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Genetic and phenotypic characterization of NKX6‐2‐related spastic ataxia and hypomyelination.

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Title: Genetic and phenotypic characterization of NKX6‐2‐related spastic ataxia and hypomyelination.
Authors: Chelban, V. (AUTHOR), Alsagob, M. (AUTHOR), Kloth, K. (AUTHOR), Chirita‐Emandi, A. (AUTHOR), Vandrovcova, J. (AUTHOR), Maroofian, R. (AUTHOR), Davagnanam, I. (AUTHOR), Bakhtiari, S. (AUTHOR), AlSayed, M. D. (AUTHOR), Rahbeeni, Z. (AUTHOR), AlZaidan, H. (AUTHOR), Malintan, N. T. (AUTHOR), Johannsen, J. (AUTHOR), Efthymiou, S. (AUTHOR), Ghayoor Karimiani, E. (AUTHOR), Mankad, K. (AUTHOR), Al‐Shahrani, S. A. (AUTHOR), Beiraghi Toosi, M. (AUTHOR), AlShammari, M. (AUTHOR), Groppa, S. (AUTHOR)
Source: European Journal of Neurology. Feb2020, Vol. 27 Issue 2, p334-342. 9p. 3 Diagrams, 1 Chart, 1 Graph.
Subjects: Leukodystrophy, Ataxia, Genetic disorders, Cerebellar ataxia, Seizures (Medicine), Recessive genes, Homozygosity
Abstract: Background and purpose: Hypomyelinating leukodystrophies are a heterogeneous group of genetic disorders with a wide spectrum of phenotypes and a high rate of genetically unsolved cases. Bi‐allelic mutations in NKX6‐2 were recently linked to spastic ataxia 8 with hypomyelinating leukodystrophy. Methods: Using a combination of homozygosity mapping, exome sequencing, and detailed clinical and neuroimaging assessment a series of new NKX6‐2 mutations in a multicentre setting is described. Then, all reported NKX6‐2 mutations and those identified in this study were combined and an in‐depth analysis of NKX6‐2‐related disease spectrum was provided. Results: Eleven new cases from eight families of different ethnic backgrounds carrying compound heterozygous and homozygous pathogenic variants in NKX6‐2 were identified, evidencing a high NKX6‐2 mutation burden in the hypomyelinating leukodystrophy disease spectrum. Our data reveal a phenotype spectrum with neonatal onset, global psychomotor delay and worse prognosis at the severe end and a childhood onset with mainly motor phenotype at the milder end. The phenotypic and neuroimaging expression in NKX6‐2 is described and it is shown that phenotypes with epilepsy in the absence of overt hypomyelination and diffuse hypomyelination without seizures can occur. Conclusions: NKX6‐2 mutations should be considered in patients with autosomal recessive, very early onset of nystagmus, cerebellar ataxia with hypotonia that rapidly progresses to spasticity, particularly when associated with neuroimaging signs of hypomyelination. Therefore, it is recommended that NXK6‐2 should be included in hypomyelinating leukodystrophy and spastic ataxia diagnostic panels. [ABSTRACT FROM AUTHOR]
Copyright of European Journal of Neurology is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
Database: Psychology and Behavioral Sciences Collection
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  Data: Genetic and phenotypic characterization of NKX6‐2‐related spastic ataxia and hypomyelination.
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  Data: <searchLink fieldCode="AR" term="%22Chelban%2C+V%2E%22">Chelban, V.</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Alsagob%2C+M%2E%22">Alsagob, M.</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Kloth%2C+K%2E%22">Kloth, K.</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Chirita‐Emandi%2C+A%2E%22">Chirita‐Emandi, A.</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Vandrovcova%2C+J%2E%22">Vandrovcova, J.</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Maroofian%2C+R%2E%22">Maroofian, R.</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Davagnanam%2C+I%2E%22">Davagnanam, I.</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Bakhtiari%2C+S%2E%22">Bakhtiari, S.</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22AlSayed%2C+M%2E+D%2E%22">AlSayed, M. D.</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Rahbeeni%2C+Z%2E%22">Rahbeeni, Z.</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22AlZaidan%2C+H%2E%22">AlZaidan, H.</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Malintan%2C+N%2E+T%2E%22">Malintan, N. T.</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Johannsen%2C+J%2E%22">Johannsen, J.</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Efthymiou%2C+S%2E%22">Efthymiou, S.</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Ghayoor+Karimiani%2C+E%2E%22">Ghayoor Karimiani, E.</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Mankad%2C+K%2E%22">Mankad, K.</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Al‐Shahrani%2C+S%2E+A%2E%22">Al‐Shahrani, S. A.</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Beiraghi+Toosi%2C+M%2E%22">Beiraghi Toosi, M.</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22AlShammari%2C+M%2E%22">AlShammari, M.</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Groppa%2C+S%2E%22">Groppa, S.</searchLink> (AUTHOR)
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  Data: <searchLink fieldCode="JN" term="%22European+Journal+of+Neurology%22">European Journal of Neurology</searchLink>. Feb2020, Vol. 27 Issue 2, p334-342. 9p. 3 Diagrams, 1 Chart, 1 Graph.
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  Data: <searchLink fieldCode="DE" term="%22Leukodystrophy%22">Leukodystrophy</searchLink><br /><searchLink fieldCode="DE" term="%22Ataxia%22">Ataxia</searchLink><br /><searchLink fieldCode="DE" term="%22Genetic+disorders%22">Genetic disorders</searchLink><br /><searchLink fieldCode="DE" term="%22Cerebellar+ataxia%22">Cerebellar ataxia</searchLink><br /><searchLink fieldCode="DE" term="%22Seizures+%28Medicine%29%22">Seizures (Medicine)</searchLink><br /><searchLink fieldCode="DE" term="%22Recessive+genes%22">Recessive genes</searchLink><br /><searchLink fieldCode="DE" term="%22Homozygosity%22">Homozygosity</searchLink>
– Name: Abstract
  Label: Abstract
  Group: Ab
  Data: Background and purpose: Hypomyelinating leukodystrophies are a heterogeneous group of genetic disorders with a wide spectrum of phenotypes and a high rate of genetically unsolved cases. Bi‐allelic mutations in NKX6‐2 were recently linked to spastic ataxia 8 with hypomyelinating leukodystrophy. Methods: Using a combination of homozygosity mapping, exome sequencing, and detailed clinical and neuroimaging assessment a series of new NKX6‐2 mutations in a multicentre setting is described. Then, all reported NKX6‐2 mutations and those identified in this study were combined and an in‐depth analysis of NKX6‐2‐related disease spectrum was provided. Results: Eleven new cases from eight families of different ethnic backgrounds carrying compound heterozygous and homozygous pathogenic variants in NKX6‐2 were identified, evidencing a high NKX6‐2 mutation burden in the hypomyelinating leukodystrophy disease spectrum. Our data reveal a phenotype spectrum with neonatal onset, global psychomotor delay and worse prognosis at the severe end and a childhood onset with mainly motor phenotype at the milder end. The phenotypic and neuroimaging expression in NKX6‐2 is described and it is shown that phenotypes with epilepsy in the absence of overt hypomyelination and diffuse hypomyelination without seizures can occur. Conclusions: NKX6‐2 mutations should be considered in patients with autosomal recessive, very early onset of nystagmus, cerebellar ataxia with hypotonia that rapidly progresses to spasticity, particularly when associated with neuroimaging signs of hypomyelination. Therefore, it is recommended that NXK6‐2 should be included in hypomyelinating leukodystrophy and spastic ataxia diagnostic panels. [ABSTRACT FROM AUTHOR]
– Name: AbstractSuppliedCopyright
  Label:
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  Data: <i>Copyright of European Journal of Neurology is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract.</i> (Copyright applies to all Abstracts.)
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        Value: 10.1111/ene.14082
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