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The clinical and molecular genetic features of idiopathic infantile periodic alternating nystagmus

Mervyn G Thomas, Moira Crosier, Susan Lindsay, Anil Kumar, Shery Thomas, Masasuke Araki, Chris J Talbot, Rebecca J McLean, Mylvaganam Surendran and Katie Taylor, et al. (2011) BRAIN. 134(3). p.892-902
abstract
Periodic alternating nystagmus consists of involuntary oscillations of the eyes with cyclical changes of nystagmus direction. It can occur during infancy (e.g. idiopathic infantile periodic alternating nystagmus) or later in life. Acquired forms are often associated with cerebellar dysfunction arising due to instability of the optokinetic-vestibular systems. Idiopathic infantile periodic alternating nystagmus can be familial or occur in isolation; however, very little is known about the clinical characteristics, genetic aetiology and neural substrates involved. Five loci (NYS1-5) have been identified for idiopathic infantile nystagmus; three are autosomal (NYS2, NYS3 and NYS4) and two are X-chromosomal (NYS1 and NYS5). We previously identified the FRMD7 gene on chromosome Xq26 (NYS1 locus); mutations of FRMD7 are causative of idiopathic infantile nystagmus influencing neuronal outgrowth and development. It is unclear whether the periodic alternating nystagmus phenotype is linked to NYS1, NYS5 (Xp11.4-p11.3) or a separate locus. From a cohort of 31 X-linked families and 14 singletons (70 patients) with idiopathic infantile nystagmus we identified 10 families and one singleton (21 patients) with periodic alternating nystagmus of which we describe clinical phenotype, genetic aetiology and neural substrates involved. Periodic alternating nystagmus was not detected clinically but only on eye movement recordings. The cycle duration varied from 90 to 280 s. Optokinetic reflex was not detectable horizontally. Mutations of the FRMD7 gene were found in all 10 families and the singleton (including three novel mutations). Periodic alternating nystagmus was predominantly associated with missense mutations within the FERM domain. There was significant sibship clustering of the phenotype although in some families not all affected members had periodic alternating nystagmus. In situ hybridization studies during mid-late human embryonic stages in normal tissue showed restricted FRMD7 expression in neuronal tissue with strong hybridization signals within the afferent arms of the vestibulo-ocular reflex consisting of the otic vesicle, cranial nerve VIII and vestibular ganglia. Similarly within the afferent arm of the optokinetic reflex we showed expression in the developing neural retina and ventricular zone of the optic stalk. Strong FRMD7 expression was seen in rhombomeres 1 to 4, which give rise to the cerebellum and the common integrator site for both these reflexes (vestibular nuclei). Based on the expression and phenotypic data, we hypothesize that periodic alternating nystagmus arises from instability of the optokinetic-vestibular systems. This study shows for the first time that mutations in FRMD7 can cause idiopathic infantile periodic alternating nystagmus and may affect neuronal circuits that have been implicated in acquired forms.
Please use this url to cite or link to this publication:
author
organization
year
type
journalArticle (original)
publication status
published
subject
keyword
FRMD7, periodic alternating nystagmus, optokinetic reflex, vestibulo-ocular reflex, in situ hybridization, DOMINANT CONGENITAL NYSTAGMUS, MUTATIONS, MOTOR, FAMILY, MODEL, 6P12, MAPS
journal title
BRAIN
Brain
volume
134
issue
3
pages
892 - 902
Web of Science type
Article
Web of Science id
000287745100023
JCR category
CLINICAL NEUROLOGY
JCR impact factor
9.457 (2011)
JCR rank
5/190 (2011)
JCR quartile
1 (2011)
ISSN
0006-8950
DOI
10.1093/brain/awq373
language
English
UGent publication?
yes
classification
A1
copyright statement
I have transferred the copyright for this publication to the publisher
id
1196123
handle
http://hdl.handle.net/1854/LU-1196123
date created
2011-03-24 13:47:12
date last changed
2011-04-28 16:47:14
@article{1196123,
  abstract     = {Periodic alternating nystagmus consists of involuntary oscillations of the eyes with cyclical changes of nystagmus direction. It can occur during infancy (e.g. idiopathic infantile periodic alternating nystagmus) or later in life. Acquired forms are often associated with cerebellar dysfunction arising due to instability of the optokinetic-vestibular systems. Idiopathic infantile periodic alternating nystagmus can be familial or occur in isolation; however, very little is known about the clinical characteristics, genetic aetiology and neural substrates involved. Five loci (NYS1-5) have been identified for idiopathic infantile nystagmus; three are autosomal (NYS2, NYS3 and NYS4) and two are X-chromosomal (NYS1 and NYS5). We previously identified the FRMD7 gene on chromosome Xq26 (NYS1 locus); mutations of FRMD7 are causative of idiopathic infantile nystagmus influencing neuronal outgrowth and development. It is unclear whether the periodic alternating nystagmus phenotype is linked to NYS1, NYS5 (Xp11.4-p11.3) or a separate locus. From a cohort of 31 X-linked families and 14 singletons (70 patients) with idiopathic infantile nystagmus we identified 10 families and one singleton (21 patients) with periodic alternating nystagmus of which we describe clinical phenotype, genetic aetiology and neural substrates involved. Periodic alternating nystagmus was not detected clinically but only on eye movement recordings. The cycle duration varied from 90 to 280 s. Optokinetic reflex was not detectable horizontally. Mutations of the FRMD7 gene were found in all 10 families and the singleton (including three novel mutations). Periodic alternating nystagmus was predominantly associated with missense mutations within the FERM domain. There was significant sibship clustering of the phenotype although in some families not all affected members had periodic alternating nystagmus. In situ hybridization studies during mid-late human embryonic stages in normal tissue showed restricted FRMD7 expression in neuronal tissue with strong hybridization signals within the afferent arms of the vestibulo-ocular reflex consisting of the otic vesicle, cranial nerve VIII and vestibular ganglia. Similarly within the afferent arm of the optokinetic reflex we showed expression in the developing neural retina and ventricular zone of the optic stalk. Strong FRMD7 expression was seen in rhombomeres 1 to 4, which give rise to the cerebellum and the common integrator site for both these reflexes (vestibular nuclei). Based on the expression and phenotypic data, we hypothesize that periodic alternating nystagmus arises from instability of the optokinetic-vestibular systems. This study shows for the first time that mutations in FRMD7 can cause idiopathic infantile periodic alternating nystagmus and may affect neuronal circuits that have been implicated in acquired forms.},
  author       = {Thomas, Mervyn G and Crosier, Moira and Lindsay, Susan and Kumar, Anil and Thomas, Shery and Araki, Masasuke and Talbot, Chris J and McLean, Rebecca J and Surendran, Mylvaganam and Taylor, Katie and Leroy, Bart and Moore, Anthony T and Hunter, David G and Hertle, Richard W and Tarpey, Patrick and Langmann, Andrea and Lindner, Susanne and Brandner, Martina and Gottlob, Irene},
  issn         = {0006-8950},
  journal      = {BRAIN},
  keyword      = {FRMD7,periodic alternating nystagmus,optokinetic reflex,vestibulo-ocular reflex,in situ hybridization,DOMINANT CONGENITAL NYSTAGMUS,MUTATIONS,MOTOR,FAMILY,MODEL,6P12,MAPS},
  language     = {eng},
  number       = {3},
  pages        = {892--902},
  title        = {The clinical and molecular genetic features of idiopathic infantile periodic alternating nystagmus},
  url          = {http://dx.doi.org/10.1093/brain/awq373},
  volume       = {134},
  year         = {2011},
}

Chicago
Thomas, Mervyn G, Moira Crosier, Susan Lindsay, Anil Kumar, Shery Thomas, Masasuke Araki, Chris J Talbot, et al. 2011. “The Clinical and Molecular Genetic Features of Idiopathic Infantile Periodic Alternating Nystagmus.” Brain 134 (3): 892–902.
APA
Thomas, M. G., Crosier, M., Lindsay, S., Kumar, A., Thomas, S., Araki, M., Talbot, C. J., et al. (2011). The clinical and molecular genetic features of idiopathic infantile periodic alternating nystagmus. BRAIN, 134(3), 892–902.
Vancouver
1.
Thomas MG, Crosier M, Lindsay S, Kumar A, Thomas S, Araki M, et al. The clinical and molecular genetic features of idiopathic infantile periodic alternating nystagmus. BRAIN. 2011;134(3):892–902.
MLA
Thomas, Mervyn G, Moira Crosier, Susan Lindsay, et al. “The Clinical and Molecular Genetic Features of Idiopathic Infantile Periodic Alternating Nystagmus.” BRAIN 134.3 (2011): 892–902. Print.