Post‐modern therapeutic approaches for progressive myoclonus epilepsy

Minassian, Berge A.

doi:10.1684/epd.2016.0862

Cited by 8 publications

(9 citation statements)

References 13 publications

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“…In this article, new therapeutic proposals are not discussed since these are covered in detail in the last article (Minassian, ). We shall focus on the medical and social measures that are available for the care of present‐day LD patients ( figure ).…”

Section: Disease Management and Therapymentioning

confidence: 99%

Lafora disease

Turnbull¹,

Tiberia²,

Striano³

et al. 2016

Epileptic Disorders

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Lafora disease (LD) is an autosomal recessive progressive myoclonus epilepsy due to mutations in the EPM2A (laforin) and EPM2B (malin) genes, with no substantial genotype‐phenotype differences between the two. Founder effects and recurrent mutations are common, and mostly isolated to specific ethnic groups and/or geographical locations. Pathologically, LD is characterized by distinctive polyglucosans, which are formations of abnormal glycogen. Polyglucosans, or Lafora bodies (LB) are typically found in the brain, periportal hepatocytes of the liver, skeletal and cardiac myocytes, and in the eccrine duct and apocrine myoepithelial cells of sweat glands. Mouse models of the disease and other naturally occurring animal models have similar pathology and phenotype. Hypotheses of LB formation remain controversial, with compelling evidence and caveats for each hypothesis. However, it is clear that the laforin and malin functions regulating glycogen structure are key. With the exception of a few missense mutations LD is clinically homogeneous, with onset in adolescence. Symptoms begin with seizures, and neurological decline follows soon after. The disease course is progressive and fatal, with death occurring within 10 years of onset. Antiepileptic drugs are mostly non‐effective, with none having a major influence on the progression of cognitive and behavioral symptoms. Diagnosis and genetic counseling are important aspects of LD, and social support is essential in disease management. Future therapeutics for LD will revolve around the pathogenesics of the disease. Currently, efforts at identifying compounds or approaches to reduce brain glycogen synthesis appear to be highly promising.

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Section: Disease Management and Therapymentioning

confidence: 99%

Lafora disease

Turnbull¹,

Tiberia²,

Striano³

et al. 2016

Epileptic Disorders

Self Cite

128

165

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“…Today we are step away from the curative therapy. Researchers are screening for small molecule inhibitors of glycogen synthase, they are using antisense oligonucleotides and Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) technics, developing gene and protein therapy 24,25 .…”

Section: Discussionmentioning

confidence: 99%

Is adjunctive perampanel beneficial for lafora disease?

Stevanović¹,

Jović²,

Kecmanović

2020

VOJNOSANIT PREGL

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Backgrund/Aim. Lafora disease (LD) is progressive myoclonus epilepsy, characterized by intractable myoclonus and seizures, inevitable neurological deterioration, brutal cognitive decline and poor prognosis. The treatment still remains purely symptomatic. Recently, two single-case studies and one case series study reported the favourable effects of perampanel in LD. Our study aimed to test the benefits reported in three separate case studies. Methods. We performed an open label, prospective study of 4 patients aged between 22 and 34 years with mutation in NHLRC1 (EPM2B) gene, treated with perampanel (6-8 mg/day) as add-on therapy. Follow-up period comprised 14-26 months. Seizure frequency, myoclonus, functional disability and cognitive performance were analysed. Results. In 3 patients, both, seizures and myoclonus, showed remarkable improvement after the drug introduction (> 50% reduction). No significant effect was seen in one case. The functional and cognitive impairment maintained at the same level, though all patients were at the later stage of the disease. Psychiatric side effects were dose related. Conclusion. Our study supports the rare, previously reported observations that perampanel is beneficial in treating LD patients. ApstraktUvod/Cilj. Laforina bolest (LB) je progresivna mioklonička epilepsija koja se odlikuje tvrdokornim mioklonusom i napadima, neumoljivim neurološkim i brutalnim kognitivnim propadanjem i lošom prognozom. Terapija je, za sada, isključivo simptomska. Nedavno su dve studije pojedinačnih slučajeva i jedna sa prikazom serije bolesnika pokazale povoljan efekat perampanela na LB. Cilj rada je bio da se istraži povoljan uticaj primene perampanela u terapiji LB, kako je to prikazano u malom broju studija u dostupnoj literaturi. Metode. Sprovedena je otvorena, prospektivna studija na 4 bolesnika, uzrasta 22-34 godine, sa mutacijom u NHLRC1 (EPM2B) genu, koji su lečeni perampanelom 6-8 mg/dnevno, kao dodatnom terapijom. Period praćenja je bio 14-26 meseci. Procenjivani su učestalost napada, mioklonus, funkcionalna onesposobljenost i kognitivno funkcionisanje. Rezultati. Nakon uvođenja terapije postignuta je značajno bolja kontrola napada i došlo je do smanjenja (> 50%) mioklonusa kod 3 bolesnika. Kod jednog bolesnika nije zapažen povoljan terapijski odgovor. Funkcionalno i kognitivno poboljšanje nije uočeno, iako su svi bolesnici bili u kasnijim stadijumima bolesti. Psihijatrijska neželjena dejstva su bila dozno zavisna. Zaključak. Našom studijom podržana su retka iskustva da je perampanel koristan u lečenju bolesnika sa LB.Ključne reči: laforina bolest; dijagnoza; antiepileptici; perampanel; lečenje, ishod.

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“…In fact, downregulating glycogen synthesis would seem to be a good solution for all glycogenoses, regardless of their different mechanisms and clinical prognoses. Recent publications have supported the validity of this approach (1,6,7). However, the absence of glycogen inflicts a large burden on the energy need of a newborn.…”

Section: (Gyg Deficiency)mentioning

confidence: 96%

“…Glycogen is a branched polysaccharide with a molecular weight of nine to ten million Daltons. The average glycogen molecule contains about 55,000 glucosyl residues linked by α-1,4 (92%) and α-1,6 (8%) glycosidic bonds (1). Glycogen synthesis is catalyzed by the actions of 3 enzymes: (a) glycogenin (GYG), the initiating enzyme that starts a primer of glucose chain attached to itself; (b) glycogen synthase (GYS), which strings glucose to extend linear chains; and (c) glycogen-branching enzyme (GBE), which attaches a short new branch to a linear chain.…”

Section: Introductionmentioning

confidence: 99%

Guaiacol as a drug candidate for treating adult polyglucosan body disease

et al. 2018

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Adult polyglucosan body disease (APBD) is a late-onset disease caused by intracellular accumulation of polyglucosan bodies, formed due to glycogen-branching enzyme (GBE) deficiency. To find a treatment for APBD, we screened 1,700 FDA-approved compounds in fibroblasts derived from APBD-modeling GBE1-knockin mice. Capitalizing on fluorescent periodic acid-Schiff reagent, which interacts with polyglucosans in the cell, this screen discovered that the flavoring agent guaiacol can lower polyglucosans, a result also confirmed in APBD patient fibroblasts. Biochemical assays showed that guaiacol lowers basal and glucose 6-phosphate-stimulated glycogen synthase (GYS) activity. Guaiacol also increased inactivating GYS1 phosphorylation and phosphorylation of the master activator of catabolism, AMP-dependent protein kinase. Guaiacol treatment in the APBD mouse model rescued grip strength and shorter lifespan. These treatments had no adverse effects except making the mice slightly hyperglycemic, possibly due to the reduced liver glycogen levels. In addition, treatment corrected penile prolapse in aged GBE1-knockin mice. Guaiacol's curative effects can be explained by its reduction of polyglucosans in peripheral nerve, liver, and heart, despite a short half-life of up to 60 minutes in most tissues. Our results form the basis to use guaiacol as a treatment and prepare for the clinical trials in APBD.

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Post‐modern therapeutic approaches for progressive myoclonus epilepsy

Cited by 8 publications

References 13 publications

Lafora disease

Lafora disease

Is adjunctive perampanel beneficial for lafora disease?

Guaiacol as a drug candidate for treating adult polyglucosan body disease

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