Identification of potential biomarkers and modifiers of CLN3-disease progression

Lebrun, AH; Storch, Stephan; Pohl, Sandra; Streichert, Thomas; Mole, SE; Ullrich, Kurt; Kohlschütter, Alfried; Braulke, Thomas; Schulz, Angela

doi:10.1055/s-0030-1265516

Cited by 2 publications

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“…Each category is scored from 3 (normal function) to 0 (no function left). As severity of seizures is highly dependent on current anticonvulsive medication, the calculated as previously described allowing to categorise patients into groups of slow (S) (> +0.5), average (A) (−0.5 to +0.5) or rapid disease progression (R) (<−0.5) 9. It should be noted that this categorisation only reflects the disease course up to the current date of examination and does not allow any prediction of the future progression of disease in each respective patient.…”

Section: Methodsmentioning

confidence: 99%

“…Ocular symptoms in CLN3 disease typically start insidiously at the age of 6–8 years, and in the majority of cases lead to rapid visual decline, followed by dementia, epilepsy, motor decline and ultimately death 6–8. In contrast to conformity of age of onset and progression of vision loss, there is a wide clinical variability between patients with CLN3 disease carrying the same mutation 9. Initial ophthalmic diagnosis is challenging due to unspecific retinal manifestations, such as optic atrophy, bull's eye maculopathy, peripheral bony spicules and vascular attenuation, all of which are commonly found in retinitis pigmentosa, cone–rod dystrophies or Stargardt disease 10–12.…”

Section: Introductionmentioning

confidence: 99%

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Novel morphological macular findings in juvenile CLN3 disease

et al. 2015

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This study represents the first prospective observational case series documenting retinal abnormalities in CLN3 disease with the aid of the spectral domain optical coherence tomography. The major finding was a characteristic, striated macular pattern in all patients studied. Particularly in early disease cases, macular striae can potentially help to discriminate CLN3 disease from other inherited forms of retinitis pigmentosa.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Novel morphological macular findings in juvenile CLN3 disease

et al. 2015

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Candidate gene networks and blood biomarkers of methamphetamine-associated psychosis: an integrative RNA-sequencing report

et al. 2016

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The clinical presentation, course and treatment of methamphetamine (METH)-associated psychosis (MAP) are similar to that observed in schizophrenia (SCZ) and subsequently MAP has been hypothesized as a pharmacological and environmental model of SCZ. However, several challenges currently exist in diagnosing MAP accurately at the molecular and neurocognitive level before the MAP model can contribute to the discovery of SCZ biomarkers. We directly assessed subcortical brain structural volumes and clinical parameters of MAP within the framework of an integrative genome-wide RNA-Seq blood transcriptome analysis of subjects diagnosed with MAP (N=10), METH dependency without psychosis (MA; N=10) and healthy controls (N=10). First, we identified discrete groups of co-expressed genes (that is, modules) and tested them for functional annotation and phenotypic relationships to brain structure volumes, life events and psychometric measurements. We discovered one MAP-associated module involved in ubiquitin-mediated proteolysis downregulation, enriched with 61 genes previously found implicated in psychosis and SCZ across independent blood and post-mortem brain studies using convergent functional genomic (CFG) evidence. This module demonstrated significant relationships with brain structure volumes including the anterior corpus callosum (CC) and the nucleus accumbens. Furthermore, a second MAP and psychoticism-associated module involved in circadian clock upregulation was also enriched with 39 CFG genes, further associated with the CC. Subsequently, a machine-learning analysis of differentially expressed genes identified single blood-based biomarkers able to differentiate controls from methamphetamine dependents with 87% accuracy and MAP from MA subjects with 95% accuracy. CFG evidence validated a significant proportion of these putative MAP biomarkers in independent studies including CLN3, FBP1, TBC1D2 and ZNF821 (RNA degradation), ELK3 and SINA3 (circadian clock) and PIGF and UHMK1 (ubiquitin-mediated proteolysis). Finally, focusing analysis on brain structure volumes revealed significantly lower bilateral hippocampal volumes in MAP subjects. Overall, these results suggest similar molecular and neurocognitive mechanisms underlying the pathophysiology of psychosis and SCZ regardless of substance abuse and provide preliminary evidence supporting the MAP paradigm as an exemplar for SCZ biomarker discovery.

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Identification of potential biomarkers and modifiers of CLN3-disease progression

Cited by 2 publications

References 0 publications

Novel morphological macular findings in juvenile CLN3 disease

Novel morphological macular findings in juvenile CLN3 disease

Candidate gene networks and blood biomarkers of methamphetamine-associated psychosis: an integrative RNA-sequencing report

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