A PTG Variant Contributes to a Milder Phenotype in Lafora Disease

Guerrero, Rosa; Vérnia, Santiago; Sanz, Raúl; Abreu-Rodríguez, Irene; Almaráz, Carmen; Garcia‐Hoyos, Maria; Michelucci, Roberto; Tassinari, C. A.; Riguzzi, P.; Nobile, Carlo; Sanz, Pascual; Serratosa, Joan; Gómez‐Garre, Pilar

doi:10.1371/journal.pone.0021294

Cited by 31 publications

(19 citation statements)

References 29 publications

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“…The uniformity of environmental and genetic background reinforces the idea that other genetic and/or environmental modifiers may influence the phenotypic spectrum in LD. Indeed, this has been shown within one family; an EPM2B patient harbouring a coding variant for the PPP1R3C gene, which encodes protein targeting to glycogen (PTG), exhibited a milder course of LD (Guerrero et al, 2011). The resulting conclusion from reports of both clinical homogeneity and heterogeneity in LD is that even among families, the disease course may or may not be identical and each LD patient is just as likely to have a clinically diverse, rather than classic, disease course.…”

Section: Phenotypic Hetero-and Homogeneitymentioning

confidence: 99%

Lafora disease

Turnbull¹,

Tiberia²,

Striano³

et al. 2016

Epileptic Disorders

129

165

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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: Phenotypic Hetero-and Homogeneitymentioning

confidence: 99%

Lafora disease

Turnbull¹,

Tiberia²,

Striano³

et al. 2016

Epileptic Disorders

129

165

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“…In the Epm2a −/− Ppp1r3c −/− double-knockout mice, glycogen and Lafora body abundance were dramatically decreased and the neurological defects of Epm2a −/− mice were resolved. Very recently, the presence of a genetic variant of PTG that decreased glycogen levels was associated with a slower progression of Lafora disease [288]. By epistasis, laforin is therefore upstream of PTG with regard to Lafora body formation.…”

Section: Lafora Disease and Glycogen Phosphorylationmentioning

confidence: 99%

Glycogen and its metabolism: some new developments and old themes

Roach

DePaoli‐Roach

Hurley

et al. 2012

Biochemical Journal

561

571

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Glycogen is a branched polymer of glucose that acts as a store of energy in times of nutritional sufficiency for utilization in times of need. Its metabolism has been the subject of extensive investigation and much is known about its regulation by hormones such as insulin, glucagon and adrenaline (epinephrine). There has been debate over the relative importance of allosteric compared with covalent control of the key biosynthetic enzyme, glycogen synthase, as well as the relative importance of glucose entry into cells compared with glycogen synthase regulation in determining glycogen accumulation. Significant new developments in eukaryotic glycogen metabolism over the last decade or so include: (i) three-dimensional structures of the biosynthetic enzymes glycogenin and glycogen synthase, with associated implications for mechanism and control; (ii) analyses of several genetically engineered mice with altered glycogen metabolism that shed light on the mechanism of control; (iii) greater appreciation of the spatial aspects of glycogen metabolism, including more focus on the lysosomal degradation of glycogen; and (iv) glycogen phosphorylation and advances in the study of Lafora disease, which is emerging as a glycogen storage disease.

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“…in a Turkish patient with late onset and preserved gait at 4‐year follow‐up. Gene variants of protein targeting to glycogen (PTG, a protein modulating glycogen synthesis), were believed to contribute to milder phenotype in LD …”

mentioning

confidence: 99%

Mild Lafora disease: Clinical, neurophysiologic, and genetic findings

et al. 2014

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SUMMARYWe report clinical, neurophysiologic, and genetic features of an Italian series of patients with Lafora disease (LD) to identify distinguishing features of those with a slowly progressive course. Twenty-three patients with LD (17 female; 6 male) were recruited. Mean age (AE SD) at the disease onset was 14.5 AE 3.9 years and mean followup duration was 13.2 AE 8.0 years. NHLRC1 mutations were detected in 18 patients; EPM2A mutations were identified in 5. Patients who maintained >10 years gait autonomy were labeled as "mild" and were compared with the remaining LD patients with a typical course. Six of 23 patients were mild and presented significantly delay in the age at onset, lower neurologic disability score at 4 years after the onset, less severe seizure phenotype, lower probability of showing both photoparoxysmal response on electroencephalography (EEG) and giant somatosensory evoked potentials, as compared to patients with typical LD. However, in both mild and typical LD patients, EEG showed disorganization of background activity and frequent epileptiform abnormalities. Mild LD patients had NHLRC1 mutations and five of six carried homozygous or compound heterozygous D146N mutation. This mutation was found in none of the patients with typical LD. The occurrence of specific NHLRC1 mutations in patients with mild LD should be taken into account in clinical practice for appropriate management and counseling.

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A PTG Variant Contributes to a Milder Phenotype in Lafora Disease

Cited by 31 publications

References 29 publications

Lafora disease

Lafora disease

Glycogen and its metabolism: some new developments and old themes

Mild Lafora disease: Clinical, neurophysiologic, and genetic findings

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