Tuesday, October 31, 2017

EBF3 deletions

Fátima Lopes, Gabriela Soares, Miguel Gonçalves-Rocha, Jorge Pinto-Basto, Patrícia Maciel. Whole Gene Deletion of EBF3 Supporting Haploinsufficiency of This Gene as a Mechanism of Neurodevelopmental Disease.  Front. Genet., 09 October 2017 | https://doi.org/10.3389/fgene.2017.00143

Mutations in early B cell factor 3 (EBF3) were recently described in patients with a neurodevelopmental disorder (NDD) that includes developmental delay/intellectual disability, ataxia, hypotonia, speech impairment, strabismus, genitourinary abnormalities, and mild facial dysmorphisms. Several large 10q terminal and interstitial deletions affecting many genes and including EBF3 have been described in the literature. However, small deletions (<1 MB) affecting almost exclusively EBF3 are not commonly reported. We performed array comparative genomic hybridization (aCGH) (Agilent 180K) and quantitative PCR analysis in a female patient with intellectual disability. A clinical comparison between our patient and overlapping cases reported in the literature was also made. The patient carries a de novo 600 Kb deletion at 10q26.3 affecting the MGMT, EBF3, and GLRX genes. The patient has severe intellectual disability, language impairment, conductive hearing loss, hypotonia, vision alterations, triangular face, short stature, and behavior problems. This presentation overlaps that reported for patients carrying EBF3 heterozygous point mutations, as well as literature reports of patients carrying large 10qter deletions. Our results and the literature review suggest that EBF3 haploinsufficiency is a key contributor to the common aspects of the phenotype presented by patients bearing point mutations and indels in this gene, given that deletions affecting the entire gene (alone or in addition to other genes) are causative of a similar syndrome, including intellectual disability (ID) with associated neurological symptoms and particular facial dysmorphisms.

See:  http://childnervoussystem.blogspot.com/2017/05/a-syndromic-neurodevelopmental-disorder.html

Phelan-McDermid syndrome and neurofibromatosis type 2

Lyons-Warren AM, Cheung SW, Holder JL Jr. Clinical Reasoning: A common cause for Phelan-McDermid syndrome and neurofibromatosis type 2: One ring to bind them. Neurology. 2017 Oct 24;89(17):e205-e209.

An 8-year-old girl with mild dysmorphic features presented for evaluation of developmental delay and staring spells. She had been born late preterm and spent 1 month in the neonatal intensive care unit. She was generally healthy other than her developmental delay, which improved somewhat with physical, occupational, and speech therapy. At the first clinic visit, her mother reported loss of previously mastered vocabulary and struggles with fine motor skills such as buttoning. She also noted repetitive movements, obsessive behaviors, and hand flapping…

Our patient's initial evaluation included an MRI brain that was unremarkable and a karyotype that revealed a ring chromosome 22 including a terminal deletion of the long arm. A ring chromosome is when the p and q arms of the chromosome fuse together and often occurs due to deletion of one arm. Subsequent high-resolution karyotype with subtelomeric fluorescent in situ hybridization analysis confirmed the diagnosis and demonstrated a double-sized ring chromosome 22 in 15% of cells. In order to better define the size of the deletion, a high-resolution aCGH was performed, which identified a 1.036-Mb deletion in the subtelomeric region of the long arm of chromosome 22 involving 20 genes including SHANK3, consistent with the diagnosis of Phelan-McDermid syndrome (PMS).

After receiving the diagnosis, the patient was lost to follow-up for several years. At age 16, the family noted a change in the patient's personality. She previously related well with other children and was described as sweet and kind. Her parents expressed concern for new episodes of unprovoked anger. Her family also noted the development of painless growths on both arms, most predominant on the left arm and wrist…

Brain MRI revealed a large, enhancing right cerebellopontine angle to internal auditory canal vestibular schwannoma and a punctate contralateral vestibular schwannoma that were not present on the prior brain MRI brain at 8 years of age. Based on these findings, MRI spine was also ordered and identified enhancing foci in multiple paraspinal areas, which were concerning for schwannomas. EEG revealed a focus of sharp transients over the left temporal region suggestive of an epileptogenic focus. The patient subsequently had an event concerning for seizure in which she was staring and nonresponsive and then fell to the ground. Audiology testing was not able to establish hearing sensitivity due to the patient's inability to complete the task. However, crossed acoustic reflexes were absent, suggesting impairment of the auditory nerve.

Given the presence of bilateral vestibular as well as spinal schwannomas, the growths on her arms were likely peripheral schwannomas. The patient was referred to oncology for further evaluation. She was determined to meet criteria for neurofibromatosis type 2 (NF2). Comprehensive auditory evaluation was difficult to obtain secondary to the patient's intellectual disability. She was evaluated by neurosurgery, who did not recommend surgical intervention as hearing was intact to voice. She was treated with bevacizumab with significant improvement in her mood and monitored with serial brain imaging every 3 months and serial spine imaging every 6 months. An ophthalmologic consultation was obtained to evaluate for ocular findings of NF2, such as cataracts, orbital meningiomas, and retinal hamartomas, which were absent.

PMS, or 22q13.3 deletion syndrome, is a rare neurologic syndrome characterized by global developmental delay leading to moderate to severe intellectual disability with severe language impairment. Additional features include poor eye contact, anxiety, and reduced social interactions consistent with autism spectrum disorder. Dysmorphic features on physical examination can include large fleshy hand, bulbous nose, long eyelashes, hypoplastic nails, dysplastic ears, and dolichocephaly as well as neonatal hypotonia. Baseline renal ultrasound is recommended as more than one-quarter of children will have renal abnormalities ranging from reflux to absent kidneys. Individuals with PMS may also have developmental structural brain abnormalities, including delayed myelination, thin corpus callosum, and arachnoid cysts. Finally, children with PMS can have sleep abnormalities, including bedtime resistance, delayed onset, sleep anxiety, parasomnias, sleep-disordered breathing, and daytime sleepiness.

Patients with PMS can have variable phenotype possibly related to size of their deletion on the long arm of chromosome 22.5 The majority of neurologic features, however, are believed to be due to haploinsufficiency of the SHANK3 gene.6 The SHANK3 protein is enriched in the postsynaptic density of excitatory synapses. Along with other members of the SHANK protein family, SHANK3 is believed to play an important role in synaptogenesis, synapse maintenance, and synapse plasticity.

NF2 is diagnosed using the Manchester criteria:

Bilateral vestibular schwannomas or

Unilateral vestibular schwannoma and at least 2 other features including meningioma, glioma, schwannoma, or juvenile posterior lenticular opacities

The hallmark feature is bilateral vestibular schwannomas. However, additional criteria allow for the diagnosis in a patient with at least 2 meningiomas and unilateral vestibular schwannoma or at least 2 meningiomas and 2 of the other features including glioma, neurofibroma, schwannoma, and cataract.7 Although schwannomas are benign, they can cause symptoms ranging from hearing loss to brainstem compression and are therefore usually monitored with serial imaging. These symptoms are caused by disruption of the NF2 gene on chromosome 22 (figure, C), which codes for merlin protein.

Ring chromosomes were first described by Lilian Morgan in 1926 and have been reported for all chromosomes. Terminal deletions can result in a ring chromosome when the truncated arm fuses with another end and forms a ring. Ring chromosomes are mitotically unstable, leading to somatic loss and resultant mosaicism. When the ring is lost during mitotic cell division, cells become monosomic for the affected chromosome. There are multiple reports of patients with ring chromosome 22, all of whom shared features of PMS, including speech delay, seizures, and autism. Rearrangements of chromosome 22, including ring 22, have also been reported to cause NF2. In the case of ring chromosome 22 due to a large, terminal deletion like in our patient, cells become monosomic for chromosome 22, and then have only 1 copy of NF2. In patients with NF2 secondary to ring chromosome 22, it is possible that aspects of their phenotype are related to mosaicism of SHANK3 haploinsufficiency. We therefore recommend that children diagnosed with PMS through aCGH should be evaluated for ring chromosome by karyotype. If ring 22 is present, they should be evaluated as recommended for children of affected parents, who have a 50% risk of developing NF2.

Monday, October 30, 2017

Meningitis C septicemia and meningitis

The parents of a baby struck by meningitis have been told she will lose all of her limbs, her sight and hearing and suffer 90 percent brain damage in the worst case doctors have seen in 25 years.

Ten-month-old Kia Gott has already had her right arm removed and is due to have one of her legs amputated on Monday.

She was rushed to hospital four weeks ago after dad Paul, 35, went to check on her in the middle of the night, sensing something was wrong.

He put a light on and saw her face, neck and chest was covered in a terrible rash - a known symptom of meningococcal septicemia.

Paramedics arrived fast but Kia's veins had collapsed so they had to drill into her tiny shin to give her emergency drugs.

While that was happening the baby girl had a mini cardiac arrest and was rushed to Bradford Royal Infirmary, West Yorks.

Crushed parents-of-three Paul and Vikki, 30, were then told the devastating news that all four limbs would have to be removed.

An MRI scan also showed signs she would be deaf, blind and have 90 percent brain damage.

Despite doctors’ shocking prognosis, Kia’s parents are clinging on to hope she can still hear and see them and her older brother Kayden, eight, and sister Elsie, who is four.

She is now off a ventilator and although still sedated she is breathing for herself.

“Paul and Vikki are traumatized," Donna Gott, Paul's aunt, said. "They know she is in a bad way but they can’t grasp she can’t hear or see them. They believe she is responding to them and their voices and when Elsie sings her nursery rhymes.

"She is yawning, moving her head and her arm - the hospital has said it’s the worst case of Meningitis C septicaemia they have seen there in 25 years," she said. “Because she is on so many drugs at the moment it’s hard to do the tests they need to find out for sure but they will keep monitoring her.

"An eye specialist has given some hope her eyes might still be healthy," Gott said. “Vikki has not left the hospital - she is feeling an immense sense of guilt and is scared if she leaves the hospital something bad will happen…

Two days before Kia fell ill she had been at her older siblings’ school in Wyke, near Bradford, West Yorks., where the family live for a family photo.

Later that week Kia’s mom took her to the doctor, worried that she “was not herself.”

Hospital consultants have since told the family that the doctor would not have been able to detect meningitis at that time.

When Paul came home from work that night, Kia did not get excited to see him - which was unusual.

The worried parents stayed up with her until midnight then went to bed.

However, Paul awoke with a start at 2 a.m. and, driven by instinct, went to check on the baby, finding her covered in the rash.

“They have a long hard road ahead of them," Gott said. "But there is hope. She will lose all four limbs but but she is responding when we talk by moving her head and her arms. She is even crying and yawning. We will have to see how she develops over the next two years."

"Her hearing and sight is affected but that doesn't mean she will never hear or see again," she said. "Paul and Vikki have accepted that it's life-changing but as long as she can hear and see they will get by."

Meningitis C septicaemia is caused by bacteria that lives in the back of throats of one in ten people, normally doing no harm.

However, if if it somehow gets into the blood system it can trigger a potentially life-threatening infection.

Gott said Kia will now face a long few months of rehabilitation and the family home will need adaptions to make it suitable for the baby when she is finally discharged from hospital.

To help pay for them the family has set up a fundraising page which had raised more than $13,000.

To make a donation visit justgiving.com/crowdfunding/emma-simpson-2.


“I am a man with Down syndrome and my life is worth living.”

Frank Stephens, a man with Down syndrome, told a congressional committee on Wednesday that his life is “worth living” while condemning the “final solution” proposed by abortion advocates who would kill babies with the genetic condition.

“Seriously, I don’t feel I should have to justify my existence. Is there really no place for us in the world?” Mr. Stephens, a screen actor and spokesman for people with Down syndrome, told the assembly. “Surely happiness is worth something.”

“Let’s be America, not Iceland or Denmark,” Stephens said, referring to recent reports chronicling the near-100 percent abortion rate of unborn children diagnosed with Down syndrome in those countries.

As Breitbart News reported in August, the vast majority of pregnant women in Iceland whose babies test positive for Down Syndrome end up aborting their children, a statistic that many tout as a sign of “progress.”

“My understanding is that we have basically eradicated, almost, Down syndrome from our society—that there is hardly ever a child with Down syndrome in Iceland anymore,” said Kari Stefansson, a geneticist and the founder of deCODE Genetics, a company that has studied nearly the entire Icelandic population’s genomes.

In his address at the Capitol, Mr. Stephens stated: “Some people say prenatal screens will identify Down syndrome in the womb, and those pregnancies will just be terminated. It’s hard for me to sit here and say those words. I completely understand that the people pushing this particular ‘final solution’ are saying that people like me should not exist.”

Last month, abortion giant Planned Parenthood won a major legal victory in Indiana guaranteeing women the right to continue aborting their children based on the child’s sex, race or genetic condition, such as Down syndrome.

U.S. District Court Judge Tanya Walton Pratt, an Obama appointee, issued a permanent injunction against Indiana’s “Sex Selective and Disability Abortion Ban,” declaring that provisions of the law “violate the Fourteenth Amendment to the United States Constitution.”

HEA 1337 outlawed abortions based on the sex or race of the child or a prenatal diagnosis of “Down syndrome or any other disability,” leading Planned Parenthood and the ACLU to bring a lawsuit against the state.

In her ruling, Judge Pratt defended sex-selective and disability-based abortions, stating that “it is a woman’s right to choose an abortion that is protected, which, of course, leaves no room for the State to examine, let alone prohibit, the basis or bases upon which a woman makes her choice.”

“The right to a pre-viability abortion is categorical,” Pratt declared, regardless of the particular motivation that drives a woman to seek it.

Several weeks ago, President Donald Trump issued a powerful statement in the defense of people with Down syndrome, calling for an end to discrimination based on genetic anomalies.

“Sadly, there remain too many people – both in the United States and throughout the world – that still see Down syndrome as an excuse to ignore or discard human life,” Trump said in an official statement recognizing Down Syndrome Awareness Month. “This sentiment is and will always be tragically misguided. We must always be vigilant in defending and promoting the unique and special gifts of all citizens in need.”

“We should not tolerate any discrimination against them, as all people have inherent dignity,” the President added.

In his testimony Wednesday, Frank Stephens echoed these same reflections at the Capitol.

“Whatever you learn today, please remember this,” Mr. Stephens declared, “I am a man with Down syndrome and my life is worth living.”


Sunday, October 29, 2017

Human rabies?

A 6-year-old male patient presented to our hospital at 12 am on a Wednesday in October with a 3-day history of fever. According to the father & mother, they used an antipyretic with partial control of fever, then they sought medical advice at a private clinic at noon on Tuesday & the physician prescribed cefotaxime, in addition to the antipyretic.

Two hours later the boy became irritable and agitated, refusing food & drinks, they said. I asked whether there was a history of vomiting or headache to exclude meningitis, but the answer was no. During discussion, I noticed that the boy was scared, hugging his father, with his own neck fully flexed with no agitation nor irritability. When I asked to examine him, the boy started to scream & became very aggressive & agitated, biting everyone & spitting everywhere with abnormal behavior & fine tremors in the hands. I auscultated the chest & heart & both were free apart from tachycardia. Temperature was 38C. There was aerophobia and inability to drink water even after the agitation episode.

I asked for history of animal bites or scratches even if it had happened a long time ago; the answer was they were not sure. I admitted the patient under the supervision of my consultant who advised to give midazolam 3mg IM as the patient was too much agitated & aggressive to insert IV line to make the boy calm & reevaluate. Our provisional diagnosis was rabies.

The boy did not sleep the whole night as I went to reevaluate him at 4 am, 6 am & 8 am. He was becoming more irritable & more aggressive. At 9 am, the consultant advised neurological & pediatric consultations who both suspected rabies as a provisional diagnosis. MRI brain, LP, CBC & full chemistry were requested, but none of them was done due to the agitation & aggressiveness of the boy. The boy arrested. CPR was done for 30 minutes but unfortunately he passed away on Thursday at 5 am. Waleed M. K. Abu Zaid, Resident of Infectious Diseases, Al Gharbia, Egypt.

Later author comment:

Dear all,

Thanks for your participation & knowledge sharing

3 days ago we came to know that there is a history of dog bite since September 2017 through an investigation team from the directorate.

Relatives were not telling us the truth though we asked them more than 10 times

So, based on the new information, rabies is the first possibility

According to the MOH case definition, this is a probable case.

Another physician commented:

I've seen rabies in TX in the 1980's.. 12 yo asian f presented with a very sore throat and fever. She had no history of exposure to animals or animal bites. She had not traveled to endemic areas. She was alert, but appeared very ill. On exam, had autonomic instability (her blood pressure fluctuated wildly with something like stroking her arm) and a Haman's crunch. Diagnosis was difficult as she had things like a pneumomediastium. By the following morning, she could not handle her secretions and became obtunded. She was combative during intubation, Rabies; indeed it was her Cambodian refugee parents that raised the diagnosis! Dx at brain biopsy showed rabies, but PCR (by CDC) said US rabies strain, not SE Asian one. A course of Ribavirin (then in development) appeared to slow her progression, but she died.


Friday, October 27, 2017

Pretreatment behavior and subsequent medication effects in childhood absence epilepsy

Shinnar RC, Shinnar S, Cnaan A, Clark P, Dlugos D, Hirtz DG, Hu F, Liu C, Masur D, Weiss EF, Glauser TA; Childhood Absence Epilepsy Study Group. Pretreatment behavior and subsequent medication effects in childhood absence epilepsy. Neurology. 2017 Oct 17;89(16):1698-1706.

To characterize pretreatment behavioral problems and differential effects of initial therapy in children with childhood absence epilepsy (CAE).
The Child Behavior Checklist (CBCL) was administered at baseline, week 16-20, and month 12 visits of a randomized double-blind trial of ethosuximide, lamotrigine, and valproate. Total problems score was the primary outcome measure.
A total of 382 participants at baseline, 310 participants at the week 16-20 visit, and 168 participants at the month 12 visit had CBCL data. At baseline, 8% (95% confidence interval [CI] 6%-11%) of children with CAE had elevated total problems scores (mean 52.9 ± 10.91). At week 16-20, participants taking valproic acid had significantly higher total problems (51.7 [98.3% CI 48.6-54.7]), externalizing problems (51.4 [98.3% CI 48.5-54.3]), attention problems (57.8 [98.3% CI 55.6-60.0]), and attention-deficit/hyperactivity problems (55.8 [98.3% CI 54.1-57.6]) scores compared to participants taking ethosuximide (46.5 [98.3% CI 43.4-49.6]; 45.8 [98.3% CI 42.9-48.7]; 54.6 [98.3% CI 52.4-56.9]; 53.0 [98.3% CI 51.3-54.8]). Lack of seizure freedom and elevated week 16-20 Conner Continuous Performance Test confidence index were associated with worse total problems scores. At month 12, participants taking valproic acid had significantly higher attention problems scores (57.9 [98.3% CI 55.6-60.3]) compared to participants taking ethosuximide (54.5 [95% CI 52.1-56.9]).
Pretreatment and ongoing behavioral problems exist in CAE. Valproic acid is associated with worse behavioral outcomes than ethosuximide or lamotrigine, further reinforcing ethosuximide as the preferred initial therapy for CAE.

This study provides Class II evidence that for children with CAE, valproic acid is associated with worse behavioral outcomes than ethosuximide or lamotrigine.

Wednesday, October 25, 2017

OPHN1 syndrome

Inspired by a patient.  Another victory for whole exome sequencing.

Nakano-Kobayashi A, Tai Y, Nadif Kasri N, Van Aelst L. The X-linked mental retardation protein OPHN1 interacts with Homer1b/c to control spine endocytic zone positioning and expression of synaptic potentiation. J Neurosci. 2014 Jun 25;34(26):8665-71.

At glutamatergic synapses, local endocytic recycling of AMPA receptors (AMPARs) is important for the supply of a mobile pool of AMPARs required for synaptic potentiation. This local recycling of AMPARs critically relies on the presence of an endocytic zone (EZ) near the postsynaptic density (PSD). The precise mechanisms that couple the EZ to the PSD still remain largely elusive, with the large GTPase Dynamin-3 and the multimeric PSD adaptor protein Homer1 as the two main players identified. Here, we demonstrate that a physical interaction between the X-linked mental retardation protein oligophrenin-1 (OPHN1) and Homer1b/c is crucial for the positioning of the EZ adjacent to the PSD, and present evidence that this interaction is important for OPHN1's role in controlling activity-dependent strengthening of excitatory synapses in the rat hippocampus. Disruption of the OPHN1-Homer1b/c interaction causes a displacement of EZs from the PSD, along with impaired AMPAR recycling and reduced AMPAR accumulation at synapses, in both basal conditions and conditions that can induce synaptic potentiation. Together, our findings unveil a novel role for OPHN1 as an interaction partner of Homer1b/c in spine EZ positioning, and provide new mechanistic insight into how genetic deficits in OPHN1 can lead to impaired synapse maturation and plasticity.

Oligophrenin-1 syndrome
The OPHN1 syndrome (MIM 300486) was first described in a 12 year-old girl, carrier of a de novo translocation t(X;12)(q11;q15) which was found to disrupt the Oligophrenin-1 (OPHN1) gene at Xq12 and encodes a RhoGTPase activating protein (RhoGAP) involved in synaptic morphogenesis and function. The girl had congenital hypotonia, severe developmental delay, moderate cognitive impairment, early-onset complex partial seizures and bilateral divergent strabismus and dysmetria. At a later reevaluation, Brain MRI showed a posterior vermis dysgenesis including partial agenesis of lobules VI and VII associated with right vermian parasagittal cleft and mild cerebellar hemisphere hypoplasia. A consistent dilatation of the lateral cerebral ventricles and mild cortical atrophy was also present. A similar clinico-radiological phenotype was found in the affected males of a family carrying a single nucleotide deletion in exon 19 of the OPHN1, initially diagnosed with non-syndromic X-linked mental retardation. Another deletion comprising exon 19 of the OPHN1 gene, was identified in a family with five affected males showing moderate to severe mental retardation, infantile-onset epilepsy, hypotonia, strabismus and ataxia. Cryptorchidism and genital hypoplasia were present in all affected males. Neuroradiological findings included cortical atrophy, enlargement of the cerebral ventricles, bilateral hypoplasia of the head of the caudate nucleus, lower vermis and cerebellar hemisphere hypoplasia. One carrier sister had mild learning disabilities and strabismus but her brain MRI was normal. A stop mutation in exon 3 and an 8 base-pair insertion in exon 9 of the OPHN1 gene were identified in two other families with a similar phenoype. In a family with a 2 base-pair deletion in exon 8 of OPHN1 leading to a premature stop codon, the affected males showed developmental and cognitive delay with IQ ranging from 46 to 54, strabismus, early-onset generalized tonic-clonic seizures, abnormal behaviour and a characteristic facial phenotype with long face, prominent forehead, infraorbital creases, deep set eyes, upturned philtrum and large ears. The obligate carrier females showed only mild cognitive impairment and subtle facial changes. Brain MRI studies performed in the propositus at age 3 months showed underdeveloped frontal lobes, loss of brain volume with enlarged lateral ventricles, prominent subarachnoid spaces and a particular square shape of the frontal horns. Cerebellar hypoplasia and vermis dysgenesis with a large cisterna magna and a retrocerebellar cyst were noted .

A de novo translocation disrupting the OPHN1 gene in a female patient and intragenic deletions of OPHN1 detected by arrayCGH, in a male patient and in two families in which affected individuals all showed the characteristic clinico-radiological phenotype associated with OPHN1 syndrome were also reported. In one family with six affected males with intellectual deficit, minor facial anomalies, cubitus valgus, with or without sensorineural deafness, a deletion of exons 16-18 in the OPHN1 gene was identified. Screening OPHN1 in a large cohort of patients led to the identification of mutations in 12% of individuals with intellectual deficit and cerebellar hypoplasia, suggesting that the screening of this gene should be implemented in boys with vermis hypoplasia, enlarged cerebral ventricles and developmental delay.


Courtesy of a colleague

Alpha-thalassemia X-linked intellectual disability syndrome

Inspired by a patient

Schenkel LC, Kernohan KD, McBride A, Reina D, Hodge A, Ainsworth PJ, Rodenhiser DI, Pare G, Bérubé NG, Skinner C, Boycott KM, Schwartz C, Sadikovic B. Identification of epigenetic signature associated with alpha thalassemia/mental retardation X-linked syndrome. Epigenetics Chromatin. 2017 Mar 10;10:10.

Alpha thalassemia/mental retardation X-linked syndrome (ATR-X) is caused by a mutation at the chromatin regulator gene ATRX. The mechanisms involved in the ATR-X pathology are not completely understood, but may involve epigenetic modifications. ATRX has been linked to the regulation of histone H3 and DNA methylation, while mutations in the ATRX gene may lead to the downstream epigenetic and transcriptional effects. Elucidating the underlying epigenetic mechanisms altered in ATR-X will provide a better understanding about the pathobiology of this disease, as well as provide novel diagnostic biomarkers.
We performed genome-wide DNA methylation assessment of the peripheral blood samples from 18 patients with ATR-X and compared it to 210 controls. We demonstrated the evidence of a unique and highly specific DNA methylation "epi-signature" in the peripheral blood of ATRX patients, which was corroborated by targeted bisulfite sequencing experiments. Although genomically represented, differentially methylated regions showed evidence of preferential clustering in pericentromeric and telometric chromosomal regions, areas where ATRX has multiple functions related to maintenance of heterochromatin and genomic integrity.
Most significant methylation changes in the 14 genomic loci provide a unique epigenetic signature for this syndrome that may be used as a highly sensitive and specific diagnostic biomarker to support the diagnosis of ATR-X, particularly in patients with phenotypic complexity and in patients with ATRX gene sequence variants of unknown significance.

Stevenson RE. Alpha-Thalassemia X-Linked Intellectual Disability Syndrome. 2000 Jun 19 [updated 2014 Nov 6]. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Mefford HC, Stephens K, Amemiya A, Ledbetter N, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2017. Available from http://www.ncbi.nlm.nih.gov/books/NBK1449/
PubMed PMID: 20301622.

Alpha-thalassemia X-linked intellectual disability (ATRX) syndrome is characterized by distinctive craniofacial features, genital anomalies, severe developmental delays, hypotonia, intellectual disability, and mild-to-moderate anemia secondary to alpha-thalassemia. Craniofacial abnormalities include small head circumference, telecanthus or widely spaced eyes, short nose, tented vermilion of the upper lip, and thick or everted vermilion of the lower lip with coarsening of the facial features over time. Although all affected individuals have a normal 46,XY karyotype, genital anomalies range from hypospadias and undescended testicles to severe hypospadias and ambiguous genitalia, to normal-appearing female external genitalia. Global developmental delays are evident in infancy and some affected individuals never walk independently or develop significant speech.
The diagnosis of ATRX syndrome is established in individuals with somatic abnormalities, intellectual disability, hypotonia, abnormal hemoglobin H production, and a family history consistent with X-linked inheritance. ATRX is the only gene in which mutation causes ATRX syndrome.
Treatment of manifestations: Calorie-dense formula and/or gavage feeding as needed for adequate nutrition; anticholinergics, botulinum toxin type A injection of the salivary glands, and/or surgical redirection of the submandibular ducts for excessive drooling; early intervention programs and special education. Prevention of secondary complications: Antibiotic prophylaxis and vaccination to prevent pneumococcal and meningococcal infection in those with asplenia. Surveillance: Regular assessment of growth in infancy and childhood; regular monitoring of developmental progress. Other: Anemia rarely requires treatment.
ATRX syndrome is inherited in an X-linked manner. The mother of a proband may be a carrier or the affected individual may have a de novo pathogenic variant. Female carriers have a 50% chance in each pregnancy of transmitting the ATRX pathogenic variant; offspring with a 46,XY karyotype who inherit the ATRX pathogenic variant will be affected; offspring with a 46,XX karyotype who inherit the pathogenic variant are unaffected female carriers. Affected individuals do not reproduce. Carrier testing for at-risk females and prenatal testing for pregnancies at increased risk are possible if the pathogenic variant in the family is known.

Tuesday, October 24, 2017

Isn't this child abuse?

A statue outside a children's hospital

Sweating blood--hematohidrosis

Italian doctors were left bewildered when a woman was admitted to the hospital for “sweating blood” from her face and hands, a new case published in a medical journal on Monday revealed.

The woman, 21, would spontaneously bleed with no visible lesions on her skin, according to the case report published in the Canadian Medical Association Journal. The woman has been suffering from the mysterious disorder for three years and would start bleeding spontaneously in her sleep or while she was physically active.

It’s unclear what triggered the bleeding, but the bleeding intensified when she was under stress. The episodes would last between one to five minutes.

The women told doctors she suffered major depression and panic disorder because of the condition and became “socially isolated.” She has no history of psychosis, the report said.

The doctors floated different theories on what caused the condition, including factitious disorder, when someone would deceive others by appearing sick. However, she continued to spontaneously bleed after she was prescribed paroxetine and clonazepam for her depression and anxiety order.
They ultimately concluded she had hematohidrosis, an uncommon disease that would cause “spontaneous discharge of ‘blood sweat’ through intact skin.” Blood can also come out of areas that don’t have sweat glands.

It’s still unclear what causes the “blood sweat.” Dr. Michelle Sholzberg, co-director of the Hemophilia Comprehensive Care program at St. Michael's Hospital, told CBC News the case is the “most unusual.”

"I can say with clarity that I've never seen a case like this — ever," Sholzberg told CBC News. "And I can say that I've seen some of the worst bleeding disorders, and I've never seen them sweat blood."

"I think this person has a very bizarre anatomical defect on a microscopic level that is resulting in this very unusual symptom," the Canadian hematologist said.


See:  Roberto Maglie, Marzia Caproni. A case of blood sweating: hematohidrosis syndrome.  . CMAJ October 23, 2017 vol. 189 no. 42

Courtesy of a colleague

Saturday, October 21, 2017

Determined resuscitation

If a miracle is defined as bringing someone back from the dead, sometimes that does happen in medicine.

The Martin family believe they witnessed a miracle after their youngest son, Gardell, died last winter when he fell into an icy stream. He and his mother, father, and six older siblings live on a big rural property in central Pennsylvania that the kids love to explore. On a warm day in March 2015 two of the boys took Gardell, not quite two years old, out to play. The toddler lost his footing and fell into a stream about a hundred yards from his home. His brothers noticed that he was gone and were frantic when they couldn’t find him. By the time emergency rescuers got to Gardell—who’d been pulled out of the water by a neighbor—the boy’s heart had stopped beating for at least 35 minutes. The EMTs began chest compression, but they couldn’t get his heart to start up again. They continued CPR as they sped the ten miles to Evangelical Community, the closest hospital. He had no heartbeat, and his body temperature was 77 degrees Fahrenheit, more than 20 degrees below normal. They prepped Gardell for a helicopter ride to Geisinger Medical Center, 18 miles away in Danville. Still no heartbeat.

“He had no signs of life whatsoever,” recalls Richard Lambert, director of pediatric sedation service and a member of the pediatric critical-care team that awaited the helicopter. “He looked like a child who was … Well, he was dusky, dark colored. His lips were blue …” Lambert’s voice trails off as he remembers that dreadful moment. He knew that children who drown in ice water sometimes recover, but he’d never known of one who’d been dead for as long as Gardell had. Even worse, the boy had a shockingly low blood pH, a sign of imminent organ failure.

An emergency room resident turned to Lambert and his colleague Frank Maffei, director of pediatric critical care for Geisinger’s Janet Weis Children’s Hospital: Maybe it was time to stop trying to revive the boy? Lambert and Maffei both wanted to keep going. All the elements were as favorable as they could be in a brink-of-death story. The water was cold, the child was young, and resuscitation efforts had been started within minutes of the drowning and had continued nonstop ever since. Let’s try just a little longer, they told the team.

So they continued. Another 10 minutes, another 20 minutes, another 25. By this time Gardell had been without pulse or breath for more than an hour and a half. He was “a flaccid, cold corpse showing no signs of life,” as Lambert describes him. But team members kept pumping, pressing, monitoring. The ones doing chest compression rotated on and off every two minutes—it’s exhausting to keep doing it right, even on a tiny chest—and others inserted catheters into his femoral vein, jugular vein, stomach, and bladder, infusing warm fluids to gradually increase his body temperature. None of it seemed to be making any difference.

Rather than call off the resuscitation entirely, Lambert and Maffei decided to bring Gardell into surgery for a cardiopulmonary bypass—the most aggressive form of active rewarming, a last-ditch effort to get his heart beating. After they scrubbed up, they checked for a pulse one more time.

Incredibly, there it was: a heartbeat, faint at first, but steady, without the rhythm abnormalities that sometimes appear after a prolonged cardiac arrest. And just three and a half days later Gardell left the hospital with his prayerful family, a little wobbly on his feet but otherwise perfectly fine.


ACTH or prednisolone for infantile spasms

A new paper finding that adrenocorticotropic hormone and prednisolone were equally effective in managing infantile spasms has contributed to a growing debate about why the more expensive ACTH is being used for therapy.

In a single randomized trial of 97 infants with West syndrome — a disorder characterized by epileptic/infantile spasms, hypsarrhythmia, and intellectual disability — synthetic adrenocorticotropic hormone (ACTH) and prednisolone were found to be equally effective at controlling seizures at one year, a team of investigators at the University of Colombo in Sri Lanka reported in the August 14 online edition of Pediatric Neurology.

The findings come on the heels of a longstanding debate among pediatric neurologists about which therapy is most cost effective. The question, they say, is this: If the two drugs are similarly effective in controlling seizures, why use the much more expensive treatment?

“The whole issue of infantile spasms therapy is controversial,” said E. Steven Roach, FAAN, chief of neurology at Nationwide Children's Hospital in Columbus, OH, and editor-in-chief of Pediatric Neurology, who was not involved with the study. “This is partly because of the shifting science and partly because Questcor bought the rights to ACTH and dramatically increased its price. We have traditionally recommended ACTH injections in the US, but it is extremely costly, and outside of the US people tend to use the cheaper prednisolone alternative. We are talking something on the order of $150,000 per treatment course [for ACTH] versus $200 [for prednisolone].”

“The Sri Lanka study is something we could not easily do here,” Dr. Roach acknowledged. “It would be too expensive to purchase natural ACTH for a study.”

But it was not always so expensive. The ACTH agent, Acthar, cost $40 a vial when it was first licensed by Questcor Pharmaceuticals in 2001, and over the years, the price hiked, in large part, according to the Federal Trade Commission (FTC), because the company bought the rights to competitive products, monopolizing the market, stifling competition, and keeping prices high.

In January, Mallinckrodt Pharmaceuticals, which acquired Questcor in 2014, agreed to pay $100 million to settle the lawsuit by the FTC and several state attorneys general, alleging that the company had violated antitrust laws in regard to Acthar.  Acthar, after several attempts by Questcor, was approved by the Food and Drug Administration (FDA) for infantile spasms in 2010…

In a phone interview, the investigator added that it is frustrating “that the field has not reached a consensus on the optimal therapy.” Among the reasons, she contends, are that different types of ACTH have been used in the various studies. Clinicians outside of the United States use a synthetic version that contains 24 amino-acids in the ACTH peptide. Synthetic ACTH is not approved by the US Food and Drug Administration (FDA) and is rarely used in the US. Mallinckrodt's H.P. Acthar Gel is the only natural ACTH substance available in the US. It contains the full 39 amino acid peptide.

The current study did not use the H.P. Acthar Gel, which is used in the US. Dr. Wanigasinghe noted that it is difficult to make sense of the conflicting results because of varying types, doses, and treatment durations of ACTH and the oral steroids. Most of the studies have had very small numbers of patients, she pointed out…

Commenting on the study, Dr. Roach agreed that “no one in this country has ever done an adequate comparison of ACTH and prednisolone for the treatment of infantile spasms. And that is why this study is so lovely. They did it. There is increasing evidence that prednisolone is just as good, yet a lot of people in the US persist in an almost fanatical preference for the injections.”

Dr. Roach, who has not received research funding related to the treatments, said that some centers are using prednisolone first and if that doesn't work to stop seizures in two weeks they will order ACTH.

The American Academy of Neurology and the Child Neurology Society developed guidelines in 2004 on treating infantile spasms, which were updated in 2012, when an advisory panel reviewed 26 articles. They concluded that there was “insufficient evidence to determine whether other forms of corticosteroids are as effective as adrenocorticotropic hormone (ACTH) for short-term treatment of infantile spasms. However, low-dose ACTH is probably as effective as high-dose ACTH.”

The sooner treatment starts, the better it could be for the long-term development of the child, the guideline concluded.

“I don't think adequate evidence was ever there,” said Dr. Roach. He noted that the guidelines were devised before the results of the Sri Lanka study and the United Kingdom Infantile Spasms Study (UKISS) were available. UKISS compared hormone treatment with vigabatrin on developmental and epilepsy outcomes to age 14 months. This multicenter randomized trial was not designed to compare the differences between ACTH and prednisolone, but a secondary analysis, published in The Lancet Neurology in 2005, showed similar results. Another study – the International Collaborative Infantile Spasm Study (ICISS) – published in the Lancet Neurology this past January also found a combination therapy to be more effective than either drug used alone.

“Some neurologists believe that ACTH is the optimal treatment for infantile spasms,” said John R. Mytinger, MD, a child neurologist at Nationwide Children's Hospital and assistant professor of clinical pediatrics and neurology at the Ohio State University College of Medicine.

“But since the price increase in the US, and with additional data, there has been more interest in using high-dose oral prednisolone as a first-line option. Prednisolone is not FDA-approved for the treatment of infantile spasms. However, there would be no incentive for a pharmaceutical company to pursue FDA approval for such an inexpensive medication.”

“Consistent with the 2013 Cochrane Database of Systematic Reviews on infantile spasms, I believe that ACTH, vigabatrin, and high-dose oral prednisolone are all reasonable first-line treatments for infantile spasms,” said Dr. Mytinger, who has not received research funding for either drug.

“Practice varies between and within centers,” Dr. Mytinger added. “What is critical is that we diagnose early and use first-line therapy. ACTH is one of our few first-line treatments; it can be very effective and some patients may require it to achieve remission. I just wish it was not so expensive.”

Shaun Hussain, MD, a pediatric neurologist the University of California, Los Angeles (UCLA) Medical Center, also agreed that there is insufficient evidence that ACTH is superior to prednisolone “because the ideal clinical study has not been done.” And that study would be: ACTH 150 U/m2/day compared to oral prednisolone 4-8 mg/kg/day, he said.

“I believe high doses of prednisolone are effective but I am not sure that it is as effective as ACTH,” said Dr. Hussain, who is on the speaker's bureau for Mallinckrodt, which manufactures the ACTH used in the US.

“ACTH is expensive but the price tag is dwarfed by the monetary and intellectual costs of not treating these children,” Dr. Hussain said. The problem, he said, is that it is very expensive and many centers order it when the child arrives in the emergency room with seizures. Timing is critically important. UCLA's protocol is to begin with prednisolone and vigabatrin and switch to ACTH within two weeks if the combination isn't working.

Mary Zupanc, MD, division chief of pediatric neurology and director of the Pediatric Comprehensive Epilepsy Program at the Children's Hospital of Orange County in Southern California and the University of California, Irvine, said the issue is complex. “I have reviewed virtually all of the literature on ACTH, prednisolone, and other therapies in the treatment of infantile spasms. I have always fallen into the ACTH camp — partly due to training, but primarily due to my review of the literature and clinical experience. I have never seen prednisone be as effective as high-dose ACTH — and this is supported by the current literature.” said Dr. Zupanc, who has served on the speaker's bureau for Questcor, which had held licensing rights to the drug prior to the company being acquired by Mallinckrodt.

 “The only way to resolve this debate is to do the right clinical study – a prospective, randomized trial comparing high-dose ACTH to high-dose prednisolone,” she said.

“There have been many neurologists looking for alternatives, even before the price increase, due to side effects of ACTH,” said Eric H. Kossoff, MD, professor of neurology and pediatrics and medical director of the Ketogenic Diet Center at Johns Hopkins Hospital. “We don't use ACTH here any longer. We did a study of our experience using oral prednisolone and ACTH [in Epilepsy & Behavior in 2009] and found that both were effective. Prednisolone is a fraction of the cost and doesn't involve injections or hospitalizations. Even if the price decreased, I'm not sure we'd use ACTH again.”

Tallie Z. Baram MD, PhD, now a professor of pediatrics, anatomy & neurobiology, neurology and physiology & biophysics at the University of California Irvine, conducted the original controlled study on high-dose natural ACTH.

In 1996, she and her colleagues reported in Pediatrics findings from a trial comparing high-dose ACTH – 150 U/m2/day — to a low dose of oral prednisone (2 mg/kg once a day) for two weeks with a subsequent taper. They randomized 29 children who were admitted to the hospital with infantile spasms to receive either the high dose of ACTH or prednisone. Dr. Baram said that 13 of the 15 patients receiving the high dose of ACTH had no more seizures within the two-week testing period. Their EEGs also returned to normal. By comparison, four of the 14 patients on prednisone (28.6 percent) had a similar response.

Dr. Baram said that her group had evidence that it was the very high dose of ACTH that led to the results. Further work showed that such high doses get into the brain and work on a completely different mechanism to stop seizure activity. Specifically, whereas the mechanism of ACTH in stopping seizures is considered only to involve releasing the baby's endogenous cortisol (the natural equivalent of prednisone or prednisolone) from the adrenal gland, or perhaps exert mild anti-inflammatory effects, high-dose ACTH got into the brain and had additional actions that prednisolone and low-dose ACTH did not. Dr. Baram indicated that ACTH targets melanocortin receptors in the brain and this shuts down a natural pro-seizure molecule, corticotropin-releasing hormone.

She added that “lower doses of ACTH may not work any better than prednisolone, because they mainly function by releasing the body's own prednisolone-like molecules.” Dr. Baram never received money from the pharmaceutical companies during the implementation of the study or afterwards.


See:  http://childnervoussystem.blogspot.com/2017/09/prednisolone-versus-acth-for-infantile.html

Friday, October 20, 2017

Consciousness after death

Death just became even more scary: scientists say people are aware they’re dead because their consciousness continues to work after the body has stopped showing signs of life.

That means that, theoretically, someone may even hear their own death being announced by medics.

The claim was made by Dr Sam Parnia, director of critical care and resuscitation research at NYU Langone School of Medicine in New York City.

He and his team are looking at people who suffered cardiac arrest, technically died, but were later revived. It’s the largest study of its type ever carried out.

Some of those studied say they had awareness of full conversations and seeing things that were going on around them, even after they were pronounced dead.

These accounts were then verified by the medical and nursing staff who were present at the time.

Death is defined as the point at which the heart no longer beats, and blood flow to the brain is cut
off. Dr Sam Parnia said: “Technically, that's how you get the time of death – it's all based on the moment when the heart stops.

“Once that happens, blood no longer circulates to the brain, which means brain function halts almost instantaneously.

“You lose all your brain stem reflexes – your gag reflex, your pupil reflex, all that is gone.”

However, there’s evidence to suggest that there’s a burst of brain energy as someone dies.

In 2013 researchers at the University of Michigan looked at the electrical signals inside the brains of nine anaesthetised rats having an induced heart attack.

They saw activity patterns which are linked to a “hyper-alerted state” in the brief period after clinical death.

Dr Parnia said: "In the same way that a group of researchers might be studying the qualitative nature of the human experience of 'love', for instance, we're trying to understand the exact features that people experience when they go through death, because we understand that this is going to reflect the universal experience we're all going to have when we die."


Treatment dilemmas in Guillain-Barré syndrome

Verboon C, van Doorn PA, Jacobs BC. Treatment dilemmas in Guillain-Barré syndrome. J Neurol Neurosurg Psychiatry. 2017 Apr;88(4):346-352.

Guillain-Barré syndrome (GBS) is an acute polyradiculoneuropathy with a highly variable clinical course and outcome. Intravenous immunoglobulin (IVIg) and plasma exchange are proven effective treatments, but the efficacy has been demonstrated mainly on motor improvement in adults with a typical and severe form of GBS. In clinical practice, treatment dilemmas may occur in patients with a relatively mild presentation, variant forms of GBS, or when the onset of weakness was more than 2 weeks ago. Other therapeutic dilemmas may arise in patients who do not improve or even progress after initial treatment. We provide an overview of the current literature about therapeutic options in these situations, and additionally give our personal view that may serve as a basis for therapeutic decision-making.

From the article

Despite the proven effectiveness of these treatments in GBS, the care of patients in clinical practice is often complex. First, outcome in many patients is still poor: 2–10% may die, 20% are still unable to walk after 6 months and many patients suffer from residual symptoms, including pain and severe fatigue. Second, the patients in whom the therapeutic effects have been demonstrated frequently represent a selected proportion of the patients (symptoms <2 weeks and who are walking with aid, bed bound or in need of artificial ventilation (GBS disability grade ≥3,).

Third, the efficacy of PE and IVIg has primarily been demonstrated related to improvement on the GBS disability scale 4 weeks after the start of treatment. However, this scale focuses on walking and does not take into account other consequences of GBS that are important in daily life, such as arm function, facial weakness, sensory deficits, pain and fatigue. Finally, as a consequence of this, the Cochrane reviews about treatment of GBS are restricted to the specific inclusion and outcome criteria of the trials being focused on the GBS disability scale….

Current personal view: Based on limited evidence we recommend to start treatment as soon as possible in patients who walk with aid, are bedbound or ventilated (level of evidence: 3). In patients who are still able to walk unaided but show rapid progression of symptoms one likely should aim to prevent further nerve damage and not wait for further clinical deterioration (level of evidence: 4)….

Current personal view: There is no information available on the effect of treatment in patients with GBS presenting 4 weeks or later after the onset of weakness. Subacute GBS or A-CIDP should be considered in patients who present after 4 weeks of onset. We suggest to start IVIg when there is clear clinical progression or a 'wait and see' policy in case of relatively mild and stable disease (level of evidence: 4)….

Current personal view: Patients with mild GBS may have long-term functional impairment, but only a beneficial effect of treatment with PE has been demonstrated (level of evidence: 2). This effect has not been demonstrated for IVIg in adult patients. Based on the effect of PE in mild cases and of IVIg in severe cases, IVIg likely may be effective in mild GBS too. We propose that treatment (either PE or IVIg) should be considered especially in mildly affected patients who develop additional features such as autonomic dysfunction, bulbar or facial weakness (level of evidence: 4). New treatment trials preferentially should study the effect of treatment not only restricted to severely affected patients with GBS…

Current personal view: Based on the results of four retrospective studies with small numbers of patients, we consider to recommend IVIg over PE in patients with pure motor GBS (level of evidence: 3). Patients with PCB, ataxic and sensory GBS might never become eligible for treatment when only the GBS disability scale is taken into account and therefore treatment should be initiated when symptoms are seriously disabling or rapidly progressing (level of evidence: 4)….
Current personal view: No RCT has been performed exclusively in patients with axonal forms of GBS, until such studies have demonstrated otherwise, we recommend to treat these patients similarly as the patients with a demyelinating form of GBS (level of evidence: 4)…

Current personal view: There currently is no indication to treat children with GBS differently than adults. IVIg seems to be effective in children with GBS (level of evidence: 2) and is preferred over PE because it is easier to administer and possibly better tolerated in small children (level of evidence: 3)…

One randomised trial compared the efficacy of PE, IVIg, and PE followed immediately by IVIg in 379 severely affected patients, but did not find significant differences between the three treatment modalities in any of the outcome measures. Thus IVIg after PE was not significantly better than IVIg or PE alone. However, all patients receiving the combination switched to IVIg regardless of recovery after PE. No trial has been conducted to show whether patients who truly do not respond to one of these two treatments, may respond after switching to the other treatment.

Whether PE after IVIg should be considered remains unclear. One small retrospective study in 46 patients reported that treatment with IVIg followed by PE was not better than IVIg alone. On the contrary, the patients who received both treatments had a worse GBS disability grade at discharge and were longer hospitalised.  The researchers conclude that this could reflect a more severe disease course in patients receiving two treatments, but it could also suggest that PE washes out IVIg, thus preventing the therapeutic effects of IVIg.

Another option for patients who continue to deteriorate after initial treatment is to repeat the same regimen of treatment, being either PE or IVIg. Most studies on PE have investigated the effect of five exchanges. One trial showed that six PEs were not superior over four in already ventilated patients but the sixth course was given as part of the study protocol and not because of lack of
improvement. A second course of IVIg may be beneficial in patients who rapidly metabolise the administered IgG. Previous studies showed that a low-serum IgG increase 2 weeks after treatment is associated with more a severe disease course and poor outcome in comparison with patients who have a high IgG increase after treatment…

Current personal view: At present there is no evidence that outcome is improved by repeating treatment (either IVIg or PE) or switch to another type of treatment (level of evidence: 2). PE after IVIg should probably be avoided (level of evidence: 4).


Children with 5'-end NF1 gene mutations are more likely to have glioma

Anastasaki C, Morris SM, Gao F, Gutmann DH. Children with 5'-end NF1 gene mutations are more likely to have glioma. Neurol Genet. 2017 Sep 22;3(5):e192.

To ascertain the relationship between the germline NF1 gene mutation and glioma development in patients with neurofibromatosis type 1 (NF1).
The relationship between the type and location of the germline NF1 mutation and the presence of a glioma was analyzed in 37 participants with NF1 from one institution (Washington University School of Medicine [WUSM]) with a clinical diagnosis of NF1. Odds ratios (ORs) were calculated using both unadjusted and weighted analyses of this data set in combination with 4 previously published data sets.
While no statistical significance was observed between the location and type of the NF1 mutation and glioma in the WUSM cohort, power calculations revealed that a sample size of 307 participants would be required to determine the predictive value of the position or type of the NF1 gene mutation. Combining our data set with 4 previously published data sets (n = 310), children with glioma were found to be more likely to harbor 5'-end gene mutations (OR = 2; p = 0.006). Moreover, while not clinically predictive due to insufficient sensitivity and specificity, this association with glioma was stronger for participants with 5'-end truncating (OR = 2.32; p = 0.005) or 5'-end nonsense (OR = 3.93; p = 0.005) mutations relative to those without glioma.

Individuals with NF1 and glioma are more likely to harbor nonsense mutations in the 5' end of the NF1 gene, suggesting that the NF1 mutation may be one predictive factor for glioma in this at-risk population.

Thursday, October 19, 2017

John's Crazy Socks

John Cronin’s message is simple, “socks, socks and more socks”, but the 21-year-old entrepreneur with Down syndrome and founder of John’s Crazy Socks’ Opens a New Window. mission is much more powerful; smashing stereotypes of what people with a disability can achieve.

“Down syndrome never holds me back,” John Cronin tells FOX Business. “I love inspiring
people.” In 2016, John was finishing high school and, like other young men, was facing a big decision of what to do next.

“He started talking to me about going in to business,” Mark X. Cronin, John’s Dad, co-founder and president of John’s Crazy Socks, tells FOX Business.

John came to his dad with some interesting ideas, including a “fun store” -- they are still trying to figure that one out -- and a food truck.

“I had a problem, my dad and I, both of us can’t cook!” jokes  John Cronin.

Eventually, John’s love for colorful sock flair became an inspiration, and in December 2016, John’s Crazy Socks, an online one-stop sock shop, opened for business.  From food-inspired knee highs to canine crew socks, John’s Crazy Sock’s now boasts over 1,300 pairs of fun, funky socks. Since opening, business has been booming.

“We are on a mission to spread happiness, and we are spreading that message through socks,” says Mark X. Cronin.

Each order is shipped out the same day which includes John’s story, often a hand written note by John, some candy and two discount cards - “one for you and one to give to a friend.”…

“I think there was an assumption on many that this was a quaint, little business, you were doing part time and on the side.  When they find out, in our first year, we are going to do $1.2 to $1.3 million dollars, that makes people sit up,” says Mark X. Cronin. “Which I would suggest is pretty good for a startup.”…

More than profit, John and Mark are dedicated to giving back.  5% of their sales go to charity, like the National Down syndrome Society, and they carry specialty socks for causes like Autism Awareness. In addition, John and Mark’s staff include employees who have a disability.

“We are demonstrating that by working with people with special needs they become an asset, they become a reason for our success, not a liability, not an obstacle.  We had to overcome that,” says Mark X. Cronin….

The team recently expanded, now headquartered in a 6,400 square foot warehouse and office in Melville, New York.  John spends his days working with fellow employees, packing orders, making phone calls and coming up with unique initiatives like the “Monday Madness Mystery Bag” and a sock-of-the-month club. Mark and John also make it a priority to keep their fans informed via John’s social media channels…

“John and I have this special partnership. We both know we need each other. We are both committed to the mission we have and we want to work together, I’m a lucky man to be able to work with my son,” says Mark X. Cronin.

“I’m telling the whole world, I really can do anything,” adds John Cronin.


Insurance coverage

Even as Congress debates whether to overhaul the nation’s health care system or to wait for ObamaCare to fail, few lawmakers are talking about the hidden health care crisis many Americans with health insurance are already facing: denied coverage.

While much attention has been paid to rising premiums and pre-existing conditions, a growing number of insured Americans with chronic or persistent conditions—up to 53 million—risk being denied coverage for medications, tests and procedures to treat their illness.

I was recently commissioned to conduct a nationwide poll of insured Americans by the Doctor-Patient Rights Project (DPRP), a new health care advocacy coalition. The results were alarming and disheartening.

Not only did it find that coverage denials for treatment of chronic conditions were widespread and common, the results suggest that those most in need of quality health care—patients treating serious chronic or persistent diseases—are most frequently denied treatment coverage by their insurers.

Ironically, these denials worsen the conditions for many patients and create an even larger health care expense either for the insurance provider or for the publicly-funded entitlement programs that are intended to serve those the private insurance system leaves behind. 

While the debate over health care reform has focused largely on increasing the number of people covered by insurance, it has ignored the burden on taxpayers that occurs when insurance providers withhold treatments to consumers who have paid for coverage.

DPRP’s poll found that more than 53 million Americans—nearly one in four with chronic or persistent illnesses—may lack access to essential treatments because their provider denies coverage.

Many of the denied consumers DPRP surveyed were denied multiple times and most had to wait more than a month before their insurer responded to their request for coverage of a prescribed treatment. While they waited, nearly a third said their condition worsened.

When insurance companies—not doctors—become the arbiters of patient health, no one should be surprised that cost concerns are prioritized. Yet even with losses from ObamaCare mandates, health insurance companies’ net income rose to $13.1 billion in 2016, up 46 percent from the year before…

One tactic, for example, called “therapeutic substitution” but known more commonly as “non-medical switching” allows insurance companies to direct pharmacists to dispense a cheaper, alternative drug in lieu of the medication the doctor prescribed. In many states, it is perfectly legal for pharmacists to make the switch without notifying the patient or the prescribing doctor beforehand.

Another cost-saving tactic insurers use is step therapies, or “fail first” policies, which require patients with a particular condition to take a less expensive medication and document its ineffectiveness before the insurer will pay for the more expensive drug treatment the doctor has prescribed.

In some cases, patients have waited years and been made to take five or six different drugs before gaining access to the recommended medication.

As more consumers experience coverage denials, it is unsurprising that they are rejecting—by wide margins—insurance company interference in treatment decisions.

DPRP’s poll found that 91 percent of consumers believe insurance providers should not have the final say in medical decision-making and should play either a secondary role or no role at all in making treatment decisions, the largest consensus the survey uncovered.

From a simple economic perspective, consumers who are denied the coverage they have purchased, and whose conditions deteriorate as a result, become greater burdens on their health plans or on the taxpayer-funded health care safety net.

Consequently, Congressional efforts to reform the nation’s health care system have little chance of succeeding until legislators address the hidden health care crisis plaguing those who are ostensibly already covered. 


Denial of coverage

The 9-month-old son of a retired NYPD officer allegedly received a letter from the family’s insurance company recently, explaining that the clinical trial he was enrolled in to treat aggressive brain cancer was “not medically necessary,” and therefore would not be covered by the provider.

The family’s plight began two months ago when Connor Richardson, then 7 months old, was diagnosed with a teratoid rhabdoid tumor, The Daily Beast reported. He underwent two major surgeries at Stony Brook University Hospital in New York to remove the tumor, but follow up exams at St. Jude Children’s Research Hospital in Memphis discovered the tumor had returned and the cancer spread to his spine.

While St. Jude provides free care to its patients, Richardson’s father, Wayne, told The Daily Beast that they were shocked to receive a letter from HIP health insurance dated Oct. 11 and addressed to their baby. Wayne said the first thing he noticed at the top of the alleged letter were the notes “Type of Review: Prospective” and “Type of Denial: Medical Necessity.”

 “The principal investigator has requested medications including methotrexate, cisplatin, cyclophosphamide, vincristine in combination with an investigational medication, alisertib,” the alleged letter purportedly said. “This combination of medications is not the standard of care for this type of cancer, and is considered experimental and investigational at this time, as evidence-based guidelines do not exist to confirm its effectiveness for his brain tumor. Therefore, this request for clinical trial treatment at St. Jude’s hospital is not medically necessary and is denied.”

Wayne told The Daily Beast that while as a parent, you don’t care what it costs to heal your child, the concern is that the insurers are denying payment to a hospital that focuses on children’s research. He plans to contest the denial, and said without the treatment, Connor would die.

“You’re taking away from them and their research … because the insurance doesn’t want to pay,” he told The Daily Beast.

Connor has been receiving treatment at St. Jude’s since the end of September. A GoFundMe page has been keeping supporters updated on his progress.


Wednesday, October 18, 2017

Intrathecal 2-hydroxypropyl-β-cyclodextrin decreases neurological disease progression in Niemann-Pick disease, type C1

Ory DS, Ottinger EA, Farhat NY, King KA, Jiang X, Weissfeld L, Berry-Kravis E, Davidson CD, Bianconi S, Keener LA, Rao R, Soldatos A, Sidhu R, Walters KA, Xu X, Thurm A, Solomon B, Pavan WJ, Machielse BN, Kao M, Silber SA, McKew JC, Brewer CC, Vite CH, Walkley SU, Austin CP, Porter FD. Intrathecal 2-hydroxypropyl-β-cyclodextrin decreases neurological disease progression in Niemann-Pick disease, type C1: a non-randomised, open-label, phase 1-2 trial.
Lancet. 2017 Aug 10. pii: S0140-6736(17)31465-4. doi:10.1016/S0140-6736(17)31465-4. [Epub ahead of print]

Niemann-Pick disease, type C1 (NPC1) is a lysosomal storage disorder characterised by progressive neurodegeneration. In preclinical testing, 2-hydroxypropyl-β-cyclodextrins (HPβCD) significantly delayed cerebellar Purkinje cell loss, slowed progression of neurological manifestations, and increased lifespan in mouse and cat models of NPC1. The aim of this study was to assess the safety and efficacy of lumbar intrathecal HPβCD.
In this open-label, dose-escalation phase 1-2a study, we gave monthly intrathecal HPβCD to participants with NPC1 with neurological manifestation at the National Institutes of Health (NIH), Bethesda, MD, USA. To explore the potential effect of 2-week dosing, three additional participants were enrolled in a parallel study at Rush University Medical Center (RUMC), Chicago, IL, USA. Participants from the NIH were non-randomly, sequentially assigned in cohorts of three to receive monthly initial intrathecal HPβCD at doses of 50, 200, 300, or 400 mg per month. A fifth cohort of two participants received initial doses of 900 mg. Participants from RUMC initially received 200 or 400 mg every 2 weeks. The dose was escalated based on tolerance or safety data from higher dose cohorts. Serum and CSF 24(S)-hydroxycholesterol (24[S]-HC), which serves as a biomarker of target engagement, and CSF protein biomarkers were evaluated. NPC Neurological Severity Scores (NNSS) were used to compare disease progression in HPβCD-treated participants relative to a historical comparison cohort of 21 NPC1 participants of similar age range.
Between Sept 21, 2013, and Jan 19, 2015, 32 participants with NPC1 were assessed for eligibility at the National Institutes of Health. 18 patients were excluded due to inclusion criteria not met (six patients), declined to participate (three patients), pursued independent expanded access and obtained the drug outside of the study (three patients), enrolled in the RUMC cohort (one patient), or too late for the trial enrolment (five patients). 14 patients were enrolled and sequentially assigned to receive intrathecal HPβCD at a starting dose of 50 mg per month (three patients), 200 mg per month (three patients), 300 mg per month (three patients), 400 mg per month (three patients), or 900 mg per month (two patients). During the first year, two patients had treatment interrupted for one dose, based on grade 1 ototoxicity. All 14 patients were assessed at 12 months. Between 12 and 18 months, one participant had treatment interrupted at 17 months due to hepatocellular carcinoma, one patient had dose interruption for 2 doses based on caregiver hardship and one patient had treatment interrupted for 1 dose for mastoiditis. 11 patients were assessed at 18 months. Between Dec 11, 2013, and June 25, 2014, three participants were assessed for eligibility and enrolled at RUMC, and were assigned to receive intrathecal HPβCD at a starting dose of 200 mg every 2 weeks (two patients), or 400 mg every two weeks (one patient). There were no dropouts in this group and all 3 patients were assessed at 18 months. Biomarker studies were consistent with improved neuronal cholesterol homoeostasis and decreased neuronal pathology. Post-drug plasma 24(S)-HC area under the curve (AUC8-72) values, an indicator of neuronal cholesterol homoeostasis, were significantly higher than post-saline plasma 24(S)-HC AUC8-72 after doses of 900 mg (p=0·0063) and 1200 mg (p=0·0037). CSF 24(S)-HC concentrations in three participants given either 600 or 900 mg of HPβCD were increased about two fold (p=0·0032) after drug administration. No drug-related serious adverse events were observed. Mid-frequency to high-frequency hearing loss, an expected adverse event, was documented in all participants. When managed with hearing aids, this did not have an appreciable effect on daily communication. The NNSS for the 14 participants treated monthly increased at a rate of 1·22, SEM 0·34 points per year compared with 2·92, SEM 0·27 points per year (p=0·0002) for the 21 patient comparison group. Decreased progression was observed for NNSS domains of ambulation (p=0·0622), cognition (p=0·0040) and speech (p=0·0423).

Patients with NPC1 treated with intrathecal HPβCD had slowed disease progression with an acceptable safety profile. These data support the initiation of a multinational, randomised, controlled trial of intrathecal HPβCD.

Courtesy of Neurology Today

FTY720 as treatment for limb-girdle muscular dystrophy

Heydemann A. Severe murine limb-girdle muscular dystrophy type 2C pathology is diminished by FTY720 treatment. Muscle Nerve. 2017 Sep;56(3):486-494.

Limb-girdle muscular dystrophy type 2C (LGMD-2C) is caused by mutations in γ-sarcoglycan and is a devastating, progressive, and fully lethal human muscle-wasting disease that has no effective treatment. This study examined the efficacy of the sphingosine-1-phosphate receptor modulator FTY720 in treating Sgcg-/- DBA2/J, a severe mouse model of LGMD-2C. FTY720 treatment was expected to target LGMD-2C disease progression at 2 key positions by reducing chronic inflammation and fibrosis.
The treatment protocol was initiated at age 3 weeks and was continued with alternate-day injections for 3 weeks.
The treatment produced significant functional benefit by plethysmography and significant reductions of membrane permeability and fibrosis. Furthermore, the protocol elevated protein levels of δ-sarcoglycan, a dystrophin-glycoprotein family member.

This study showed that FTY720 is an effective muscular dystrophy treatment when therapy is initiated early in the disease progression. Muscle Nerve 56: 486-494, 2017.

Autoantibodies in epilepsy

Dubey D, Singh J, Britton JW, Pittock SJ, Flanagan EP, Lennon VA, Tillema JM, Wirrell E, Shin C, So E, Cascino GD, Wingerchuk DM, Hoerth MT, Shih JJ, Nickels KC, McKeon A. Predictive models in the diagnosis and treatment of autoimmune epilepsy. Epilepsia. 2017 Jul;58(7):1181-1189.

To validate predictive models for neural antibody positivity and immunotherapy response in epilepsy.
We conducted a retrospective study of epilepsy cases at Mayo Clinic (Rochester-MN; Scottsdale-AZ, and Jacksonville-FL) in whom autoimmune encephalopathy/epilepsy/dementia autoantibody testing profiles were requested (06/30/2014-06/30/2016). An Antibody Prevalence in Epilepsy (APE) score, based on clinical characteristics, was assigned to each patient. Among patients who received immunotherapy, a Response to Immunotherapy in Epilepsy (RITE) score was assigned. Favorable seizure outcome was defined as >50% reduction of seizure frequency at the first follow-up.
Serum and cerebrospinal fluid (CSF) from 1,736 patients were sent to the Mayo Clinic Neuroimmunology Laboratory for neural autoantibody evaluation. Three hundred eighty-seven of these patients met the diagnostic criteria for epilepsy. Central nervous system (CNS)-specific antibodies were detected in 44 patients. Certain clinical features such as new-onset epilepsy, autonomic dysfunction, viral prodrome, faciobrachial dystonic seizures/oral dyskinesia, inflammatory CSF profile, and mesial temporal magnetic resonance imaging (MRI) abnormalities had a significant association with positive antibody results. A significantly higher proportion of antibody-positive patients had an APE score ≥4 (97.7% vs. 21.6%, p < 0.01). Sensitivity and specificity of an APE score ≥4 to predict presence of specific neural auto-antibody were 97.7% and 77.9%, respectively. In the subset of patients who received immunotherapy (77), autonomic dysfunction, faciobrachial dystonic seizures/oral dyskinesia, early initiation of immunotherapy, and presence of antibodies targeting plasma membrane proteins (cell-surface antigens) were associated with favorable seizure outcome. Sensitivity and specificity of a RITE score ≥7 to predict favorable seizure outcome were 87.5% and 83.8%, respectively.
APE and RITE scores can aid diagnosis, treatment, and prognostication of autoimmune epilepsy. A PowerPoint slide summarizing this article is available for download in the Supporting Information section here.

Dubey D, Alqallaf A, Hays R, Freeman M, Chen K, Ding K, Agostini M, Vernino S. Neurological Autoantibody Prevalence in Epilepsy of Unknown Etiology. JAMA Neurol. 2017 Apr 1;74(4):397-402.

Autoimmune epilepsy is an underrecognized condition, and its true incidence is unknown. Identifying patients with an underlying autoimmune origin is critical because these patients' condition may remain refractory to conventional antiseizure medications but may respond to immunotherapy.
To determine the prevalence of neurological autoantibodies (Abs) among adult patients with epilepsy of unknown etiology.
Consecutive patients presenting to neurology services with new-onset epilepsy or established epilepsy of unknown etiology were identified. Serum samples were tested for autoimmune encephalitis Abs as well as thyroperoxidase (TPO) and glutamic acid decarboxylase 65 (GAD65) Abs. An antibody prevalence in epilepsy (APE) score based on clinical characteristics was assigned prospectively. Data were collected from June 1, 2015, to June 1, 2016.
Presence of neurological Abs. A score based on clinical characteristics was assigned to estimate the probability of seropositivity prior to antibody test results. Good seizure outcome was estimated on the basis of significant reduction of seizure frequency at the first follow-up or seizure freedom.
Of the 127 patients (68 males and 59 females) enrolled in the study, 15 were subsequently excluded after identification of an alternative diagnosis. Serum Abs suggesting a potential autoimmune etiology were detected in 39 (34.8%) cases. More than 1 Ab was detected in 7 patients (6.3%): 3 (2.7%) had TPO-Ab and voltage-gated potassium channel complex (VGKCc) Ab, 2 (1.8%) had GAD65-Ab and VGKCc-Ab, 1 had TPO-Ab and GAD65-Ab, and 1 had anti-Hu Ab and GAD65-Ab. Thirty-two patients (28.6%) had a single Ab marker. Among 112 patients included in the study, 15 (13.4%) had TPO-Ab, 14 (12.5%) had GAD65-Ab, 12 (10.7%) had VGKCc (4 of whom were positive for leucine-rich glioma-inactivated protein 1 [LGI1] Ab), and 4 (3.6%) had N-methyl-D-aspartate receptor (NMDAR) Ab. Even after excluding TPO-Ab and low-titer GAD65-Ab, Abs strongly suggesting an autoimmune cause of epilepsy were seen in 23 patients (20.5%). Certain clinical features, such as autonomic dysfunction, neuropsychiatric changes, viral prodrome, faciobrachial dystonic spells or facial dyskinesias, and mesial temporal sclerosis abnormality on magnetic resonance imaging, correlated with seropositivity. The APE score was a useful tool in predicting positive serologic findings. Patients who were Ab positive were more likely to have good seizure outcome than were patients with epilepsy of unknown etiology (15 of 23 [65.2%] vs 24 of 89 [27.0%]; odds ratio, 4.8; 95% CI, 1.8-12.9; P = .002). In patients who were seropositive, reduction in seizure frequency was associated with use of immunomodulatory therapy.

Among adult patients with epilepsy of unknown etiology, a significant minority had detectable serum Abs suggesting an autoimmune etiology. Certain clinical features (encoded in the APE score) could be used to identify patients with the highest probability of harboring neurological Abs.

Courtesy of a colleague