NOTCH1-Related Leukoencephalopathy: A Novel Variant and Literature Review
<i>NOTCH1</i>-related leukoencephalopathy is a new diagnostic entity linked to heterozygous gain-of-function variants in <i>NOTCH1</i> that neuroradiologically show some overlap with the inflammatory microangiopathy Aicardi-Goutières syndrome (AGS). To report a 16-year-old bo...
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MDPI AG
2024-03-01
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| Series: | International Journal of Molecular Sciences |
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| author | Stefania Della Vecchia Alessandra Tessa Rosa Pasquariello Luis Seabra Yanick J. Crow Roberta Battini |
| author_facet | Stefania Della Vecchia Alessandra Tessa Rosa Pasquariello Luis Seabra Yanick J. Crow Roberta Battini |
| author_sort | Stefania Della Vecchia |
| collection | DOAJ |
| description | <i>NOTCH1</i>-related leukoencephalopathy is a new diagnostic entity linked to heterozygous gain-of-function variants in <i>NOTCH1</i> that neuroradiologically show some overlap with the inflammatory microangiopathy Aicardi-Goutières syndrome (AGS). To report a 16-year-old boy harbouring a novel <i>NOTCH1</i> mutation who presented neuroradiological features suggestive of enhanced type I interferon signalling. We describe five years of follow-up and review the current literature on <i>NOTCH1</i>-related leukoencephalopathy. Clinical evaluation, standardised scales (SPRS, SARA, CBCL, CDI-2:P, WISCH-IV and VABS-2) and neuroradiological studies were performed, as well as blood DNA analysis. For the literature review, a search was performed on Pubmed, Scopus and Web of Science up to December 2023 using the following text word search strategy: (<i>NOTCH1</i>) AND (leukoencephalopathy). Our patient presents clinical features consistent with other reported cases with NOTCH1 mutations but is among the minority of patients with an onset after infancy. During the five-year follow-up, we observed an increase in the severity of spasticity and ataxia. However, at the age of 16 years, our proband is still ambulatory. As for other reported patients, he manifests psychiatric features ranging from hyperactivity during childhood to anxiety and depression during adolescence. The neuroradiological picture remained essentially stable over five years. In addition to the typical findings of leukoencephalopathy with cysts and calcifications already described, we report the presence of T2-hyperintensity and T1-hypotensity of the transverse pontine fibres, enhancement in the periventricular white matter after gadolinium administration and decreased NAA and Cho peaks in the periventricular white matter on MRS. We identified a novel heterozygous variant in <i>NOTCH1</i> (c.4788_4799dup), a frame insertion located in extracellular negative regulatory region (NRR)-domain as in previously published cases. Blood interferon signalling was not elevated compared to controls. This case provides further data on a new diagnostic entity, i.e., NOTCH1-related leukoencephalopathy. By describing a standardised five-year follow-up in one case and reviewing the other patients described to date, we outline recommendations relating to monitoring in this illness, emphasising the importance of psychiatric and gastroenterological surveillance alongside neurological and neuropsychological management. Studies are needed to better understand the factors influencing disease onset and severity, which are heterogeneous. |
| first_indexed | 2024-04-25T00:27:36Z |
| format | Article |
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| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-04-25T00:27:36Z |
| publishDate | 2024-03-01 |
| publisher | MDPI AG |
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| series | International Journal of Molecular Sciences |
| spelling | doaj.art-4d67b7220736480294da3c5d74b302532024-03-12T16:46:37ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672024-03-01255286410.3390/ijms25052864NOTCH1-Related Leukoencephalopathy: A Novel Variant and Literature ReviewStefania Della Vecchia0Alessandra Tessa1Rosa Pasquariello2Luis Seabra3Yanick J. Crow4Roberta Battini5Department of Molecular Medicine and Neurogenetics, IRCCS Fondazione Stella Maris, 56128 Pisa, ItalyDepartment of Molecular Medicine and Neurogenetics, IRCCS Fondazione Stella Maris, 56128 Pisa, ItalyDepartment of Developmental Neuroscience, IRCCS Fondazione Stella Maris, 56128 Pisa, ItalyLaboratory of Neurogenetics and Neuroinflammation, Institut Imagine, University of Paris, 75015 Paris, FranceLaboratory of Neurogenetics and Neuroinflammation, Institut Imagine, University of Paris, 75015 Paris, FranceDepartment of Developmental Neuroscience, IRCCS Fondazione Stella Maris, 56128 Pisa, Italy<i>NOTCH1</i>-related leukoencephalopathy is a new diagnostic entity linked to heterozygous gain-of-function variants in <i>NOTCH1</i> that neuroradiologically show some overlap with the inflammatory microangiopathy Aicardi-Goutières syndrome (AGS). To report a 16-year-old boy harbouring a novel <i>NOTCH1</i> mutation who presented neuroradiological features suggestive of enhanced type I interferon signalling. We describe five years of follow-up and review the current literature on <i>NOTCH1</i>-related leukoencephalopathy. Clinical evaluation, standardised scales (SPRS, SARA, CBCL, CDI-2:P, WISCH-IV and VABS-2) and neuroradiological studies were performed, as well as blood DNA analysis. For the literature review, a search was performed on Pubmed, Scopus and Web of Science up to December 2023 using the following text word search strategy: (<i>NOTCH1</i>) AND (leukoencephalopathy). Our patient presents clinical features consistent with other reported cases with NOTCH1 mutations but is among the minority of patients with an onset after infancy. During the five-year follow-up, we observed an increase in the severity of spasticity and ataxia. However, at the age of 16 years, our proband is still ambulatory. As for other reported patients, he manifests psychiatric features ranging from hyperactivity during childhood to anxiety and depression during adolescence. The neuroradiological picture remained essentially stable over five years. In addition to the typical findings of leukoencephalopathy with cysts and calcifications already described, we report the presence of T2-hyperintensity and T1-hypotensity of the transverse pontine fibres, enhancement in the periventricular white matter after gadolinium administration and decreased NAA and Cho peaks in the periventricular white matter on MRS. We identified a novel heterozygous variant in <i>NOTCH1</i> (c.4788_4799dup), a frame insertion located in extracellular negative regulatory region (NRR)-domain as in previously published cases. Blood interferon signalling was not elevated compared to controls. This case provides further data on a new diagnostic entity, i.e., NOTCH1-related leukoencephalopathy. By describing a standardised five-year follow-up in one case and reviewing the other patients described to date, we outline recommendations relating to monitoring in this illness, emphasising the importance of psychiatric and gastroenterological surveillance alongside neurological and neuropsychological management. Studies are needed to better understand the factors influencing disease onset and severity, which are heterogeneous.https://www.mdpi.com/1422-0067/25/5/2864heterozygous <i>NOTCH1</i> mutationleukoencephalopathy with calcifications and cysts |
| spellingShingle | Stefania Della Vecchia Alessandra Tessa Rosa Pasquariello Luis Seabra Yanick J. Crow Roberta Battini NOTCH1-Related Leukoencephalopathy: A Novel Variant and Literature Review International Journal of Molecular Sciences heterozygous <i>NOTCH1</i> mutation leukoencephalopathy with calcifications and cysts |
| title | NOTCH1-Related Leukoencephalopathy: A Novel Variant and Literature Review |
| title_full | NOTCH1-Related Leukoencephalopathy: A Novel Variant and Literature Review |
| title_fullStr | NOTCH1-Related Leukoencephalopathy: A Novel Variant and Literature Review |
| title_full_unstemmed | NOTCH1-Related Leukoencephalopathy: A Novel Variant and Literature Review |
| title_short | NOTCH1-Related Leukoencephalopathy: A Novel Variant and Literature Review |
| title_sort | notch1 related leukoencephalopathy a novel variant and literature review |
| topic | heterozygous <i>NOTCH1</i> mutation leukoencephalopathy with calcifications and cysts |
| url | https://www.mdpi.com/1422-0067/25/5/2864 |
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