A novel missense mutation in the ATPase, Na+/K+
transporting, alpha 3 polypeptide (ATP1A3) gene has been identified in a family
affected by two distinctly different neurodegenerative conditions — alternating
hemiplegia of childhood (AHC) and rapid-onset dystonia parkinsonism (RDP),
according to a new study presented here June 21 at the International Congress
of Parkinson's Disease and Movement Disorders.
Sergio A. Rodríguez-Quiroga, MD, of the neurogenetics unit
and movement disorders section of the University Centre of Neurology in the JM
Ramos Mejia Hospital, and his colleagues described the clinical and molecular
features in 13 members of a family whose genetic history came to light after a
19-year-old was first diagnosed with RDP.
Clinical histories and the sequencing of the ATP1A3 gene in
dozens of family members revealed that 12 others shared the symptoms of both
conditions. Many of them also had a diagnosis of epilepsy.
The scientists identified a novel missense mutation in
ATP1A3 that was present only in the affected members of this family. This
mutation has not been reported in RDP or AHC before.
"We believe that AHC and RDP represent a phenotypic
continuum of ATP1A3-related disorders," said Dr. Rodríguez-Quiroga. While
in the original case, the young man, now 22, had classic symptoms of RDP —
anarthria, mild dysphagia, hypotonia, and severe bradykinesia in four limbs
with a rostrocaudal gradient of involvement — other family members with the
mutation had hemiplegia, epilepsy, and cognitive impairment.
"The family history was consistent with an autosomal
dominant inheritance," he said. The phenotypes range from seizures only,
cognitive impairment, and development delay, to hemiplegia, dystonia,
parkinsonism, and bulbar impairment.
"Our study
highlights the variability in the neurological spectrum of symptoms that
subjects with ATP1A3 mutations could have," both in severity and age of
onset, he said.
"Variants in other genes or other triggers could
influence the symptom severity and age of onset," Dr. Rodríguez-Quiroga
added. Identifying these triggers could lead to the development of prevention
strategies and treatments. The researchers are evaluating other affected members
of the family for a more precise description of the distinct phenotypes.
That these conditions fall on a continuum "is not a
surprise," said Kenneth Silver, MD, associate professor of pediatrics and
neurology at the University of Chicago, who has consulted on a few hundred
cases of AHC and was not involved with the study. "As we expand the
spectrum, there will be cases that share many of the features of these
conditions."
"Now, we need to figure out what is wrong with the gene
to produce these symptoms," he added. "The findings from this case
study suggest that this is a spectrum of disorders that appear in one
family. It's the same genetic mutation,
but it is expressed differently."
"This new finding lends support to the idea of an
intermediate phenotype and intrafamilial variability," said Suzanne D.
DeBrosse, MD, clinical assistant professor of genetics and genome sciences,
pediatrics, and neurology at Case Western Reserve University, who was not
involved with the study. "This could make a valuable contribution to our
understanding of the variability of ATP1A3-related disorders within
families."
http://journals.lww.com/neurotodayonline/blog/NeurologyTodayConferenceReportersMDSInternationalCongress/pages/post.aspx?PostID=11&cid=MR-eJP-AANNTCR-MDSJune29-Neurology-WNT-NoPromo
S.A. Rodríguez-Quiroga, D. González-Moron, S.A.
Vishnopolska, G.L. Vigo, M. Cordoba, N. Medina, T. Arakaki, N.S. Garretto, M.A.
Kauffman. Expanding the spectrum of ATP1A3 related disorders: Continuum from
alternating hemiplegia of childhood to rapid-onset dystonia parkinsonism?
[abstract]. Mov Disord. 2016; 31 (suppl 2).
http://www.mdsabstracts.org/abstract/expanding-the-spectrum-of-atp1a3-related-disorders-continuum-from-alternating-hemiplegia-of-childhood-to-rapid-onset-dystonia-parkinsonism/
No comments:
Post a Comment