Cargando…

Extrastriatal changes in patients with late-onset glutaric aciduria type I highlight the risk of long-term neurotoxicity

BACKGROUND: Without neonatal initiation of treatment, 80–90% of patients with glutaric aciduria type 1 (GA1) develop striatal injury during the first six years of life resulting in a complex, predominantly dystonic movement disorder. Onset of motor symptoms may be acute following encephalopathic cri...

Descripción completa

Detalles Bibliográficos
Autores principales: Boy, Nikolas, Heringer, Jana, Brackmann, Renate, Bodamer, Olaf, Seitz, Angelika, Kölker, Stefan, Harting, Inga
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5402644/
https://www.ncbi.nlm.nih.gov/pubmed/28438223
http://dx.doi.org/10.1186/s13023-017-0612-6
_version_ 1783231267675832320
author Boy, Nikolas
Heringer, Jana
Brackmann, Renate
Bodamer, Olaf
Seitz, Angelika
Kölker, Stefan
Harting, Inga
author_facet Boy, Nikolas
Heringer, Jana
Brackmann, Renate
Bodamer, Olaf
Seitz, Angelika
Kölker, Stefan
Harting, Inga
author_sort Boy, Nikolas
collection PubMed
description BACKGROUND: Without neonatal initiation of treatment, 80–90% of patients with glutaric aciduria type 1 (GA1) develop striatal injury during the first six years of life resulting in a complex, predominantly dystonic movement disorder. Onset of motor symptoms may be acute following encephalopathic crisis or insidious without apparent crisis. Additionally, so-called late-onset GA1 has been described in single patients diagnosed after the age of 6 years. With the aim of better characterizing and understanding late-onset GA1 we analyzed clinical findings, biochemical phenotype, and MRI changes of eight late-onset patients and compared these to eight control patients over the age of 6 years with early diagnosis and start of treatment. RESULTS: No late-onset or control patient had either dystonia or striatal lesions on MRI. All late-onset (8/8) patients were high excretors, but only four of eight control patients. Two of eight late-onset patients were diagnosed after the age of 60 years, presenting with dementia, tremor, and epilepsy, while six were diagnosed before the age of 30 years: Three were asymptomatic mothers identified by following a positive screening result in their newborns and three had non-specific general symptoms, one with additional mild neurological deficits. Frontotemporal hypoplasia and white matter changes were present in all eight and subependymal lesions in six late-onset patients. At comparable age a greater proportion of late-onset patients had (non-specific) clinical symptoms and possibly subependymal nodules compared to control patients, in particular in comparison to the four clinically and MR-wise asymptomatic low-excreting control patients. CONCLUSIONS: While clinical findings are non-specific, frontotemporal hypoplasia and subependymal nodules are characteristic MRI findings of late-onset GA1 and should trigger diagnostic investigation for this rare disease. Apart from their apparent non-susceptibility for striatal injury despite lack of treatment, patients with late-onset GA1 are not categorically different from early treated control patients. Differences between late-onset patients and early treated control patients most likely reflect greater cumulative neurotoxicity in individuals remaining undiagnosed and untreated for years, even decades as well as the higher long-term risk of high excretors for intracerebral accumulation of neurotoxic metabolites compared to low excretors. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13023-017-0612-6) contains supplementary material, which is available to authorized users.
format Online
Article
Text
id pubmed-5402644
institution National Center for Biotechnology Information
language English
publishDate 2017
publisher BioMed Central
record_format MEDLINE/PubMed
spelling pubmed-54026442017-04-27 Extrastriatal changes in patients with late-onset glutaric aciduria type I highlight the risk of long-term neurotoxicity Boy, Nikolas Heringer, Jana Brackmann, Renate Bodamer, Olaf Seitz, Angelika Kölker, Stefan Harting, Inga Orphanet J Rare Dis Research BACKGROUND: Without neonatal initiation of treatment, 80–90% of patients with glutaric aciduria type 1 (GA1) develop striatal injury during the first six years of life resulting in a complex, predominantly dystonic movement disorder. Onset of motor symptoms may be acute following encephalopathic crisis or insidious without apparent crisis. Additionally, so-called late-onset GA1 has been described in single patients diagnosed after the age of 6 years. With the aim of better characterizing and understanding late-onset GA1 we analyzed clinical findings, biochemical phenotype, and MRI changes of eight late-onset patients and compared these to eight control patients over the age of 6 years with early diagnosis and start of treatment. RESULTS: No late-onset or control patient had either dystonia or striatal lesions on MRI. All late-onset (8/8) patients were high excretors, but only four of eight control patients. Two of eight late-onset patients were diagnosed after the age of 60 years, presenting with dementia, tremor, and epilepsy, while six were diagnosed before the age of 30 years: Three were asymptomatic mothers identified by following a positive screening result in their newborns and three had non-specific general symptoms, one with additional mild neurological deficits. Frontotemporal hypoplasia and white matter changes were present in all eight and subependymal lesions in six late-onset patients. At comparable age a greater proportion of late-onset patients had (non-specific) clinical symptoms and possibly subependymal nodules compared to control patients, in particular in comparison to the four clinically and MR-wise asymptomatic low-excreting control patients. CONCLUSIONS: While clinical findings are non-specific, frontotemporal hypoplasia and subependymal nodules are characteristic MRI findings of late-onset GA1 and should trigger diagnostic investigation for this rare disease. Apart from their apparent non-susceptibility for striatal injury despite lack of treatment, patients with late-onset GA1 are not categorically different from early treated control patients. Differences between late-onset patients and early treated control patients most likely reflect greater cumulative neurotoxicity in individuals remaining undiagnosed and untreated for years, even decades as well as the higher long-term risk of high excretors for intracerebral accumulation of neurotoxic metabolites compared to low excretors. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13023-017-0612-6) contains supplementary material, which is available to authorized users. BioMed Central 2017-04-24 /pmc/articles/PMC5402644/ /pubmed/28438223 http://dx.doi.org/10.1186/s13023-017-0612-6 Text en © The Author(s). 2017 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research
Boy, Nikolas
Heringer, Jana
Brackmann, Renate
Bodamer, Olaf
Seitz, Angelika
Kölker, Stefan
Harting, Inga
Extrastriatal changes in patients with late-onset glutaric aciduria type I highlight the risk of long-term neurotoxicity
title Extrastriatal changes in patients with late-onset glutaric aciduria type I highlight the risk of long-term neurotoxicity
title_full Extrastriatal changes in patients with late-onset glutaric aciduria type I highlight the risk of long-term neurotoxicity
title_fullStr Extrastriatal changes in patients with late-onset glutaric aciduria type I highlight the risk of long-term neurotoxicity
title_full_unstemmed Extrastriatal changes in patients with late-onset glutaric aciduria type I highlight the risk of long-term neurotoxicity
title_short Extrastriatal changes in patients with late-onset glutaric aciduria type I highlight the risk of long-term neurotoxicity
title_sort extrastriatal changes in patients with late-onset glutaric aciduria type i highlight the risk of long-term neurotoxicity
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5402644/
https://www.ncbi.nlm.nih.gov/pubmed/28438223
http://dx.doi.org/10.1186/s13023-017-0612-6
work_keys_str_mv AT boynikolas extrastriatalchangesinpatientswithlateonsetglutaricaciduriatypeihighlighttheriskoflongtermneurotoxicity
AT heringerjana extrastriatalchangesinpatientswithlateonsetglutaricaciduriatypeihighlighttheriskoflongtermneurotoxicity
AT brackmannrenate extrastriatalchangesinpatientswithlateonsetglutaricaciduriatypeihighlighttheriskoflongtermneurotoxicity
AT bodamerolaf extrastriatalchangesinpatientswithlateonsetglutaricaciduriatypeihighlighttheriskoflongtermneurotoxicity
AT seitzangelika extrastriatalchangesinpatientswithlateonsetglutaricaciduriatypeihighlighttheriskoflongtermneurotoxicity
AT kolkerstefan extrastriatalchangesinpatientswithlateonsetglutaricaciduriatypeihighlighttheriskoflongtermneurotoxicity
AT hartinginga extrastriatalchangesinpatientswithlateonsetglutaricaciduriatypeihighlighttheriskoflongtermneurotoxicity