CLN6‐related continuum phenotype caused by aberrant splicing
Abstract Neuronal ceroid lipofuscinoses (NCLs) are genetically heterogeneous neurodegenerative disorders, characterized by progressive cognitive and motor decline, epilepsy, visual impairment, and shortened life‐expectancy. CLN6‐related NCLs include both late‐infantile and adult myoclonic form. We r...
Saved in:
| Main Authors: | , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Wiley
2025-02-01
|
| Series: | Epilepsia Open |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/epi4.13119 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1825206493184524288 |
|---|---|
| author | Federica Invernizzi Barbara Castellotti Chiara Reale Celeste Panteghini Isabel Colangelo Roberta Solazzi Francesca Ragona Lucio Giordano Jessica Galli Davide Rossi Sebastiano Gianluca Marucci Valeria Cuccarini Giuseppe Didato Cinzia Gellera Barbara Garavaglia Tiziana Granata Laura Canafoglia |
| author_facet | Federica Invernizzi Barbara Castellotti Chiara Reale Celeste Panteghini Isabel Colangelo Roberta Solazzi Francesca Ragona Lucio Giordano Jessica Galli Davide Rossi Sebastiano Gianluca Marucci Valeria Cuccarini Giuseppe Didato Cinzia Gellera Barbara Garavaglia Tiziana Granata Laura Canafoglia |
| author_sort | Federica Invernizzi |
| collection | DOAJ |
| description | Abstract Neuronal ceroid lipofuscinoses (NCLs) are genetically heterogeneous neurodegenerative disorders, characterized by progressive cognitive and motor decline, epilepsy, visual impairment, and shortened life‐expectancy. CLN6‐related NCLs include both late‐infantile and adult myoclonic form. We report a 21‐year‐old patient, with mild developmental delay, who developed occipital seizures at 14 years, and subsequently cognitive decline, cortical myoclonus, and photosensitivity at low and higher frequencies. Overall, the picture suited progressive myoclonus epilepsy. Electroretinogram was normal. A skin biopsy revealed a mixed storage of curvilinear and fingerprint profiles. A brain MRI showed severe cortical atrophy. Performing genetic analyses, two biallelic variants were identified in the CLN6 gene, each inherited from one of the healthy parents, one c.722T>C, p.(Met241Thr) already described in the late‐infantile form and the other one c.486+28T>C, intronic and novel, causing aberrant splicing. In the patient, the expression of the allele containing c.722T>C variant was increased, in comparison with the carrier parent. The peculiar genetic pattern observed in the patient could explain a milder clinical picture when compared with late‐infantile form, since CLN6 expression was partially preserved. However, the presence of a delay, and the early cognitive decline suggested a continuum phenotype connecting late‐infantile and adult CLN6‐related forms. Plain Language Summary We report a patient with CLN6 disease who developed symptoms at an intermediate age: 9 years for mild intellectual disability and 14 years for occipital seizures and progressive myoclonus epilepsy, without visual impairment. The patient is compound heterozygous for a CLN6 missense variant c.722T>C, p.(Met241Thr) already described in the late‐infantile form and for a novel intronic variant c.486+28T>C, causing aberrant splicing. In the patient, the expression of the allele containing c.722T>C variant was increased, compared with the carrier parent. The splice site variant had a milder effect. The peculiar genetic pattern may explain the continuum phenotype between late‐infantile and adult forms. |
| format | Article |
| id | doaj-art-8aebcdaf92ef4dfab45f4b1584c09d3a |
| institution | Kabale University |
| issn | 2470-9239 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Wiley |
| record_format | Article |
| series | Epilepsia Open |
| spelling | doaj-art-8aebcdaf92ef4dfab45f4b1584c09d3a2025-02-07T09:12:45ZengWileyEpilepsia Open2470-92392025-02-0110134835410.1002/epi4.13119CLN6‐related continuum phenotype caused by aberrant splicingFederica Invernizzi0Barbara Castellotti1Chiara Reale2Celeste Panteghini3Isabel Colangelo4Roberta Solazzi5Francesca Ragona6Lucio Giordano7Jessica Galli8Davide Rossi Sebastiano9Gianluca Marucci10Valeria Cuccarini11Giuseppe Didato12Cinzia Gellera13Barbara Garavaglia14Tiziana Granata15Laura Canafoglia16Unit of Medical Genetics and Neurogenetics Fondazione IRCCS Istituto Neurologico Carlo Besta Milan ItalyUnit of Medical Genetics and Neurogenetics Fondazione IRCCS Istituto Neurologico Carlo Besta Milan ItalyUnit of Medical Genetics and Neurogenetics Fondazione IRCCS Istituto Neurologico Carlo Besta Milan ItalyUnit of Medical Genetics and Neurogenetics Fondazione IRCCS Istituto Neurologico Carlo Besta Milan ItalyUnit of Medical Genetics and Neurogenetics Fondazione IRCCS Istituto Neurologico Carlo Besta Milan ItalyDepartment of Paediatric Neuroscience, European Reference Network EPIcare Fondazione IRCCS Istituto Neurologico Carlo Besta Milan ItalyDepartment of Paediatric Neuroscience, European Reference Network EPIcare Fondazione IRCCS Istituto Neurologico Carlo Besta Milan ItalyChild Neuropsychiatric Division CRE Spedali Civili Brescia ItalyChild Neuropsychiatric Division CRE Spedali Civili Brescia ItalyNeurophysiopathology Fondazione IRCCS Istituto Neurologico Carlo Besta Milan ItalyNeuropathology Unit Fondazione IRCCS Istituto Neurologico Carlo Besta Milan ItalyNeuroradiology Unit Fondazione IRCCS Istituto Neurologico Carlo Besta Milan ItalyEpilepsy Unit, Department of Diagnostic and Technology, European Reference Network EPIcare Fondazione IRCCS Istituto Neurologico Carlo Besta Milan ItalyUnit of Medical Genetics and Neurogenetics Fondazione IRCCS Istituto Neurologico Carlo Besta Milan ItalyUnit of Medical Genetics and Neurogenetics Fondazione IRCCS Istituto Neurologico Carlo Besta Milan ItalyDepartment of Paediatric Neuroscience, European Reference Network EPIcare Fondazione IRCCS Istituto Neurologico Carlo Besta Milan ItalyIntegrated Diagnostics for Epilepsy, Department of Diagnostic and Technology, European Reference Network EPIcare Fondazione IRCCS Istituto Neurologico Carlo Besta Milan ItalyAbstract Neuronal ceroid lipofuscinoses (NCLs) are genetically heterogeneous neurodegenerative disorders, characterized by progressive cognitive and motor decline, epilepsy, visual impairment, and shortened life‐expectancy. CLN6‐related NCLs include both late‐infantile and adult myoclonic form. We report a 21‐year‐old patient, with mild developmental delay, who developed occipital seizures at 14 years, and subsequently cognitive decline, cortical myoclonus, and photosensitivity at low and higher frequencies. Overall, the picture suited progressive myoclonus epilepsy. Electroretinogram was normal. A skin biopsy revealed a mixed storage of curvilinear and fingerprint profiles. A brain MRI showed severe cortical atrophy. Performing genetic analyses, two biallelic variants were identified in the CLN6 gene, each inherited from one of the healthy parents, one c.722T>C, p.(Met241Thr) already described in the late‐infantile form and the other one c.486+28T>C, intronic and novel, causing aberrant splicing. In the patient, the expression of the allele containing c.722T>C variant was increased, in comparison with the carrier parent. The peculiar genetic pattern observed in the patient could explain a milder clinical picture when compared with late‐infantile form, since CLN6 expression was partially preserved. However, the presence of a delay, and the early cognitive decline suggested a continuum phenotype connecting late‐infantile and adult CLN6‐related forms. Plain Language Summary We report a patient with CLN6 disease who developed symptoms at an intermediate age: 9 years for mild intellectual disability and 14 years for occipital seizures and progressive myoclonus epilepsy, without visual impairment. The patient is compound heterozygous for a CLN6 missense variant c.722T>C, p.(Met241Thr) already described in the late‐infantile form and for a novel intronic variant c.486+28T>C, causing aberrant splicing. In the patient, the expression of the allele containing c.722T>C variant was increased, compared with the carrier parent. The splice site variant had a milder effect. The peculiar genetic pattern may explain the continuum phenotype between late‐infantile and adult forms.https://doi.org/10.1002/epi4.13119Kufs' diseaseneuronal ceroidlipofuscinosisoccipital seizuresphotoparoxysmal responseprogressive myoclonus epilepsy |
| spellingShingle | Federica Invernizzi Barbara Castellotti Chiara Reale Celeste Panteghini Isabel Colangelo Roberta Solazzi Francesca Ragona Lucio Giordano Jessica Galli Davide Rossi Sebastiano Gianluca Marucci Valeria Cuccarini Giuseppe Didato Cinzia Gellera Barbara Garavaglia Tiziana Granata Laura Canafoglia CLN6‐related continuum phenotype caused by aberrant splicing Epilepsia Open Kufs' disease neuronal ceroidlipofuscinosis occipital seizures photoparoxysmal response progressive myoclonus epilepsy |
| title | CLN6‐related continuum phenotype caused by aberrant splicing |
| title_full | CLN6‐related continuum phenotype caused by aberrant splicing |
| title_fullStr | CLN6‐related continuum phenotype caused by aberrant splicing |
| title_full_unstemmed | CLN6‐related continuum phenotype caused by aberrant splicing |
| title_short | CLN6‐related continuum phenotype caused by aberrant splicing |
| title_sort | cln6 related continuum phenotype caused by aberrant splicing |
| topic | Kufs' disease neuronal ceroidlipofuscinosis occipital seizures photoparoxysmal response progressive myoclonus epilepsy |
| url | https://doi.org/10.1002/epi4.13119 |
| work_keys_str_mv | AT federicainvernizzi cln6relatedcontinuumphenotypecausedbyaberrantsplicing AT barbaracastellotti cln6relatedcontinuumphenotypecausedbyaberrantsplicing AT chiarareale cln6relatedcontinuumphenotypecausedbyaberrantsplicing AT celestepanteghini cln6relatedcontinuumphenotypecausedbyaberrantsplicing AT isabelcolangelo cln6relatedcontinuumphenotypecausedbyaberrantsplicing AT robertasolazzi cln6relatedcontinuumphenotypecausedbyaberrantsplicing AT francescaragona cln6relatedcontinuumphenotypecausedbyaberrantsplicing AT luciogiordano cln6relatedcontinuumphenotypecausedbyaberrantsplicing AT jessicagalli cln6relatedcontinuumphenotypecausedbyaberrantsplicing AT daviderossisebastiano cln6relatedcontinuumphenotypecausedbyaberrantsplicing AT gianlucamarucci cln6relatedcontinuumphenotypecausedbyaberrantsplicing AT valeriacuccarini cln6relatedcontinuumphenotypecausedbyaberrantsplicing AT giuseppedidato cln6relatedcontinuumphenotypecausedbyaberrantsplicing AT cinziagellera cln6relatedcontinuumphenotypecausedbyaberrantsplicing AT barbaragaravaglia cln6relatedcontinuumphenotypecausedbyaberrantsplicing AT tizianagranata cln6relatedcontinuumphenotypecausedbyaberrantsplicing AT lauracanafoglia cln6relatedcontinuumphenotypecausedbyaberrantsplicing |