A monozygotic twin pair with highly discordant Gaucher phenotypes

Biegstraaten, Marieke; Schaik, Ivo N. van; Aerts, Johannes M. F. G.; Langeveld, Mirjam; Mannens, Marcel M.A.M.; Bour, L.J.; Sidransky, Ellen; Tayebi, Nahid; Fitzgibbon, E. J.; Hollak, Carla E. M.

doi:10.1016/j.bcmd.2010.10.007

Cited by 59 publications

(42 citation statements)

References 9 publications

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“…Although the vast majority of such monozygotic twin pairs have been found to be concordant in terms of their clinical phenotypes (e.g. Miesfeldt et al 1998; Munhoz et al 2008; McDade et al 2012), others are quite discordant (Matsuo et al 2000; Amann et al 2001; Martin et al 2003; Holmgren et al 2004; Lachmann et al 2004; Czlonkowska et al 2009; Biegstraaten et al 2011; Fencl et al 2012; Iatropoulos et al 2012), suggesting that the environment can often play an important role in determining both the penetrance and expressivity of pathological mutations. [It should be borne in mind that there are various alternative genetic explanations for discordant phenotypes in monozygotic twins, including de novo post-zygotic mutation (Kentsis et al 2009; Vogt et al 2011), compensatory mutations (Mankad et al 2006) and somatic copy number variation (Bruder et al 2008) that obviate the need for a major contribution from the environment, as well as acquired epigenetic differences (Galetzka et al 2012; Bennett et al 2008)].…”

Section: Gene–environment Interactions and Penetrancementioning

confidence: 99%

Where genotype is not predictive of phenotype: towards an understanding of the molecular basis of reduced penetrance in human inherited disease

et al. 2013

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Some individuals with a particular disease-causing mutation or genotype fail to express most if not all features of the disease in question, a phenomenon that is known as ‘reduced (or incomplete) penetrance’. Reduced penetrance is not uncommon; indeed, there are many known examples of ‘disease-causing mutations’ that fail to cause disease in at least a proportion of the individuals who carry them. Reduced penetrance may therefore explain not only why genetic diseases are occasionally transmitted through unaffected parents, but also why healthy individuals can harbour quite large numbers of potentially disadvantageous variants in their genomes without suffering any obvious ill effects. Reduced penetrance can be a function of the specific mutation(s) involved or of allele dosage. It may also result from differential allelic expression, copy number variation or the modulating influence of additional genetic variants in cis or in trans. The penetrance of some pathogenic genotypes is known to be age- and/or sex-dependent. Variable penetrance may also reflect the action of unlinked modifier genes, epigenetic changes or environmental factors. At least in some cases, complete penetrance appears to require the presence of one or more genetic variants at other loci. In this review, we summarize the evidence for reduced penetrance being a widespread phenomenon in human genetics and explore some of the molecular mechanisms that may help to explain this enigmatic characteristic of human inherited disease.

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Section: Gene–environment Interactions and Penetrancementioning

confidence: 99%

Where genotype is not predictive of phenotype: towards an understanding of the molecular basis of reduced penetrance in human inherited disease

et al. 2013

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“…Although the spectrum of disease is thought to correlate in part with residual enzyme activity (Cox and Schofield, 1997), there is substantial clinical heterogeneity, even among siblings and identical twins (Lachmann et al, 2004;; Biegstraaten et al, 2011).…”

Section: Gaucher Diseasementioning

confidence: 99%

Glucocerebrosidase mutations and the pathogenesis of Parkinson disease

Beavan

Schapira

2013

Annals of Medicine

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“…Type 1 Gaucher disease is characterized by variability in signs, symptoms, severity,24,33 and progression, even among siblings with the same genotype and in monozygotic twins 34,35. The age of onset also is variable and the mean severity of disease shows marked differences among different ethnic groups.…”

Section: Clinical Features and Natural History Of Diseasementioning

confidence: 99%

Imiglucerase in the treatment of Gaucher disease: a history and perspective

Deegan

Cox

2012

DDDT

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The scientific and therapeutic development of imiglucerase (Cerezyme®) by the Genzyme Corporation is a paradigm case for a critical examination of current trends in biotechnology. In this article the authors argue that contemporary interest in treatments for rare diseases by major pharmaceutical companies stems in large part from an exception among rarities: the astonishing commercial success of Cerezyme. The fortunes of the Genzyme Corporation, latterly acquired by global giant Sanofi SA, were founded on the evolution of a blockbuster therapy for a single but, as it turns out, propitious ultra-orphan disorder: Gaucher disease.

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A monozygotic twin pair with highly discordant Gaucher phenotypes

Cited by 59 publications

References 9 publications

Where genotype is not predictive of phenotype: towards an understanding of the molecular basis of reduced penetrance in human inherited disease

Where genotype is not predictive of phenotype: towards an understanding of the molecular basis of reduced penetrance in human inherited disease

Glucocerebrosidase mutations and the pathogenesis of Parkinson disease

Imiglucerase in the treatment of Gaucher disease: a history and perspective

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