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A novel protein truncating mutation in L2HGDH causes L-2-hydroxyglutaric aciduria in a consanguineous Pakistani family

BACKGROUND: L-2-hydroxyglutaric aciduria (L2HGA) is a rare neurometabolic disorder that occurs due to accumulation of L-2-hydroxyglutaric acid in the cerebrospinal fluid (CSF), plasma and urine. The clinical manifestation of L2HGA includes intellectual disability, cerebellar ataxia, epilepsy, speech...

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Autores principales: Muzammal, Muhammad, Ali, Muhammad Zeeshan, Brugger, Beatrice, Blatterer, Jasmin, Ahmad, Safeer, Taj, Sundas, Shah, Syed Khizar, Khan, Saadullah, Enzinger, Christian, Petek, Erwin, Wagner, Klaus, Khan, Muzammil Ahmad, Windpassinger, Christian
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer US 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8748340/
https://www.ncbi.nlm.nih.gov/pubmed/34719772
http://dx.doi.org/10.1007/s11011-021-00832-2
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author Muzammal, Muhammad
Ali, Muhammad Zeeshan
Brugger, Beatrice
Blatterer, Jasmin
Ahmad, Safeer
Taj, Sundas
Shah, Syed Khizar
Khan, Saadullah
Enzinger, Christian
Petek, Erwin
Wagner, Klaus
Khan, Muzammil Ahmad
Windpassinger, Christian
author_facet Muzammal, Muhammad
Ali, Muhammad Zeeshan
Brugger, Beatrice
Blatterer, Jasmin
Ahmad, Safeer
Taj, Sundas
Shah, Syed Khizar
Khan, Saadullah
Enzinger, Christian
Petek, Erwin
Wagner, Klaus
Khan, Muzammil Ahmad
Windpassinger, Christian
author_sort Muzammal, Muhammad
collection PubMed
description BACKGROUND: L-2-hydroxyglutaric aciduria (L2HGA) is a rare neurometabolic disorder that occurs due to accumulation of L-2-hydroxyglutaric acid in the cerebrospinal fluid (CSF), plasma and urine. The clinical manifestation of L2HGA includes intellectual disability, cerebellar ataxia, epilepsy, speech problems and macrocephaly. METHODS: In the present study, we ascertained a multigenerational consanguineous Pakistani family with 5 affected individuals. Clinical studies were performed through biochemical tests and brain CT scan. Locus mapping was carried out through genome-wide SNP genotyping, whole exome sequencing and Sanger sequencing. For in silico studies protein structural modeling and docking was done using I-TASSER, Cluspro and AutoDock VINA tools. RESULTS: Affected individuals presented with cognitive impairment, gait disturbance, speech difficulties and psychomotor delay. Radiologic analysis of a male patient revealed leukoaraiosis with hypoattenuation of cerebral white matter, suggestive of hypomyelination. Homozygosity mapping in this family revealed a linkage region on chromosome 14 between markers rs2039791 and rs781354. Subsequent whole exome analysis identified a novel frameshift mutation NM_024884.3:c.180delG, p.(Ala62Profs*24) in the second exon of L2HGDH. Sanger sequencing confirmed segregation of this mutation with the disease phenotype. The identification of the most N-terminal loss of function mutation published thus far further expands the mutational spectrum of L2HGDH. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s11011-021-00832-2.
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spelling pubmed-87483402022-01-20 A novel protein truncating mutation in L2HGDH causes L-2-hydroxyglutaric aciduria in a consanguineous Pakistani family Muzammal, Muhammad Ali, Muhammad Zeeshan Brugger, Beatrice Blatterer, Jasmin Ahmad, Safeer Taj, Sundas Shah, Syed Khizar Khan, Saadullah Enzinger, Christian Petek, Erwin Wagner, Klaus Khan, Muzammil Ahmad Windpassinger, Christian Metab Brain Dis Original Article BACKGROUND: L-2-hydroxyglutaric aciduria (L2HGA) is a rare neurometabolic disorder that occurs due to accumulation of L-2-hydroxyglutaric acid in the cerebrospinal fluid (CSF), plasma and urine. The clinical manifestation of L2HGA includes intellectual disability, cerebellar ataxia, epilepsy, speech problems and macrocephaly. METHODS: In the present study, we ascertained a multigenerational consanguineous Pakistani family with 5 affected individuals. Clinical studies were performed through biochemical tests and brain CT scan. Locus mapping was carried out through genome-wide SNP genotyping, whole exome sequencing and Sanger sequencing. For in silico studies protein structural modeling and docking was done using I-TASSER, Cluspro and AutoDock VINA tools. RESULTS: Affected individuals presented with cognitive impairment, gait disturbance, speech difficulties and psychomotor delay. Radiologic analysis of a male patient revealed leukoaraiosis with hypoattenuation of cerebral white matter, suggestive of hypomyelination. Homozygosity mapping in this family revealed a linkage region on chromosome 14 between markers rs2039791 and rs781354. Subsequent whole exome analysis identified a novel frameshift mutation NM_024884.3:c.180delG, p.(Ala62Profs*24) in the second exon of L2HGDH. Sanger sequencing confirmed segregation of this mutation with the disease phenotype. The identification of the most N-terminal loss of function mutation published thus far further expands the mutational spectrum of L2HGDH. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s11011-021-00832-2. Springer US 2021-11-01 2022 /pmc/articles/PMC8748340/ /pubmed/34719772 http://dx.doi.org/10.1007/s11011-021-00832-2 Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Original Article
Muzammal, Muhammad
Ali, Muhammad Zeeshan
Brugger, Beatrice
Blatterer, Jasmin
Ahmad, Safeer
Taj, Sundas
Shah, Syed Khizar
Khan, Saadullah
Enzinger, Christian
Petek, Erwin
Wagner, Klaus
Khan, Muzammil Ahmad
Windpassinger, Christian
A novel protein truncating mutation in L2HGDH causes L-2-hydroxyglutaric aciduria in a consanguineous Pakistani family
title A novel protein truncating mutation in L2HGDH causes L-2-hydroxyglutaric aciduria in a consanguineous Pakistani family
title_full A novel protein truncating mutation in L2HGDH causes L-2-hydroxyglutaric aciduria in a consanguineous Pakistani family
title_fullStr A novel protein truncating mutation in L2HGDH causes L-2-hydroxyglutaric aciduria in a consanguineous Pakistani family
title_full_unstemmed A novel protein truncating mutation in L2HGDH causes L-2-hydroxyglutaric aciduria in a consanguineous Pakistani family
title_short A novel protein truncating mutation in L2HGDH causes L-2-hydroxyglutaric aciduria in a consanguineous Pakistani family
title_sort novel protein truncating mutation in l2hgdh causes l-2-hydroxyglutaric aciduria in a consanguineous pakistani family
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8748340/
https://www.ncbi.nlm.nih.gov/pubmed/34719772
http://dx.doi.org/10.1007/s11011-021-00832-2
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