display oligonucleotide microarray hybridization and quantitative reverse transcriptase polymerase chain reaction: Elevated cathepsin S levels, suggesting its role in apoptosis initiation in ULD (Lieuallen 2001).
    • Elevated mRNA levels of β2-microglobulin, apolipoprotein D, fibronectin 1, Gfap, and C1qB in CSTB-deficient mice, indicating glial activation (Lieuallen 2001).
  • Neuroprotective role of CSTB:
    • Endogenous neuroprotective mechanism: Elevation of EPM1 mRNA and CSTB levels in response to seizures induced by kindling brain stimulation (D'Amato 2000).
  • Research challenges:
    • Determining the pathophysiologically relevant function of CSTB and identifying any alternate functions.
    • Lack of genetic heterogeneity in ULD hinders the genetic unraveling of a second pathway intersecting with the CSTB pathway.

Lafora Disease

Clinical Characteristics

  • LD: Autosomal recessive PME.
  • Onset: Between ages 9 and 18 years, following a period of normal development (Minassian 2002).
    • Retrospective family observations: Some “slowness” in childhood compared to unaffected children.
    • Subphenotype: Learning disabilities in childhood associated with particular mutations (Ganesh 2002).
    • Febrile and rare afebrile seizures: More common in LD than in the general population (Minassian 2002).
  • Symptoms bringing clinical attention:
    • Myoclonic jerks
    • Generalized seizure
    • Decline in school performance
    • Behavioral changes (depression, apathy, disinhibition, delusions)
    • Visual (occipital ictal) hallucinations
  • EEG findings: Slowing of background with irregular spike-wave discharges.
  • Disease acceleration: Worsening of all manifestations, additional seizure types, and cognitive and behavioral decline within 2 years of diagnosis.
    • Myoclonus: Frequent during wakeful hours, especially in the early morning, ceases with sleep. Affects walking, leading to wheelchair dependence.
    • Stimulus-sensitive myoclonus: Provoked by movement, intention, light changes, and exacerbated by emotion.
    • Cognitive decline, emotional lability, visual hallucinations, delusions, disinhibited behavior, and social rejection.
    • Within 5 to 10 years: Bed bound, usually tube fed, almost constant myoclonus and ictal confusion.
  • Antiepileptic treatment:
    • Traditional: Valproic acid.
    • Recent: Zonisamide shown to have a significant effect on seizures and myoclonus, becoming the first-line choice (Yoshimura 2001, Kyllerman 1998).
    • Temporary help: Piracetam and levetiracetam against myoclonus (Boccella 2003).
    • Ketogenic diet: Important therapeutic modality, showing potential to slow disease progression by reducing carbohydrate intake.

Neurophysiology

  • EEG:
    • Slow background activity with dominant theta-delta components interrupted by recurrent posterior or diffuse multiple spikes discharges (Tassinari 1978).
    • Prominent generalized or segmental spontaneous myoclonus with clear EEG paroxysms.
    • Negative myoclonus associated with polyspike-wave discharges (Shibasaki 2002).
  • Somatosensory evoked potentials (SEPs):
    • Large amplitude cortical SEPs indicate aberrant integration of somatosensory stimuli involving motor cortex.
    • Somatosensory afferent stimuli abnormally facilitating motor cortex excitability in PME (Reutens 1993, Manganotti 2001).
  • Spectral analyses:
    • Beta-gamma oscillations between motor cortex and muscle during movement-activated myoclonic discharges.
    • Pathologically exaggerated fast rhythms likely drive the generation of cortical myoclonus (Brown 1999, Panzica 2003).

Pathology

  • Lafora bodies (LB):
    • Present in the brain and almost every other organ, particularly liver and muscle.laforabodyLafora body

       

    • Largely found in neurons, localizing in the perikaryal region and dendrites.
    • Stain strongly with periodic acid–Schiff, composed of polyglucosan (Sakai 1970).
    • Unlike glycogen, polyglucosans lack a regular branching pattern and resemble starch more closely.
    • Newly forming polyglucosan fibrils physically associated with the endoplasmic reticulum (ER) or ribosomes (Collins 1968, Toga 1968).

Genetics of Lafora Disease

  • EPM2A gene:
    • Identified using positional cloning on chromosome 6q24 (Minassian 1998).
    • Encodes laforin, a protein with two isoforms: A (ER localization) and B (nucleus localization) (Ganesh 2002).
    • A total of 36 or more mutations identified, accounting for ~48% of LD cases (Minassian 1998, Ganesh 2002).
  • EPM2B gene:
    • Genetic locus heterogeneity demonstrated, leading to the identification of EPM2B on 6p22.3 in a French-Canadian isolate (Chan 2003).
    • Encodes malin, a protein with a RING finger motif and six NHL-repeat motifs (Chan 2003).
    • Malin acts as an E3 ubiquitin ligase, targeting specific substrates for degradation.
  • Further genetic heterogeneity:
    • 88% of LD families accounted for by mutations in EPM2A (48%) and EPM2B (40%) (Chan 2003).
    • Third genome-wide linkage scan underway to identify additional LD genes.

Laforin Protein–Protein Interactors

  • Three candidate protein partners identified using yeast two-hybrid experiments:
    • EPM2AIP1: Interacts with intact laforin, localizes to the ER (Ianzano 2003).
    • HIRIP5: Contains NifU-like and MurD ligase domains, potential substrate for laforin (Ganesh 2003).
    • R5: Involved in glycogen metabolism, interacts with laforin in the same region as enzymes regulated by protein phosphatase (PP1) (Fernandez-Sanchez 2003).

Epm2a Knockout Mouse Model

  • Generated to study LD:
    • Prominent periodic acid–Schiff (PAS)-positive inclusions in neurons starting at 2 months of age.
    • Neurodegeneration and presence of LB predating any phenotypical anomalies.
    • Behavioral impairments, myoclonic seizures, ataxia, and EEG epileptiform activity observed later (Ganesh 2002).

Pathogenesis of Lafora Disease

  • LB composition: Polyglucosans with irregular branching, likely due to defects in glycogen metabolism enzymes.
  • Comparison with other conditions:
    • Andersen disease (glycogen storage disease type IV) and adult polyglucosan body disease (APBD) involve polyglucosans but differ in clinical presentation and intracellular compartment localization (Raben 2001, Pederson 2003, Robitaille 1980).
  • Neuronal degeneration: Linked to the presence of polyglucosans in dendrites and perikaryal regions, affecting neuronal signaling and causing hyperexcitability.
  • EPM2B-encoded malin: Likely an E3 ubiquitin ligase, targeting specific substrates for degradation (Hatakeyama 2003).

Key Research Goals

  • Identification of additional LD genes.
  • Understanding the polyglucosan biochemical pathway.
  • Exploring the dendritic compartmentalization of LB.
  • Examining the independence of neurodegeneration from LB accumulation.
  • Determining the roles of neurodegeneration and LB in the epilepsy of LD.



References 

 

Key source:

Delgado-Escueta, A. V., Guerrini, R., Medina, M. T., Genton, P., Bureau, M., Dravet, C., Perez-Gosiengfiao, K. T., Martinez-Juarez, I. E., & Duron, R. M. (Eds.). (2004). Myoclonic Epilepsies: Advances in Neurology (1st ed.). Lippincott Williams & Wilkins.

Related Articles

Lafora disease
2024-06-01 08:34:20

Details
Hits: 181

Text is available under the Cc by nc sa iconCC Attribution-Noncommercial-Share Alike 4.0 International; additional terms may apply. 

Recent Articles

Similar Items