Recurrent generalized seizures, visual loss, and palinopsia as phenotypic features of neuronal ceroid lipofuscinosis due to progranulin gene mutation

Canafoglia, Laura; Morbin, Michela; Scaioli, V.; Pareyson, Davide; D’Incerti, Ludovico; Fugnanesi, Valeria; Tagliavini, Fabrizio; Berkovic, Samuel F.; Franceschetti, Silvana

doi:10.1111/epi.12632

Cited by 56 publications

(43 citation statements)

References 13 publications

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“…Electron microscopy analysis showed some consistency with previous findings (e.g. CLN11), whereas the CLN3 patient in this study showed curvilinear bodies in contrast to a study highlighting fingerprint patterns as the major inclusion type …”

Section: Discussionsupporting

confidence: 90%

Paediatric‐onset neuronal ceroid lipofuscinosis: first symptoms and presentation at diagnosis

Dozières‐Puyravel

Nasser

Elmaleh‐Bergès

et al. 2019

Develop Med Child Neuro

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Neuronal ceroid lipofuscinoses (NCLs) are rare, progressive disorders. Through this series of 20 patients with NCL, we illustrate differences between subtypes in their presenting symptoms and clinical, imaging, and electrophysiological results to raise awareness of symptom diversity. Data were available on presenting symptoms, genetics, magnetic resonance imaging (MRI), electroencephalography (including with low‐frequency intermittent photic stimulation), visual responses, and electron microscopy. Causal mutations were identified in 10 patients. Eleven patients had neuronal ceroid lipofuscinosis type 2 (CLN2) disease and their most common presenting symptom was seizures, although motor and language defects were also reported. Five patients with CLN2 disease showed abnormalities at initial MRI, but only three showed a photic response with low‐frequency stimulation. Seizures were not as common a presenting symptom in other NCL subtypes. Patients with NCLs present with diverse symptoms, which may not be characteristic in early disease stages. These signs and symptoms should lead to rapid diagnostic confirmatory testing for NCLs. What this paper adds Disease presentation is not uniform for neuronal ceroid lipofuscinoses. Characteristic clinical test results may not be identified in early disease stages.

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Section: Discussionsupporting

confidence: 90%

Paediatric‐onset neuronal ceroid lipofuscinosis: first symptoms and presentation at diagnosis

Dozières‐Puyravel

Nasser

Elmaleh‐Bergès

et al. 2019

Develop Med Child Neuro

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“…Vision loss and retinal atrophy are early phenotypes in most patients with NCL. Our recent observations of moderate retinal thinning in heterozygous GRN mutation carriers, compared to nearly complete vision loss and severe retinal atrophy in homozygous GRN mutation carriers (18), suggest a relationship between GRN gene dosage and the severity of retinal involvement. We also found that lipofuscinosis and membrane-bound storage material deposition—pathologic hallmarks of NCL—occurred in heterozygous GRN mutation carriers, consistent with what has been seen in homozygous GRN mutation carriers.…”

Section: Discussionmentioning

confidence: 77%

Individuals with progranulin haploinsufficiency exhibit features of neuronal ceroid lipofuscinosis

et al. 2017

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Heterozygous mutations in the GRN gene lead to progranulin (PGRN) haploinsufficiency and cause frontotemporal dementia (FTD), a neurodegenerative syndrome of older adults. Homozygous GRN mutations, on the other hand, lead to complete PGRN loss and cause neuronal ceroid lipofuscinosis (NCL), a lysosomal storage disease usually seen in children. Given that the predominant clinical and pathological features of FTD and NCL are distinct, it is controversial whether the disease mechanisms associated with complete and partial PGRN loss are similar or distinct. We show that PGRN haploinsufficiency leads to NCL-like features in humans, some occurring before dementia onset. Noninvasive retinal imaging revealed preclinical retinal lipofuscinosis in heterozygous GRN mutation carriers. Increased lipofuscinosis and intracellular NCL-like storage material also occurred in postmortem cortex of heterozygous GRN mutation carriers. Lymphoblasts from heterozygous GRN mutation carriers accumulated prominent NCL-like storage material, which could be rescued by normalizing PGRN expression. Fibroblasts from heterozygous GRN mutation carriers showed impaired lysosomal protease activity. Our findings indicate that progranulin haploinsufficiency caused accumulation of NCL-like storage material and early retinal abnormalities in humans and implicate lysosomal dysfunction as a central disease process in GRN-associated FTD and GRN-associated NCL.

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“…Approximately 5% of the CLN mutations have been associated with adult-onset neurological phenotypes (from 17 to 43 yrs) divided into three different subtypes: Kufs diseases, characterized by progressive myoclonus epilepsy and cognitive decline (Type A), or behavioral anomalies, dementia, motor dysfunction, ataxia and extrapyramidal and suprabulbar signs (Type B) [4,18]; adult NCLs which include autosomal dominant Parry disease due to DNJC5 mutations [13] and the recessive NCL type 11 associated with mutations in the progranulin gene [7] (Table 1).…”

Section: Discussionmentioning

confidence: 99%

Adult-onset autosomal recessive ataxia associated with neuronal ceroid lipofuscinosis type 5 gene (CLN5) mutations

et al. 2014

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Autosomal recessive inherited ataxias are a growing group of genetic disorders. We report two Italian siblings presenting in their mid-50s with difficulty in walking, dysarthria and progressive cognitive decline. Visual loss, ascribed to glaucoma, manifested a few years before the other symptoms. Brain MRI showed severe cerebellar atrophy, prevalent in the vermis, with marked cortical atrophy of both hemispheres. Exome sequencing identified a novel homozygous mutation (c.935G>A;p.Ser312Asn) in the ceroid neuronal lipofuscinosis type 5 gene (CLN5). Bioinformatics predictions and in vitro studies showed that the mutation was deleterious and likely affects ERlysosome protein trafficking. Our findings support CLN5 hypomorphic mutations cause autosomal recessive cerebellar ataxia, confirming other reports showing CLN mutations are associated with adult-onset neurodegenerative disorders. We suggest CLN genes should be considered in the molecular analyses of patients presenting with adult-onset autosomal recessive cerebellar ataxia.

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Recurrent generalized seizures, visual loss, and palinopsia as phenotypic features of neuronal ceroid lipofuscinosis due to progranulin gene mutation

Cited by 56 publications

References 13 publications

Paediatric‐onset neuronal ceroid lipofuscinosis: first symptoms and presentation at diagnosis

Paediatric‐onset neuronal ceroid lipofuscinosis: first symptoms and presentation at diagnosis

Individuals with progranulin haploinsufficiency exhibit features of neuronal ceroid lipofuscinosis

Adult-onset autosomal recessive ataxia associated with neuronal ceroid lipofuscinosis type 5 gene (CLN5) mutations

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