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Clinically severe CACNA1A alleles affect synaptic function and neurodegeneration differentially - New Publication
PLoS Genet. 2017 Jul 24;13(7):e1006905. doi: 10.1371/journal.pgen.1006905. [Epub ahead of print]Clinically severe CACNA1A alleles affect synaptic function and neurodegeneration differentially.
Luo X1, Rosenfeld JA1, Yamamoto S1,2, Harel T1,3, Zuo Z1, Hall M4, Wierenga K4, Pastore MT5, Bartholomew D5, Delgado MR6, Rotenberg J7, Lewis RA1,3,8,9, Emrick L1,8, Bacino CA1, Eldomery MK1,3, Coban Akdemir Z1,3, Xia F1, Yang Y1, Lalani SR1, Lotze T8, Lupski JR1,3,8,9, Lee B1, Bellen HJ1,2,10, Wangler MF1,2; Members of the UDN. Author information
1 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX.
2 Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX.
3 Baylor-Hopkins Center for Mendelian Genomics, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX.
4 University of Oklahoma Health Sciences Center, Oklahoma City, OK.
5 Nationwide Children's Hospital & The Ohio State University, Columbus, OH.
6 Department of Neurology and Neurotherapeutics, UT Southwestern Medical Center andTexas Scottish Rite Hospital, Dallas, TX.
7 Houston Specialty Clinic, Houston, TX.
8 Department of Pediatrics, Baylor College of Medicine, Houston, TX.
9 Texas Children's Hospital, Houston, TX.
10 Howard Hughes Medical Institute, Houston TX.
Dominant mutations in CACNA1A, encoding the α-1A subunit of the neuronal P/Q type voltage-dependent Ca2+ channel, can cause diverse neurological phenotypes.
Rare cases of markedly severe early onset developmental delay and congenital ataxia can be due to de novo CACNA1A missense alleles, with variants affecting the S4 transmembrane segments of the channel, some of which are reported to be loss-of-function.
Exome sequencing in five individuals with severe early onset ataxia identified one novel variant (p.R1673P), in a girl with global developmental delay and progressive cerebellar atrophy, and a recurrent, de novo p.R1664Q variant, in four individuals with global developmental delay, hypotonia, and ophthalmologic abnormalities.
Given the severity of these phenotypes we explored their functional impact in Drosophila. We previously generated null and partial loss-of-function alleles of cac, the homolog of CACNA1A in Drosophila. Here, we created transgenic wild type and mutant genomic rescue constructs with the two noted conserved point mutations.
The p.R1673P mutant failed to rescue cac lethality, displayed a gain-of-function phenotype in electroretinograms (ERG) recorded from mutant clones, and evolved a neurodegenerative phenotype in aging flies, based on ERGs and transmission electron microscopy.
In contrast, the p.R1664Q variant exhibited loss of function and failed to develop a neurodegenerative phenotype.
Hence, the novel R1673P allele produces neurodegenerative phenotypes in flies and human, likely due to a toxic gain of function.
Full article is here.
I am gratified (a few butterflies) to present Grand Rounds at The Woman's Hospital of Texas to day on Epilepsy Update for Primary Care Pediatrics and Hospitalists. I will post a pdf later.
Add Academy Diagnostics to ECW / other EMR to send orders for Outpatient Sleep & EEG Testing for Kids and Adults in Texas
Sleep referrals are complex these days.
· Home sleep test? In-Lab Test?
· Adult patients fail with home tests.
· Patients fail home AUTO CPAP.
For 10 years Academy and its physician experts have welcomed infants and children of all ages & complexity. Academy's affiliated Houston AND San Antonio specialists can be seen HERE.
What can you do for your patients and to make the office flow smoothly?
Optimize your EMR function by adding Academy Diagnostics:
In eClinicalWorks or another EMR, add Academy Diagnostics to seamlessly refer your sleep and EEG procedures via P2P or other systems, by the following:
1) Add us to your Referring providers
a. Last Name = Academy
b. First Name = Diagnostics
c. Specialty = Sleep Medicine
Academy Diagnostics - Houston
7505 FANNIN ST
HOUSTON, TX 77054
Phone: 832-659-0248 Fax: 832-659-0261
Academy Diagnostics – San Antonio
8215 FREDERICKSBURG RD
SAN ANTONIO, TX 78229-3355
Phone: 210-616-9500 Fax: 210-616-0400
2) You can also
Please notify us if you have questions about procedure codes.
Our PDF of order forms can be found HERE
Academy Diagnostics Staff
Illustration of Linked Procedures - (Sleep and EEG/Neuro)
PEDIATRIC SLEEP PROCEDURES (under 6) Newborns can have sleep studies by day.
o 95782 Pediatric Diagnostic Polysomnogram (Sleep Study)
o 95783 Pediatric CPAP Titration (If Polysomnogram is positive for OSA or a previous study was performed and results are available)
PEDIATRIC (Over 6 Years) AND ADULT SLEEP PROCEDURES
o 95810 Diagnostic Polysomnogram (Sleep Study) (HST if required by insurance)
o 95811 CPAP Titration (If polysomnogram is positive for OSA or a previous study was performed and results are available.)
o 95811 Split Night Study (Treatment portion to be performed only if the patient meets criteria.)
o 95805 Multiple Sleep Latency Test (MSLT) following a Diagnostic Polysomnogram
o 95805 Maintenance of Wakefulness Test (MWT)
HOME Sleep Testing - Adults
Sample Linked DIAGNOSIS Must indicate at least one qualifying diagnosis:
o G47.33 Obstructive Sleep Apnea
o G47.37 Central Sleep Apnea
o E66.01 Obesity Hypoventilation Syndrome
o G47.61 Periodic Limb Movement Disorder
o F51.8 Sleep Related Movement Disorders, unspecifed
o G47.419 Narcolepsy
o F51.13 Organic Hypersomnia/EDS
o G47.54 Parasomnias
o G47.20 Disruption of 24 hr Sleep/Wake Cycle Other Qualifying Code ___________________
PRE-TEST ESSENTIAL Data for Adults PRE-EXISTING CONDITIONS NOTE: Please indicate if the following Are Applicable
o E66.01 Morbid Obesity (Needs additional diagnosis)
o Pulmonary Disease (Respiratory Failure, COPD, Hypoxemia)
oNeurologic OR Neuromuscular Disease (Epilepsy, Dementia, ALS, Parkinson’s, etc.)
o Significant Cardiac Disease (CHF, Atrial Fibrillation, Pulmonary Hypertension, Arrhythmias)
oAll other conditions ______________________
PRE-Test Essential Data for Adults
Ht:________________ Wt:________________ Neck Circumference________ BMI_________
*Epworth Sleepiness Scale (ESS = 10 or more)
Neuro-Diagnostics - EEG
o Routine EEG (Greater than one hour)
o Extended Video EEG Monitoring (Greater than 14 hours)
R40.4 Transient alteration of awareness
R55 Syncope and collapse
G40.389 Epilepsy, unspecified
R56.9 Other Convulsions (e.g. seizure NOS)
R56 ConvulsionsHOME Sleep Testing - Adults
CPT Code 95806 Sleep study, unattended, simultaneous recording of heart rate, oxygen saturation, respiratory airflow and respiratory effort.
HCPCS Code G0399 Home sleep test with Type III portable monitor, unattended; minimum of four channels: two respiratory movement/airflow, one ECG/heart rate and one oxygen saturation
High dose meant 25 units per gland! I typically use under 20 % of this dose,- The high rate of side reflects reflects the dosing. The reported risk of adverse effects in this study was 3% for those receiving UNDER 25 25 units. JR
Dev Med Child Neurology
2017 May;59(5):531-537. doi: 10.1111/dmcn.13333. Epub 2016 Nov 30.
Negative effects of submandibular botulinum neurotoxin A injections on oral motor function in children with drooling due to central nervous system disorders.
van Hulst K1, Kouwenberg CV2, Jongerius PH3, Feuth T4, van den Hoogen FJ5, Geurts AC1, Erasmus CE2.Author aims of this study were: (1) to determine the incidence and nature of adverse effects on oral motor function after first injections of botulinum neurotoxin A (BoNT-A) in submandibular glands for excessive drooling in children with central nervous system disorders; and (2) to identify independent predictors of these adverse effects.
METHOD:A cohort study involved 209 children (123 males, 86 females, aged 4-27y, median 8y 4mo), who received submandibular BoNT-A injections for drooling. Adverse effects were categorized into swallowing, eating, drinking, articulation, and other problems. Univariable logistic regression was used to study differences in patients with and without adverse effects. Possible predictors were identified using multivariable logistic regression.
RESULTS:Transient adverse effects occurred in 33% of the 209 BoNT-A treatments. Almost 80% of these were mild, versus 8.7% severe. Approximately 54% of the adverse effects spontaneously resolved within 4 weeks; 3% still existed after 32 weeks. A diagnosis of cerebral palsy, higher range of BoNT-A dosage, and a pre-treatment drooling quotient <18% were found to be independent predictors of adverse effects.
INTERPRETATION: Before using submandibular BoNT-A injections for drooling, potential adverse effects should be discussed. Oral motor function needs to be monitored, because existing dysphagia may be worsened. The identified clinical predictors could be helpful to optimize patient selection.
© 2016 The Authors. Developmental Medicine & Child Neurology published by John Wiley & Sons Ltd on behalf of Mac Keith Press.
You are invited to a town hall meeting to discuss special education in the Houston Independent School District. Parents will have an opportunity to ask questions and share their input.
There will be multiple ways for parents to submit questions about special education services in HISD:
1 Ask a question during the town hall meetings.
2 Submit your question electronically at computer stations set up at each town hall meeting location.
3 Email SpecialEducation@HoustonISD.org or visit HoustonISD.org/SpecialEducation to submit a question electronically.
4 Ask your school for a special education comment card, fill it out, and return it to your school’s front office.
5 Call your school’s main office to request that a comment card be mailed to you.
You are invited to a town hall meeting to discuss special education in the Houston Independent School District. Parents will have an opportunity to ask questions and share their input.
Contact: Sharon Cole-Braxton • Senior Manager, ARD/IEP Services • 713-556-7025 • scolebra@HoustonISD.org
WEDNESDAY APRIL 5
Hattie Mae White
Educational Support Center
4400 W 18th St,
Houston, TX 77092
WEDNESDAY APRIL 19
East Field Office
1102 Telephone Rd,
Houston, TX 77023
WEDNESDAY MAY 17
South Field Office
4040 W Fuqua St,
Houston, TX 77045
Abstract for poster at ASHG 2016 De novo missense variants in CACNA1A can cause congenital cerebellar ataxia with global developmental delayJ.A. Rosenfeld, T. Harel1, X. Luo1, S. Yamamoto1, M. Hall2, K. Wierenga2, M. Pastore3, D.Bartholomew3, M. Delga
Abstract for American Society Human Genetics 2016
De novo missense variants in CACNA1A can cause congenital cerebellar ataxia with global
J.A. Rosenfeld1, T. Harel1, X. Luo1, S. Yamamoto1, M. Hall2, K. Wierenga2, M. Pastore3, D.
Bartholomew3, M. Delgado4, J. Rotenberg5, R.A. Lewis1, M. Almannai1, L. Emrick1, T. Lotze1, M.
Ummat1, C.A. Bacino1, M. Eldomery1, Z. Coban Akdemir1, F. Xia1, H. Bellen1, J. Lupski1, Y. Yang1,
B. Lee1, S.R. Lalani1, M. Wangler1, Members of the UDN. 1) Molecular & Human Genetics, Baylor
College of Medicine, Houston, TX; 2) University of Oklahoma Health Sciences Center, Oklahoma
City, OK; 3) Nationwide Children's Hospital & The Ohio State University, Columbus, OH; 4) Texas
Scottish Rite Hospital, Dallas, TX; 5) Houston Specialty Clinic, Houston, TX
Variants in CACNA1A [MIM 601011], encoding the α-1A subunit of the neuronal P/Q type voltage dependent
Ca2+ channel, are known causes of ataxia: triplet repeat expansions extending a
polyglutamine tract in the protein cause adult-onset spinocerebellar ataxia, type 6 [MIM 183086], and
heterozygous variants (typically loss-of-function) cause childhood-onset episodic ataxia, type 2 [MIM
108500]. Additionally, missense variants in the gene cause autosomal dominant familial hemiplegic
migraines [MIM 141500]. We report five individuals with congenital, non-fluctuating ataxia,
hypotonia, ophthalmologic abnormalities, and global developmental delay. Four individuals had a
recurrent, de novo c.4991G>A/p.R1664Q variant, which has been described previously in another
individual with early-onset, persistent limb and trunk ataxia. The fifth individual has a de novo
missense variant, c.5018G>C/p.R1673P. Both missense variants alter arginine residues within the
fourth transmembrane domain, changing the pattern of positive charges within the voltage sensor.
This pattern is also altered by other severe pathogenic alleles, suggesting that more severe clinical
phenotypes could result from disruption of this specific domain. A sixth individual with a severe
presentation of neonatal stroke and subsequent refractory epilepsy had a de novo variant within this
transmembrane domain, c.5075T>A/p.L1692Q. To explore the functional consequences of these
variants, we generated a loss-of-function (LOF) allele in the homologous gene (cac) in Drosophila
that will allow expression of these human variant forms. This LOF allele recapitulates the lethal
phenotypes previously observed in cac mutant flies. Human variants will be assessed through their
ability to rescue the loss of cac in Drosophila photoreceptors, where conditional knockout causes
neurodegeneration, synaptic transmission deficits and neuronal accumulation of autophagic vesicles.
This cohort, combined with previous reports, shows that variants in CACNA1A can cause congenital
non-fluctuating cerebellar ataxia and other severe neonatal presentations, thus expanding the spectrum
of ataxia and other features associated with this important neuronal calcium channel gene. Functional
studies in model organisms will provide further insight into this disease spectrum.
A study claims that certain signs of autism may be seen as early as the first month of life. Specifically, lack of eye contact at that age may indicate autism in a young child.
The first signs of autism may be visible as early as the first month of a child's life, according to a study published in the scientific journal Nature.
"These are the earliest signs of autism ever observed," says lead study author Warren Jones.
Researchers at the Marcus Autism Center in Atlanta followed 110 children from birth to age 3, at which point a diagnosis of autism was ascertained. Fifty-nine babies were considered "high risk" for developing an autism spectrum disorder (ASD) because they had siblings with autism; 51 were considered "low risk" because they did not have first, second or third-degree relatives with ASD.
Data was collected at 2, 3, 4 ,5, 6, 9, 12, 15 and 24 months of age. Each time, the children watched videos showing actresses playing the role of a caregiver. "Every baby watched the same videos, and then we could measure what was different about the responses of infants later diagnosed with autism versus infants who were typically-developing," Jones says.
Lack of eye contact is one of the red flags when it comes to autism - a group of neurodevelopmental disorders that can cause significant social, communication and behavioral challenges.
Jones, who is the director of research at Marcus Autism Center and assistant professor in the Department of Pediatrics at Emory University School of Medicine, says he really expected the children later diagnosed with autism would have diminished eye contact from birth. Instead, he and his colleagues measures how much time each baby was looking at the eyes of the caregiver in the video.
"Basically from birth, (all) babies will look more at the eye part of faces," says Jones. But at about 4 to 6 weeks, he says the attention to eyes decreases, then in typical babies picks up again at 2 months. Jones found, "in the first 6 months of life we're seeing a decline in the amount of looking at other people's eyes in children who later are diagnosed with autism."
The research suggests that a baby's initial eye contact ability may be an almost a reflex-like behavior, but then there may be a second phase of development that depends on different brain and gene systems which lead to social interaction, Jones says. That's where a typically developing child's development may differ from a child with autism.
The study authors conclude that "the observation of this decline in eye fixation - rather than outright absence - offers a promising opportunity for early intervention."
This is not something parents are going to see by just holding their baby, Jones points out. This type of eye-tracking requires sophisticated technology that can track even the slightest movement of the eye.
"It's a very interesting study with intriguing results. " says Wendy Stone, a longtime autism researcher and director of the Research in Early Autism Detection & Intervention (READI) lab at the University of Washington. But, she adds, "many researchers in this field have not seen behaviors under 6 months to be predictive of later diagnosis."
She also cautions that babies looking at videos of their mothers are not the same as the actual stimuli created by a mom interacting with her baby. "Are these babies less interested in eyes because mouths are more interesting to look at and more attractive because there's more movements? To me that's one of the big questions," says Stone.
Dr. Max Wiznitzer, a pediatric neurologist and autism specialist at the Rainbow and Babies Children's Hospital in Cleveland, Ohio, says this new study is a continuation of previous work in babies. He says this research makes sense to him. "There's a decrease in the amount of attention to eyes as an early marker of social behavior (think of it as a primitive level of socialization)." Wiznitzer suggests the failure to establish these early social skills has ramifications later as "social behavior shifts into more sophisticated patterns."
If this research bears out, then maybe at some point a pediatric practice could track eye movements as one way to diagnose a child with autism, says Stone. "But we're really, really far away from that."
Wiznitzer says this may explain why the autism symptoms may be more apparent at 18 to 24 months, "even though 'subclinical' onset was months earlier." He also suggests these study results may offer another explanation why the measles, mumps and rubella vaccine, which isn't administered until a baby is at least 12 months old, cannot be blamed for causing autism.
Everyone agrees this research needs to be replicated in bigger studies with more children, Wiznitzer says. "The authors are correct that a replication study using a larger number (of children) is necessary. Before that time, I would not devote extensive resources towards assessing eye attention in infants or designing major intervention programs."
Jones says, "what we really want to do is create growth charts for social behavior, just like we have growth charts for charting a child's height and weight." He says these those are the kind of tools that pediatricians need and parents are looking for.
Read more here
What are the standards of care for managing neurologic problems and spasticity in cerebral palsy? What is the data? Its more than baclofen...
Systematic Review of Interventions fo Cerebral Palsy - AACPDM
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