Thursday, March 29, 2018

The European Court of Human Rights as an arbiter of human life

On Wednesday, the European Court of Human Rights (ECHR) in Strasbourg denied a British couple’s application to review the decision that would bar them from prolonging their baby's life.

Tom Evans and Kate James’ son Alfie has a degenerative brain disorder, and has been a patient at Alder Hey Childrens’ Hospital since December 2016. The hospital wanted the courts to permit them to disconnect Alfie’s ventilator, but in the meantime, Tom and Kate had found a hospital in Rome to give their son proper care and treatment.

On February 20, a High Court judge had agreed with the hospital that Alfie should be disconnected from the ventilator. He stated, “Alfie's need now is for good quality palliative care. He requires peace, quiet and privacy in order that he may conclude his life as he has lived it, with dignity,” adding, “In the light of the parents’ entirely understandable concern, a professor was instructed to review the clinical history, the ECGs and the MRI scans. It is beyond doubt they confirm a rapidly destructive brain disease. The professor also reviewed the birth records and family history, and noted that the MRI scan raised the possibility of either underlying degenerative disorder or a metabolic disorder.”

After an appeal, on March 6, Lord Justices McFarlane and McCombe and Lady Justice King of the Great Britain’s second highest court concurred with the ruling of Judge Hayden. Last week Great Britain’s Supreme Court agreed.

A spokesman for the ECHR said judges found the couple’s application inadmissible, and even more astonishingly, found no appearance of any human rights violation.

Last week, Evans posted on the Facebook of “Alfie’s Army,” “Alfie isn’t dying or unstable he is growing, putting weight on, responding etc. He is not dying so Alder Hey do not have the right to remove his life from his parents or himself!!!” 

Evans continued that he asked the hospital if he could take Alfie home “to a suitable setting with the private facilities and team to let him die in his own time with no further escalation of treatment and we will never return to Alder Hey and we will buy the vent and pay for the team out of Alfie’s medical funds!!! We are being denied this!!!!! Alder Hey want Alfie dead and on their time scale with their plans!!! Whose son is he??? Does he belong to the government or me and Kate???!!!


Dysfunction of NaV1.4, a skeletal muscle voltage-gated sodium channel, in sudden infant death syndrome

Roope Männikkö, Leonie Wong, David J Tester, Michael G Thor, Richa Sud, Dimitri M Kullmann, Mary G Sweeney, Costin Leu, Sanjay M Sisodiya, David R FitzPatrick,  Margaret J Evans, Iona J M Jeffrey, , Jacob Tfelt-Hansen, Marta C Cohen, Peter J Fleming, Amie Jaye, Michael A Simpson, Michael J Ackerman, Michael G Hanna, Elijah R Behr, Emma Matthews.  Dysfunction of NaV1.4, a skeletal muscle voltage-gated sodium channel, in sudden infant death syndrome: a case-control study. Lancet.  Online first.


Sudden infant death syndrome (SIDS) is the leading cause of post-neonatal infant death in high-income countries. Central respiratory system dysfunction seems to contribute to these deaths. Excitation that drives contraction of skeletal respiratory muscles is controlled by the sodium channel NaV1.4, which is encoded by the gene SCN4A. Variants in NaV1.4 that directly alter skeletal muscle excitability can cause myotonia, periodic paralysis, congenital myopathy, and myasthenic syndrome. SCN4A variants have also been found in infants with life-threatening apnoea and laryngospasm. We therefore hypothesised that rare, functionally disruptive SCN4A variants might be over-represented in infants who died from SIDS.

We did a case-control study, including two consecutive cohorts that included 278 SIDS cases of European ancestry and 729 ethnically matched controls without a history of cardiovascular, respiratory, or neurological disease. We compared the frequency of rare variants in SCN4A between groups (minor allele frequency <0·00005 in the Exome Aggregation Consortium). We assessed biophysical characterisation of the variant channels using a heterologous expression system.

Four (1·4%) of the 278 infants in the SIDS cohort had a rare functionally disruptive SCN4A variant compared with none (0%) of 729 ethnically matched controls (p=0·0057).

Rare SCN4A variants that directly alter NaV1.4 function occur in infants who had died from SIDS. These variants are predicted to significantly alter muscle membrane excitability and compromise respiratory and laryngeal function. These findings indicate that dysfunction of muscle sodium channels is a potentially modifiable risk factor in a subset of infant sudden deaths.

From the manuscript

Research in context

Evidence before this study

Sudden infant death syndrome (SIDS) is the sudden and unexpected death of an apparently healthy infant. It is the leading cause of post-neonatal infant death in high-income countries. Placing infants to sleep in a prone position is associated with a higher risk of sudden death but unidentified risk factors remain. We searched PubMed for papers published in English up to March 1, 2017, reviewing the cause or risk of SIDS using the terms “sudden infant death”, “SIDS”, “sudden unexpected death in infancy”, and “risk factors”. Multiple risk factors have been proposed on the basis of epidemiological, pathological, and genetic studies that include the notion of a vulnerable infantile period due to immature homoeostatic and autonomic regulatory pathways or genetic variation—eg, cardiac channel gene variants. Respiratory failure is ultimately believed to contribute to death.

Added value of this study

To our knowledge, this study is the first to consider direct failure of the respiratory muscles due to dysfunction of the skeletal muscle ion channel NaV1.4 in the pathogenesis of SIDS. We compared rare variants in the SCN4A gene, which codes for the NaV1.4 channel, among infants who had died of SIDS with variants from ethnically matched controls. We also studied the functional consequences of rare variants in both cases and controls using a heterologous cell system. Only infants who had died from SIDS carried variants that significantly disrupted channel function.

Implications of all the available evidence

Our data are compatible with the clinical features of SIDS and provides new mechanistic clues to death. Developmental regulation of the sodium channel and respiratory muscle fibre types might affect the risk of SIDS. Future research is required to define this relationship, and our findings should be retested in similar and other ethnic groups. Sodium channel dysfunction found in muscle channelopathies can be treated. Studies should assess whether such treatments could ameliorate the risk of sudden death for infants carrying SCN4A gene variants…

Two developmental factors might combine with the functional effects of the SCN4A variants we identified to render respiratory muscles more susceptible to contractile failure—eg, in response to hypoxia. First, developmental alterations in skeletal muscle sodium channel expression: during embryogenesis two different sodium channel isoforms, the cardiac isoform NaV1.5 (encoded by SCN5A) and the skeletal muscle isoform NaV1.4 are expressed in skeletal muscle although NaV1.4 predominates. The expression of NaV1.5 progressively decreases over the first 2 years after birth. The expression of NaV1.4 progressively increases after birth but the level before the age of 5 years is 25–40% of that seen in adulthood. The presence of NaV1.5 expression could compensate to some degree for variant-induced NaV1.4 dysfunction and to the delay in onset of symptoms reported in patients with myotonia who have NaV1.4 dysfunction.

Low expression of NaV1.4 in infantile muscle is likely to be particularly crucial in fast twitch respiratory muscles because their ability to maintain the amplitude of successive action potentials when under increased demand—eg, in the presence of hypoxia—is dependent on the density of sodium channels. This suggestion is supported by the observation that the capacity of muscle fibres from NaV1.4 heterozygous null mice to generate sustained action potentials diminishes with repeated stimulation. The enhanced sodium channel inactivation we observed with the Val1442Met variant will reduce channel availability, which could be particularly detrimental during such high frequency stimulation.

Second, developmental alterations in respiratory muscle fibre typing: the proportion of fast and slow twitch fibres in respiratory muscles is regulated developmentally. Fast twitch fibres that rely more heavily on the density of sodium channels predominate in these muscles in infants, compared with those older than 2 years of age.

Courtesy of:

An infant born to a mother with anti-N-methyl-d-aspartate receptor encephalitis

Chourasia N, Watkins MW, Lankford JE, Kass JS, Kamdar A. An Infant Born to a Mother With Anti-N-Methyl-d-Aspartate Receptor Encephalitis. Pediatr Neurol. 2018 Feb;79:65-68.


Anti-N-Methyl-D-Aspartate receptor (NMDAR) encephalitis is an autoimmune disorder that often affects women of childbearing age, and maternal-fetal transfer of anti-NMDAR antibodies during pregnancy has been documented in both symptomatic and asymptomatic women. The effects of these antibodies on the fetus, however, are incompletely understood.

This term infant exhibited depressed respiratory effort, poor feeding, and abnormal movements after birth. Magnetic resonance imaging revealed diffuse cerebral edema with ischemic and hemorrhagic injury. Her mother had experienced anti-NMDAR encephalitis secondary to an ovarian teratoma 18 months earlier. The baby's serum NMDAR antibody titer was elevated at 1:320. Intravenous immunoglobulin did not result in clinical improvement, and care was withdrawn on day of life 20. Her mother had an elevated serum NMDAR antibodies (1:80), positive CSF antibody titers, and a new ovarian teratoma.

Routine testing of NMDAR antibodies in pregnant women with a previous history of anti-NMDAR encephalitis may be warranted. Infants born to these mothers should be closely monitored throughout pregnancy and after birth.

Courtesy of  a colleague

Tuesday, March 27, 2018

SLC39A14 causing hypermanganesemia associated with infantile onset dystonia

Inspired by a colleague's patient

Marti-Sanchez L, Ortigoza-Escobar JD, Darling A, Villaronga M, Baide H, Molero-Luis M, Batllori M, Vanegas MI, Muchart J, Aquino L, Artuch R, Macaya A, Kurian MA, Dueñas P. Hypermanganesemia due to mutations in SLC39A14: further insights into Mn deposition in the central nervous system. Orphanet J Rare Dis. 2018 Jan 30;13(1):28.


The SLC39A14, SLC30A10 and SLC39A8 are considered to be key genes involved in manganese (Mn) homeostasis in humans. Mn levels in plasma and urine are useful tools for early recognition of these disorders. We aimed to explore further biomarkers of Mn deposition in the central nervous system in two siblings presenting with acute dystonia and hypermanganesemia due to mutations in SLC39A14. These biomarkers may help clinicians to establish faster and accurate diagnosis and to monitor disease progression after chelation therapy is administered.

A customized gene panel for movement disorders revealed a novel missense variant (c.311G > T; p.Ser104Ile) in SLC39A14 gene in two siblings presenting at the age of 10 months with acute dystonia and motor regression. Mn concentrations were analyzed using inductively coupled mass spectrometry in plasma and cerebrospinal fluid, disclosing elevated Mn levels in the index case compared to control patients. Surprisingly, Mn values were 3-fold higher in CSF than in plasma. We quantified the pallidal index, defined as the ratio between the signal intensity in the globus pallidus and the subcortical frontal white matter in axial T1-weighted MRI, and found significantly higher values in the SLC39A14 patient than in controls. These values increased over a period of 10 years, suggesting the relentless pallidal accumulation of Mn. Following genetic confirmation, a trial with the Mn chelator Na2CaEDTA led to a reduction in plasma Mn, zinc and selenium levels. However, parents reported worsening of cervical dystonia, irritability and sleep difficulties and chelation therapy was discontinued.

Our study expands the very few descriptions of patients with SLC39A14 mutations. We report for the first time the elevation of Mn in CSF of SLC39A14 mutated patients, supporting the hypothesis that brain is an important organ of Mn deposition in SLC39A14-related disease. The pallidal index is an indirect and non-invasive method that can be used to rate disease progression on follow-up MRIs. Finally, we propose that patients with inherited defects of manganese transport should be initially treated with low doses of Na2CaEDTA followed by gradual dose escalation, together with a close monitoring of blood trace elements in order to avoid side effects.

Juneja M, Shamim U, Joshi A, Mathur A, Uppili B, Sairam S, Ambawat S, Dixit R, Faruq M. A novel mutation in SLC39A14 causing hypermanganesemia associated with infantile onset dystonia. J Gene Med. 2018 Mar 2:e3012.


Mutations in SLC39A14 cause a recessive disorder of manganese (Mn) metabolism that manifests as childhood onset progressive neurodegeneration characterized by parkinsonism and dystonia.

The present study genetically investigated a case of hypermanganesemia. We describe a family where an affected child with a history of progressive neurodegeneration showed symptoms of dystonia with increased levels of blood Mn and altered signal intensities in globus pallidus and dentate nucleus. Whole exome sequencing was conducted to genetically investigate the pathology in the child, which allowed us to identify a novel homozygous causal mutation in SLC39A14.

Insilico modeling of the novel homozygous causal mutation in SLC39A14 predicted that it was deleterious, affecting Mn binding and transportation of metal by transmembrane instability of the protein structure. The clinical features of other reported mutations in SLC39A14 were also reviewed and the clinical spectrum in our case conforms to the described neurological abnormalities.

We conclude that the mutation identified in SLC39A14 in our case is a novel variation linked to recessive disorders of hypermaganesemia and dystonia.

Monday, March 26, 2018

Behavioral interventions as a treatment for epilepsy

Haut SR, Lipton RB, Cornes S, Dwivedi AK, Wasson R, Cotton S, Strawn JR, Privitera M. Behavioral interventions as a treatment for epilepsy: A multicenter randomized controlled trial. Neurology. 2018 Mar 13;90(11):e963-e970.


To evaluate the effect of a stress-reduction intervention in participants with medication-resistant epilepsy.

Adults with medication-resistant focal epilepsy (n = 66) were recruited from 3 centers and randomized to 1 of 2 interventions: (1) progressive muscle relaxation (PMR) with diaphragmatic breathing, or (2) control focused-attention activity with extremity movements. Following an 8-week baseline period, participants began 12 weeks of double-blind treatment. Daily self-reported mood and stress ratings plus seizure counts were completed by participants using an electronic diary, and no medication adjustments were permitted. The primary outcome was percent reduction in seizure frequency per 28 days comparing baseline and treatment; secondary outcomes included stress reduction and stress-seizure interaction.

In the 66 participants in the intention-to-treat analysis, seizure frequency was reduced from baseline in both treatment groups (PMR: 29%, p < 0.05; focused attention: 25%, p < 0.05). PMR and focused attention did not differ in seizure reduction (p = 0.38), although PMR was associated with stress reduction relative to focused attention (p < 0.05). Daily stress was not a predictor of seizures.

Both PMR and the focused-attention groups showed reduced seizure frequency compared to baseline in participants with medication-resistant focal seizures, although the 2 treatments did not differ. PMR was more effective than focused attention in reducing self-reported stress.

"Despite advances in pharmacotherapy, at least one-third of individuals with epilepsy continue to experience seizures," the authors write. 

This has led to an "increasing interest in behavioral interventions," especially in medically refractory seizures, because "stress is a frequently reported seizure trigger or precipitant in persons with epilepsy," they add.

Previous research suggests improved outcomes with a mindfulness-based approach or behavioral interventions, but these studies have been "limited by small sample sizes, inadequate control groups, and nonseizure primary outcomes."

To fill this gap, the researchers performed the first double-blind, randomized controlled trial of a stress-reduction intervention in people with medication-resistant epilepsy.

The primary outcome was percentage reduction in seizure frequency per 28 days between baseline and treatment…

Participants were randomly assigned to one of the two behavioral techniques.

The first, PMR, involved diaphragmatic breathing and a 16–muscle group practice, in which each muscle set was tensed vigorously without straining for 5 to 10 seconds, and then released. 

The focused attention intervention was considered to be the control. Participants practiced a series of movements matched to PMR, but without the systematic muscle relaxation. They also engaged in other attentional tasks, such as writing down activities of the previous day.

Both groups were informed that they would engage in one of two possible behavioral techniques to be practiced daily but were not informed about which was hypothesized to be the active intervention…

Also commenting on the study for Medscape Medical News, Steven Schachter, MD, professor of neurology, Beth Israel Deaconess Medical Center, Boston, Massachusetts, who was not involved with the study, called the relationship between stress, anxiety, and seizures in people with epilepsy "a fruitful area for research."

The authors "should be congratulated for their rigorous study design," and their "interesting results suggest a clinical benefit for behavioral interventions and highlight the need for further studies," Shachter said.                                                                                                                                                                                                                                                                                                             Most participants in both treatment groups reported that stress, as well as seizures, was reduced by treatment, with no difference between the groups.                                                     

Haut acknowledged being surprised by the results. 

"We were starting to get the feeling that patients were finding both inventions helpful during the study, although focused attention was not designed for relaxation and was our control group, with PMR being the treatment group," she said.

"People were finding that the experience of writing down how they were feeling on a regular basis multiple times a day was apparently having some benefit for them," she added.

She noted that the response both groups experienced "shows that there is the potential for different people to respond to different interventions."                                                                                                                                                                                                                                              

Miss Amazing

A 380-pound girl with a rare condition that causes her to constantly be hungry was crowned a pageant queen in Mississippi.

Anna Hankins, 15, suffers from Prader-Willi Syndrome, an incurable genetic disorder in which patients develop an insatiable appetite, leading to chronic overeating and obesity, according to the National Institutes of Health.

At two years old, Anna developed an insatiable appetite and was diagnosed with the condition, that affects one in 15,000 babies born in the United States.

"When she was little, the first words out of her mouth were 'I'm hungry' and the last ones were 'I'm hungry'", her mother, Jennifer told SWNS.

Throughout her childhood, Anna’s hunger has been out of control. "We would get up in the morning, and [found out that] in the middle of the night she had gotten up and made a whole cake,” her mother said.

The mother of two said she had to lock the fridge and cabinets to prevent Anna from raiding them. "We would clean her room and find empty food wrappers and candy wrappers — anything she could get her hands on.”

The teenager from Louisville, Miss., is on a 900 calorie-a-day food plan but, because her body does not break down food properly, she cannot lose weight. She currently weighs 380 pounds.

Due to her weight, Anna is unable to dress herself and needs oxygen to help her breathe.

"I have Prader-Willi Syndrome and I get hungry a lot. It can be difficult to deal with sometimes,” Anna told SWNS.

But one way that’s helped boost the teenager’s self-esteem is by taking part in the Miss Amazing pageant, which celebrates women and girls with disabilities.

"I love Miss Amazing. My favorite thing is singing and makeup and hair," Anna said.

Anna first got involved in the pageant world in fourth grade and has since participated in three events, most recently in November, winning the state title each time.

Lori Brasfield-Sanders, director of Miss Amazing Mississippi, told SWNS, "The biggest misconception people have regarding people with disabilities is that they cannot lead full, engaging lives.”

She added, "Anna is an amazing ambassador; she is very popular and she loves participating.”

Saturday, March 24, 2018

CHD2 mutations 2

Carvill G, Helbig I, Mefford H. CHD2-Related Neurodevelopmental Disorders. 2015 Dec 10. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Stephens K, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2018. Available from


CHD2-related neurodevelopmental disorders are characterized by early-onset epileptic encephalopathy (i.e., refractory seizures and cognitive slowing or regression associated with frequent ongoing epileptiform activity). Seizure onset is typically between ages six months and four years. Seizure types typically include drop attacks, myoclonus, and a rapid onset of multiple seizure types associated with generalized spike-wave on EEG, atonic-myoclonic-absence seizures, and clinical photosensitivity. Intellectual disability and/or autism spectrum disorders are common. To date only 32 individuals with a CHD2-related neurodevelopmental disorder have been reported; thus, better understanding of the phenotypic spectrum of CHD2-related neurodevelopmental disorders is likely to evolve over time.

The diagnosis of a CHD2-related neurodevelopmental disorder is established in a proband with a heterozygous CHD2 single-nucleotide pathogenic variant, small indel (insertion/deletion) pathogenic variant, or a partial- or whole-gene deletion detected on molecular genetic testing.

Treatment of manifestations: Seizures should be managed by an experienced pediatric neurologist. At this time, no specific guidelines regarding choice of specific antiepileptic drugs (AEDs) exist, as the best AED regimen for CHD2-related neurodevelopmental disorders is not yet established. Most patients remain refractory to treatment and require multiple AEDs. Agents/circumstances to avoid: Because clinical photosensitivity may result in injuries due to the consequences of induced seizures, it is recommended that stimuli which may provoke seizures (e.g., intensely flickering lights) be avoided.

CHD2-related neurodevelopmental disorders are inherited in an autosomal dominant manner. To date, all CHD2-related neurodevelopmental disorders have resulted from a de novo pathogenic variant (i.e., no familial occurrences are known). However, because of the possibility of germline mosaicism in a parent, the risk of recurrence is presumed to be greater than in the general population. Prenatal testing for pregnancies presumed to be at increased risk is possible.

Caputo D, Trivisano M, Vigevano F, Fusco L. CHD2-epilepsy: Polygraphic documentation of self-induced seizures due to fixation-off sensitivity. Seizure. 2018 Mar 3;57:8-10.


CHD2 gene has been described in association with different types of childhood myoclonic epilepsy and is emerging as a gene involved in photosensitivity alone or combined with epilepsy. Recent studies suggest that CHD2 could be responsible for a proper phenotype characterized by infantile-onset generalized epilepsy, intellectual disability, and photosensitivity and in particular with self-induced seizures. We report the case of a child with CHD2 mutation and mild developmental impairment that since the age of 3 years started with myoclonic seizures apparently well responding to antiepileptic drugs and that subsequently developed intractable self-induced seizures. Through an accurate Video-EEG polygraphic analysis, we demonstrated that seizures are related to an abnormal increase of epileptiform activity after eye-closure or loss of fixation as observed in the Fixation-Off Sensitivity (FOS) phenomenon. In conclusion our study adds relevant features of the CHD2-epilepsy phenotype and confirms that CHD2 mutations produce a distinctive form of myoclonic epilepsy with visual-sensitive seizures.

Meganathan K, Lewis EMA, Gontarz P, Liu S, Stanley EG, Elefanty AG, Huettner JE, Zhang B, Kroll KL. Regulatory networks specifying cortical interneurons from human embryonic stem cells reveal roles for CHD2 in interneuron development. Proc Natl Acad Sci U S A. 2017 Dec 26;114(52):E11180-E11189.


Cortical interneurons (cINs) modulate excitatory neuronal activity by providing local inhibition. During fetal development, several cIN subtypes derive from the medial ganglionic eminence (MGE), a transient ventral telencephalic structure. While altered cIN development contributes to neurodevelopmental disorders, the inaccessibility of human fetal brain tissue during development has hampered efforts to define molecular networks controlling this process. Here, we modified protocols for directed differentiation of human embryonic stem cells, obtaining efficient, accelerated production of MGE-like progenitors and MGE-derived cIN subtypes with the expected electrophysiological properties. We defined transcriptome changes accompanying this process and integrated these data with direct transcriptional targets of NKX2-1, a transcription factor controlling MGE specification. This analysis defined NKX2-1-associated genes with enriched expression during MGE specification and cIN differentiation, including known and previously unreported transcription factor targets with likely roles in MGE specification, and other target classes regulating cIN migration and function. NKX2-1-associated peaks were enriched for consensus binding motifs for NKX2-1, LHX, and SOX transcription factors, suggesting roles in coregulating MGE gene expression. Among the NKX2-1 direct target genes with cIN-enriched expression was CHD2, which encodes a chromatin remodeling protein mutated to cause human epilepsies. Accordingly, CHD2 deficiency impaired cIN specification and altered later electrophysiological function, while CHD2 coassociated with NKX2-1 at cis-regulatory elements and was required for their transactivation by NKX2-1 in MGE-like progenitors. This analysis identified several aspects of gene-regulatory networks underlying human MGE specification and suggested mechanisms by which NKX2-1 acts with chromatin remodeling activities to regulate gene expression programs underlying cIN development.

Lebrun N, Parent P, Gendras J, Billuart P, Poirier K, Bienvenu T. Autism spectrum disorder recurrence, resulting of germline mosaicism for a CHD2 gene missense variant. Clin Genet. 2017 Dec;92(6):669-670.


Germline mosaicism for a novel missense variant p.Thr645Met located in the SNF2-related ATP dependent helicase domain of CHD2 in 2 affected siblings with autism spectrum disorder.

Bernardo P, Galletta D, Iasevoli F, D'Ambrosio L, Troisi S, Gennaro E, Zara F, Striano S, de Bartolomeis A, Coppola A. CHD2 mutations: Only epilepsy? Description of cognitive and behavioral profile in a case with a new mutation. Seizure. 2017 Oct;51:186-189.


The chromodomain helicase DNA binding domain 2 ( CHD2 ) gene (OMIM: 602119 ) was originally characterized by Woodage et al. and has been repeatedly reported to play a pivotal role in cerebrocortical development. CHD2 gene mutations was recently described in patients with photosensitive epilepsies, with myoclonic-atonic epilepsy (MAE), Lennox–Gastaut syndrome (LGS), Dravet syndrome (DS) and other forms of epileptic encephalopathies featuring generalized epilepsy with intellectual disability (ID). Furthermore there is emerging evidence suggesting that CHD2 might contribute to a broad spectrum of neurodevelopmental disorders (NDDs) including developmental delay, ID, autism spectrum disorders (ASD), with phenotypic variability among individuals. Here we describe a patient with an unreported de novo CHD2 frameshift mutation presenting with mild facial dysmorphism, infantile epilepsy, ID and severe behavioral disorder. This case expands the clinical spectrum of manifestations associated with CHD2 mutations and supports a multidisciplinary approach for a detailed and careful description of the epilepsy-cognition-behavior complex.

Friday, March 23, 2018

Human after all

Sanchita Bhattacharya, Jian Li, Alexandra Sockell, Matthew J. Kan, Felice A. Bava, Shann-Ching Chen, María C. Ávila-Arcos, Xuhuai Ji, Emery Smith, Narges B. Asadi, Ralph S. Lachman, Hugo Y.K. Lam, Carlos D. Bustamante, Atul J. Butte, and Garry P. Nolan.  Whole-genome sequencing of Atacama skeleton shows novel mutations linked with dysplasia. Genome Res. Published in Advance March 22, 2018.


Over a decade ago, the Atacama humanoid skeleton (Ata) was discovered in the Atacama region of Chile. The Ata specimen carried a strange phenotype—6-in stature, fewer than expected ribs, elongated cranium, and accelerated bone age—leading to speculation that this was a preserved nonhuman primate, human fetus harboring genetic mutations, or even an extraterrestrial. We previously reported that it was human by DNA analysis with an estimated bone age of about 6–8 yr at the time of demise. To determine the possible genetic drivers of the observed morphology, DNA from the specimen was subjected to whole-genome sequencing using the Illumina HiSeq platform with an average 11.5× coverage of 101-bp, paired-end reads. In total, 3,356,569 single nucleotide variations (SNVs) were found as compared to the human reference genome, 518,365 insertions and deletions (indels), and 1047 structural variations (SVs) were detected. Here, we present the detailed whole-genome analysis showing that Ata is a female of human origin, likely of Chilean descent, and its genome harbors mutations in genes (COL1A1, COL2A1, KMT2D, FLNB, ATR, TRIP11, PCNT) previously linked with diseases of small stature, rib anomalies, cranial malformations, premature joint fusion, and osteochondrodysplasia (also known as skeletal dysplasia). Together, these findings provide a molecular characterization of Ata's peculiar phenotype, which likely results from multiple known and novel putative gene mutations affecting bone development and ossification.

Nearly two decades ago, the rumors began: In the Atacama Desert of northern Chile, someone had discovered a tiny mummified alien.

An amateur collector exploring a ghost town was said to have come across a white cloth in a leather pouch. Unwrapping it, he found a six-inch-long skeleton.

Despite its size, the skeleton was remarkably complete. It even had hardened teeth. And yet there were striking anomalies: it had 10 ribs instead of the usual 12, giant eye sockets and a long skull that ended in a point.

Ata, as the remains came to be known, ended up in a private collection, but the rumors continued, fueled in part by a U.F.O. documentary in 2013 that featured the skeleton. On Thursday, a team of scientists presented a very different explanation for Ata — one without aliens, but intriguing in its own way.

Ata’s bones contain DNA that not only shows she was human, but that she belonged to the local population. What’s more, the researchers identified in her DNA a group of mutations in genes related to bone development.

Some of these mutations might be responsible for the skeleton’s bizarre form, causing a hereditary disorder never before documented in humans…

Antonio Salas Ellacuriaga, a geneticist at the University of Santiago de Compostela in Spain who was not involved in the new study, called it “a very beautiful example of how genomics can help to disentangle an anthropological and archaeological dilemma.”

“DNA autopsies,” as Dr. Ellacuriaga calls them, could help shed light on medical disorders “by looking to the past to understand the present.”

The research, published in the journal Genome Research, began in 2012, when Garry P. Nolan, an immunologist at Stanford University, got wind of the U.F.O. documentary, “Sirius,” while it was still in production.

Dr. Nolan emailed the producers and offered to look for DNA in the mummy. The skeleton’s owner agreed to X-ray images as well as bone marrow samples taken from the ribs and right humerus.

Once Dr. Nolan and his colleagues received the samples, they were able to retrieve fragments of DNA from bone marrow cells without much struggle. “We could tell this was human right away,” said Atul Butte, a computational biologist at the University of California, San Francisco, and a co-author of the new study.

The scientists eventually managed to reconstruct much of Ata’s genome. She was a girl, they found, most closely related to indigenous Chileans. But she also had a substantial amount of European ancestry.

The scientists have not carried out any precise dating of the skeleton, so they can’t say exactly when Ata lived. But her European heritage suggested it was sometime after Chile was colonized in the 1500s…

The research, published in the journal Genome Research, began in 2012, when Garry P. Nolan, an immunologist at Stanford University, got wind of the U.F.O. documentary, “Sirius,” while it was still in production.

Dr. Nolan emailed the producers and offered to look for DNA in the mummy. The skeleton’s owner agreed to X-ray images as well as bone marrow samples taken from the ribs and right humerus.

Once Dr. Nolan and his colleagues received the samples, they were able to retrieve fragments of DNA from bone marrow cells without much struggle. “We could tell this was human right away,” said Atul Butte, a computational biologist at the University of California, San Francisco, and a co-author of the new study.

The scientists eventually managed to reconstruct much of Ata’s genome. She was a girl, they found, most closely related to indigenous Chileans. But she also had a substantial amount of European ancestry.

The scientists have not carried out any precise dating of the skeleton, so they can’t say exactly when Ata lived. But her European heritage suggested it was sometime after Chile was colonized in the 1500s.
After death, DNA disintegrates into fragments, which become smaller over the centuries. Ata’s DNA fragments are still large, another clue that she’s less than 500 years old.

While her elongated head was striking, it wasn’t the strangest feature of Ata’s skeleton. Despite being the size of a human fetus, about the length of a pen, her bones were as developed in some ways as those of a 6-year-old.

Ralph S. Lachman, an expert on hereditary bone diseases at Stanford University, examined her X-rays. He concluded that her constellation of symptoms did not match any known disease. The scientists reasoned that Ata might have had mutations for a disorder that had never before been described.

Sanchita Bhattacharya, a researcher in Dr. Butte’s lab, searched for mutations in Ata’s DNA and identified 2.7 million variants throughout the genome. She whittled this list to 54 rare mutations that could potentially shut down the gene in which they were located.

“I was amazed by how much you can tell from the genetic blueprint,” said Ms. Bhattacharya.

Many of those genes, it turned out, are involved in building skeletons. Some have already been linked to conditions ranging from scoliosis to dwarfism to having an abnormal number of ribs.

But some of Ata’s mutations are new to science. It’s possible some caused her skeleton to mature quickly even while failing to grow to normal stature.

Ms. Bhattacharya speculates that such a disorder would have caused the child to be stillborn. And she stressed that these mutations are, for now, only theoretical candidates.

Other experts concurred. “There is no single slam-dunk finding that explains the bizarre appearance of this individual,” said Daniel G. MacArthur, a geneticist at the Broad Institute who was not involved in the study.

Yet understanding what happened to Ata might shed light on skeletal deformities seen today. That may require engineering stem cells with each of the 54 mutations, growing them in a dish, and then looking for telling changes in their development.

And Dr. Nolan has heard stories about similar skeletons in other parts of the world. If he were able to examine them, he might discover some of these mutations in their DNA, as well.

Even more direct confirmation might be possible if researchers paid closer attention to stillbirths.

Although there are 24,000 stillbirths in the United States alone each year, doctors generally don’t record the features of the fetuses, let alone study their DNA. With so little data, there’s no way to know if Ata was unique.

“This could be a trigger to look into more such cases,” said Albert Zink, an anthropologist at the European Research Academy in Bolzano, Italy, who was not involved in the new study.

While Dr. Nolan began the project as “a lark,” he believes the evidence now requires that the mummy be returned to Chile for proper treatment as human remains.

“One has to respect these things,” he said.

Courtesy of a colleague

Thursday, March 22, 2018

Neck-tongue syndrome

Allen NM, Dafsari HS, Wraige E, Jungbluth H. Neck-Tongue Syndrome: An Underrecognized Childhood Onset Cephalalgia. J Child Neurol. 2018 Jan 1:883073818756681. doi: 10.1177/0883073818756681. [Epub ahead of print]

Neck-tongue syndrome is a rarely reported headache disorder characterized by occipital and/or upper neck pain triggered by sudden rotatory head movement and accompanied by abnormal sensation and/or posture of the ipsilateral tongue. Although onset is thought to be in childhood, most of the limited number of cases reported so far were adults. Here the authors describe 3 cases, 2 girls and 1 boy, with neck-tongue syndrome. In each child additional headache symptoms occurred, headache improved over time in all, spontaneously in 2 and coinciding with gabapentin treatment in the other. Investigations were consistently unremarkable. Review of the literature reveals a usually self-limiting disorder, with early onset and variable additional features. Awareness of neck-tongue syndrome among pediatric neurologists and other practitioners is important, to allow for timely diagnosis and informed management of an underreported headache disorder with childhood onset.

Patient 1, an 11-year-old female, presented with a 5-month history of severe recurrent episodes of unilateral shooting and burning posterior neck pain lasting approximately 1 minute, triggered by head turning. Her first episode occurred while watering the garden and included a brief altered sensation affecting the right half of her body; there was no other history of trauma and initial symptoms resolved prior to presentation. Subsequently recurrent episodes of unilateral neck pain were rapidly followed by ipsilateral tongue hemianesthesia lasting 10 to 60 seconds. Occasional residual dull neck ache occurred, but no other headache or migraine symptomatology developed. Episodes alternated but were more right-sided. Frequency averaged once to twice weekly (up to 5/week) with episode-free weeks. Gabapentin treatment led to complete resolution, but was discontinued due to side effects (dizziness and weight gain despite dose reduction). Topical (neck) lidocaine patch 5% (nightly) reduced episodes to twice monthly with significantly less pain intensity at follow-up after 1 year. Examination revealed peripheral joint hypermobility, but was otherwise normal. Perinatal and developmental histories were unremarkable. Baseline laboratory investigations and contrast magnetic resonance imaging (MRI) of the brain and C-spine were normal…

The neck/occiput pain brought about by sudden head turning, in primary neck-tongue syndrome, is thought to be due to a temporary subluxation at the lateral atlantoaxial joint and compression/stretch of C2 and its roots, in particular impingement of the C2 ventral ramus. Tongue symptoms are explained by afferent proprioceptive fibers from the lingual nerve of trigeminal origin which anastomose with the hypoglossal nerve within the tongue, then travel through the ansa cervicalis to continue via the ventral ramus of C2.2-4 Where symptomatology is persistent, or follows minor trauma, secondary pathology (eg, arthritic disease) should be investigated…

The evidence-base for treating neck-tongue syndrome is anecdotal, due to only a very small number of cases reported to date (approximately 40). However in many cases such as patients 2 and 3 here, neck-tongue syndrome resolves or improves over time, requiring no or little prophylactic pharmacologic therapy. Patient 1 was treated with both gabapentin and topical lidocaine as preventive treatments, as symptoms had a greater impact on function. Some of her symptomatology was burning, and intense, so a trial of neuropathic pain medications appeared justified, given their benefit in related pain disorders,including neuralgiform headaches. The gabapentin response was immediate, but symptoms returned when the medication was discontinued due to other side effects. Symptoms subsequently resolved with lidocaine. While the authors discuss therapeutic benefit in this patient, it must be acknowledged that the observed improvement may just have reflected the natural history of the condition.

Reinstatement of neck-tongue syndrome in the International Classification of Headache Disorders may help clinicians recognize and manage this distinct headache disorder. Awareness that additional symptoms often occur in neck-tongue syndrome, and that onset is far more common in childhood may help improve diagnosis. Further reports are required to better understand the pathophysiology, epidemiology and natural history of neck-tongue syndrome.

Wednesday, March 21, 2018

Pediatric intracranial hypertension

Aylward SC, Reem RE. Pediatric Intracranial Hypertension. Pediatr Neurol. 2017 Jan;66:32-43.

Primary (idiopathic) intracranial hypertension has been considered to be a rare entity, but with no precise estimates of the pediatric incidence in the United States. There have been attempts to revise the criteria over the years and adapt the adult criteria for use in pediatrics. The clinical presentation varies with age, and symptoms tending to be less obvious in younger individuals. In the prepubertal population, incidentally discovered optic disc edema is relatively common. By far the most consistent symptom is headache; other symptoms include nausea, vomiting tinnitus, and diplopia. Treatment mainstays include weight loss when appropriate and acetazolamide. Furosemide may exhibit a synergistic benefit when used in conjunction with acetazolamide. Surgical interventions are required relatively infrequently, but include optic nerve sheath fenestration and cerebrospinal fluid shunting. Pain and permanent vision loss are the two major complications of this disorder and these manifestations justify aggressive treatment. Once intracranial hypertension has resolved, up to two thirds of patients develop a new or chronic headache type that is different from their initial presenting headache.

Until very recently, there have been no concrete estimates of pediatric intracranial hypertension in the United States. Unless physicians are paying attention to the literature, they may not even be using the current nomenclature for the condition, and use the older term “pseudotumor cerebri” instead.

Shawn Aylward MD, member of the Division of Neurology at Nationwide Children’s Hospital and director of the hospital’s Intracranial Hypertension Clinic, has sought to both spotlight and more clearly define the condition in a series of publications in the last year. While pediatric intracranial hypertension may be rare, his clinic saw 173 unique patients in 2016, and he is well aware that physicians can miss it.

“When it is not frequently encountered, it is often forgotten,” says Dr. Aylward, who is also an assistant professor of Clinical Pediatrics at The Ohio State University College of Medicine. “The stereotypical intracranial hypertension patient is postpubertal and overweight. Many clinicians would consider the condition if that patient presented with headaches or vision problems. But a slender, young child with headaches? Or an asymptomatic child who is discovered to have optic disc edema during a routine ophthalmic exam? Some clinicians may not think about it.”

Dr. Aylward was lead author of a recent invited review in Pediatric Neurology detailing the incidence, evaluation, diagnosis and treatment of pediatric intracranial hypertension – along with calling for the use of the terms “primary intracranial hypertension” and “secondary intracranial hypertension” (when a clear cause of increased cranial pressure can be found). “Pseudotumor cerebri” and “idiopathic intracranial hypertension” remain in wide use but can lead to confusion, says Dr. Aylward.

He was also the lead author of a 2016 publication in Pediatric Neurology examining the presentations of intracranial hypertension in a large pediatric cohort drawn from the Intracranial Hypertension Registry at the Intracranial Hypertension Research Foundation. While likely a population with more severe manifestations of the disease, the publication confirmed much of what researchers had found in smaller studies:

Headache was a reported symptom in 96.5 percent of patients with primary intracranial hypertension and 98.4 percent of those with secondary intracranial hypertension

Bilateral optic nerve edema was found in 89.3 percent and 78.7 percent, respectively

Most practitioners consider postpubertal obese females to be the classic intracranial hypertension patient, but only 21.2% of patients fit this description

Prepubertal primary intracranial hypertension patients had a female-to-male ratio of 1:1.04 (lower than that found in the literature) but postpubertal patients had a ratio of 6:1 (higher than ratios reported elsewhere)

Because of various findings about the prevalence of optic nerve edema, a fundoscopic exam is essential in an initial evaluation for intracranial hypertension.

“If clinicians are not comfortable with fundoscopy, they should refer the patients to an ophthalmologist, ” says Dr. Aylward. “Our clinic is a joint venture between Neurology and Ophthalmology at Nationwide Children’s, and it is common that a patient comes to us over concerns for edema found by an outside practitioner. It’s important that after such a finding, we see a patient relatively quickly.”

Defining and treating pediatric intracranial hypertension is important, and it’s been an obvious focus of the clinic at Nationwide Children’s. With so many patients being followed, Dr. Aylward and his colleagues believe they can now begin moving toward researching potential causes.

“We have this all this data, from children who have been evaluated, diagnosed and treated here,” he says. “We are now trying to figure out why they have this condition at all.” contentId=161947&orgId=5492&et_rid=279164201&et_cid=7406163&utm_medium=ET-Email&

High amplitude background slow waves in normal children

Mytinger JR, Weber A, Vidaurre J. High Amplitude Background Slow Waves in Normal Children Aged 3 to 18 Months: Implications for the Consideration of Hypsarhythmia. J Clin Neurophysiol. 2018 Mar;35(2):151-154.


To assess for the presence of high amplitude EEG background slow waves in normal young children.

One hundred children with normal development ages 3 to 18 months had normal EEGs for spells and did not have seizures or epilepsy. Three electroencephalographers retrospectively reviewed 5 minutes of stable stage II sleep to measure background slow waves for peak-to-peak amplitudes. A standard 10-20 longitudinal bipolar montage was used. Interrater agreement was assessed by intraclass correlation coefficient.

Interrater agreement between reviewers in the assessment of recurrent slow wave amplitudes was excellent (intraclass correlation coefficient = 0.97). Slow wave amplitudes were the highest in the posterior head regions for all patients. We found recurring slow waves of <200 µV, 200 to 299 µV, 300 to 399 µV, 400 to 499 µV, and >500 µV in 17%, 49%, 30%, 3% and 1%, respectively.

Although hypsarhythmia typically includes high amplitude background slow waves of >200 or >300 µV, we found that 83% and 34% of normal children had recurring posterior background slow waves of >200 or >300 µV, respectively. These data may be useful in the EEG background assessment of young children, for determining the presence or absence of hypsarhythmia, and determining treatment response in children with epileptic spasms.

Infantile spasms often co-occur with hypsarhythmia, and high-amplitude slow waves are considered a hallmark of that hypsarhythmia. But pediatric epileptologists at Nationwide Children’s Hospital regularly see electroencephalograms (EEGs) of young children with high-amplitude slow waves who have not experienced infantile spasms.

Should those children be followed? If they have high-amplitude waves, are they at risk for development of epileptic encephalopathy?

In what appears to be the first study of its kind, physician-researchers at Nationwide Children’s reviewed EEGs of 100 normal children, ages 3 months to 18 months, and found that the large majority of them showed recurring posterior slow waves of 200 µV or greater. In fact, more than 30 percent of children had waves of 300 µV or greater. 

As long as those kinds of waves stay in the brain’s posterior regions, and in the absence of other signs of hypsarhythmia like EEG epochs of severe disorganization and multifocal spikes, the waves appear to be normal, says John Mytinger, MD, director of Infantile Spasms program at Nationwide Children’s and lead author of the study.

“Other authors have described these high amplitude slow waves in the back of head, but we didn’t know how common they were,” says Dr. Mytinger, who is also an assistant professor of Clinical Pediatrics and Neurology at The Ohio State University College of Medicine. “We don’t want to confuse kids who have those waves with ones who may go on to develop an epileptic encephalopathy.”

The study also has an important implication for children who have experienced infantile spasms, says Dr. Mytinger. Effective treatment in those children can result in electrographic improvement, but epileptologists still regularly see high-amplitude posterior slow waves. These findings show that the waves, by themselves, are not reasons for concern.

“Ultimately, this study demonstrates that when we conduct EEGs on young children who have not experienced infantile spasms, serial EEGs or frequent clinical evaluation may not be necessary given that  high-amplitude posterior slow waves are normal,” says Dr. Mytinger. “While we still need to follow children who have experienced infantile spasms, the isolated finding of these waves on a post-treatment EEG is likely normal and additional treatment is not indicated.”

Prediction of mutations favored by natural selection

Akbari A, Vitti JJ, Iranmehr A, Bakhtiari M, Sabeti PC, Mirarab S, Bafna V.  Identifying the favored mutation in a positive selective sweep. Nat Methods. 2018 Feb 19. doi: 10.1038/nmeth.4606. [Epub ahead of print]


Most approaches that capture signatures of selective sweeps in population genomics data do not identify the specific mutation favored by selection. We present iSAFE (for "integrated selection of allele favored by evolution"), a method that enables researchers to accurately pinpoint the favored mutation in a large region (5 Mbp) by using a statistic derived solely from population genetics signals. iSAFE does not require knowledge of demography, the phenotype under selection, or functional annotations of mutations.

In a new study published in Nature Methods, scientists have developed a new algorithm that allows for the prediction of mutations favored by natural selection in large regions of the human genome. What does this new study mean for treatment options for genetic disorders?

Researchers needed to study the sequenced genome of a population size of 1000 individuals, so they turned to computational techniques to help perform this project. Researchers created an algorithm entitled iSAFE, which is able to analyze a certain region of the genome and determine which mutation is favored by which selection. Previous studies have been able to detect which regions of the human genome are evolving under which selection pressure, but have not been able to shed light on the specific mutation that responds to that particular selective pressure. This algorithm however, does not need to know the function of the genomic region it is analyzing nor does it require any demographic information since it works by reading population genetic signals imprinted on the genomes of the sampled individuals to identify the mutation. During nature selection, neighboring mutations can essentially “hitchhike” with a mutation that is under positive selection causing a loss in genetic diversity near that mutation. iSAFE is able to exploit the signals of neighboring mutations in order to pinpoint the location of the favored mutation. The algorithm is shedding light on the possibility of understand genetic disorders and possibly pinpoint underlying causes of those disorders; hopefully, paving the way to potential therapeutic targets.

A team of scientists has developed an algorithm that can accurately pinpoint, in large regions of the human genome, mutations favored by natural selection. The finding provides deeper insight into how evolution works, and ultimately could lead to better treatments for genetic disorders. For example, adaptation to chronic hypoxia at high altitude can suggest targets for cardiovascular and other ischemic diseases. 

The sequenced genome of a single individual yields about half a terabyte of data of information—that's about as much information as you'll find on 106 DVDs. A population sample of size 1000 individuals contains 1000 times as much information. So to examine such a massive amount of data, researchers turned to computational techniques.

"Computer science and data science are playing a significant role to better understand the code of life and uncover the hidden patterns in our genome," said Ali Akbari, the paper's first author and a Ph.D. student in electrical and computer engineering at the University of California San Diego. "We are analyzing massively large sets of human genomic data to ultimately improve our understanding of genetic basis of diseases."

Researchers detail the algorithm, dubbed iSAFE, in the Feb. 19 issue of Nature Methods.

Many existing genomic analysis approaches can detect which regions of the human genome are evolving under selection pressure. Often, these regions are large, covering millions of base-pairs and do not shed light on the specific mutations that are responding to the selection pressure. iSAFE doesn't need to know the function of the genomic region it is analyzing or any demographic information for the human population it belongs to. Instead, the researchers used population genetic signals imprinted in the genomes of the sampled individuals and machine learning techniques to reliably identify the mutation favored by selection.

In natural selection, neighboring mutations 'hitchhike' with the mutation that is under positive selection, leading to a loss of genetic diversity near the favored mutation. iSAFE exploits signals in the neighboring sequences, the so-called "shoulder regions" to pinpoint the favored mutation.

"Finding the favored mutation among tens of thousands of other, hitchhiking, mutations was like a needle in a haystack problem," said Akbari, who works in the research group of computer science professor Vineet Bafna at the Jacobs School of Engineering at UC San Diego.

To test the algorithm, researchers ran iSAFE on regions of the genome that are home to known favored mutations. The algorithm ranked the correct mutation as the top one out of more than 21,000 possibilities in 69 percent of cases, as opposed to state of the art methods, which only did this in 10 percent of cases.

The algorithm also identified a host of previously unknown mutations, including five that involve genes related to pigmentation. In these cases, iSAFE identified identical mutations in multiple non-African populations. This suggests an early response to the onset of selection as humans migrated out of Africa.

Tuesday, March 20, 2018

De novo 12q22.q23.3 duplication associated with temporal lobe epilepsy

Maria Stella Vari, Monica Traverso, Tommaso Bellini, Francesca Madia, Francesca Pinto, Pasquale Striano, Carlo Minetti and Federico Zara.  De novo 12q22.q23.3 duplication associated with temporal lobe epilepsy.  Seizure: European Journal of Epilepsy,  In press.

Temporal lobe epilepsy (TLE) is the most common form of focal epilepsy and may be
associated with acquired central nervous system lesions (symptomatic cases) or be genetic in
the origin.

Family studies have shown that relatives of patients with temporal lobe epilepsy are at higher
risk of suffering from seizures and EEG abnormalities compared to relatives of controls.
Therefore, various susceptibility genes and environmental factors are believed to be involved
in the aetiology of TLE, which is considered to be a heterogeneous, polygenic, and complex disorder.
Rare point mutations in LGI1, DEPDC5 and RELN have been reported in families with a monogenic type of TLE and only a few anaedoctical copy number variations (CNVs) have been described in TLE.

We report a partial duplication of the long arm of chromosome 12 detected by whole-genome
array comparative genomic hybridization in a 5-years old girl with temporal lobe epilepsy…

This girl was the second child of Caucasian healthy non-consanguineous parents. Familial
history was unremarkable. The girl was born at 37 weeks + 5 days gestation by a cesarean
section. Perinatal and neonatal periods were uneventfully. At birth, she weighted 3460 g (75-
90th centile), length was 51 cm (90th centile), and occipitofrontal circumference (OFC) was
34,5 cm (75-90th centile). The girl’s development milestones were mildly delayed: she
acquired head control at 4 months, sitting position at 10 months, and she started walking at
17 months. She pronounced her first words at age of 2 years and 5 months. At 30 months, the
patient experienced a simple tonic-clonic seizure during fever.

At 3 years and 3 months of life, she was admitted to our department due to a second febrile
seizure, characterized by loss of contact, oromasticatory automatisms, and left head
deviation, lasting about 5 minutes with post-ictal somnolence. In the following months, the
girls suffered from weekly dyscognitive seizures with impaired contact and oromasticatory or
gestural automatisms, lasting up to a few minutes…

Inter-ictal EEG revealed high voltage paroxysmal anomalies in the posterior region of the
right temporal area, more evident during sleep recordation (Fig 1B). 1.5 Tesla Brain MRI was
unremarkable. Treatment with carbamazepine (30 mg/Kg/day) resulted in complete seizure
control and disappearance of EEG abnormalities. At 24-month-follow-up the patient is still

Genetic analysis by 44K kit array-CGH (Agilent Technologies, Inc) revealed a 12 Mb de
novo duplication on chromosome 12q22-q23.3 (arr [hg19]12q22q23.3(94.135.069-

This is the first reported case of de novo 12q22-q23.3 duplication associated with temporal
lobe epilepsy.

We identified a patient with an overlapping de novo duplication which was already described
in the DECIPHER v8.9 database (ID 258582) (FIG 2B). Both Decipher’s patient and our case
share dysmorphic features, focal epilepsy, and intellectual disability; in addition, patient
258582 also featured obesity, myopia, and strabismus.

In our case, the 12Mb duplication at 12q22-q23.3 encompasses 67 genes, many of which
have an established function in brain development and functioning.

In 2004 a locus for TLE was mapped in this region by linkage analysis performed on a large
family segregating idiopathic temporal lobe epilepsy and febrile seizures in 21 members. The
reported phenotype was characterised by temporal lobe epilepsy with average age of onset at
eight years, recurrence of febrile seizures in about half of the individuals, no hippocampal
sclerosis, and a usually good prognosis. Additional evidence for an epilepsy at this locus
was provided by a second, large Caucasian family study showing febrile and afebrile focal

Comparative analysis of the locus identified by Claes et al. and duplicated regions in our case
and in patient 258582 shows an overlapping genomic segment of about 6.1 Mb. This region
includes 27 genes and, among these, DEPDC4 represents an appealing candidate for a
causative role. Indeed, DEPDC4 gene belongs to the IML1 family of proteins involved in Gprotein
signaling pathways, regulating cells growth and development which also include
DEPDC5. Mutations in this gene have been identified in autosomal dominant focal epilepsy
with variable foci and in few families with familial TLE.

Saturday, March 17, 2018

State medical board investigation

They fell like dominos, one after another: first, my medical privileges, then my Ohio Medical License, then my state license, then my board certification, finally my DEA license. While, like most physicians, I had concerns about malpractice suit, a medical board investigation never crossed my mind.

I suppose that’s why the certified letter from an investigator with my state medical board took me by surprise. I was alleged to be “an unregistered terminal distributor of dangerous drugs.” I told the investigator everything. I hadn’t distributed anything. Seven months previously, my husband of 37 years announced that he was getting a divorce. I had no home, no marriage, no job, no doctor, not even a car. I couldn’t stop crying. I couldn’t eat. Worst of all, I couldn’t sleep. I tried alcohol; it didn’t help. In desperation, I had ordered a bottle of Xanax from a wholesaler.

That was it. I signed a release of medical records to confirm my statements and document the help I was getting and the progress I was making. I hadn’t seen any patients during that time, violated any laws, or driven under the influence. Since I wasn’t in any legal jeopardy, I didn’t need a lawyer.

Then the second certified letter arrived. The Board had reason to believe that I was “unable to practice according to acceptable and prevailing standards of care by reason of mental illness or physical illness…” I was ordered to submit to a forensic psychiatric exam. Failure to do so would constitute “an admission of the allegations…and a default and final order may thereupon be entered without the taking of testimony or presentation of evidence.” If I didn’t submit to their demands, I could lose my license.

The interview went smoothly. I had no personal or family history of alcoholism or addiction. I could spell W-O-R-L-D backwards. I did my serial 7s down to 57 and my presidents down to Kennedy, at which point the psychiatrist had said, “Enough!” I was still in therapy and taking an antidepressant, but I was back to work and feeling good. I thought that was it.

But again, I was wrong. Four months later, I got a third certified letter. This time the Board ordered me to submit to a 72-hour inpatient addiction evaluation. Knowing what was at stake, I submitted.

When I arrived at the rehab hospital, my phone, wallet and keys were confiscated, and my car, suitcase and body were searched. During my stay, I was assailed with questions I couldn’t answer, questions like “What’s your drug of choice?” and “Does your family know about your addiction?” I submitted to observed urine drug tests, sleep deprivation and hours of interrogation, group therapy and lectures on alcoholism. The cognitive dissonance was unbearable.

On the morning of the third day in rehab, I was told that, since I was still in denial about my addiction, I would have to stay in rehab at least 28 more days. I had packed for three.

I refused. I was reminded of the consequences to my career. I still refused. I had given the rehab hospital permission to contact my husband, my daughter, my brother and a longtime colleague. They would confirm that, except for that brief period, I was the epitome of sobriety. The nightmare would be over.

It wasn’t. Six weeks later, the fourth certified letter arrived. It stated: “We have reason to believe that you pose an imminent threat to your patients and we thereby are suspending your medical license.” I had to stop practicing immediately. I could have a hearing. It would be adversarial, but it was my last chance to salvage my career.

I prepared assiduously in the 15 days leading up to the hearing. I was an articulate, consistent and contrite defendant, but a terrible lawyer. After eight hours of testimony, the Board’s lawyer concluded that my children were enablers, my spouse was lying, my colleagues were clueless and I was a hopeless drunk full of excuses. Nonetheless, I was hopeful.

Shortly thereafter, the fifth certified letter arrived. I was offered a chance to face my accusers, the eight members of the state medical board, for five minutes at a public hearing. I took the offer. Three and a half minutes into my statement, the Board’s spokesman interrupted me and read a perfunctory statement echoing their lawyer’s sentiments. I was numb.

Two weeks later, the sixth certified letter arrived. It said, “There is clear and convincing evidence that you are impaired in your ability to practice medicine and your Ohio license had been permanently revoked.” The seventh certified letter said my state license was suspended, the eighth, that my Board certification was revoked, and the ninth, that my DEA license was invalidated.

It’s taken me months to be able to write about this. Months to get past the shame of a personal crisis made public, to recover from the pain of the ordeal, and to accept that never again could I practice the profession to which I had dedicated my entire adult life.

I have learned over these months that countless other unwary practitioners have been victims of the same disciplinary fervor. I know now that, to keep their licenses, most of these physicians will submit to what’s demanded of them and they will stay silent to protect their reputations. I, however, was physically, emotionally and financially unable to submit to my Board’s final demand. As a result, I lost everything professionally. I have nothing to lose by speaking out.

My colleagues need to know that if a Board investigator contacts you, you must immediately contact your lawyer. Unlike in a civil case, Boards can presume you’re guilty and ignore exculpatory evidence. Unlike in a criminal case, Boards don’t have to advise of your civil rights because you don’t have any. They can coerce you into medically unnecessary treatment, rob you of your personal freedom, publicly defame you and deprive you of your livelihood, all with complete impunity.

State legislatures cannot abridge the civil rights of its citizens. However, they allow state medical boards to do so based on the rationale that medical professionals must adhere to higher standards than average citizens. I accept that. However, boards should not be allowed to violate our civil rights when evaluating whether or not we are adhering to those standards. Perhaps in the long run, we can repeal the laws that allow this travesty. For now, any of you who can speak up, please do. Talk to your colleagues, your medical society, your state representative. For those who can’t speak up, please know this: you aren’t a pariah, you aren’t worthless, and you definitely aren’t alone.

Friday, March 16, 2018

Sinus infection spreading to brain

What 13-year-old Marquel Brumley initially believed was a common cold turned into a deadly infection — and his family is sharing the boy's story to warn others just days after his death.

"Marquel was healthy; he had no health issues at all," Brumley's aunt, Nicole Alexander, told Fox News.

The eighth-grader went to an urgent care in Flint, Michigan when he started to notice cold symptoms. He was told it was a sinus infection caused by a virus and would likely get better on its own.

"A sinus infection does not typically need to be treated with antibiotics in order to get better," the Centers for Disease Control and Prevention (CDC) explains on its website. "If you or your child is diagnosed with a sinus infection, your healthcare professional can decide if antibiotics are needed."

Brumley continued to suffer from the cold symptoms for weeks and soon started to experience severe headaches.

He visited the emergency room several times. Each time, doctors diagnosed him with a migraine and he was eventually sent home.

Last week, Brumley's pain was so severe he returned to a local hospital for treatment. It was there that doctors discovered the sinus infection had spread to his brain, causing multiple blood clots.

He was transferred to C.S. Mott Children's Hospital in Ann Arbor, Michigan, where he was rushed into surgery. The teen suffered multiple strokes due to the infection and was left in a coma.

"The doctors [did] everything they [could] to reduce the pressure in his brain," Peggy Gilbert, another relative of the boy, explained in a post on a GoFundMe page, which is raising money to pay Brumley's medical bills and cover funeral expenses.

Brumley remained in a coma in "critical condition" at the hospital. For days, doctors conducted tests to see if Brumley was responsive, but there was no change.

"They are going to run three tests on determine if he is still with us or not, if he passes even one then he is still with us, if he fails all of them, than legally he is gone," Gilbert posted on Facebook on March 8. "So today I am praying for one breath, just one!"

Three days later, Alexander confirmed Brumley did not take his own breath and he died later that day.

Alexander was shocked by how quickly Brumley's sinus infection turned deadly and hoped to share his story in hopes of preventing families, like hers, from facing similar fates.

"I think it is very important to express how serious a sinus infection can be, not to take them lightly or to blow them off," Alexander added.

The teen, a straight-A student who played football and the trumpet in band, is being remembered as a "goofball," who "loved helping people."

"He wanted to build houses, loved playing video games...he loved his mom and sister fiercely, and was their protector," Alexander said.

Nearly 400 people have donated to Brumley's page, raising more than $12,700 in just eight days.

"The love and support everyone has shown is overwhelming and so appreciated. Marquel was a very kind and loving person that will be missed terribly," Gilbert wrote in a recent update on the fundraising page.

Alexander added that the family is taking comfort in knowing Brumley was an organ donor, learning Thursday that he saved seven lives.