Lafora disease: Severe phenotype associated with homozygous deletion of the NHLRC1 gene

Kecmanović, M; Jović, N.; Cukic, Mirjana; Keckarević-Marković, Milica; Keckarević, Dušan; Stevanović, Galina; Romac, Stanka

doi:10.1016/j.jns.2012.12.006

Cited by 12 publications

(10 citation statements)

References 17 publications

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“…One patient was homozygous for the entire gene deletion because we could not amplify the whole region of the NHLRC1 gene. This conclusion was supported by the data obtained in the quantitative PCR ran on the patient's mother's sample that we published earlier .…”

Section: Resultssupporting

confidence: 85%

“…D6S1665 D6S1643 D6S1959 D6S1688 NHLRC1 D6S1567 D6S274 D6S1605 D6S289 n 214 264 193 172 108 166 135 213 2 210 264 193 172 108 166 143 223 1 224 264 197 172 108 166 143 223 1 Chromosomes carrying c.1048-1049delGA mutation 214 230 189 172 108 166 143 219 1 216 226 185 172 108 166 137 217 1 214 264 193 172 108 166 143 221 2 216 226 185 172 108 166 143 221 1 216 264 193 172 108 166 143 221 1 In four patients sequencing analysis revealed homozygous change, but one of the parents did not have the same sequence change; therefore we assumed that a deletion of the entire NHLRC1 gene happened on the other chromosome ( Figure 1). The presence of this mutation was confirmed using quantitative PCR (13). One patient was homozygous for the entire gene deletion because we could not amplify the whole region of the NHLRC1 gene.…”

Section: Resultsmentioning

confidence: 99%

“…In four patients sequencing analysis revealed homozygous change, but one of the parents did not have the same sequence change; therefore we assumed that a deletion of the entire NHLRC1 gene happened on the other chromosome (Figure ). The presence of this mutation was confirmed using quantitative PCR . One patient was homozygous for the entire gene deletion because we could not amplify the whole region of the NHLRC1 gene.…”

Section: Resultsmentioning

confidence: 99%

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Clinical and genetic data on Lafora disease patients of Serbian/Montenegrin origin

et al. 2015

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Lafora disease (LD) is an autosomal recessive, progressive disorder characterized by myoclonus and seizures, inexorable neurologic deterioration, cognitive decline and poor prognosis. LD is caused by mutations either in the EPM2A or in NHLRC1 genes. Here we report clinical and genetic findings on 14 LD patients from 10 families of Serbian/Montenegrin origin. Molecular diagnostics was performed by sequencing the coding regions of the EPM2A and NHLRC1 genes. In addition, haplotype analysis of the chromosomes carrying the two most frequent mutations (c.1048-1049delGA and deletion of the whole NHLRC1 gene) using eight different markers flanking the NHLRC1 gene was conducted. We identified one new mutation (c.1028T>C) along with the 3 previously reported mutations (c.1048-1049delGA, c.990delG, deletion of the whole NHLRC1 gene), all of which were located on the NHLRC1 gene. The two predominant mutations (c.1048-1049delGA and complete NHLRC1 gene deletion) appear to be founder mutations. In addition to documenting the genetic heterogeneity observed for LD, our study suggests that mutations in the NHLRC1 gene may be a common cause of LD in the Serbian/Montenegrin population, primarily because of a founder effect.

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Section: Resultssupporting

confidence: 85%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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Clinical and genetic data on Lafora disease patients of Serbian/Montenegrin origin

et al. 2015

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“…A Malian family with the NHLRC1 gene mutation presented with severe cognitive decline 4–5 years after the onset of disease. 25 Kecmanovi et al 26 reported a Montenegrin patient with deletion of the entire NHLRC1 gene and a clinical course more progressive than in most individuals with NHLRC1 mutations. Also, a lower quality of medical care in some of these LD cases with the faster disease progression could not be excluded.…”

Section: Are Defects In Malin and Laforin Gene Clinically Indistinguimentioning

confidence: 99%

Genetics of Lafora progressive myoclonic epilepsy: current perspectives

Kecmanović

Keckarević-Marković

Keckarević

et al. 2016

TACG

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Lafora disease (LD) is a fatal neurodegenerative disorder caused by loss-of-function mutations in either laforin glycogen phosphatase gene (EPM2A) or malin E3 ubiquitin ligase gene (NHLRC1). LD is associated with gradual accumulation of Lafora bodies (LBs). LBs are aggregates of polyglucosan, a long, linear, poorly branched, hyperphosphorylated, insoluble form of glycogen. Loss-of-function mutations either in the EPM2A or in the NHLRC1 gene lead to polyglucosan formation. One hypothesis on LB formation is based on findings that laforin–malin complex downregulates glycogen synthase (GS) through malin-mediated ubiquitination, and the other one is based on findings that laforin dephosphorylates glycogen. According to the first hypothesis, polyglucosan formation is a result of increased GS activity, and according to the second, an increased glycogen phosphate leads to glycogen conformational change, unfolding, precipitation, and conversion to polyglucosan, while GS remains bound to the precipitating glycogen. In this review, we summarize all the recent findings that have important implications for the treatment of LD, all of them showing that partial inhibition of GS activity may be sufficient to prevent the progression of the disease. The current perspective in LD is high-throughput screening for small molecules that act on the disease pathway, that is, partial inhibitors of GS, which opens a therapeutic window for potential treatment of this fatal disease.

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“…First symptoms of the disease are resistant myoclonic seizures, myoclonus, generalized or focal occipital seizures, and photosensitivity on electroencephalography (EEG) in patients with previously normal neurologic development. 1 This is followed by not only worsening of seizures but also deterioration in cognitive and neurologic functions such as dysarthria, ataxia, and dementia. After the first symptoms, most patients die within 10 years of diagnosis, because of status epilepticus or complications associated with the degeneration of the nervous system.…”

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confidence: 99%

Three Patients With Lafora Disease

et al. 2014

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Lafora disease is a rare, fatal, autosomal recessive hereditary disease characterized by epilepsy, myoclonus and progressive neurological deterioration. Diagnosis is made by polyglucosan inclusion bodies (Lafora bodies) shown in skin biopsy. Responsible mutations of Lafora disease involves either the EPM2A or NHLRC1 (EPM2B) gene. Mutations in the NHLRC1 gene are described as having a more benign clinical course and a later age of death compared with EPM2A mutations. We report 2 genetic mutations and clinical courses of Lafora disease in 3 adolescents with homozygote NHLRC1 mutation and novel homozygous EPM2A mutation.

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Lafora disease: Severe phenotype associated with homozygous deletion of the NHLRC1 gene

Cited by 12 publications

References 17 publications

Clinical and genetic data on Lafora disease patients of Serbian/Montenegrin origin

Clinical and genetic data on Lafora disease patients of Serbian/Montenegrin origin

Genetics of Lafora progressive myoclonic epilepsy: current perspectives

Three Patients With Lafora Disease

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