About 14% of cerebral palsy cases may be tied to brain wiring genes
Study points to genes that control the establishment of neural circuits
during early development

Date:
September 28, 2020
Source:
NIH/National Institute of Neurological Disorders and Stroke
Summary:
Researchers confirm that about 14% of all cases of cerebral palsy, a
disabling brain disorder for which there are no cures, may be linked
to a patient's genes and suggest that many of those genes control
how brain circuits become wired during early development. The
results led to recommended changes in the treatment of at least
three patients, highlighting the importance of understanding the
role genes play in the disorder.



FULL STORY ==========================================================================
In an article published in Nature Genetics, researchers confirm that about
14% of all cases of cerebral palsy, a disabling brain disorder for which
there are no cures, may be linked to a patient's genes and suggest that
many of those genes control how brain circuits become wired during early development. This conclusion is based on the largest genetic study of
cerebral palsy ever conducted. The results led to recommended changes in
the treatment of at least three patients, highlighting the importance of understanding the role genes play in the disorder. The work was largely
funded by the National Institute of Neurological Disorders and Stroke
(NINDS), part of the National Institutes of Health.


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"Our results provide the strongest evidence to date that a significant
portion of cerebral palsy cases can be linked to rare genetic mutations,
and in doing so identified several key genetic pathways involved," said
Michael Kruer, M.D., a neurogeneticist at Phoenix Children's Hospital
and the University of Arizona College of Medicine -- Phoenix and a
senior author of the article. "We hope this will give patients living
with cerebral palsy and their loved ones a better understanding of the
disorder and doctors a clearer roadmap for diagnosing and treating them." Cerebral palsy affects approximately one in 323 children in the United
States.

Signs of the disorder appear early in childhood resulting in a wide range
of permanently disabling problems with movement and posture, including spasticity, muscle weakness, and abnormal gait. Nearly 40% of patients
need some assistance with walking. In addition, many patients may also
suffer epileptic seizures, blindness, hearing and speech problems,
scoliosis, and intellectual disabilities.

Since its first official description in 1862, scientists have hotly
debated whether cerebral palsy is caused by problems at birth. For
instance, it is known that babies born prematurely or who experience
a lack of blood flow or oxygen during birth have a greater chance
of suffering from the disorder. Later though, researchers concluded
that a majority (85-90%) of all cases are congenital, or born with
the disease, and some studies had suggested that cerebral palsy could
be inherited. Despite this, the causes of many children's cases had
remained elusive.

Then in 2004, scientists discovered the first genetic mutation known
to cause cerebral palsy. Since then several more mutations have been
identified and depending on how an experiment was performed, scientists
have estimated that anywhere from 2 to 30% of all cases may be linked
to a misspelling in a patient's DNA. In this study, the researchers
provided support for a previous estimate and highlighted which genes
may play a critical role in the disorder.

"Cerebral palsy is one of neurology's oldest unresolved mysteries. The
results from this study show how advances in genomic research provide scientists with the hard evidence they need to unravel the causes behind
this and other debilitating neurological disorders," said Jim Koenig,
Ph.D., program director at NINDS.



==========================================================================
The study was led by Sheng Chih (Peter) Jin, Ph.D., assistant professor
of genetics at Washington University School of Medicine, St. Louis,
and Sara A.

Lewis, Ph.D., a post-doc in the lab Dr. Kruer leads.

The researchers searched for what are known as "de novo," or spontaneous, mutations in the genes of 250 families from the United States, China,
and Australia through a collaboration made possible by the International Cerebral Palsy Genomics Consortium. These rare mutations are thought to
happen when cells accidentally make mistakes copying their DNA as they
multiply and divide.

An advanced technique, called whole exome sequencing, was used to read out
and compare the exact codes of each gene inscribed in the chromosomes of
the patients with that of their parents. Any new differences represented
de novo mutations that either happened while a parent's sperm or egg
cell multiplied or after conception.

Initially the researchers found that the cerebral palsy patients had
higher levels of potentially harmful de novo mutations than their
parents. Many of these mutations appeared to be concentrated in genes
that are highly sensitive to the slightest changes in the DNA letter
code. In fact, they estimated that about 11.9% of the cases could be
explained by damaging de novo mutations. This was especially true for the idiopathic cases which had no known cause and represented the majority
(62.8%) of cases in the study.

Approximately another 2% of the cases appeared to be linked to recessive,
or weaker, versions of genes. This raised the estimate of cases that
could be linked to genetic problems from 11.9% to 14%, as has been
previously reported.

Moreover, the results led to recommendations for more tailored treatments
of three patients.



==========================================================================
"The hope of human genome research is that it will help doctors find the
best, most personalized, matches between treatments and diseases. These
results suggest that this may be possible for some patients with cerebral palsy," said Chris Wellington, program director in the Division of
Genome Sciences at the NIH's National Institute of Human Genome Research,
which also provided support for the study.

When the researchers looked more closely at the results, they found that
eight genes had two or more damaging de novo mutations. Four of these
genes, labeled RHOB, FBXO31, DHX32, and ALK, were newly implicated in
CP while the other four had been identified in previous studies.

The researchers were especially surprised by the RHOB and FBXO31
results. Two cases in the study had the same spontaneous mutation in
RHOB. Likewise, two other cases had the same de novo mutation in FBXO31.

"The odds of this randomly happening are incredibly low. This suggests
that these genes are highly linked to cerebral palsy," said Dr. Jin.

The researchers also looked at the genes behind other brain development disorders and found that about 28% of the cerebral palsy genes identified
in this study have been linked to intellectual disability, 11% to epilepsy
and 6.3% to autism spectrum disorders. In contrast, the researchers found
no significant overlap between cerebral palsy genes and those involved
with the neurodegenerative disorder Alzheimer's disease which attacks
the brain later in life.

"Our results support the idea that cerebral palsy is not one narrow
disease but a spectrum of overlapping neurodevelopmental problems,"
said Dr. Lewis.

Further analysis of the results suggested that many of the genes they
found in this study, including six of the eight genes that had two or
more de novo mutations, control the wiring of neural circuits during
early development.

Specifically, these genes are known to be involved in either the
construction of protein scaffolds that line the perimeters of neural
circuits or in the growth and extension of neurons as they wire up.

Experiments on fruit flies, formally known as Drosophila melanogaster, supported this idea. To do this, the researchers mutated fly versions
of the wiring genes they identified in the cerebral palsy patients. They
found that mutations in 71% of these genes caused flies to have problems
with movement, including walking, turning, and balancing. The results
suggested that these genes play a critical role in movement. They
estimated that there was only a 3% chance these problems would happen
if they had blindly mutated any gene in the fly genome.

"Treatments for cerebral palsy patients have not changed for decades,"
said Dr.

Kruer. "In the future, we plan to explore how these results can be used
to change that."

========================================================================== Story Source: Materials provided by NIH/National_Institute_of_Neurological_Disorders_and Stroke. Note:
Content may be edited for style and length.


========================================================================== Journal Reference:
1. Sheng Chih Jin, Sara A. Lewis, Somayeh Bakhtiari, Xue Zeng,
Michael C.

Sierant, Sheetal Shetty, Sandra M. Nordlie, Aureliane Elie, Mark A.

Corbett, Bethany Y. Norton, Clare L. van Eyk, Shozeb Haider,
Brandon S.

Guida, Helen Magee, James Liu, Stephen Pastore, John B. Vincent,
Janice Brunstrom-Hernandez, Antigone Papavasileiou, Michael
C. Fahey, Jesia G.

Berry, Kelly Harper, Chongchen Zhou, Junhui Zhang, Boyang Li,
Jennifer Heim, Dani L. Webber, Mahalia S. B. Frank, Lei Xia,
Yiran Xu, Dengna Zhu, Bohao Zhang, Amar H. Sheth, James R. Knight,
Christopher Castaldi, Irina R. Tikhonova, Francesc Lo'pez-Gira'ldez,
Boris Keren, Sandra Whalen, Julien Buratti, Diane Doummar,
Megan Cho, Kyle Retterer, Francisca Millan, Yangong Wang, Jeff
L. Waugh, Lance Rodan, Julie S. Cohen, Ali Fatemi, Angela E. Lin,
John P. Phillips, Timothy Feyma, Suzanna C.

MacLennan, Spencer Vaughan, Kylie E. Crompton, Susan M. Reid,
Dinah S.

Reddihough, Qing Shang, Chao Gao, Iona Novak, Nadia Badawi, Yana A.

Wilson, Sarah J. McIntyre, Shrikant M. Mane, Xiaoyang Wang, David J.

Amor, Daniela C. Zarnescu, Qiongshi Lu, Qinghe Xing, Changlian Zhu,
Kaya Bilguvar, Sergio Padilla-Lopez, Richard P. Lifton, Jozef Gecz,
Alastair H. MacLennan, Michael C. Kruer. Mutations disrupting
neuritogenesis genes confer risk for cerebral palsy. Nature
Genetics, 2020; DOI: 10.1038/ s41588-020-0695-1 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2020/09/200928152847.htm

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