Thursday, August 29, 2019

Novel neonatal variants of the carbamoyl phosphate synthetase 1 deficiency

Beibei Yan, Chao Wang, Kaihui Zhang, Haiyan Zhang, Min Gao, Yuqiang Lv, Xiaoying Li1, Yi Liu and Zhongtao Gai.  Novel Neonatal Variants of the Carbamoyl Phosphate Synthetase 1 Deficiency: Two Case Reports and Review of Literature.  Front. Genet., 22 August 2019 |

Carbamoyl phosphate synthetase I (CPS1) deficiency (CPS1D), is a rare autosomal recessive disorder, characterized by life-threatening hyperammonemia. In this study, we presented the detailed clinical features and genetic analysis of two patients with neonatal-onset CPS1D carrying two compound heterozygous variants of c.1631C > T (p.T544M)/c.1981G > T (p.G661C), and c.2896G > T (p.E966X)/c622-3C > G in CPS1 gene, individually. Out of them, three variants are novel, unreported including a missense (c.1981G > T, p.G661C), a nonsense (c.2896G > T, p.E966X), and a splicing change of c.622-3C > G. We reviewed all available publications regarding CPS1 mutations, and in total 264 different variants have been reported, with majority of 157 (59.5%) missense, followed by 35 (13.2%) small deletions. This study expanded the mutational spectrum of CPS1. Moreover, our cases and review further support the idea that most (≥90%) of the mutations were “private” and only 10% recurred in unrelated families.

I am beautiful like my mother

Despite being bullied because of her physical appearance, Nia is full of joy and changing the way her community cares for others.

The Indonesian girl, whose full name is Karunia, was born without fingers and toes, a rare congenital condition called Apert Syndrome that makes her look different.

“There are some who bully Nia,” Chandra, her father, told Compassion Australia. “They mock her by saying, ‘Hey, look, it’s Nia, the deformed girl’.”

But she finds hope in what her dad, a farmer in East Indonesia, tells her.

“’You are God’s gift’,” he firmly tells her. “When they bully you, you can say that you are God’s gift and not a creation of any man.”

When Nia was born, her parents were grateful to God but didn't know what to do and how best to take care of her.

"I just cried and wondered why God had entrusted this to me,” says Angelina, Nia's mother.

Nia endured a lot of pain, high fevers and, sometimes, she struggled to breathe with the condition that doesn't have a cure--not to mention the stares and fearful looks people in the small community gave the little girl.

With little education, and struggling to care for Nia, who needed specialized care, the desperate couple registered their baby girl into a program with Compassion International, which helped give her regular medical checkups and get funds for surgery to give Nia fingers on her right hand.

“I started to feel strong,” says Angelina. “I told my husband that I love her even more than if I had a healthy child without disabilities. It is because of the strength of God.”

Nia with her parents, Chandra and Angelina. They received a lot of help from their church and Compassion Australia in caring for their daughter with special needs.

Eventually, Nia was old enough and healthy enough to start the Child Sponsorship Program offered by Compassion, and while she's learning, she's also teaching others about self-acceptance and how to combat bullying.

“I am beautiful like my mother,” she says. “When my friends mocked me because I don’t have normal fingers, my mom taught me to say back to them that this is what Jesus gave me.”

Tuesday, August 27, 2019

A memorable flight

A Texas mom praised a United Airlines crew and passengers who accommodated her four-year-old son with autism who did not want to sit still on their flight home from a family vacation.

Lori Gabriel, of Cypress, who was about half an hour from Houston, told Fox News on Tuesday that on August 6 she was on a flight from San Diego to George Bush Intercontinental Airport in Houston with her son, Braysen, who usually loves to fly, when he “had a meltdown.”

“It was time for takeoff and Braysen had slipped out of his seatbelt and he wanted to sit on the floor. So, we were trying to get him back into his chair and get his seatbelt back on, and that’s when he had his meltdown and started kicking, screaming and hitting,” Gabriel told Fox News.

She said as she was trying to get him back in the chair, a flight attendant came over and told her the flight couldn’t take off until he was seated.

“I said, ‘I am sorry.’ I told her he’s autistic,” Gabriel said, adding that she was worried they were going to get kicked off the flight “since he wouldn’t sit down and I would have understood that because it’s a safety issue.”

Gabriel said the flight attendant was “so nice” and let her hold Braysen on her lap for takeoff. She said after the seatbelt sign had been turned off, “I just couldn’t hold him anymore because he was fighting me the entire time and that’s when he sat on the floor.”

Gabriel said a passenger sitting across from them, a United flight attendant who was not working during the flight, was being nice and said it was not a problem when he was kicking her feet as he was on the ground.

Gabriel said her son then made his way up to first-class and was “messing” with a man’s seat. Gabriel said the man told her not to worry about it and that he didn’t mind, even introducing himself to Braysen and giving him high-fives.

Gabriel, who shared what had happened on her Facebook page, said instead of handling the situation in a negative manner, members of the flight crew chose to accommodate her son’s needs.
She added they allowed Braysen to sit wherever he wanted.

“Huge thank you to United Airlines they accommodated his needs, made sure we were all OK, worked around where he choose to sit,” Gabriel wrote on Facebook after she had landed in Texas, adding that the flight attendants “couldn’t have done a better job.”

United Airlines responded to Gabriel’s shoutout on social media, “It sure sounds like Braysen and your family had a great flight. We are happy that our crew was able to make it an enjoyable experience. We are overjoyed to see that we have such loving and supportive passengers on board as well!”

Gabriel also thanked the man sitting in first class.

“To the man in first-class seat 6C, you rock. Thanks for playing with Braysen and not minding him kicking your seat or messing with you! He loved your high fives!” Gabriel wrote in the Facebook post.

Gabriel told Fox News that at the end of the flight, the flight attendant who was sitting across from them gave her a hug and a handwritten note, writing that she commended Gabriel for her strength and said her family was “loved and supported.”

The woman wrote that she commended Gabriel for her strength and said her family was “loved and supported.”

“Do not ever let anyone make you feel as though you are an inconvenience or a burden. He is a blessing,” the woman wrote. “God bless your patience, your love, your support and your strength. Continue to be a super woman.”

In response, Gabriel posted a picture of the note on her Facebook page and wrote, “To the lady that wrote me this note in seat 7D thank you, you may not know how much that means to us when we feel defeated. Thank you for helping and being kind.”

Gabriel told Fox News that the woman “in seat 7D,” now identified as Camille Vaughn, saw the Facebook post and commented on it on Tuesday, writing, “Blessed to see this. Blessed to have met your family and made a difference. Thank you for sharing and I hope to one day see you again #Superwoman.”

“She made me speechless when she found me,” Gabriel told Fox News.

Gabriel said Braysen has been on flights to Kentucky and back before the San Diego flights and said there were no issues. She noted those flights were not as long as the trip back from San Diego, which was three and a half hours long versus two.

“I just never had so many strangers be so kind,” Gabriel told Fox News on Tuesday.

“It shows me that there are still good people in the world. It shows me that me and my family can go on vacations, we can go where all other families go. We can go anywhere, theme parks, we can do anything anyone else can because there are people who are caring and understanding.”

Hippotherapy revisited

Tomoko Mutoh, Tatsushi Mutoh, Hirokazu Tsubone, Makoto Takada, Misato Doumura, Masayo Ihara, Hideo Shimomura, Yasuyuki Taki and Masahiro Ihara.  Impact of Long-Term Hippotherapy on the Walking Ability of Children With Cerebral Palsy and Quality of Life of Their Caregivers Front. Neurol., 13 August 2019 |

Background: Cerebral palsy (CP) is a permanent motor disorder that occurs at birth or during early infancy. Despite advances in fetal and maternal medicine, the incidence of CP remains high. Hippotherapy has gradually been recognized as an excellent rehabilitation tool for children with CP. However, a scientific basis for how it achieves long-term functional improvements or provides additional benefits to patients' caregivers remains unknown.

Objectives: We performed a prospective trial to determine how hippotherapy affects the gross motor and gait functions in children with CP and how it may also impact the quality of life (QOL) of patients' caregivers.

Methods: In total, 24 children with CP (11 boys, 13 girls; age: 4–14 years; Gross Motor Function Classification System [GMFCS] II-III) underwent a program (30 min/day, once a week) of hippotherapy or day-care recreation (control) over a 1-year intervention and a 3-month follow-up period. Assessment measures used for the children were gait parameters for a 5-m walk test, Gross Motor Function Measure (GMFM)-66, and GMFM dimension-E (GMFM-E). The QOL of the caregivers was estimated using a brief version of the World Health Organization Quality Of Life (WHOQOL-BREF) self-assessment questionnaire.

Results: In addition to better GMFM-66 and GMFM-E scores, hippotherapy was associated with increased cadence, step length, and mean acceleration; stabilized horizontal/vertical displacement of patients; and better relationship between the psychological status and QOL of the caregivers than those seen in the control group (p < 0.05). Additionally, the initially improved children's step length and their caregivers' psychological QOL domain (particularly in the “positive feeling” facet) tended to be preserved up to the 3-month follow-up.

Conclusion: These data suggest that compared with common day-care recreational activities, a 1-year program of once-weekly hippotherapy can improve not only the walking ability of children with CP but also the psychological health and QOL of their caregivers.

Mutoh T, Mutoh T, Tsubone H, Takada M, Doumura M, Ihara M, Shimomura H, Taki Y, Ihara M. Effect of hippotherapy on gait symmetry in children with cerebral palsy: A pilot study. Clin Exp Pharmacol Physiol. 2019 May;46(5):506-509.

We aimed to investigate the effect of hippotherapy on gait symmetry in children with cerebral palsy (CP). Twelve children with Gross Motor Function Classification System (GMFCS) levels II-IV received weekly hippotherapy lesson for 1 year. Gait analyses were performed during a 5-m walking test, using a portable, tri-axial accelerometer-based motion recorder. The baseline symmetry index derived from the Lissajous index (LI) figure before hippotherapy was greater than the LI in age-matched normal subjects (P < 0.01). Hippotherapy was associated with a decreased LI (-10.4 ± 4.9%, P = 0.018) and an improved GMFCS score (-0.6 ± 0.7, P = 0.02). These data suggest that hippotherapy has a beneficial effect on symmetry of the trunk movement in children with CP.

Mutoh T, Mutoh T, Tsubone H, Takada M, Doumura M, Ihara M, Shimomura H, Taki Y, Ihara M. Impact of serial gait analyses on long-term outcome of hippotherapy in children and adolescents with cerebral palsy. Complement Ther Clin Pract. 2018 Feb;30:19-23.

The aim of this study was to obtain data of gait parameters on predicting long-term outcome of hippotherapy. In 20 participants (4-19 years; GMFCS levels I to III) with cerebral palsy (CP), gait and balance abilities were examined after 10-m walking test using a portable motion recorder. Hippotherapy was associated with increased Gross Motor Function Measure (GMFM)-66 at 1 year from the baseline (P < 0.001). Hippotherapy increased stride length, walking speed, and mean acceleration and decreased horizontal/vertical displacement ratio over time (P < 0.05). Stride length and mean acceleration at 6 weeks predicted the elevation of GMFM-66 score. These data suggest that 1-year outcome of hippotherapy on motor and balance functions can be assessed from the early phase by serial monitoring of the gait parameters.

Mutoh T, Mutoh T, Takada M, Doumura M, Ihara M, Taki Y, Tsubone H, Ihara M. Application of a tri-axial accelerometry-based portable motion recorder for the quantitative assessment of hippotherapy in children and adolescents with cerebral palsy. J Phys Ther Sci. 2016 Oct;28(10):2970-2974.

[Purpose] This case series aims to evaluate the effects of hippotherapy on gait and balance ability of children and adolescents with cerebral palsy using quantitative parameters for physical activity. [Subjects and Methods] Three patients with gait disability as a sequela of cerebral palsy (one female and two males; age 5, 12, and 25 years old) were recruited. Participants received hippotherapy for 30 min once a week for 2 years. Gait parameters (step rate, step length, gait speed, mean acceleration, and horizontal/vertical displacement ratio) were measured using a portable motion recorder equipped with a tri-axial accelerometer attached to the waist before and after a 10-m walking test. [Results] There was a significant increase in step length between before and after a single hippotherapy session. Over the course of 2 year intervention, there was a significant increase in step rate, gait speed, step length, and mean acceleration and a significant improvement in horizontal/vertical displacement ratio. [Conclusion] The data suggest that quantitative parameters derived from a portable motion recorder can track both immediate and long-term changes in the walking ability of children and adolescents with cerebral palsy undergoing hippotherapy.


Monday, August 26, 2019

Think beyond Charcot-Marie-Tooth disease

Alderson J, Ghosh PS. Clinical Reasoning: Pes cavus and neuropathy: Think beyond Charcot-Marie-Tooth disease. Neurology. 2019 Aug 20;93(8):e823-e826.

An 18-year-old woman was referred to a neuromuscular clinic for neuropathy and tremors. She had been born full-term and had mildly delayed walking at 14 months. She was a toe-walker, clumsy, and when running, had difficulty keeping up with her peers. She was diagnosed with attention-deficit/hyperactivity disorder (ADHD) at age 7 and was found to have high arches and difficulty with heel-walking. EMG and nerve conduction studies (NCS) were performed, showing demyelinating neuropathy. With her history and EMG/NCS findings, she was diagnosed with Charcot-Marie-Tooth (CMT) disease. Symptoms progressed over the next few years, characterized by tripping, occasional falls, and continued difficulty running. She could climb stairs without the use of a handrail, but was very cautious going down the stairs. She also developed tremors in the hands (left > right), which would worsen when she approached objects. There was no loss of sensation, paresthesias, bladder or bowel problems, or hearing or visual symptoms. She graduated from high school and was accepted into college. Family history was negative for neurologic disorders. Neurologic examination showed normal mental status and cranial nerves. There were no abnormal eye movements or corticobulbar findings (no brisk jaw jerk, gag reflex, dysarthria, or pseudobulbar palsy). She had ankle contractures and pes cavus. She had mild lower limb spasticity without atrophy or fasciculations, and 5−/5 weakness of distal extremity muscles, including bilateral abductor digiti minimi, first dorsal interossei, tibialis anterior, and extensor hallucis longus. Tendon reflexes were 2+ in the upper extremities and brisk (3+) in the lower extremities; plantars were extensor. Sensation was intact to light touch, pain, temperature, and proprioception, but vibration was mildly reduced at the toes. She had cerebellar intention tremors (left > right) and mild dysmetria on finger-to-nose testing without appreciable dysdiadochokinesia. Her gait was mildly wide-based and tandem gait was impaired....

Though pes cavus is commonly seen in CMT, it would be unusual to have brisk reflexes in the demyelinating form of CMT. CMT most commonly causes distal weakness, atrophy, and sensory loss with arreflexia, though rare CMT subtypes can have pyramidal features...

In our patient, presence of upper and lower motor neuron and possibly cerebellar findings could suggest neurometabolic disorders like late-onset leukodystrophies. Leukodystrophies are a heterogeneous group of inherited disorders with highly variable phenotype and genotype.6 Presence of demyelinating neuropathy could further narrow the differential diagnosis6: X-linked adrenoleukodystrophy (adrenomyeloneuropathy in female patients), Krabbe disease (KD), metachromatic leukodystrophy, cerebrotendinous xanthomatosis (treatable condition that should be screened by checking cholestanol levels even in absence of tendon xanthomas), and Pelizaeus-Merzbacher-like disease (no nystagmus)...

Laboratory tests showed normal blood counts, vitamin levels (B12, folate, E), lactate, glucose, renal, liver, and thyroid functions, C-reactive protein, homocysteine, methylmalonic acid, and copper. Treatable causes of myeloneuropathy due to B12 and copper deficiencies were ruled out; cholestanol levels were not checked. Very long-chain fatty acids were normal, making adrenomyeloneuropathy less likely, though it can be normal in female carriers. MRI spine performed during the first evaluation was normal so was not repeated. MRI brain showed nonenhancing, confluent, symmetrical callosal and periventricular white matter lesions without much progression from the previous MRI . MRI changes could suggest leukodystrophies, though lack of progression was unusual. Lumbar puncture was not performed. NCS showed prolonged distal latencies and slow conduction velocities with preserved amplitudes of both the sensory and motor responses, similar to a previous study and consistent with demyelinating neuropathy. Needle EMG showed mild chronic reinnervation changes in the tibialis anterior muscle. Electrodiagnostic features along with the clinical course were more consistent with hereditary demyelinating neuropathy rather than an acquired demyelinating neuropathy. Genetic panel for CMT, which included the following genes, was negative at first evaluation: PMP22, Cx32, MPZ, ERG2, NFL, GDAP1, LITAF, MFN2, SH3TC2, FIG4.

As the differential diagnosis was broad at this stage (complex HSP, leukodystrophies), whole exome sequencing (WES) was performed as the next diagnostic step. In this case, WES identified 2 known pathogenic mutations in the galactocerebrosidase gene (GALC): maternally inherited deletion of exons 11–17 (3′end) and paternally inherited c. 857G>A, p.G286D. GALC enzyme activity was low in the plasma, thus confirming KD. Lysosomal enzyme screening test is useful in diagnosing KD. Genetic counseling was provided and the patient was referred to the Genetics and Metabolism clinic for further evaluation and management...

KD occurs in approximately 1 in 250,000 births in the United States. Clinically KD can be divided into 2 major phenotypes: infantile-onset (<12 months, 85%–90%) characterized by progressive neurologic deterioration in infancy and death before age 2 years and later onset (>12 months, 10%–15%) with slower disease progression. Within the later-onset type, patients can be further subdivided into late infantile (up to 3 years), juvenile (3–8 years), or adulthood, which is clinically more heterogeneous and less severe.7,8 Our patient fits into juvenile-onset KD.

Children older than 6 years often exhibit behavioral symptoms (ADHD and mood disorders) first, followed by motor difficulties.  They often decline rapidly after disease onset followed by more gradual progression over years; survival has been reported up to 26 years. Our patient presented around age 7 with ADHD symptoms with slow progression and preserved cognitive function. Pes cavus has been reported before the diagnosis of KD (as seen in our patient) and is suggestive of peripheral neuropathy. Most patients with infantile-onset KD have abnormal NCS with disease severity correlating with degree of demyelinating neuropathy.10 Our patient had demyelinating neuropathy at age 7, which remained stable over a decade. About half of the patients with later-onset KD have p.G286D mutation, as was seen in our patient. However, it is difficult to predict the clinical course as there is significant variability within the same family.

Treatment of KD depends on the age at diagnosis and stage of the disease. For children <6 months with stage II/III infantile-onset KD, treatment is largely supportive. Asymptomatic newborns identified by prenatal testing (based on positive family history) or abnormal newborn screening followed by additional testing and confirmed infantile-onset KD are candidates for hematopoietic stem cell transplant (HSCT) before 14 days. There is no consensus regarding HSCT in asymptomatic newborns with abnormal newborn screening results presumed to be at risk for later-onset KD. Preclinical studies are conducted for several potential treatment options including enzyme replacement therapy, neural stem cell transplantation, substrate reduction therapy, and chemical chaperone therapy.

It is important to think beyond CMT when there are atypical clinical findings and radiologic abnormalities in spite of the presence of pes cavus and demyelinating neuropathy.

Sunday, August 25, 2019


Russian psychologist Alexander Luria documented the famous case of mnemonist Solomon Shereshevsky, who was quite different from the first documented hyperthymestic known as AJ (real name Jill Price) in that Shereshevsky could memorize virtually unlimited amounts of information deliberately, while AJ could not – she could only remember autobiographical information (and events she had personally seen on the news or read about). In fact, she was not very good at memorizing anything at all, according to the study published in Neurocase.  Hyperthymestic individuals appear to have poorer than average memory for arbitrary information. Another striking parallel drawn between the two cases was that Shereshevsky exemplified an interesting case of synesthesia  and it has been suggested that superior autobiographical memory is intimately tied to time-space synaesthesia.

Hyperthymestic abilities can have a detrimental effect. The constant, irrepressible stream of memories has caused significant disruption to AJ's life. She described her recollection as "non-stop, uncontrollable and totally exhausting" and as "a burden".  AJ is prone to getting lost in remembering. This can make it difficult to attend to the present or future, as she is permanently living in the past. Others who have hyperthymesia do not display any of these traits, however.

AJ displays considerable difficulty in memorizing allocentric information. "Her autobiographical memory, while incredible, is also selective and even ordinary in some respects," – McGaugh. This was demonstrated by AJ's poor performance on standardised memory tests. At school, AJ was an average student, unable to apply her exceptional memory to her studies.

Deficits in executive functioning and anomalous lateralisation were also identified in AJ. These cognitive deficiencies are characteristic of frontostriatal disorders.

Even those with a high level of hyperthymesia do not remember exactly everything in their lives or have "perfect memory". Studies have shown that it is a selective ability, as shown by AJ's case, and they can have comparative difficulty with rote memorization and therefore cannot apply their ability to school and work…

It has been proposed that the initial encoding of events by such people includes semantic processing, and therefore semantic cues are used in retrieval. Once cued, the memory is retrieved as episodic and follows a pattern similar to that of a spreading activation model. This is particularly evident in AJ's case. She describes how one memory triggers another, which in turn triggers another and how she is powerless to stop it: "It's like a split screen; I'll be talking to someone and seeing something else."[1] This theory serves to explain why hyperthymestics have both a sense of 'knowing' (semantic memory) and 'remembering' (episodic memory) during recollection.

One writer claimed hyperthymesia may be a result of reviewing memories constantly to an obsessive-compulsive degree.  However AJ has completely dismissed this article as "a load of crap" and others with hyperthymesia claim to never revisit uneventful memories. Other findings have shown that the tendencies to absorb new information and fantasize are personality traits that are higher in hyperthymestics than the rest of the population. These traits: absorption and fantasizing also correlated with one of the tests that measures superior autobiographical memory within the hyperthymestic sample.

An MRI study conducted on AJ provides a plausible argument as to the neurological foundation of her superior memory.  Both the temporal lobe and the caudate nucleus were found to be enlarged. The hippocampus, located in the medial temporal lobe, is involved in the encoding of declarative memory (memory for facts and events), while the temporal cortex is involved in the storage of such memory.  The caudate nucleus is primarily associated with procedural memory, in particular habit formation, and is, therefore, intrinsically linked to obsessive-compulsive disorder. Parker and colleagues speculated that a defective frontostriatal circuit could be responsible for the observed executive function deficits in hyperthymesia. This circuit plays a crucial role in neurodevelopmental disorders. Given the parallels in some aspects of behavior, AJ's hyperthymestic abilities possibly stem from atypical neurodevelopment. Scientists now need to ascertain if and how these brain areas are connected to establish a coherent neurological model for superior autobiographical memory.

As of April 2016, six cases of hyperthymesia have been confirmed in peer-reviewed articles, first being that of "AJ" (real name Jill Price) in 2006. More cases have been identified that are yet to be published. AJ's case was originally reported by researchers from the University of California, Irvine, Elizabeth Parker, Larry Cahill, and James McGaugh, and is credited as being the first case of hyperthymesia. AJ can apparently recall every day of her life from when she was 14 years old: "Starting on February 5th, 1980, I remember everything. That was a Tuesday."

In March 2009, AJ was interviewed for an article in Wired magazine by Gary Marcus, a cognitive psychologist at New York University.  Price's brain had been subject to a brain scan and the hippocampus and prefrontal cortex had been reportedly normal. Marcus claimed, however, that her brain resembled "those of people with obsessive-compulsive disorder" and suggested that her remarkable memory might be "the byproduct of obsession", claiming also that "the memory woman clings tightly to her past". Price has since reacted angrily to such claims and McGaugh has also expressed skepticism about this explanation.  Price gave her first interview in over a year for the UK's Channel 4 documentary The Boy Who Can't Forget, and provided an insight into just how difficult life can be for people who have this ability.

Parker ES, Cahill L, McGaugh JL. A case of unusual autobiographical remembering. Neurocase. 2006 Feb;12(1):35-49.

This report describes AJ, a woman whose remembering dominates her life. Her memory is "nonstop, uncontrollable, and automatic." AJ spends an excessive amount of time recalling her personal past with considerable accuracy and reliability. If given a date, she can tell you what she was doing and what day of the week it fell on. She differs from other cases of superior memory who use practiced mnemonics to remember vast amounts of personally irrelevant information. We propose the name hyperthymestic syndrome, from the Greek word thymesis meaning remembering, and that AJ is the first reported case.

Friday, August 23, 2019

Effect on EEG of total corpus callosotomy for pharmacoresistant infantile spasms

Baba S, Vakorin VA, Doesburg SM, Nagamori C, Cortez MA, Honda R, Ono T, Toda K, Nishimoto H, Ebihara T, Sakai K, Ochi A, Snead OC 3rd, Baba H, Otsubo H. EEG before and after total corpus callosotomy for pharmacoresistant infantile spasms: Fast oscillations and slow-wave connectivity in hypsarrhythmia. Epilepsia. 2019 Aug 13. doi: 10.1111/epi.16295. [Epub ahead of print]


We analyzed the features of fast oscillations (FOs) and connectivity in hypsarrhythmia to identify biomarkers for predicting seizure outcomes after total corpus callosotomy (TCC) in children with pharmacoresistant infantile spasms (IS). We hypothesize that the power of FOs and connectivity of slow waves in hypsarrhythmia would indicate the prognosis of IS.

We retrospectively identified 42 children with pharmacoresistant IS who underwent TCC from 2009 to 2014 at Nagasaki Medical Center. We collected preoperative hypsarrhythmia for 200 seconds from each child. Children were categorized into three groups with interictal epileptic discharges on EEG at 6 months after TCC: group A, no epileptic discharge; group B, lateralized epileptic discharges; and group C; bilateral epileptic discharges. We analyzed spectral power and phase synchronization in preoperative hypsarrhythmia among the three groups.

We found 10 children in group A, 10 children in group B, and 22 children in group C. All group A and 1 in group B achieved seizure freedom after TCC. Six (67%) of 9 group B children who underwent further surgeries achieved seizure freedom. Ten (45%) of group C children had seizure reduction >50% after TCC, and 13 (87%) of 15 children who underwent further surgeries had residual seizures. The clinical profiles of the three groups did not differ significantly. The power of FOs (≥45 Hz) in hypsarrhythmia was significantly stronger in group C at the midline and temporal regions than in groups B and A (P = .014). The connectivity of theta (4-9 Hz) and FOs (29-70 Hz) tended to increase in group C, compared with the increased connectivity of 1-2 Hz in group A (P = .08).

The increased power and connectivity of FOs in hypsarrhythmia may correlate with pharmacoresistant and surgically resistant seizures in IS. The existence and connectivity of FOs are associated with unilateral/bilateral cortical epileptogenicity in hypsarrhythmia. Prominent slow waves and connectivity without FOs might correlate with seizure freedom after TCC. Modulation of the callosal system with subcortical/cortical epileptic discharges might play a role in generating hypsarrhythmia and IS.

Courtesy of:

A change of heart

Dr Alin Gragossian was in the middle of her third year as an emergency medicine resident at Drexel in December of 2018 when she became critically ill and ultimately required a heart transplant to survive. She now joins us just 7 months after her surgery to discuss her remarkable journey.

I was an ICU resident, so I was doing my admissions. As an ICU resident, we run the codes on the floors. That particular day, my attending noticed that I was getting really short of breath with every sentence that I was speaking.

Not only that, but when I was going to the code — I usually take the stairs everywhere when I'm in the hospital, just to get some exercise — I found myself stopping in the middle because I was so short of breath going up the stairs. That happened again another time when I was on the subway. This all happened in a few days and progressively got worse until December 21, which is when I went to the hospital. I tried to make an appointment with primary care, but this was right before Christmas, so many places were closed and I didn't have time.

Then things got worse, and on that particular Friday, I went to the emergency room. They got a chest x-ray and I remember everybody said I looked sick. My attending came in and he said, "You don't look good; something's definitely wrong."

As ER doctors, we have a really good way of telling when someone's about to crash. But I was like, "No, I'm fine." He said, "Your lips are blue. You look very pale. Your heart rate is in the 140s." And I said, "I think it's just anxiety." It definitely wasn't.

I wanted to leave against medical advice, but he did not let me. By then, I was admitted just to find out what this was. Initially, we tried to empirically treat it as a possible pneumonia. It looked like a multifocal viral pneumonia. Looking back, it was pleural effusions, but it was very unclear as to what was going on.

I was so lucky to have been in the hospital because I would have died if I had been at home. I looked up at my monitor and I remember that my heart rate was going down. It was in the 50s, then 40s, and then 30s. And that's the last I remember.

I asked the residents what had happened after the fact, a couple of months ago. One of the residents said that they couldn't feel pulses at all. I was blue, cold, and sweaty. She said I looked at her and I said, "Please don't let me die tonight." Every time I say that, I get chills.

Eventually, later on in the day, we got an echo and it showed hypokinesis and dilated chambers, and my ejection fraction was 5%. My heart was the problem, so I was switched to the cardiac critical unit. And then once I went there, I had to go to the cath lab.

When they did my first right heart cath, they were worried because my cardiac index was 1.2 initially, and all the numbers were just terrible. At that point, the cardiologist said, "We're going to take you back upstairs, we're going to start you on milrinone, and we're going to have to talk about what to do next."

I remember the attending came in and he said, "This looks like it's pretty chronic. It doesn't look like it's a myocarditis that happened overnight. We're going to have to transfer you in case you're going to need advanced heart failure therapy" — so a VAD, a balloon pump, an Impella, or a heart transplant.

Eventually I was transferred to the University of Pennsylvania, where I received all of my care…

It was a big shock. I remember I was sad, angry, and in shock, but the way I was thinking — and they called it the most ER doctor way of thinking — I said, "I just need the heart to get out of here." That's all I cared about.

I was like, all right, we have a diagnosis, we have a treatment option, and I've got to get out of here. That was my way of thought. I did have a transplant therapist talk to me every day. I journaled all the time. I tried to process it as well as I could.

At the end of the day, I didn't see it as a terrible option. Some people see transplant as the worst thing that they're going to get. I saw it as the coolest thing ever because it was a second chance at life. I didn't see it as an end; I saw it as a new beginning…

There was this weird sense of if that's going to happen, it's going to happen. There was this very unusual sense of calm around it. But for the most part, I also trusted everybody. Ironically, I was going to be starting on critical care fellowship — we're in medicine; we do a lot of cool things. There was a part of me that was very sure that things would be okay, if that helps.

Of course, there was a part of me that was afraid. But I was enlisted and then I got the transplant…

Around 7:30, the nurse came in with the phone. I don't remember her name and I don't remember much from the conversation other than, "We found a heart; do you accept it?" I was so in shock that the first thing I said was, "Yes. I'll go call my mom now."

At 2 AM I was going to the OR. As they were wheeling me in, I remember that that's when I was finally like, "Oh my God, they are going to open my chest and take my heart out — and that's good. I'm going to be on ECMO."

That's when it all hit me. I remember I looked at my mom, and I said, "Mom, what if I die?" She said something along the lines of, "If you needed to die, you would have died already. You went through almost-death at least four times during your hospitalization."…

She made me feel better by saying that and she kept telling me, "There's so much more you need to do in this world. You would have already died if you needed to."

Around 4:00 or 4:30 AM, they sedated and intubated me. I think at that time they did some more work and then they started on my surgery after a couple hours. That was the day of my surgery…
For the most part, what motivates me right now in my life is my organ donor and her family. I'm not living for them, but there is a part of me that's living for her…

That's how I see it. That's one of the ways I move forward. In all honesty, this is my second chance at life. There are people who don't accept it. I think a lot of it has to do with your mindset. I think it also has to do with how chronic it might be. Maybe because this was so acute, I reacted to it differently. I'm not sure.

For the most part, people always tell me that I'm one of those people who — there could be three people coding around me and I'm just very calm about it. Maybe that's just my demeanor; I don't know. In the emergency room at work, they always tell me that I'm patient and calm. And I'm like, well, I don't know, maybe…

My dad, when he was in his late 30s, went to his primary care for some reason. He was tachycardic and ended up, incidentally, finding out that he has cardiomyopathy. His ejection fraction at the time was 15%. Because we didn't know the rest of the history, they thought it was probably from myocarditis.

They put my dad on carvedilol and a couple other medications. They wanted to enlist him, and he only tells me this now. I'm like, "Dad, you should've told me this. It would have been great to know this a few months ago."

They told him that he needed to get enlisted for a heart transplant. He was the perfect candidate; he was young and healthy otherwise, and his EF was so low. In the meantime, he needed a defibrillator and all that, but he refused everything, just like his daughter. Stubborn, just like me. He refused those and then he started some medications.

His EF right now is around 40%, so he was able to remodel his heart and they were able to work on it like that. Because he got better and we didn't know the rest of the history, they thought it was due to myocarditis. It's really important to know your family history…

I think it's important to be empathetic toward your patients. Communication is key. There are many little things I learned while I was hospitalized, especially about patient care. Because I'm in emergency medicine and I was going to be doing ICU, I saw many things that I could learn from or possibly do differently later.

One of the main things was communication. As doctors, we don't realize that we each have different goals from different specialties. When a cardiologist would come in and say, "Her heart is failing" but then the ICU doctor would come in and say, "She's stable," my parents felt very confused. I understand it because I'm a doctor, but somebody who is not probably wouldn't.

The main thing I want to tell others, especially in healthcare, is to remember the reason why you went into all of this. I like to tell my co-residents that we get jaded often, especially in the ER and in the ICU, and we don't see what happens with our patients very often.

I'm like, hey, look at me: I almost died and here I am jogging 2 miles a day. Remember that what you do really matters. It really does. And don't be so jaded.

Monday, August 19, 2019

KCNMA1-linked channelopathy

Cole S. Bailey, Hans J. Moldenhauer, Su Mi Park, Sotirios Keros, Andrea L. Meredith.  KCNMA1-linked channelopathy.  The Journal of General Physiology Aug 2019, jgp.201912457; DOI: 10.1085/jgp.201912457


KCNMA1 encodes the pore-forming α subunit of the “Big K+” (BK) large conductance calcium and voltage-activated K+ channel. BK channels are widely distributed across tissues, including both excitable and nonexcitable cells. Expression levels are highest in brain and muscle, where BK channels are critical regulators of neuronal excitability and muscle contractility. A global deletion in mouse (KCNMA1−/−) is viable but exhibits pathophysiology in many organ systems. Yet despite the important roles in animal models, the consequences of dysfunctional BK channels in humans are not well characterized. Here, we summarize 16 rare KCNMA1 mutations identified in 37 patients dating back to 2005, with an array of clinically defined pathological phenotypes collectively referred to as “KCNMA1-linked channelopathy.” These mutations encompass gain-of-function (GOF) and loss-of-function (LOF) alterations in BK channel activity, as well as several variants of unknown significance (VUS). Human KCNMA1 mutations are primarily associated with neurological conditions, including seizures, movement disorders, developmental delay, and intellectual disability. Due to the recent identification of additional patients, the spectrum of symptoms associated with KCNMA1 mutations has expanded but remains primarily defined by brain and muscle dysfunction. Emerging evidence suggests the functional BK channel alterations produced by different KCNMA1 alleles may associate with semi-distinct patient symptoms, such as paroxysmal nonkinesigenic dyskinesia (PNKD) with GOF and ataxia with LOF. However, due to the de novo origins for the majority of KCNMA1 mutations identified to date and the phenotypic variability exhibited by patients, additional evidence is required to establish causality in most cases. The symptomatic picture developing from patients with KCNMA1-linked channelopathy highlights the importance of better understanding the roles BK channels play in regulating cell excitability. Establishing causality between KCNMA1-linked BK channel dysfunction and specific patient symptoms may reveal new treatment approaches with the potential to increase therapeutic efficacy over current standard regimens.

Association between maternal fluoride exposure during pregnancy and IQ scores

Green R, Lanphear B, Hornung R, et al. e in Offspring in Canada. JAMA Pediatr. Published online August 19, 2019. doi:10.1001/jamapediatrics.2019.1729

Key points

Question  Is maternal fluoride exposure during pregnancy associated with childhood IQ in a Canadian cohort receiving optimally fluoridated water?

Findings  In this prospective birth cohort study, fluoride exposure during pregnancy was associated with lower IQ scores in children aged 3 to 4 years.

Meaning  Fluoride exposure during pregnancy may be associated with adverse effects on child intellectual development, indicating the possible need to reduce fluoride intake during pregnancy.


Importance  The potential neurotoxicity associated with exposure to fluoride, which has generated controversy about community water fluoridation, remains unclear.

Objective  To examine the association between fluoride exposure during pregnancy and IQ scores in a prospective birth cohort.

Design, Setting, and Participants  This prospective, multicenter birth cohort study used information from the Maternal-Infant Research on Environmental Chemicals cohort. Children were born between 2008 and 2012; 41% lived in communities supplied with fluoridated municipal water. The study sample included 601 mother-child pairs recruited from 6 major cities in Canada; children were between ages 3 and 4 years at testing. Data were analyzed between March 2017 and January 2019.

Exposures  Maternal urinary fluoride (MUFSG), adjusted for specific gravity and averaged across 3 trimesters available for 512 pregnant women, as well as self-reported maternal daily fluoride intake from water and beverage consumption available for 400 pregnant women.

Main Outcomes and Measures  Children’s IQ was assessed at ages 3 to 4 years using the Wechsler Primary and Preschool Scale of Intelligence-III. Multiple linear regression analyses were used to examine covariate-adjusted associations between each fluoride exposure measure and IQ score.

Results  Of 512 mother-child pairs, the mean (SD) age for enrollment for mothers was 32.3 (5.1) years, 463 (90%) were white, and 264 children (52%) were female. Data on MUFSG concentrations, IQ scores, and complete covariates were available for 512 mother-child pairs; data on maternal fluoride intake and children’s IQ were available for 400 of 601 mother-child pairs. Women living in areas with fluoridated tap water (n = 141) compared with nonfluoridated water (n = 228) had significantly higher mean (SD) MUFSG concentrations (0.69 [0.42] mg/L vs 0.40 [0.27] mg/L; P = .001; to convert to millimoles per liter, multiply by 0.05263) and fluoride intake levels (0.93 [0.43] vs 0.30 [0.26] mg of fluoride per day; P = .001). Children had mean (SD) Full Scale IQ scores of 107.16 (13.26), range 52-143, with girls showing significantly higher mean (SD) scores than boys: 109.56 (11.96) vs 104.61 (14.09); P = .001. There was a significant interaction (P = .02) between child sex and MUFSG (6.89; 95% CI, 0.96-12.82) indicating a differential association between boys and girls. A 1-mg/L increase in MUFSG was associated with a 4.49-point lower IQ score (95% CI, −8.38 to −0.60) in boys, but there was no statistically significant association with IQ scores in girls (B = 2.40; 95% CI, −2.53 to 7.33). A 1-mg higher daily intake of fluoride among pregnant women was associated with a 3.66 lower IQ score (95% CI, −7.16 to −0.14) in boys and girls.

Conclusions and Relevance  In this study, maternal exposure to higher levels of fluoride during pregnancy was associated with lower IQ scores in children aged 3 to 4 years. These findings indicate the possible need to reduce fluoride intake during pregnancy.

An influential medical journal published a study Monday that links fluoride consumption during pregnancy with lower childhood IQs—a finding that could undermine decades of public-health messaging, fire up conspiracy theorists, and alarm mothers-to-be.

The research was expected to be so controversial that JAMA Pediatrics included an editor’s note saying the decision to publish it was not easy and that it was subjected to “additional scrutiny.”

“It is the only editor’s note I’ve ever written,” Dimitri Christakis, editor in chief of JAMA Pediatrics and a pediatrician, told The Daily Beast. “There was concern on the journal’s editorial team about how this would play out in the public eye and what the public-health implications would be.”…

The new study, vetted by the premier medical publisher in the U.S., is seen as more rigorous, although some experts found it unconvincing, saying the results were statistically borderline and the methodology was flawed.

“When we started in this field, we were told that fluoride is safe and effective in pregnancy,” said study co-author Christine Till of York University in Toronto. “But when we looked for the evidence to suggest that it’s safe, we didn’t find any studies done on pregnant women.”… 

Specifically, they found a 1 mg per liter increase in concentration of fluoride in urine was associated with a 4.5 point decrease in IQ among boys—though not girls. Another translation: The boys of mothers with the most fluoride in the urine had IQs about 3 points lower than the boys of mothers with the least amount.

Although critics of the study pointed to the different results by gender as a red flag, when the researchers measured fluoride exposure by examining the women’s fluid intake, they found lower IQs in boys and girls. A 1 mg increase per day was associated with a 3.7-point  IQ deficit among both.

While medical organizations are not advising that pregnant women avoid fluoridated water—and the study has no implications for the use of fluoride after birth—Green believes the results are significant enough to warrant a change in behavior.

“What we recommend is lowering fluoride ingestion during pregnancy,” she said…

Before publication, the study was subjected to two statistical reviews, with the researchers combing through the data to make sure that the results were not skewed by the mothers’ education, income levels, or other factors.

The findings were astonishing to JAMA editors, who had been told throughout their medical training that fluoridation was completely safe and that opponents were wingnuts relying on “junk science.”…

The CDC declined to discuss the study, saying it does not comment on outside research.  The American Academy of Pediatrics said it is looking forward to future studies “to see if they demonstrate the same results or provide more conclusive evidence.” The American College of Obstetricians and Gynecologists, which recommends that pregnant women use fluoridated toothpaste and mouth rinses, isn’t making any changes for now….

Sophia Lubin, an OB-GYN in Brooklyn, New York, said she’s never had a patient ask her about fluoridated water, but expects she will be questioned about it now.

“As an obstetrician, you always have to think about two people—the mother and the baby,” she said. ”And oral health is important for mothers.”

She anticipates telling women that if they are truly concerned, they can switch to bottled water during pregnancy. But she doesn’t think, at this point, that she will tell patients they should not drink from the tap.

One part of the study that struck her was how much fluoride is in black tea, which soaks it up from soil. She said she is more likely to tell patients to cut back on tea than on water, since it’s important they stay hydrated.

“This left me with a lot more questions than answers,” Lubin said…

The study authors noted a number of limitations, the most significant of which is that they did not assess how much fluoride the children were exposed to after birth.

Dr. Stuart Ritchie, a neuroscientist at King’s College London, called the finding “pretty weak.”

“They might be interesting as part of a larger set of studies on this question, but alone they shouldn’t move the needle much at all on the question of the safety of fluoride,” he wrote.

But in an analysis that accompanied the study, Harvard Professor David Bellinger said that while “high-quality epidemiological studies” are needed, “the hypothesis that fluoride is a neurodevelopmental toxicant must now be given serious consideration.”

Those kinds of studies take time—which doesn’t help millions of parents-to-be who may be looking for advice now.

“The question that needs to be asked to every pediatrician, scientist, and epidemiologist is what they’re going to tell pregnant women,” said Christakis, who says he will advise his pregnant friends and family to avoid fluoridated water.

“We can’t tell them to wait years for another study. They have to decide what to tell their patients now.”

Sunday, August 18, 2019

Medical child abuse revisited 5

A Texas woman accused of exposing her son to unneeded medical tests and procedures — including taking him to hospitals more than 320 times — has pleaded guilty to recklessly causing injury to a child, according to a report.

Kaylene Bowen-Wright pleaded guilty this past Thursday in Dallas County court, the Fort Worth Star-Telegram reported.

Sentencing for the 35-year-old, who faces up to 20 years in prison, is set for October.

Child Protective Services removed the boy from her care in 2017 after it was alerted by a Dallas hospital that medical staff determined he didn’t have cancer or many of the symptoms Bowen reported.

In its petition for removal, the newspaper reported, CPS said the boy had been to hospitals and pediatric centers in Dallas and Houston at least 323 times in all, and he had 13 major surgeries between 2009 and 2016.

The boy’s father, Ryan Crawford, told the newspaper Friday: “I am happy that she decided to do the right thing. Eventually the lies had to stop.”

Crawford was made the sole managing conservator of the now 10-year-old.

“Medical abuse is underreported every day,” the father added. “Now it’s time to move forward, and make sure no child has to suffer the abuse my son endured.”

Bowen, who also goes by the last name of Wright, had even started or been the subject of fundraisers, claiming that Christopher was dying, initially from a rare genetic disorder and later from cancer.

Authorities alleged she had her son fitted with a feeding tube that fed directly into his small intestine and led to multiple life-threatening blood infections. They said she also tried to get him on the lung transplant list and had him in hospice care.

Crawford had tried to convince Dallas County family court judges for years that his son was not sick but they believed Bowen. One judge even prohibited Crawford from visits with his son, who was then 3.

Dallas hospital staff sounded the alarm with CPS, which led to the boy’s removal and Bowen’s arrest.

Crawford is the sole managing conservator of Christopher and gets to make all the decisions regarding where his son lives, attends school and the medical treatment he receives. Bowen is allowed supervised visits.

Crawford said his son, now 10, does well academically and is very athletic. The boy has no medical issues and has only needed to go to the doctor for physicals each year, Crawford said.

A Dobyns potpourri

Holt RJ, Young RM, Crespo B, Ceroni F, Curry CJ, Bellacchio E, Bax DA, Ciolfi A, Simon M, Fagerberg CR, van Binsbergen E, De Luca A, Memo L, Dobyns WB, Mohammed AA, Clokie SJH, Zazo Seco C, Jiang YH, Sørensen KP, Andersen H, Sullivan J, Powis Z, Chassevent A, Smith-Hicks C, Petrovski S, Antoniadi T, Shashi V, Gelb BD, Wilson SW, Gerrelli D, Tartaglia M, Chassaing N, Calvas P, Ragge NK. De Novo Missense Variants in FBXW11 Cause Diverse Developmental Phenotypes Including Brain, Eye, and Digit Anomalies. Am J Hum Genet. 2019
Jul 23. pii: S0002-9297(19)30268-X. doi: 10.1016/j.ajhg.2019.07.005. [Epub ahead of print]

The identification of genetic variants implicated in human developmental disorders has been revolutionized by second-generation sequencing combined with international pooling of cases. Here, we describe seven individuals who have diverse yet overlapping developmental anomalies, and who all have de novo missense FBXW11 variants identified by whole exome or whole genome sequencing and not reported in the gnomAD database. Their phenotypes include striking neurodevelopmental, digital, jaw, and eye anomalies, and in one individual, features resembling Noonan syndrome, a condition caused by dysregulated RAS signaling. FBXW11 encodes an F-box protein, part of the Skp1-cullin-F-box (SCF) ubiquitin ligase complex, involved in ubiquitination and proteasomal degradation and thus fundamental to many protein regulatory processes. FBXW11 targets include β-catenin and GLI transcription factors, key mediators of Wnt and Hh signaling, respectively, critical to digital, neurological, and eye development. Structural analyses indicate affected residues cluster at the surface of the loops of the substrate-binding domain of FBXW11, and the variants are predicted to destabilize the protein and/or its interactions. In situ hybridization studies on human and zebrafish embryonic tissues demonstrate FBXW11 is expressed in the developing eye, brain, mandibular processes, and limb buds or pectoral fins. Knockdown of the zebrafish FBXW11 orthologs fbxw11a and fbxw11b resulted in embryos with smaller, misshapen, and underdeveloped eyes and abnormal jaw and pectoral fin development. Our findings support the role of FBXW11 in multiple developmental processes, including those involving the brain, eye, digits, and jaw.

Kanca O, Andrews JC, Lee PT, Patel C, Braddock SR, Slavotinek AM, Cohen JS, Gubbels CS, Aldinger KA, Williams J, Indaram M, Fatemi A, Yu TW, Agrawal PB, Vezina G, Simons C, Crawford J, Lau CC; Undiagnosed Diseases Network, Chung WK, Markello TC, Dobyns WB, Adams DR, Gahl WA, Wangler MF, Yamamoto S, Bellen HJ, Malicdan MCV. De Novo Variants in WDR37 Are Associated with Epilepsy, Colobomas, Dysmorphism, Developmental Delay, Intellectual Disability, and Cerebellar Hypoplasia. Am J Hum Genet. 2019 Aug 1;105(2):413-424.

WD40 repeat-containing proteins form a large family of proteins present in all eukaryotes. Here, we identified five pediatric probands with de novo variants in WDR37, which encodes a member of the WD40 repeat protein family. Two probands shared one variant and the others have variants in nearby amino acids outside the WD40 repeats. The probands exhibited shared phenotypes of epilepsy, colobomas, facial dysmorphology reminiscent of CHARGE syndrome, developmental delay and intellectual disability, and cerebellar hypoplasia. The WDR37 protein is highly conserved in vertebrate and invertebrate model organisms and is currently not associated with a human disease. We generated a null allele of the single Drosophila ortholog to gain functional insights and replaced the coding region of the fly gene CG12333/wdr37 with GAL4. These flies are homozygous viable but display severe bang sensitivity, a phenotype associated with seizures in flies. Additionally, the mutant flies fall when climbing the walls of the vials, suggesting a defect in grip strength, and repeat the cycle of climbing and falling. Similar to wall clinging defect, mutant males often lose grip of the female abdomen during copulation. These phenotypes are rescued by using the GAL4 in the CG12333/wdr37 locus to drive the UAS-human reference WDR37 cDNA. The two variants found in three human subjects failed to rescue these phenotypes, suggesting that these alleles severely affect the function of this protein. Taken together, our data suggest that variants in WDR37 underlie a novel syndromic neurological disorder.

Monteiro FP, Curry CJ, Hevner R, Elliott S, Fisher JH, Turocy J, Dobyns WB, Costa LA, Freitas E, Kitajima JP, Kok F. Biallelic loss of function variants in ATP1A2 cause hydrops fetalis, microcephaly, arthrogryposis and extensive cortical malformations. Eur J Med Genet. 2019 Jan 25. pii: S1769-7212(18)30802-4. doi:10.1016/j.ejmg.2019.01.014. [Epub ahead of print]

The Na+/K+- ATPase acts as an ion pump maintaining the essential plasma membrane potential in all mammalian cell types, and is essential for many cellular functions. There are four α isoforms (α1, α2, α3 and α4) with distinct expression patterns, kinetic properties and substrate affinity. The α2-isoform is encoded by ATP1A2 and evidence supports its utmost importance in Cl- homeostasis in neurons, and in the function of respiratory neurons at birth. Monallelic pathogenic variants in ATP1A2 are associated with familial hemiplegic migraine type 2 (FHM2) and on rare occasions with alternating hemiplegia of childhood 1 (AHC1). To date, no instances of biallelic loss of function variants have been reported in humans. However, Atp1a2 homozygous loss of function knockout mice (α2-/- mice) show severe motor deficits, with lack of spontaneous movements, and are perinatally lethal due to absent respiratory activity. In this report we describe three newborns from two unrelated families, who died neonatally, presenting in utero with an unusual form of fetal hydrops, seizures and polyhydramnios. At birth they had multiple joint contractures (e.g. arthrogryposis), microcephaly, malformations of cortical development, dysmorphic features and severe respiratory insufficiency. Biallelic loss of function variants in ATP1A2, predicted to be pathogenic were found on whole exome sequencing. We propose that this is a distinctive new syndrome caused by complete absence of Na+/K+- ATPase α2-isoform expression.

Peripheral nervous system alterations in infant and adult neurofibromatosis type 2

Godel T, Bäumer P, Farschtschi S, Gugel I, Kronlage M, Hofstadler B, Heiland S, Gelderblom M, Bendszus M, Mautner VF. Peripheral nervous system alterations in infant and adult neurofibromatosis type 2. Neurology. 2019 Aug 6;93(6):e590-e598.


To examine the involvement of dorsal root ganglia and peripheral nerves in children with neurofibromatosis type 2 compared to healthy controls and symptomatic adults by in vivo high-resolution magnetic resonance neurography.

In this prospective multicenter study, the lumbosacral dorsal root ganglia and sciatic, tibial, and peroneal nerves were examined in 9 polyneuropathy-negative children diagnosed with neurofibromatosis type 2 by a standardized magnetic resonance neurography protocol at 3T. Volumes of dorsal root ganglia L3 to S2 and peripheral nerve lesions were assessed and compared to those of 29 healthy children. Moreover, dorsal root ganglia volumes and peripheral nerve lesions were compared to those of 14 adults with neurofibromatosis type 2.

Compared to healthy controls, dorsal root ganglia hypertrophy was a consistent finding in children with neurofibromatosis type 2 (L3 +255%, L4 +289%, L5 +250%, S1 +257%, and S2 +218%, p < 0.001) with an excellent diagnostic accuracy. Moreover, peripheral nerve lesions occurred with a high frequency in those children compared to healthy controls (18.89 ± 11.11 vs 0.90 ± 1.08, p < 0.001). Children and adults with neurofibromatosis type 2 showed nonsignificant differences in relative dorsal root ganglia hypertrophy rates (p = 0.85) and peripheral nerve lesions (p = 0.28).

Alterations of peripheral nerve segments occur early in the course of neurofibromatosis type 2 and are evident even in children not clinically affected by peripheral polyneuropathy. While those early alterations show similar characteristics compared to adults with neurofibromatosis type 2, the findings of this study suggest that secondary processes might be responsible for the development and severity of associated polyneuropathy.

Courtesy of a colleague

Thursday, August 15, 2019

First birthday for infant with predicted six hour survival

A young infant born with a severe heart defect is being hailed as a miracle baby as she is set to celebrate her first birthday just months after being taken off life support with few prospects of survival.

Phoenix Da'Vine, who is set to turn 1 on August 25, was born with a major heart defect known as Double Outlet Right Ventricle, which required several surgeries to ensure her survival, Monique Goldring, the girl’s mother, said in a GoFundMe post.

“Phoenix's first palliative surgery took place on September 4, 2018 where she had a pulmonary arterial (PA) band surgically placed to limit the amount of blood that was flowing to her lungs in order to prevent congestive heart failure. Unfortunately, Phoenix was unable to tolerate the PA band, so she required a second surgery,” Goldring wrote at the time.

A second surgery was performed a short time later on October 30 to remove the band.

Several months later in March, Phoenix went into cardiac arrest and suffered serious complications as a result.

It was not immediately clear from the GoFundMe post where Phoenix's family was from or what hospital performed the procedures.

Her doctors told WJLA that Phoenix suffered major brain damage due to a lack of oxygen and was placed on life support.

Sometime later, doctors informed Goldring that her daughter would likely not have a good quality of life and they discussed taking her off life support, a decision she eventually agreed to.

"I prayed. I asked her to let me know if she's tired," Goldring told the local station. "She turned around and looked directly at me. That's when I knew she was tired."

Phoenix was taken off life support in April with the promise of only six hours to live.

Hours turned into days. Despite the odds, Phoenix will now go on to celebrate her birthday later this month.

"The doctors say she won't walk, won't talk. I stress that she may not be doing those things right now but I was also told that she would be gone in six hours. So, I am going to just sit back and watch her thrive,” Goldring said.

According to WJLA [], Phoenix still requires two surgeries that doctors have refused to continue with, fearing she will not survive. She lives on oxygen and feeding tubes along with around-the-clock care.

Doctors told Monique she would only have six hours when they take her off life support.

Monique and the rest of the family prepared for their final goodbyes.

"Watch over your mommy in heaven. We will never forget you or your family" a nurse wrote. Even doctors and nurses wrote heartfelt messages for Monique as they prepared to take her off life support in April 2019.

"I went home that night. A lot of people will think that's crazy but I was at peace with her," says Monique. "I called the next morning and they said she was up and hanging out."

A few seconds, hours, days, and months later - Phoenix is now at home and will soon celebrate her first birthday on August 25th...

"She is continuing to defy the medical odds by living and thriving beyond what many expected" explains Johnson.

"We have to celebrate this milestone" laughs Monique.

Phoenix lives on oxygen, feeding tubes and around the clock medication with the help of Monique and her family and friends.

However, baby Phoenix is still in need of two surgeries. According to Monique, Inova and Children's National have declined to move forward fearing that she will not survive the surgery.

But, Monique won't stop there. "I am desperately hoping that somebody will look at her case and perform this surgery on her."

Wednesday, August 14, 2019

Migraine practice guidelines

Practice guideline update summary: Pharmacologic treatment for pediatric migraine prevention
Maryam Oskoui, Tamara Pringsheim, Lori Billinghurst, Sonja Potrebic, Elaine M. Gersz, David Gloss, Yolanda Holler-Managan, Emily Leininger, Nicole Licking, Kenneth Mack, Scott W. Powers, Michael Sowell, M. Cristina Victorio, Marcy Yonker, Heather Zanitsch, Andrew D. Hershey. Practice guideline update summary: Pharmacologic treatment for pediatric migraine prevention.  Neurology Aug 2019,


Objective To provide updated evidence-based recommendations for migraine prevention using pharmacologic treatment with or without cognitive behavioral therapy in the pediatric population.

Methods The authors systematically reviewed literature from January 2003 to August 2017 and developed practice recommendations using the American Academy of Neurology 2011 process, as amended.

Results Fifteen Class I–III studies on migraine prevention in children and adolescents met inclusion criteria. There is insufficient evidence to determine if children and adolescents receiving divalproex, onabotulinumtoxinA, amitriptyline, nimodipine, or flunarizine are more or less likely than those receiving placebo to have a reduction in headache frequency. Children with migraine receiving propranolol are possibly more likely than those receiving placebo to have an at least 50% reduction in headache frequency. Children and adolescents receiving topiramate and cinnarizine are probably more likely than those receiving placebo to have a decrease in headache frequency. Children with migraine receiving amitriptyline plus cognitive behavioral therapy are more likely than those receiving amitriptyline plus headache education to have a reduction in headache frequency.

Recommendations The majority of randomized controlled trials studying the efficacy of preventive medications for pediatric migraine fail to demonstrate superiority to placebo. Recommendations for the prevention of migraine in children include counseling on lifestyle and behavioral factors that influence headache frequency and assessment and management of comorbid disorders associated with headache persistence. Clinicians should engage in shared decision-making with patients and caregivers regarding the use of preventive treatments for migraine, including discussion of the limitations in the evidence to support pharmacologic treatments.

Maryam Oskoui, Tamara Pringsheim, Yolanda Holler-Managan, Sonja Potrebic, Lori Billinghurst, David Gloss, Andrew D. Hershey, Nicole Licking, Michael Sowell, M. Cristina Victorio, Elaine M. Gersz, Emily Leininger, Heather Zanitsch, Marcy Yonker, Kenneth Mack.  Practice guideline update summary: Acute treatment of migraine in children and adolescents. Neurology Aug 2019,


Objective To provide evidence-based recommendations for the acute symptomatic treatment of children and adolescents with migraine.

Methods We performed a systematic review of the literature and rated risk of bias of included studies according to the American Academy of Neurology classification of evidence criteria. A multidisciplinary panel developed practice recommendations, integrating findings from the systematic review and following an Institute of Medicine–compliant process to ensure transparency and patient engagement. Recommendations were supported by structured rationales, integrating evidence from the systematic review, related evidence, principles of care, and inferences from evidence.

Results There is evidence to support the efficacy of the use of ibuprofen, acetaminophen (in children and adolescents), and triptans (mainly in adolescents) for the relief of migraine pain, although confidence in the evidence varies between agents. There is high confidence that adolescents receiving oral sumatriptan/naproxen and zolmitriptan nasal spray are more likely to be headache-free at 2 hours than those receiving placebo. No acute treatments were effective for migraine-related nausea or vomiting; some triptans were effective for migraine-related phonophobia and photophobia.

Recommendations Recommendations for the treatment of acute migraine in children and adolescents focus on the importance of early treatment, choosing the route of administration best suited to the characteristics of the individual migraine attack, and providing counseling on lifestyle factors that can exacerbate migraine, including trigger avoidance and medication overuse.

Childrens heart surgery issues

Several children died after heart surgery at one of the country's top hospitals, leading doctors to declare that they wouldn't even send their own kids there for surgery.

In a months-long investigation, The New York Times found death rates in the pediatric cardiac unit of the University of North Carolina Children's Hospital was about five percent, higher than the two-to-three percent average of most hospitals in the country.

At least four deaths were confirmed in just a three-month period alone.

Secret audio recordings obtained by The Times showed that several physicians questioned the care that patients were receiving.
UNC Health does not provide its mortality data to the public website of The Society of Thoracic Surgeons.

But in raw data shared with The Times, the hospital had higher death rates than almost all of the other hospitals, 82 in total, that do share their data.

Between July 2013 and June 2017, about a four-year period, the mortality rate was 4.7 percent.

The Times reported that children were experiencing complications following low-risk procedures and deaths after high-risk surgeries.

Between March and May 2016, at least two infants died following their respective operations.

And a two-year-old girl's parents were told she should recover well from her surgery, only to be put on life support later that night.
So, in June 2016, the nine pediatric cardiologists who worked at the hospital at the time met with top administrative staff to discuss these cases.

An unknown source secretly recorded this meeting, and that recording was obtained by The Times. 

Dr Timothy Hoffman, the chief of pediatric cardiology, told his colleagues in one of the recordings: 'It's a nightmare right now. We are in crisis, and everyone is aware of that.' 

In another recording, cardiologist Dr Blair Robinson said that he wouldn't send his own children to UNC for care.

'I ask myself: "Would I have my children have surgery here?"' Dr Robinson is heard telling the other doctors.

'In the past, I'd always felt like the answer was "yes" for something simple...But now, when I look myself in the mirror, and what's gone on the past month, I can't say that.'..
But hospital administrators brushed these concerns aside.

Dr Kevin Kelly, the head of Children's Hospital, is heard telling the cardiologists in one recording that performing fewer surgeries could lead to job cuts...

In the secretly recorded meetings, cardiologists said they could point to a few examples of why their patients were doing so poorly after surgery. 

One reason was that two pediatric cardiac intensivists, which treat children with complex congenital and acquired heart defects, had left UNC in 2015.

The hospital also didn't have a cardiac intensive care unit, which is an ICU that focuses on diseases and surgeries related to the heart.

Worries were also expressed about Dr Michael Mill, who was the chief surgeon at the time.

The Times revealed that a few weeks before the meeting, Dr Mill had not gone to the hospital on a weekend to perform a transplant surgery on a baby when a donor heart became available.

The baby eventually received another heart at Duke Children's Hospital, also in North Carolina, but physicians at UNC were 'horrified'...

UNC told the Times that Dr Mill is currently taking a leave from the hospital for family medical reasons.

This is not the first heart surgery program to come under fire for questionable practices.

In 2018, the Tampa Bay Times reported that Johns Hopkins All Children's Hospital in Florida had experienced a death rate among pediatric heart surgery patients that had tripled.

The team stopped performing surgeries in the aftermath of the investigation...
 Meanwhile, The Times is suing UNC to obtain risk-adjusted mortality data to confirm other deaths.

The hospital insists its program is 'very strong' and criticized the newspaper's report.

'We are proud of our pediatric congenital heart surgery program, and our current team is receiving top results that would place us among the best in the nation,' UNC Health wrote in a statement in part.

'We have been engaged in continuous quality improvement efforts for decades and have made significant improvements in the past 10+ years. 

'To characterize today's program as anything but strong, would not only be misleading, but not factual. To say we ignored issues would also be false.'

Movement disorder in ataxia-telangiectasia: treatment with amantadine

 A colleague reports a similar experience

Nissenkorn A, Hassin-Baer S, Lerman SF, Levi YB, Tzadok M, Ben-Zeev B. Movement disorder in ataxia-telangiectasia: treatment with amantadine sulfate. J Child Neurol. 2013 Feb;28(2):155-60.

Ataxia-telangiectasia is a cerebellar neurodegenerative disorder presenting with ataxia, chorea, myoclonus, and bradykinesia. Literature on treatment of movement disorders is scarce. We treated 17 children (aged 11.2 ± 3.9 years) for 8 weeks with the dopaminergic and anti-N-methyl-d-aspartate (NMDA) agent amantadine sulfate 6.3 ± 0.87 mg/kg/d. Ataxia was assessed by using the International Cooperative Ataxia Scale, parkinsonism by the Unified Parkinson Disease Rating Scale, and chorea/myoclonus by the Abnormal Involuntary Movement Scale. Responders were considered those patients who had at least 20% improvement in the summation of the 3 scales. Overall, 76.5% of patients were responders, with a mean 29.3% improvement. Ataxia, involuntary movements, and parkinsonism improved significantly (25.3%, 32.5%, and 29.5%, respectively); (P < .001, t test). Side effects were mild and transient, and they did not lead to drug discontinuation. Amantadine is a well-tolerated and effective treatment for motor symptoms in ataxia telangiectasia. Assessment of long-term effects and a double-blind study should follow.