Unverricht–Lundborg disease: Homozygosity for a new splicing mutation in the cystatin B gene

Pinto, Eugénia; Freitas, Joel; Duarte, Ana Patrícia; Ribeiro, Isaura; Ribeiro, Diogo; Lima, José Lopes; Chaves, João; Amaral, Olga

doi:10.1016/j.eplepsyres.2011.11.004

Cited by 11 publications

(12 citation statements)

References 13 publications

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“…One heterozygous patient (Patient 5) carrying the c.133C>T mutation, presented with repeated convulsive seizures resistant to rational pharmacologic treatment at disease onset, but had a milder phenotype than the other patients did. This agrees with observations of another patient (Pinto et al, 2012) with a homozygous point mutation in exon1 (c.66G>A; p.Q22Q) that possibly alters a splicing site, who presented with a picture mimicking photosensitive idiopathic epilepsy. Our findings further indicate that disease presentation in heterozygous patients, may extend to phenotypes mimicking resistant idiopathic epilepsy at onset, although generally associated with a more severe course.…”

Section: Discussionsupporting

confidence: 90%

Electroclinical presentation and genotype–phenotype relationships in patients with Unverricht‐Lundborg disease carrying compound heterozygous CSTB point and indel mutations

et al. 2012

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SUMMARYPurpose: Unverricht-Lundborg disease (EPM1A) is frequently due to an unstable expansion of a dodecamer repeat in the CSTB gene, whereas other types of mutations are rare. EPM1A due to homozygous expansion has a rather stereotyped presentation with prominent action myoclonus. We describe eight patients with five different compound heterozygous CSTB point or indel mutations in order to highlight their particular phenotypical presentations and evaluate their genotype-phenotype relationships. Methods: We screened CSTB mutations by means of Southern blotting and the sequencing of the genomic DNA of each proband. CSTB messenger RNA (mRNA) aberrations were characterized by sequencing the complementary DNA (cDNA) of lymphoblastoid cells, and assessing the protein concentrations in the lymphoblasts. The patient evaluations included the use of a simplified myoclonus severity rating scale, multiple neurophysiologic tests, and electroencephalography (EEG)-polygraphic recordings. To highlight the particular clinical features and disease time-course in compound heterozygous patients, we compared some of their characteristics with those observed in a series of 40 patients carrying the common homozygous expansion mutation observed at the C.

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Section: Discussionsupporting

confidence: 90%

Electroclinical presentation and genotype–phenotype relationships in patients with Unverricht‐Lundborg disease carrying compound heterozygous CSTB point and indel mutations

et al. 2012

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“…EPM1 is characterized by onset at age of 6–16 years and the symptoms include stimulus-sensitive myoclonus, tonic-clonic epileptic seizures and ataxia [1]. EPM1 is most commonly caused by a homozygous dodecamer repeat expansion mutation in the promoter region of the cystatin B ( CSTB ) gene, although thirteen other disease-causing mutations in CSTB are currently known [2]–[5]. The causative mutations lead to reduced expression of the cystatin B (CSTB) protein [6], [7] that is a ubiquitously expressed inhibitor of lysosomal cysteine cathepsins B, H, K, L, and S. Despite the fact that the causative gene mutations for EPM1 are known, the underlying mechanisms leading to the characteristic symptoms of the disease remain elusive.…”

Section: Introductionmentioning

confidence: 99%

Progressive Volume Loss and White Matter Degeneration in Cstb-Deficient Mice: A Diffusion Tensor and Longitudinal Volumetry MRI Study

et al. 2014

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Unverricht-Lundborg type progressive myoclonus epilepsy (EPM1, OMIM 254800) is an autosomal recessive disorder characterized by onset at the age of 6 to 16 years, incapacitating stimulus-sensitive myoclonus and tonic-clonic epileptic seizures. It is caused by mutations in the gene encoding cystatin B. Previously, widespread white matter changes and atrophy has been detected both in adult EPM1 patients and in 6-month-old cystatin B–deficient mice, a mouse model for the EPM1 disease. In order to elucidate the spatiotemporal dynamics of the brain atrophy and white matter changes in EPM1, we conducted longitudinal in vivo magnetic resonance imaging and ex vivo diffusion tensor imaging accompanied with tract-based spatial statistics analysis to compare volumetric changes and fractional anisotropy in the brains of 1 to 6 months of age cystatin B–deficient and control mice. The results reveal progressive but non-uniform volume loss of the cystatin B–deficient mouse brains, indicating that different neuronal populations possess distinct sensitivity to the damage caused by cystatin B deficiency. The diffusion tensor imaging data reveal early and progressive white matter alterations in cystatin B–deficient mice affecting all major tracts. The results also indicate that the white matter damage in the cystatin B–deficient brain is most likely secondary to glial activation and neurodegenerative events rather than a primary result of CSTB deficiency. The data also show that diffusion tensor imaging combined with TBSS analysis provides a feasible approach not only to follow white matter damage in neurodegenerative mouse models but also to detect fractional anisotropy changes related to normal white matter maturation and reorganisation.

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“…Dermal fibroblasts were also obtained from a normal control. Fibroblasts were cultured and expanded and the genotype was confirmed as described elsewhere [4] .…”

Section: Methodsmentioning

confidence: 99%

“…Clinically, ULD is characterized by myoclonus action, tonic–clonic seizures and an onset at age 6–15 with gradual worsening. Cystatin B (CSTB; ID: 1476) gene mutations cause ULD [2] , and CSTB lesions often lead to abnormal RNA processing [3] , [4] . The CSTB gene is located on the region 21q22.3 and encodes a protein from the cystatin superfamily.…”

Section: Introductionmentioning

confidence: 99%

“…In Portugal the cases identified are extremely rare and the finding of a distinct patient led to the need to expand the molecular and cellular characterization in order to provide the means to improve methods, procedures and possible treatments. The patient had a late onset and presented a slow progressive form [4] in addition to homozygosity for a rare mutation. Since no consanguinity was acknowledged, a situation of underdiagnosis and increased risk for that particular mutation was envisaged.…”

Section: Introductionmentioning

confidence: 99%

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Characterization of a rare Unverricht–Lundborg disease mutation

Duarte

Ribeiro

Chaves

et al. 2015

Molecular Genetics and Metabolism Reports

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Cystatin B (CSTB) gene mutations cause Unverricht–Lundborg disease (ULD), a rare form of myoclonic epilepsy. The previous identification of a Portuguese patient, homozygous for a unique splicing defect (c.66G > A; p.Q22Q), provided awareness regarding the existence of variant forms of ULD. In this work we aimed at the characterization of this mutation at the population level and at the cellular level. The cellular fractionation studies here carried out showed mislocalization of the protein and add to the knowledge on this disease.

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Unverricht–Lundborg disease: Homozygosity for a new splicing mutation in the cystatin B gene

Cited by 11 publications

References 13 publications

Electroclinical presentation and genotype–phenotype relationships in patients with Unverricht‐Lundborg disease carrying compound heterozygous CSTB point and indel mutations

Electroclinical presentation and genotype–phenotype relationships in patients with Unverricht‐Lundborg disease carrying compound heterozygous CSTB point and indel mutations

Progressive Volume Loss and White Matter Degeneration in Cstb-Deficient Mice: A Diffusion Tensor and Longitudinal Volumetry MRI Study

Characterization of a rare Unverricht–Lundborg disease mutation

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