CLN2/TPP1 deficiency: The novel mutation IVS7-10A&gt;G causes intron retention and is associated with a mild disease phenotype

Bessa, Carlos; Teixeira, Carla; Dias, Ana Cristi Basile; Alves, Marta; Rocha, Silvia Faria da; Lacerda, Lúcia; Loureiro, Lívia O.; Guimarães, António; Ribeiro, Maria Gil

doi:10.1016/j.ymgme.2007.08.124

Cited by 31 publications

(24 citation statements)

References 30 publications

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“…Table 1 lists the mutations found in this South American cohort, including those published in earlier works by our group (Kohan et al, 2008; Kohan et al, 2009) or other authors (Sleat et al, 1999; Bessa et al, 2008; Kousi et al, 2012). We have added to the mutational spectrum those of 18 additional subjects, identifying four novel mutations.…”

Section: Discussionmentioning

confidence: 99%

“…The presence of novel splice sites that compete with the wild-type sites would allow the alternative existence of normal and mutated mRNAs, which may in turn be related to some residual enzyme activity that ameliorates the pathological phenotype. In fact, the I7 c.887-10A>G mutation was extensively studied byBessa et al (2008). They found this intronic mutation in homozygous condition in one Portuguese patient exhibiting a protracted phenotype and residual TPP1 activity.…”

Section: Discussionmentioning

confidence: 99%

“…Pathologic material has been characterized in the literature by lysosomal deposits with mainly CB morphology (Wisniewski et al, 1999). Variant forms with a later onset or protracted disease course have been reported worldwide in a small number of patients (Hartikainen et al, 1999; Wisniewski et al, 1999; Zhong et al, 2000; Steinfeld et al, 2002; Bessa et al, 2008; Elleder et al, 2008). In most cases, the phenotype of these individuals resembled juvenile forms (J-NCL) and the patients were usually compound heterozygotes (Mole et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

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Neuronal ceroid lipofuscinosis type CLN2: A new rationale for the construction of phenotypic subgroups based on a survey of 25 cases in South America

Kohan

Carabelos

Xin

et al. 2013

Gene

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Tripeptidyl-peptidase 1 (TPP1) null or residual activity occurs in neuronal ceroid lipofuscinosis (NCL) with underlying TPP1/CLN2 mutations. A survey of 25 South American CLN2 affected individuals enabled the differentiation of two phenotypes: classical late-infantile and variant juvenile, each in approximately 50% of patients, with residual TPP1 activity occurring in approximately 32%. Each individual was assigned to one of three subgroups: (I) n=11, null TPP1 activity in leukocytes; (II) n=8, residual TPP1 activity of 0.60–15.85 nmol/h/mg (nr 110–476); (III) n=6, activity not measured in leukocytes. Curvilinear bodies (CB) appeared in almost all studied CLN2 subjects; the only exceptions occurred in cases of subgroup II: two individuals had combined CBs/fingerprints (FPs), and one case had pure FPs. There were 15 mutations (4 first published in this paper, 3 previously observed in South America by our group, and 8 previously observed by others). In subgroup I, mutations were either missense or nonsense; in subgroups II and III, mutations prevailed at the non-conserved intronic site, c.887-10A>G (intron 7), and to a lesser extent at c.89+5G>C (intron 2), in heterozygous combinations. Grouping phenotypically and genetically known individuals on the basis of TPP1 activity supported the concept that residual enzyme activity underlies a protracted disease course. The prevalence of intronic mutations at nonconserved sites in subgroup II individuals indicates that some alternative splicing might allow some residual TPP1 activity.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Neuronal ceroid lipofuscinosis type CLN2: A new rationale for the construction of phenotypic subgroups based on a survey of 25 cases in South America

Kohan

Carabelos

Xin

et al. 2013

Gene

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“…4 Nonclassic presentations (ie, juvenile, adult, or infantile onset) exist as well. 3,[5][6][7][8] On conventional MR imaging, a marked supratentorial and infratentorial atrophy with ventriculomegaly is the typical finding. In addition, a progressive-but-mild increase of WM signal intensity on T2WI and increased ADC values are observed.…”

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confidence: 99%

Volumetric Description of Brain Atrophy in Neuronal Ceroid Lipofuscinosis 2: Supratentorial Gray Matter Shows Uniform Disease Progression

Löbel¹,

Sedlacik²,

Nickel³

et al. 2016

AJNR Am J Neuroradiol

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BACKGROUND AND PURPOSE:Experimental therapies for ceroid lipofuscinosis, neuronal, 2 (CLN2), a genetic disorder of childhood associated with progressive brain atrophy, are currently being developed. Because quantitative descriptions of the natural course of brain volume loss are needed to evaluate novel therapies, we performed MR imaging volumetry of patients with CLN2 to identify a suitable MR imaging marker of disease progression.

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“…It is now recognized that mutations in all genes are distributed across many countries, albeit with higher incidence in some ethnic groups due to founder effects. Among the many recognized variants of NCL human forms (recent reviews in [3,6,11]), eight causal genes have been identified: CLN10/CTSD [12][13][14], CLN1/PPT1 [3,6,[15][16][17][18], CLN2/TPP1 [6,[18][19][20][21], CLN3 [22][23][24][25], CLN5 [26][27][28][29][30], CLN6 [31][32][33][34], CLN7/ MFSD8 [35][36][37][38][39], CLN8 [40][41][42]. The genes CLCN6 [43], and CLCN7 [44], and possibly SGSH [45], may also contribute to rare forms of NCL.…”

Section: Introductionmentioning

confidence: 99%

Therapeutic Approaches to the Challenge of Neuronal Ceroid Lipofuscinoses

Kohan¹,

Cismondi²,

Oller-Ramírez³

et al. 2011

CPB

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The Neuronal Ceroid Lipofuscinoses (NCLs) are lysosomal storage diseases (LSDs) affecting the central nervous system (CNS), with generally with recessive inheritance. They are characterized by pathological lipofuscin-like material accumulating in cells. The clinical phenotypes at all onset ages show progressive loss of vision, decreasing cognitive and motor skills, epileptic seizures and premature death, with dementia without visual loss prominent in the rarer adult forms. Eight causal genes, CLN10/CTSD, CLN1/PPT1, CLN2/TPP1, CLN3, CLN5, CLN6, CLN7/MFSD8, CLN8, with more than 269 mutations and 49 polymorphisms (http://www.ucl.ac.uk/ncl) have been described. Other NCL genes are hypothesized, including CLN4 and CLN9; CLCN6, CLCN7 and possibly SGSH are under study. Some therapeutic strategies applied to other LSDs with significant systemic involvement would not be effective in NCLs due to the necessity of passing the blood brain barrier to prevent the neurodegeneration, repair or restore the CNS functionality. There are therapies for the NCLs currently at preclinical stages and under phase 1 trials to establish safety in affected children. These approaches involve enzyme replacement, gene therapy, neural stem cell replacement, immune therapy and other pharmacological approaches. In the next decade, progress in the understanding of the natural history and the biochemical and molecular cascade of events relevant to the pathogenesis of these diseases in humans and animal models will be required to achieve significant therapeutic advances.

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CLN2/TPP1 deficiency: The novel mutation IVS7-10A>G causes intron retention and is associated with a mild disease phenotype

Cited by 31 publications

References 30 publications

Neuronal ceroid lipofuscinosis type CLN2: A new rationale for the construction of phenotypic subgroups based on a survey of 25 cases in South America

Neuronal ceroid lipofuscinosis type CLN2: A new rationale for the construction of phenotypic subgroups based on a survey of 25 cases in South America

Volumetric Description of Brain Atrophy in Neuronal Ceroid Lipofuscinosis 2: Supratentorial Gray Matter Shows Uniform Disease Progression

Therapeutic Approaches to the Challenge of Neuronal Ceroid Lipofuscinoses

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