GNAO1 mutations

Inspired by a colleague’s patient

Iodice A, Pisani F. Status dystonicus: management and prevention in children at high risk. Acta Biomed. 2019 Sep 6;90(3):207-212.

Abstract

BACKGROUND:

Status dystonicus (SD) is a movement disorder emergency associated with significant morbidity and life-threatening events that requires immediate and effective treatment. Nevertheless, SD is currently an under-recognized and undertreated condition, partly due to the lack of a standard definition and because it can be the acute complicated course of both primary and secondary dystonias. In subjects with SD, due to  the delay of identification and  lacking prevention of trigger and precipitant factors, intensive care management is consistently required.

OBJECTIVES:

We performed a critical review of this topic, outlining clinical features and linked genetic disorders to recognize subject at higher risk of SD, describing precipitant and trigger factors and proposing potential pharmacological treatment strategies in order to prevent hospitalization.

RESULTS:

Genetic predisposition included: primary dystonias particularly in the case of  TOR1A mutation; epileptic encephalopathy such as ARX and GNAO1 genetic variants and neurodegenerative disorders as PANK2. Early recognition of SD should be oriented by the following sign and symptoms: fever, tachycardia, respiratory change, hypertension, sweating and autonomic instability, elevated serum CK. Pain, fever and dehydration are main trigger factors that have to be prevented or quickly controlled. Achieving sleep could be the first therapeutic option in those with high risk of developing SD. Recently, enteral or transdermal clonidine as safety and efficacy therapeutic alternative was proposed.

CONCLUSION:

Recognizing high risk children for Status dystonicus from the onset of subtle signs and avoiding trigger factors could drive towards better management avoiding intensive treatments.

Malaquias MJ, Fineza I, Loureiro L, Cardoso L, Alonso I, Magalhães M. GNAO1 mutation presenting as dyskinetic cerebral palsy. Neurol Sci. 2019 Oct;40(10):2213-2216.  

No abstract

From the paper:

We report a new case of a GNAO1 mutation, in an 18-year-old girl with global development delay, hypotonia, and HMD, from an early age with a long period of stabilization, mimicking a full-term dyskinetic cerebral palsy.

The phenotypic spectrum associated with mutations in GNAO1 has revealed a genetic overlap between epileptic encephalopathies, developmental delay/intellectual disability, and HMD. A biochemical analysis of 15 different GNAO1 mutant alleles, conducted by Feng et al., established that gain-of-function (GOF) and normal-function (NF) mutations for inhibition of cAMP are associated with the phenotype of movement disorder, while the loss-of-function (LOF) mutations are related to epileptic encephalopathy phenotype. To our knowledge, seven other cases of GNAO1 mutation (c.625C>T) with normal function have been previously reported, all with movement disorder phenotype.

Patients with GNAO1 mutations can present with a severe, progressive HMD with prolonged life-threatening exacerbations which are refractory to medication. However, our patient presented with a more indolent course, completely free from epileptic seizures, which was reported in very few other cases. Among patients with movement disorder, tetrabenazine appears to be the most effective drug  and GPi-DBS, the most effective treatment. Nevertheless, our patient experienced some benefit with dopaminergic therapy (gait, chorea, and tremor). A positive response to dopaminergic drugs was not common in previously published cases. The identification of GNAO1 mutation as the cause made us consider early GPi-DBS as a valid treatment option for this patient.

Our case highlights the genotype-phenotype correlation which is important for early diagnosis, the variable long-term outcome of the disease, and that the dopamine replacement therapy is a valid therapeutic option in advanced stages of this condition, possibly because of a secondary dopaminergic deficiency in the late disease course.

Gerald B, Ramsey K, Belnap N, Szelinger S, Siniard AL, Balak C, Russell M, Richholt R, De Both M, Claasen AM, Schrauwen I, Huentelman MJ, Craig DW, Rangasamy S, Narayanan V. Neonatal epileptic encephalopathy caused by de novo GNAO1 mutation misdiagnosed as atypical Rett syndrome: Cautions in interpretation of genomic test results. Semin Pediatr Neurol. 2018 Jul;26:28-32.

Abstract

Epileptic encephalopathies are childhood brain disorders characterized by a variety of severe epilepsy syndromes that differ by the age of onset and seizure type. Until recently, the cause of many epileptic encephalopathies was unknown. Whole exome or whole genome sequencing has led to the identification of several causal genes in individuals with epileptic encephalopathy, and the list of genes has now expanded greatly. Genetic testing with epilepsy gene panels is now done quite early in the evaluation of children with epilepsy, following brain imaging, electroencephalogram, and metabolic profile. Early infantile epileptic encephalopathy (EIEE1; OMIM #308350) is the earliest of these age-dependent encephalopathies, manifesting as tonic spasms, myoclonic seizures, or partial seizures, with severely abnormal electroencephalogram, often showing a suppression-burst pattern. In this case study, we describe a 33-month-old female child with severe, neonatal onset epileptic encephalopathy. An infantile epilepsy gene panel test revealed 2 novel heterozygous variants in the MECP2 gene; a 70-bp deletion resulting in a frameshift and truncation (p.Lys377ProfsX9) thought to be pathogenic, and a 6-bp in-frame deletion (p.His371_372del), designated as a variant of unknown significance. Based on this test result, the diagnosis of atypical Rett syndrome (RTT) was made. Family-based targeted testing and segregation analysis, however, raised questions about the pathogenicity of these specific MECP2 variants. Whole exome sequencing was performed in this family trio, leading to the discovery of a rare, de novo, missense mutation in GNAO1 (p. Leu284Ser). De novo, heterozygous mutations in GNAO1 have been reported to cause early infantile epileptic encephalopathy-17 (EIEE17; OMIM 615473). The child's severe phenotype, the family history and segregation analysis of variants and prior reports of GNAO1-linked disease allowed us to conclude that the GNAO1 mutation, and not the MECP2 variants, was the cause of this child's neurological disease. With the increased use of genetic panels and whole exome sequencing, we will be confronted with lists of gene variants suspected to be pathogenic or of unknown significance. It is important to integrate clinical information, genetic testing that includes family members and correlates this with the published clinical and scientific literature, to help one arrive at the correct genetic diagnosis.

Okumura A, Maruyama K, Shibata M, Kurahashi H, Ishii A, Numoto S, Hirose S, Kawai T, Iso M, Kataoka S, Okuno Y, Muramatsu H, Kojima S. A patient with a GNAO1 mutation with decreased spontaneous movements, hypotonia, and dystonic features. Brain Dev. 2018 Nov;40(10):926-930.

Abstract

We report on a 4-year-old girl with a de novo GNAO1 mutation who had neurological findings, including decreased spontaneous movements, hypotonia, and dystonic features. She was referred to our hospital because of delayed psychomotor development. She showed hypotonia and decreased spontaneous movements. Voluntary movements of the limbs were more frequent in the lower extremities than in the upper extremities. Occasional dyskinetic features, such as awkward hand/foot posturing and grimacing, were seen during the voluntary movements. Serum metabolic screening, head magnetic resonance imaging, and electroencephalography were unremarkable. Whole-exome sequencing revealed a de novo mutation in the patient's GNAO1 gene, c.709 G > A (p.E237K). We calculated the free-energy change using the FoldX Suite to evaluate the impact of the E237K mutation. The FoldX calculations showed an increased free-energy change in the active state of the GNAO1 protein, indicating that the E237K mutation destabilizes the active state complexes. No seizures, chorea, tremor, or myoclonia, which are frequently reported in patients with GNAO1 mutations, were observed as of the last follow up. Our patient will improve the understanding of early neurological features in patients with GNAO1 mutations.

Feng H, Khalil S, Neubig RR, Sidiropoulos C. A mechanistic review on GNAO1-associated movement disorder. Neurobiol Dis. 2018 Aug;116:131-141.

Abstract

Mutations in the GNAO1 gene cause a complex constellation of neurological disorders including epilepsy, developmental delay, and movement disorders. GNAO1 encodes Gαo, the α subunit of Go, a member of the Gi/o family of heterotrimeric G protein signal transducers. Go is the most abundant membrane protein in the mammalian central nervous system and plays major roles in synaptic neurotransmission and neurodevelopment. GNAO1 mutations were first reported in early infantile epileptic encephalopathy 17 (EIEE17) but are also associated with a more common syndrome termed neurodevelopmental disorder with involuntary movements (NEDIM). Here we review a mechanistic model in which loss-of-function (LOF) GNAO1 alleles cause epilepsy and gain-of-function (GOF) alleles are primarily associated with movement disorders. We also develop a signaling framework related to cyclic AMP (cAMP), synaptic vesicle release, and neural development and discuss gene mutations perturbing those mechanisms in a range of genetic movement disorders. Finally, we analyze clinical reports of patients carrying GNAO1 mutations with respect to their symptom onset and discuss pharmacological/surgical treatments in the context of our mechanistic model.

Hemispherectomy and cognitive outcome

Kliemann D, Adolphs R, Tyszka JM, Fischl B, Yeo BTT, Nair R, Dubois J, Paul LK. Intrinsic Functional Connectivity of the Brain in Adults with a Single Cerebral Hemisphere. Cell Rep. 2019 Nov 19;29(8):2398-2407

Abstract

A reliable set of functional brain networks is found in healthy people and thought to underlie our cognition, emotion, and behavior. Here, we investigated these networks by quantifying intrinsic functional connectivity in six individuals who had undergone surgical removal of one hemisphere. Hemispherectomy subjects and healthy controls were scanned with identical parameters on the same scanner and compared to a large normative sample (n = 1,482). Surprisingly, hemispherectomy subjects and controls all showed strong and equivalent intrahemispheric connectivity between brain regions typically assigned to the same functional network. Connectivity between parts of different networks, however, was markedly increased for almost all hemispherectomy participants and across all networks. These results support the hypothesis of a shared set of functional networks that underlie cognition and suggest that between-network interactions may characterize functional reorganization in hemispherectomy.

______________________________________________________________________ 

Many people think of their brain as an overstuffed attic. Every square-inch is either crammed with information or working overtime to help the body function properly. So is it even conceivable that a person be normal with just half a brain?

Yes, apparently it is, according to a new analysis that assessed brain health among six adults who had undergone a hemispherectomy as children. The highly invasive surgery, which entails removal or severing of half the brain, had been part of a pediatric epilepsy treatment to reduce seizure risk.

"The people with hemispherectomies that we studied were remarkably high-functioning," study author Dorit Kliemann said in a statement. "They have intact language skills. When I put them in the [brain] scanner, we made small talk, just like the hundreds of other individuals I have scanned," she explained.

"You can almost forget their condition when you meet them for the first time," added Kliemann, who is a post-doctoral scholar in cognitive neuroscience at the California Institute of Technology, in Pasadena.

Kliemann and her team noted that the six patients in the study had all struggled with relentless epileptic seizures from a very early age, with one patient initially struck by seizures just minutes after birth.

Hemispherectomies are typically performed as a means to bring such "intractable" epilepsy under control, the team explained. The aim is to isolate whichever half (or hemisphere) of the brain is affected by the disease. That can mean either actual removal of the problematic half of the brain or a cutting off of all physical connections between the two halves.

All of the patients had undergone full removal of half their brain. The youngest patient was just 3 months old at the time of surgery, while the oldest had been 11. Four involved excision of the right side of the brain, while two had the left side removed.

Now in their 20s and 30s, the six patients agreed to undergo functional MRI brain scans while awake at the Caltech Brain Imaging Center.

Brain activity was tracked in areas tasked with regulating vision, movement, emotion and thought processes.

Results were then stacked up against those of six healthy adults who also underwent scans, and with data previously collected on nearly 1,500 healthy adults (average age of 22).

Because brain networks devoted to a single regulatory function often span both hemispheres of the brain, the team expected to see weaker neural activity among the hemispherectomy patients. That was not the case.

In fact, scans revealed normal in-network communication and activity function. And communication running between different regulatory networks was actually found to be stronger than normal among hemispherectomy patients.

Dr. Joseph Sirven, a professor of neurology with the Mayo Clinic in Florida and editor-in-chief of Epilepsy.com, said the findings did not strike him as entirely surprising. He said he often sees patients functioning at a very high level post-hemispherectomy.

"But what surprises me is the degree of compensation that was noted," added Sirven, who was not part of the study team.

"And if we could figure out the way that the brain compensates in this dramatic setting, and harness this compensatory mechanism for patients affected by stroke, traumatic brain injury or other conditions, that would be a very big deal," Sirven noted.

That thought was echoed by Kliemann. "As remarkable as it is that there are individuals who can live with half a brain, sometimes a very small brain lesion -- like a stroke or a traumatic brain injury or a tumor -- can have devastating effects," she noted. 

That is why it's so important to get a better understanding of exactly how the brains of hemispherectomy patients managed to reorganize and compensate for the loss of half a brain, Kliemann said. Because doing so could eventually lead to new "targeted intervention strategies" to help other types of patients struggling with the debilitating effects of a variety of brain injuries, she theorized.

https://www.webmd.com/brain/news/20191119/they-had-half-their-brains-removed-heres-what-happened-after#2

Dietary interventions for autism spectrum disorder: A meta-analysis

Fraguas D, Díaz-Caneja CM, Pina-Camacho L, Moreno C, Durán-Cutilla M, Ayora M, González-Vioque E, de Matteis M, Hendren RL, Arango C, Parellada M. Dietary Interventions for Autism Spectrum Disorder: A Meta-analysis. Pediatrics. 2019 Nov;144(5).

CONTEXT: Dietary interventions such as restrictive diets or supplements are common treatments for young people with autism spectrum disorder (ASD). Evidence for the efficacy of these interventions is still controversial.

OBJECTIVE: To assess the efficacy of specific dietary interventions on symptoms, functions, and clinical domains in subjects with ASD by using a meta-analytic approach.

DATA SOURCES: Ovid Medline, PsycINFO, Embase databases.

STUDY SELECTION: We selected placebo-controlled, double-blind, randomized clinical trials assessing the efficacy of dietary interventions in ASD published from database inception through September 2017.

DATA EXTRACTION: Outcome variables were subsumed under 4 clinical domains and 17 symptoms and/or functions groups. Hedges’ adjusted g values were used as estimates of the effect size of each dietary intervention relative to placebo.

RESULTS: In this meta-analysis, we examined 27 double-blind, randomized clinical trials, including 1028 patients with ASD: 542 in the intervention arms and 486 in the placebo arms. Participant-weighted average age was 7.1 years. Participant-weighted average intervention duration was 10.6 weeks. Dietary supplementation (including omega-3, vitamin supplementation, and/or other supplementation), omega-3 supplementation, and vitamin supplementation were more efficacious than the placebo at improving several symptoms, functions, and clinical domains. Effect sizes were small (mean Hedges’ g for significant analyses was 0.31), with low statistical heterogeneity and low risk of publication bias.

LIMITATIONS: Methodologic heterogeneity among the studies in terms of the intervention, clinical measures and outcomes, and sample characteristics.

CONCLUSIONS: This meta-analysis does not support nonspecific dietary interventions as treatment of ASD but suggests a potential role for some specific dietary interventions in the management of some symptoms, functions, and clinical domains in patients with ASD.

Courtesy of:  https://www.mdlinx.com/journal-summaries/dietary-interventions-asd-autism-spectrum-disorder/2019/11/07/7584074?spec=neurology

From the paper

Meta-analyses revealed the following:

Dietary supplementation (omega-3, vitamin supplementation, and/or other supplementation) was more effective than placebo in treating the following symptoms and/or functions groups: anxiety and/or affect, autistic general psychopathology, behavioral problems and impulsivity, global severity, hyperactivity and irritability, language (general), and social-autistic and stereotypies, restricted and repetitive behaviors. Dietary supplementation (omega-3, vitamin supplementation, and/or other supplementation) was more effective than placebo in treating the following clinical domains: core symptoms, associated symptoms, autism global, and clinical global impression.

Omega-3 supplementation was more effective than placebo in treating the following symptoms and/or functions groups: language (general) and social-autistic (see Table 2). Omega-3 supplementation was more effective than placebo in treating the following clinical domains: core symptoms and associated symptoms.

Vitamin supplementation was more effective than placebo in treating the following symptoms and/or functions groups: global severity, language (general), stereotypies, restricted and repetitive behaviors, behavioral problems and impulsivity, and hyperactivity and irritability. Vitamin supplementation was more effective than placebo in treating the following clinical domains: core symptoms, associated symptoms, and clinical global impression 

.

For all types of dietary intervention, significant meta-analyses revealed small effect size  relative to placebo, low statistical heterogeneity, and low risk of publication bias.

Giggle incontinence

Inspired by a patient

Logan BL, Blais S. Giggle incontinence: Evolution of concept and treatment. J Pediatr Urol. 2017 Oct;13(5):430-435.

Abstract

BACKGROUND:

Giggle incontinence is a sudden and involuntary episode of urinary incontinence that is provoked by an episode of laughter. Decades of case studies and small research studies have formed the basis of what is known about giggle incontinence; however, much remains unknown about this type of incontinence, leaving the recommendations for clinical management somewhat unguided.

METHODS:

A systematic review of 22 articles on the topic of "giggle incontinence" and related terms was conducted, including all published articles and commentaries since the term was first seen in print in 1959.

RESULTS:

This review provides a historical context for the diagnosis, a summary of what is known about its etiology, and a summary of current treatments.

CONCLUSIONS:

There is disagreement about the pathophysiology of laughter incontinence, with two differing explanations. The first emphasizes the neurologic origin of the cascade of events during laughter and urination, and draws a likeness to cataplexy and other CNS disorders, and emphasizes treatment with methylphenidate. The second emphasizes urologic dysfunction, with biofeedback and bladder retraining as the recommended therapy. Comprehensive treatment of children with laughter incontinence requires an appreciation of both concepts. Since inception of the concept there has been question about the appropriateness of the term "giggle incontinence." This review encourages discussion among readers/clinicians about the term and the essential qualities of the diagnosis.

Telli O, Hamidi N, Kayis A, Suer E, Soygur T, Burgu B. Can the success of structured therapy for giggle incontinence be predicted? Int Braz J Urol. 2016 Mar-Apr;42(2):334-8.

Abstract

INTRODUCTION:

To evaluate possible factors that can guide the clinician to predict potential cases refractoriness to medical treatment for giggle incontinence (GI) and to examine the effectiveness of different treatment modalities.

MATERIAL AND METHODS:

The data of 48 children referred to pediatric urology outpatient clinic between 2000 and 2013 diagnosed as GI were reviewed. Mean age, follow-up, GI frequency, associated symptoms, medical and family history were noted. Incontinence frequency differed between several per day to less than once weekly. Children were evaluated with uroflowmetry-electromyography and post-void residual urine. Clinical success was characterized as a full or partial response, or nonresponse as defined by the International Children's Continence Society. Univariate analysis was used to find potential factors including age, sex, familial history, GI frequency, treatment modality and dysfunctional voiding to predict children who would possibly not respond to treatment.

RESULTS:

Mean age of the patients was 8.4 years (range 5 to 16). Mean follow-up time and mean duration of asymptomatic period were noted as 6.7±1.4 years and 14.2±2.3 months respectively. While 12 patients were treated with only behavioral urotherapy (Group-1), 11 patients were treated with alpha-adrenergic blockers and behavioral urotherapy (Group-2) and 18 patients with methylphenidate and behavioral urotherapy (Group-3). Giggle incontinence was refractory to eight children in-group 1; six children in-group 2 and eight children in-group 3. Daily GI frequency and dysfunctional voiding diagnosed on uroflowmetry-EMG were found as outstanding predictive factors for resistance to treatment modalities.

CONCLUSIONS:

A variety of therapies for GI have more than 50% failure rate and a standard treatment for GI has not been established. The use of medications to treat these patients would not be recommended, as they appear to add no benefit to symptoms and may introduce severe adverse effects.

Chang JH, Lee KY, Kim TB, Yoon SJ, Lee T, Kim KH. Clinical and urodynamic effect of methylphenidate for the treatment of giggle incontinence (enuresis risoria). Neurourol Urodyn. 2011 Sep;30(7):1338-42.

Abstract

AIMS:

We retrospectively investigated the efficacy of methylphenidate (MPH) in giggle incontinence (GI), and the relationship between GI and urodynamic parameters.

METHODS:

Nine (n = 9) female GI patients underwent 1 year of treatment with 5 mg MPH. Three questionnaires, voiding diaries, and UDS were conducted before and after treatment. The severity of GI was classified into mild, moderate, and severe. Clinical success was characterized as: full response, response, partial response, and non-response.

RESULTS:

The mean age of all patients was 16.2 ± 2.3 years. Five patients had mild, one had moderate, and three had severe grade incontinent. All patients reported complete cessation of wetting after MPH treatment. The mean duration of asymptomatic period was 7 ± 3.2 months. There were no statistically significant score changes in all three questionnaires: Urgency Perception Scale (UPS), Overactive Bladder Symptom Score (OABSS) and Primary Overactive Symptom Questionnaire (POSQ), and voiding diaries (P > 0.05). In UDS, there were no statistically significant altered parameters, except maximum urethral closure pressure (MUCP) and maximum urethral pressure (MUP). After treatment, the mean MUCP was increased from 52.2 ± 6.8 to 73.0 ± 5.4 cmH(2) O (P < 0.05), and the mean MUP was increased from 48.6 ± 7.3 to 70.2 ± 5.0 cmH(2) O (P < 0.05).

CONCLUSIONS:

MPH can be a viable option for the primary treatment of GI, and it may be related to increasing urethral closure pressure. It was not possible to establish if a relationship between GI and detrusor overactivity exists.

Sher PK, Reinberg Y. Successful treatment of giggle incontinence with methylphenidate. J Urol. 1996 Aug;156(2 Pt 2):656-8.

Abstract

PURPOSE:

Giggle incontinence, the second most common type of childhood enuresis unrelated to disease, is notoriously difficult to treat. However, the association of laughter or emotion precipitated alteration of muscle tone is suggestive of a functional relationship to cataplexy, a part of the narcoleptic syndrome complex that may respond to stimulant medication.

MATERIALS AND METHODS:

Two boys and 5 girls (mean age 10.9 years) with giggle incontinence, a positive family history of giggle incontinence (4 patients) and no evidence of urological disease were treated with methylphenidate for 1 to 5 years.

RESULTS:

All patients responded positively with complete cessation of enuresis to varying dose schedules of methylphenidate.

CONCLUSIONS:

These results suggest that giggle incontinence is a centrally mediated and likely hereditary disorder that may share a common pathophysiological basis with the narcolepsy/cataplexy syndrome.

Sher PK. Successful treatment of giggle incontinence with methylphenidate. Pediatr Neurol. 1994 Feb;10(1):81. (no abstract)

Diffusion tensor imaging is associated with motor outcomes of very preterm born children

Lahti K, Saunavaara V, Munck P, Uusitalo K, Koivisto M, Parkkola R, Haataja L; PIPARI Study Group. Diffusion tensor imaging is associated with motor outcomes of very preterm born children at 11 years of age. Acta Paediatr. 2019 Sep 10. doi:10.1111/apa.15004. [Epub ahead of print]

Abstract

AIM:

Very preterm children born <32 weeks of gestation are at risk for motor difficulties such as cerebral palsy and developmental coordination disorder. This study explores the association between diffusion tensor imaging metrics at term and motor outcomes at 11 years of age.

METHODS:

A cohort of 37 very preterm infants (mean gestational age 29 4/7, SD 2 0/7) born in 2004-2006 in Turku University Hospital underwent diffusion tensor imaging at term. A region of interest analysis of fractional anisotropy and mean diffusivity was performed. Motor outcomes at 11 years of age were measured with the Movement Assessment Battery for Children - Second Edition.

RESULTS:

The diffusion metrics of the corpus callosum (genu P = .005, splenium P = .049), the left corona radiata (P = .035) and the right optic radiation (P = .017) were related to later motor performance. Mean diffusivity decreased and fractional anisotropy increased in proportion to the improving performance.

CONCLUSION:

The diffusion metrics of the genu and splenium of the corpus callosum, the left corona radiata and the right optic radiation at term were associated with motor skills at 11 years of age. Diffusion tensor imaging should be further studied as a potential tool in recognising children at risk for motor impairment.

Courtesy of:  https://www.mdlinx.com/journal-summaries/developmental-coordination-disorder-diffusion-tensor-imaging/2019/11/12/7584696?spec=neurology

Cerebellar agenesis 2

Since his birth 33 years ago, Jonathan Keleher has been living without a cerebellum, a structure that usually contains about half the brain's neurons.

This exceedingly rare condition has left Jonathan with a distinctive way of speaking and a walk that is slightly awkward. He also lacks the balance to ride a bicycle.

But all that hasn't kept him from living on his own, holding down an office job and charming pretty much every person he meets.

"I've always been more into people than anything else," Jonathan tells me when I meet him at his parents' house in Concord, Mass., a suburb of Boston. "Why read a book or why do anything when you can be social and talk to people?"

Jonathan is also making an important contribution to neuroscience. By allowing scientists to study him and his brain, he is helping to change some long-held misconceptions about what the cerebellum does. And that, in turn, could help the hundreds of thousands of people whose cerebellums have been damaged by a stroke, infection or disease.

For decades, the cerebellum has been the "Rodney Dangerfield of the brain," says Dr. Jeremy Schmahmann, a professor of neurology at Harvard and Massachusetts General Hospital. It gets no respect because most scientists only know about its role in balance and fine motor control.

You can learn a lot about that role by watching someone who's been pulled over for drunken driving, Schmahmann says. "The state trooper test is a test of cerebellar function. So the effect of alcohol on cerebellar function is identified by everybody who's ever done walking a straight line or touching their finger to the nose."

But Schmahmann and a small group of other scientists have spent decades building a case that the cerebellum does a lot more than let people pass a sobriety test.

First, they showed that it has connections to brain areas that perform higher functions, like using language, reading maps and planning. Then, a few years ago, researchers began to do functional MRI studies that suggested that the cerebellum was actively involved in these tasks.

"The big surprise from functional imaging was that when you do these language tasks and spatial tasks and thinking tasks, lo and behold the cerebellum lit up," Schmahmann says.

Some of the most compelling evidence, though, has come from research on a handful of people who have no cerebellum, people like Jonathan Keleher.

For the first few years, his future looked highly uncertain, says his mother, Catherine. "All his milestones were late: sitting up, walking, talking."

But during that time doctors and developmental health experts still didn't know why Jonathan was having so much trouble. And that turned out to be a good thing, says his father, Richard. "Not knowing what the diagnosis was we said, 'Well, let's assume he can do everything,' " he says.

So Jonathan got special education, speech therapy and physical therapy. His father even came up with a sort of beach therapy.

"He wasn't walking," Richard says. "And I found that if I took him to the beach, he would try to walk."

Jonathan was 5 when a brain scan finally revealed the problem. And eventually he was referred to Schmahmann, who has spent his entire career studying the cerebellum.

n image of Jonathan's brain is on a computer screen the day I visit Schmahmann's lab. He points to an area just above the brain stem. "He has this remarkable black space down here, which is where the cerebellum is supposed to be," Schmahmann says. "It's a very big area of nothingness there."

Research on Jonathan and people like him supports the idea that the cerebellum really has just one job: It takes clumsy actions or functions and makes them more refined. "It doesn't make things. It makes things better," Schmahmann says.

That's pretty straightforward when it comes to movement. The brain's motor cortex tells your legs to start walking. The cerebellum keeps your stride smooth and steady and balanced.

"What we now understand is what that cerebellum is doing to movement, it's also doing to intellect and personality and emotional processing," Schmahmann says.

Unless you don't have a cerebellum. Then, Schmahmann says, a person's thinking and emotions can become as clumsy as their movements.

Jonathan got a reminder of this at a busy intersection soon after he got his driver's license. There was a bus behind him, cars whizzing by, and his brain simply couldn't coordinate all the information. So he totaled his father's car.

"Reaction time, not my strong suit," Jonathan says, adding that he doesn't drive anymore.

Emotional complexity is another challenge for Jonathan, says his sister, Sarah Napoline. She says her brother is a great listener, but isn't introspective.

"He doesn't really get into this deeper level of conversation that builds strong relationships, things that would be the foundation for a romantic relationship or deep enduring friendships," she says. Jonathan, who is sitting beside her, says he agrees.

Jonathan also needed to be taught a lot of things that people with a cerebellum learn automatically, Sarah says: how to speak clearly, how to behave in social situations and how to show emotion.

Yet Jonathan is now able to do all of those things. He's done it by training other areas of his brain to do the jobs usually done by the cerebellum, Schmahmann says.

It's taken decades, Richard says. He adds that it couldn't have happened at all if his son were less resilient and determined.

"There are times when I realize how brave my son has been," he says. "Being out there on his own, going down to the beach and falling down again and again and again and again. It's pretty impressive."

https://www.npr.org/sections/health-shots/2015/03/16/392789753/a-man-s-incomplete-brain-reveals-cerebellum-s-role-in-thought-and-emotion

Courtesy of:  https://www.foxnews.com/health/woman-dizziness-missing-cerebellum

Cerebellar agenesis

Yu F, Jiang QJ, Sun XY, Zhang RW. A new case of complete primary cerebellar agenesis: clinical and imaging findings in a living patient. Brain. 2015 Jun;138(Pt 6):e353.

We read with great interest the articles previously published in Brain by Glickstein (1994) and Boyd (2010) describing the clinical evidence and review of cerebellar agenesis. Here we report a new case of a living patient whom we believe to be another patient with cerebellar agenesis. Cerebellar agenesis is an extremely rare condition implying complete absence of the cerebellum. The pathogenesis and molecular basis of this disease remain unknown. There are very few reported cases of complete cerebellar agenesis, making it challenging and controversial to understand the degree of cerebellum development necessary to avoid deficits in motor and non-motor functions. Further, a detailed description of neurological findings in a living adult with cerebellar agenesis is almost non-existent; most cases are reported based on autopsy reports. The patient presents with mild mental impairment and medium motor deficits. CT and MRI scans revealed no remnants of any cerebellar tissues, verifying complete absence of the cerebellum. A comprehensive literature review reveals novel implications for differential diagnosis. We conclude that primary cerebellar agenesis is actually the same diagnosis as Chiari malformation IV.

A 24-year-old female patient was admitted to hospital complaining of dizziness and the inability to walk steadily for more than 20 years, and nausea and vomiting for ∼1 month. She is married with a daughter, and her pregnancy and delivery were described as uneventful. Her parents had no history of neurological disorders. Her four sisters and one brother are described as neurologically normal. According to her mother, she was 4 years old before she could stand unassisted, and did not begin to walk unassisted until the age of 7, with a persistently unsteady gait. She never ran or jumped. Her speech was not intelligible until 6 years of age and she did not enter school. A neurological examination revealed she could cooperate and fully orientate. A verbal analysis test revealed her word comprehension and expression remained intact and she had no sign of aphasia, but mild to moderate signs of cerebellar dysarthria. The patient has mild voice tremor with slurred pronunciation and her voice quality is slightly harsh. Cerebellar ataxia including Romberg’s sign, and there is evidence of heel-knee-tibia impairment. The patient experienced mild to moderate dysmetria in reaching the nose when administered the finger-to-nose test. Pronation-supination alternating movements were slightly irregular and slowed. While she is able to walk unsteadily without support, her gait is moderately unsteady. The patient has evidence of tandem gait and moderately reduced gait speed. There is no focal paresis but the muscle tone is mildly increased. Evaluation of the sensory system showed no abnormalities, no deformities of the fingers and toes were observed, and her complete blood count and urinalysis were normal.

The patient has low posterior fossa density and no cerebellar tissue following CT analysis [A]. No recognizable cerebellar structures are present, and the posterior fossa was filled by CSF when analysed by cranial MRI [B]. The mesencephalon, pons, and medulla oblongata were present. The mesencephalon had a normal aspect, and the aqueduct of Sylvian seemed patent. The pons was hypoplastic, due to volume reduction of the pontine prominence. The medulla oblongata was attenuated and no hindbrain herniation was detected. A membranous structure present at both lateral sides of the pons formed a large cyst, which occupied most of the normal-sized posterior fossa. Tentorial attachment and straight sinus were normal, as was the pattern of cortical gyri, the corpus callosum, the cerebral peduncle and aqueduct. The shape and relative proportions of the third ventricle and lateral ventricle were preserved with no hydrocephalus. In addition to CT and MRI findings, magnetic resonance angiography also demonstrated vascular characteristics of this patient consistent with complete cerebellar agenesis. The posterior inferior cerebellar artery, anterior inferior cerebellar artery and superior cerebellar artery were absent bilaterally, indicating an avascular posterior fossa. The basal artery, posterior cerebral artery and their branches were normal. Complete lack of the efferent and afferent limbs of the cerebellum was diagnosed by diffusion tension imaging analysis

With these findings, the patient was diagnosed with complete primary cerebellar agenesis...

Primary cerebellum agenesis, a rare condition marked by absence of the cerebellum, was first described by Combettes (1831). Only eight living cases have been reported prior to this study. The clinical presentation of primary cerebellum agenesis varies from degrees of cerebellar dysfunction and developmental delay at an early age. Oftentimes, primary cerebellum agenesis is diagnosed as Chiari malformation type IV, a condition defined by an incomplete or underdeveloped cerebellum. Primary cerebellum agenesis is associated with severe developmental anomies resulting in a high mortality rate; few reports on the subject have been published. The 24-year-old female we report, with mild mental retardation and cerebellar ataxia, was diagnosed with complete primary cerebellar agenesis based on CT and MRI scans. This patient presents with complete cerebellum agenesis with a complete lack of the efferent and afferent limbs of the cerebellum, a relatively normal-sized posterior fossa, a normal brain and spine without syringomyelia or encephalocele. This case is the ninth reported case of this diagnosis...

Most individuals with complete primary cerebellar agenesis are infants or children with severe mental impairment, epilepsy, hydrocephaly and other gross lesions of the CNS. In even more rare instances, adults have been discovered with apparent complete primary cerebellar agenesis, but detailed neurological descriptions of these findings in a living adult are lacking. Complete primary cerebellar agenesis diagnosis usually occurs by autopsy. Cerebellar deficiency arises very early in embryogenesis and the developmental plasticity and functional compensation with the remaining brain tissue is remarkable. In our case, complete absence of the cerebellum results in only mild to moderate motor deficiency, dysarthria and ataxia, although clearly present, were less than would be expected in completely absence of the cerebellum. This surprising phenomenon supports the concept of extracerebellar motor system plasticity, especially cerebellum loss, occurring early in life. In this series of nine living cases, three patients were male, six female. One patient was noted of consanguinity whereas others had no family history of genetic disorders and their siblings were reported as neurologically normal. All patients were related with uneventful pregnancy and delivery and blood count, chemistry and serological test were normal. Only one patient was completely normal in neurological examinations (three mental development normal). The other eight patients all showed cerebellar symptoms from motor, language to mental development...

The vascular changes induced by cerebellum malformations are not well characterized, and few data are available addressing the effect of complete primary cerebellum agenesis on the vascular system. Pascual-Castroviejo (1978) reported his study of arterial changes in different types of cerebellar defects and found that the posterior inferior cerebellar artery was hypoplastic or aplastic in a large number of cases. In cases of extremely severe cerebellar malformation with almost complete agenesis of the vermis and the hemispheres, the circulation is quite poor and the posterior fossa arteries are very thin. In this case, we find that all of the posterior circulation blood vessels, including the bilateral posterior inferior cerebellar artery, anterior inferior cerebellar artery and superior cerebellar artery, are completely defected. The conclusion that the severity of the posterior fossa’s vascular alterations is directly related to the degree of cerebellar hypoplasia, may be reasonable. At least, our case demonstrates this fact...

Congenital conditions that affect the cerebellum are not uncommon, the most common forms being the Dandy-Walker malformation and the Chiari malformation. Therefore, the differential diagnosis of primary cerebellum agenesis includes these two malformations. Dandy-Walker is easily diagnosed on the basis of the classic triad: (i) complete or partial agenesis of the vermis; (ii) cystic dilation of the fourth ventricle; and (iii) enlarged posterior fossa, with upward displacement of the transverse sinuses, tentorium and torcula. Also it may be accompanied by other developmental anomalies such as callosal agenesis, but the brainstem is normal. Chiari malformation, subdivided into four types, is a common malformation of the brain where the cerebellum protrudes into the spinal canal, causing many symptoms, mostly due to obstruction of CSF outflow. Type I, typically difficult to diagnose and not apparent oftentimes until adulthood, refers to elongation of the cerebellar tonsils forcing protrusion through the base of the skull. Type II includes the herniation of the cerebellar vermis, brainstem and fourth ventricle through the foramen magnum, associated with myelomeningocele and multiple brain anomalies. Hydrocephalus and syringomyelia are common, and the posterior fossa is often small. Type III, the most severe form of hindbrain herniation, covers cases with herniation of the cerebellum and brainstem into posterior encephalocele. Type IV is an extremely rare condition with few patients reported in the literature. It is characterized by loss of cerebellar development, hypoplasia, and reduced cerebellum size. It may occur as a rare autosomal recessive disease. Considering the previous descriptions of anatomical changes related to Chiari malformation IV, it is our opinion and conclusion that it actually represents primary cerebellar agenesis.

https://academic.oup.com/brain/article/138/6/e353/269537

Courtesy of: https://www.foxnews.com/health/woman-dizziness-missing-cerebellum

Let the baby die

The parents of an infant diagnosed with two rare birth defects said last week that they have been told to stop asking for money to cover medical bills and to just “let the baby die,” according to a report.

KC Ahlers said he posted six signs around the Franklin Park Mall in Toledo, Ohio, to spread awareness about an upcoming fundraiser for his 4-month-old son, RJ. The father told WTVG on Friday that he discovered three additional signs posted next to his that read: “Stop asking for money. Let the baby die. It’s called Darwinism. Happy Holidays.”

 “I came out. I saw it. Immediately took the one down. There were other ones that were up, but somebody, some other good Samaritans kicked them down,” Ahlers told the station.

Ahlers said his son was born with two rare birth defects. He was diagnosed with Agenesis of the Corpus Callosum, which affects brain development, and Mosaic Trisomy 9 Syndrome, a rare chromosomal disorder. Only about 50 percent of infants born with Mosaic Trisomy 9 Syndrome survive to age two, the father said.

The family raised $4,000 in an October fundraiser to pay for an expensive genetic test. Ahlers’ signs were meant to advertise a December 15 fundraiser to cover the cost of his son’s additional medical bills. The family’s GoFundMe page has raised more than $20,000 to fund treatments and tests from various specialists, some of which they say insurance has deemed “not medically necessary.” 

In response to the signs telling him to let his baby die, Ahler said, “We want to raise our son to not reciprocate hatred. We want to battle hatred with love.”

“We obviously know somebody that did this is disturbed and we hope they get help,” he continued. “But, we’re going to keep taking your signs down as we see them because this town doesn’t need hatred. This town needs love.”

https://www.foxnews.com/us/ohio-parents-let-baby-die-signs-birth-defect-genetic-disorder

See:  https://childnervoussystem.blogspot.com/2019/10/mosaic-trisomy-9.html

Variant EEF1A2 in a Rett syndrome‐like patient

Simranpreet Kaur,  Nicole J. Van Bergen1, Wendy Anne Gold,  Stefanie Eggers, Sebastian Lunke, Susan M. White,  Carolyn Ellaway, John Christodoulou. Whole exome sequencing reveals a de novo missense variant in EEF1A2 in a Rett syndrome‐like patient.  Clinical Case Reports. https://onlinelibrary.wiley.com/doi/epdf/10.1002/ccr3.2511

Abstract

Using whole exome sequencing, we found a pathogenic variant in the EEF1A2 gene in a patient with a Rett syndrome‐like (RTT‐like) phenotype, further confirming the association between EEF1A2 and Rett syndrome RTT and RTT‐like phenotypes. Using whole exome sequencing, we found a pathogenic variant in the EEF1A2 gene in a patient with a Rett syndrome‐like (RTT‐like) phenotype, further confirming the association between EEF1A2 and Rett syndrome RTT and RTT‐like phenotypes.

Courtesy of ResearchGate

Lopes F, Barbosa M, Ameur A, Soares G, de Sá J, Dias AI, Oliveira G, Cabral P, Temudo T, Calado E, Cruz IF, Vieira JP, Oliveira R, Esteves S, Sauer S, Jonasson I, Syvänen AC, Gyllensten U, Pinto D, Maciel P. Identification of novel genetic causes of Rett syndrome-like phenotypes. J Med Genet. 2016 Mar;53(3):190-9.

Abstract

BACKGROUND:

The aim of this work was to identify new genetic causes of Rett-like phenotypes using array comparative genomic hybridisation and a whole exome sequencing approach.

METHODS AND RESULTS:

We studied a cohort of 19 Portuguese patients (16 girls, 3 boys) with a clinical presentation significantly overlapping Rett syndrome (RTT). Genetic analysis included filtering of the single nucleotide variants and indels with preference for de novo, homozygous/compound heterozygous, or maternally inherited X linked variants. Examination by MRI and muscle biopsies was also performed. Pathogenic genomic imbalances were found in two patients (10.5%): an 18q21.2 deletion encompassing four exons of the TCF4 gene and a mosaic UPD of chromosome 3. Variants in genes previously implicated in neurodevelopmental disorders (NDD) were identified in six patients (32%): de novo variants in EEF1A2, STXBP1 and ZNF238 were found in three patients, maternally inherited X linked variants in SLC35A2, ZFX and SHROOM4 were detected in two male patients and one homozygous variant in EIF2B2 was detected in one patient. Variants were also detected in five novel NDD candidate genes (26%): we identified de novo variants in the RHOBTB2, SMARCA1 and GABBR2 genes; a homozygous variant in EIF4G1; compound heterozygous variant in HTT.

CONCLUSIONS:

Network analysis reveals that these genes interact by means of protein interactions with each other and with the known RTT genes. These findings expand the phenotypical spectrum of previously known NDD genes to encompass RTT-like clinical presentations and identify new candidate genes for RTT-like phenotypes.

Nusinersen updates

De Vivo DC, Bertini E, Swoboda KJ, Hwu WL, Crawford TO, Finkel RS, Kirschner J, Kuntz NL, Parsons JA, Ryan MM, Butterfield RJ, Topaloglu H, Ben-Omran T, Sansone VA, Jong YJ, Shu F, Staropoli JF, Kerr D, Sandrock AW, Stebbins C, Petrillo M, Braley G, Johnson K, Foster R, Gheuens S, Bhan I, Reyna SP, Fradette S, Farwell W; NURTURE Study Group. Nusinersen initiated in infants during the presymptomatic stage of spinal muscular atrophy: Interim efficacy and safety results from the Phase 2 NURTURE study. Neuromuscul Disord. 2019 Sep 12. pii:S0960-8966(19)31127-7.

Abstract

Spinal muscular atrophy (SMA) is a neurodegenerative disease associated with severe muscle atrophy and weakness in the limbs and trunk. We report interim efficacy and safety outcomes as of March 29, 2019 in 25 children with genetically diagnosed SMA who first received nusinersen in infancy while presymptomatic in the ongoing Phase 2, multisite, open-label, single-arm NURTURE trial. Fifteen children have two SMN2 copies and 10 have three SMN2 copies. At last visit, children were median (range) 34.8 [25.7-45.4] months of age and past the expected age of symptom onset for SMA Types I or II; all were alive and none required tracheostomy or permanent ventilation. Four (16%) participants with two SMN2 copies utilized respiratory support for ≥6 h/day for ≥7 consecutive days that was initiated during acute, reversible illnesses. All 25 participants achieved the ability to sit without support, 23/25 (92%) achieved walking with assistance, and 22/25 (88%) achieved walking independently. Eight infants had adverse events considered possibly related to nusinersen by the study investigators. These results, representing a median 2.9 years of follow up, emphasize the importance of proactive treatment with nusinersen immediately after establishing the genetic diagnosis of SMA in presymptomatic infants and emerging newborn screening efforts.

Pechmann, Astrid | Baumann, Matthias | Bernert, Günther | Flotats-Bastardas, Marina | Gruber-Sedlmayr, Ursula | von der Hagen, Maja | Hasselmann, Oswald | Hobbiebrunken, Elke | Horber, Veronka | Johannsen, Jessika | Kellersmann, Anna | Köhler, Cornelia | von Moers, Arpad | Müller-Felber, Wolfgang | Plecko, Barbara | Reihle, Christof | Schlachter, Kurt | Schreiber, Gudrun | Schwartz, Oliver | Smitka, Martin | Steiner, Elisabeth | Stoltenburg, Corinna | Stüve, Burkhard | Theophil, Manuela | Weiß, Claudia | Wiegand, Gert | Wilichowski, Ekkehard | Winter, Benedikt | Wittmann, Wolfgang | Schara, Ulrike | Kirschner, Janbernd  Treatment with Nusinersen – Challenges Regarding the Indication for Children with SMA Type 1.  Journal of Neuromuscular Diseases.  In press.

Abstract: 

The natural history of patients with spinal muscular atrophy (SMA) has changed due to advances in standard care and development of targeted treatments. Nusinersen was the first drug approved for the treatment of all SMA patients. The transfer of clinical trial data into a real-life environment is challenging, especially regarding the advice of patients and families to what extent they can expect a benefit from the novel treatment. We report the results of a modified Delphi consensus process among child neurologists from Germany, Austria and Switzerland about the indication or continuation of nusinersen treatment in children with SMA type 1 based on different clinical case scenarios.

Pechmann et al. Courtesy of ResearchGate

WWOX encephalopathy

Inspired by a patient

Yang C, Zhang Y, Song Z, Yi Z, Li F. Novel compound heterozygous mutations in the WWOX gene cause early infantile epileptic encephalopathy. Int J Dev Neurosci. 2019 Oct 24;79:45-48. doi: 10.1016/j.ijdevneu.2019.10.003. [Epub ahead of print]

Abstract

Defects of WW domain-containing oxidoreductase (WWOX) has been associated with autosomal recessive spinocerebellar ataxia type 12 (SCAR12) and severe early-onset epileptic encephalopathy. The mutations in this gene can lead to global developmental delay, acquired microcephaly, and epilepsy. We report an infant with an autosomal recessive severe early-onset epileptic encephalopathy. Whole exome sequencing analysis was applied to the patient. Novel compound heterozygous mutations in the WWOX gene, c.173-2A > G and c.775 T > C (p.Ser259Pro), were identified. The present study expands our knowledge of WWOX mutations and related phenotypes, and provides new information on the genetic defects associated with this disease for clinical diagnosis.

Mori T, Goji A, Toda Y, Ito H, Mori K, Kohmoto T, Imoto I, Kagami S. A 16q22.2-q23.1 deletion identified in a male infant with West syndrome. Brain Dev. 2019 Nov;41(10):888-893.

Abstract

In partial monosomy of the distal part of chromosome 16q, abnormal facial features, intellectual disability (ID), and feeding dysfunction are often reported. However, seizures are not typical and the majority of them were seizure-free. Here we present the case of a 16q22.2-q23.1 interstitial deletion identified in a male patient with severe ID, facial anomalies including forehead protrusions and flat nose bridge, patent ductus arteriosus, bilateral vocal cord atresia treated by tracheotomy, and West syndrome, which were developed 10 months after birth. Although phenobarbital, sodium valproate (VPA), and zonisamide were not effective as monotherapies or combination therapies, the patient's epileptic seizures and electroencephalogram anomalies disappeared following combined therapy with lamotrigine and VPA. Although WW Domain Containing Oxidoreductase (WWOX), which is known as a cause of autosomal recessive epileptic encephalopathy, was included within the 6.8-Mb deleted region which identified by targeted panel sequencing and validated by chromosomal microarray analysis, no pathogenic variants were detected in the other allele of WWOX. Therefore, it is possible that other genes within or outside of the long deleted region or their interactions may cause West syndrome in this patient.

Ben-Salem S, Al-Shamsi AM, John A, Ali BR, Al-Gazali L. A novel whole exon deletion in WWOX gene causes early epilepsy, intellectual disability and optic atrophy. J Mol Neurosci. 2015 May; 56(1):17-23.

Abstract

Recent studies have implicated the WW domain-containing oxidoreductase encoding gene (WWOX) in a severe form of autosomal recessive neurological disorder. This condition showed an overlapping spectrum of clinical features including spinocerebellar ataxia associated with generalized seizures and delayed psychomotor development to growth retardation, spasticity, and microcephaly. We evaluated a child from a consanguineous Emirati family that presented at birth with growth retardation, microcephaly, epileptic seizures, and later developed spasticity and delayed psychomotor development. Screening for deletions and duplications using whole-chromosomal microarray analysis identified a novel homozygous microdeletion encompassing exon 5 of the WWOX gene. Analysis of parental DNA indicated that this deletion was inherited from both parents and lies within a large region of homozygosity. Sanger sequencing of the cDNA showed that the deletion resulted in exon 5 skipping leading to a frame-shift and creating a premature stop codon at amino acid position 212. Quantification of mRNA revealed striking low level of WWOX expression in the child and moderate level of expression in the mother compared to a healthy control. To the best of our knowledge, this is the first homozygous germline structural variation in WWOX gene resulting in truncated transcripts that were presumably subject to NMD pathway. Our findings extend the clinical and genetic spectrum of WWOX mutations and support a crucial role of this gene in neurological development.

Peter B, Dinu V, Liu L, Huentelman M, Naymik M, Lancaster H, Vose C, Schrauwen I. Exome Sequencing of Two Siblings with Sporadic Autism Spectrum Disorder and Severe Speech Sound Disorder Suggests Pleiotropic and Complex Effects. Behav Genet. 2019 Jul;49(4):399-414.

Abstract

Recent studies of autism spectrum disorder (ASD) and childhood apraxia of speech (CAS) have resulted in conflicting conclusions regarding the comorbidity of these disorders on phenotypic grounds. In a nuclear family with two dually affected and one unaffected offspring, whole-exome sequences were evaluated for single nucleotide and indel variants and CNVs. The affected siblings but not the unaffected sibling share a rare deleterious compound heterozygous mutation in WWOX, implicated both in ASD and motor control. In addition, one of the affected children carries a rare deleterious de novo mutation in the ASD candidate gene RIMS1. The two affected children but not their unaffected sibling inherited deleterious variants with relevance for ASD and/or CAS. WWOX, RIMS1, and several of the genes harboring the inherited variants are expressed in the brain during prenatal and early postnatal development. Results suggest compound heterozygosity as a cause of ASD and CAS, pleiotropic gene effects, and potentially additional, complex genetic effects.

Medical mayhem 13

A South Dakota neurosurgeon made millions by performing unnecessary and invasive surgeries in order to profit from medical devices in which he had a financial interest, according to a federal complaint filed Wednesday.

Dr. Wilson Asfora carried out operations using medical devices he invented and also received kickbacks from other medical companies whose devices he used, all without disclosing the arrangement to patients, the Justice Department alleged in the lawsuit, which was obtained by the Argus Leader.

Asfora allegedly implanted the devices during complex spinal surgeries which should not have been performed, authorities say, alleging that the doctor "received numerous warnings that he was performing medically unnecessary procedures – which were ‘excessive,’ ‘quite aggressive,’ and went ‘against conventional neurosurgical teaching and practice’ – with the devices in which he had a financial interest.”

The federal complaint includes warnings from Asfora’s own lawyers and warnings from medical professionals that his behavior was illegal.

Asfora worked out of two Sioux City hospitals, Sanford Medical Center and the Sioux Falls Specialty Hospital. He sold the devices to the hospitals at enormous markups, meaning he made money for the surgeries he performed as well as the devices he used.

In one case Asfora allegedly told a medical device company he could increase the number of surgeries he performed. The complaint also alleges he went to great lengths to hide his conflicts with the hospitals.

As a result, Sanford Health will be required to hire an outside auditor to monitor the health system’s billing as part of an agreement reached with the federal government. The agreement allows Sanford to continue participating in Medicare and other federal programs, despite the claims against Asfora.

https://www.foxnews.com/us/south-dakota-doctor-made-millions-of-dollars-on-unneeded-dangerous-surgeries-feds-say

Eastern equine encephalitis and trick-or-treating

After this week’s thriller of a storm, fall is certainly here. Unfortunately, that doesn’t mean mosquitoes have quieted their activity.

Until the first hard frost of the season, a period of at least four consecutive hours of temperatures below 28 degrees, the threat of EEE (Eastern equine encephalitis virus), which is spread by mosquitoes, is still in the air. Which means some Massachusetts cities are reconsidering the times trick-or-treaters will be allowed on the streets, especially in communities still at critical risk.

Most communities deemed “high and critical” risk—such as Framingham, Sudbury, and Hopkinton, among others—have already made changes to regularly scheduled outdoor activities like school football games.

But as Halloween approaches and there’s still no sign of frosty temps, towns are looking at other ways to minimize risk. The mayor of Methuen, James Jajuga, announced on October 4, trick-or-treating will be limited from 4:30 p.m.-6 p.m. instead of the traditional hours of 5-7 p.m.

“Based on the weather projections for the rest of this month, it is unlikely that such a hard frost will happen before Halloween,” Jajuga said in a statement. “While no one welcomes this inconvenience, I will continue to prioritize the health and safety of the children and other residents of Methuen.”

Officials in Uxbridge, Easton, Carver, Grafton, and Brookfield—other communities in Massachusetts at high risk for the virus—are waiting a little longer before coming to a decision about changing the time. Jeffrey Landine, the chairman of the Brookfield Recreation Committee, said officials have been discussing contingency plans for Halloween, according to the Boston Globe.

This season alone, there have been 12 human cases of EEE reported and four deaths in the state of Massachusetts. The State Department of Public Health urges those in critical areas to be inside by 6 p.m. and to wear long pants and sleeves while outside in the evenings.

It’s rare to wish for the first hard freeze, but in this case, it would most certainly be welcomed.

https://www.bostonmagazine.com/health/2019/10/18/eee-trick-or-treaters-boston/

A Mineyko potpourri

Aleksandra Mineyko, Adam Kirton, Lori Billinghurst, Nana Nino Tatishvili, Max Wintermark, Gabrielle deVeber, Christine Fox on behalf of the SIPS Investigators.  Seizures and outcome one year after neonatal and childhood cerebral sinovenous thrombosis.  Pediatric Neurology.  In press.  https://doi.org/10.1016/j.pediatrneurol.2019.08.012

Abstract

Background

Pediatric cerebral sinovenous thrombosis (CSVT) is a treatable cause of brain injury, acute symptomatic seizures and remote epilepsy. Our objective was to prospectively study epilepsy and neurologic outcomes in neonates and children one year after CSVT diagnosis.

Methods

Patients with CSVT were enrolled prospectively from 21 international sites through the Seizures in Pediatric Stroke (SIPS) Study. Clinical data including acute symptomatic seizures and CSVT risk factors were collected at diagnosis. A blinded neuroradiologist reviewed acute imaging. At one year, outcomes including seizure recurrence, epilepsy diagnosis, anticonvulsant use, and modified Engel score were collected. Neurological outcomes were assessed using the modified Rankin score (mRS) and the King’s Outcome Scale of Childhood Head Injury (KOSCHI).

Results

Twenty-four participants with CSVT were enrolled (67% male, 21% neonates). Headache was the most common presenting symptom in non-neonates (47%, 9/19). Nine (37.5%) presented with acute symptomatic seizures. Six (25%; 95% CI = 10%- 47%) developed epilepsy by 1-year follow-up. No clinical predictors associated with epilepsy were identified. KOSCHI and mRS scores at 1 year were favorable in 71%. Half of CSVT patients who developed epilepsy (3/6) did not have infarcts, hemorrhage, or seizures identified during the acute hospitalization

Conclusion

Our study provides a prospective estimate that epilepsy occurs in approximately one quarter of patients by one year after diagnosis of CSVT. Later epilepsy can develop in the absence of acute seizures or parenchymal injury associated with the CSVT.

Courtesy of:  https://www.mdlinx.com/journal-summaries/pediatric-stroke-cerebral-sino-venous-thrombosis/2019/10/24/7582775?spec=neurology

Mineyko A, Kirton A. Long-Term Outcome After Bilateral Perinatal Arterial Ischemic Stroke. Pediatr Neurol. 2019 Aug 2. pii: S0887-8994(19)30587-9.  doi:10.1016/j.pediatrneurol.2019.07.013. [Epub ahead of print]

Abstract

AIM:

We aimed to characterize the phenotype and outcomes of children with bilateral, large vessel perinatal arterial ischemic stroke.

METHODS:

Patients with bilateral, large vessel perinatal arterial ischemic stroke were identified from a large, population-based cohort (Alberta Perinatal Stroke Project). Subjects were included if stroke involving a major cerebral artery territory was documented in both cerebral hemispheres on magnetic resonance imaging. Standardized variables were extracted from charts including clinical presentations, associated potential risk factors, and outcomes. Outcome measures included the Pediatric Stroke Outcome Measure, Gross Motor Function Classification System, and epilepsy frequency score. Electroencephalographies were reviewed for sleep, epileptiform activity, and background.

RESULTS:

Of 174 children with perinatal arterial ischemic stroke, eight (5%) had bilateral large artery infarcts. Patients were followed for a mean of 9.7 years (range 1.8 to 14.6 years). One child died. All children had a total Pediatric Stroke Outcome Measure of ≥2 (median 8, range 2 to 10) and Gross Motor Function Classification System ≥ II. Seven of eight (88%) children had a history of epilepsy.

CONCLUSIONS:

Children with bilateral, large vessel perinatal stroke are at high risk of severe cognitive and motor sequelae. Epilepsy may also be more common than unilateral strokes. Cautious discussions with families regarding prognosis are recommended.

Zika virus and Alice in Wonderland

The patient came to the clinic stating that 'she felt bewitched'", Venezuelan physician Dr Alberto Paniz Mondolfi told Medscape. She was a 15-year-old girl saying that she had "an enormous head and hands compared to the trunk, and complaining that she couldn't even drink water because she saw the glass either too close or too far from her mouth.

"Visual hallucinations were not restricted to the patient's body, they extended to family members and those around them. The teenager also presented with telopsia, when objects appear to be more distant than they actually are. She suffered numerous episodes throughout the day, and asymptomatic moments generated anxiety attacks," said the doctor.

With this combination of symptoms, the patient from the city of Barquisimeto, Venezuela, contacted the Department of Infectious Diseases and Tropical Medicine at the Barquisimeto Diagnostic Institute (BDI) where Dr Mondolfi works, because the visual hallucinations began 10 days after the young woman had symptoms corresponding to an acute Zika virus infection: fever of 39ºC (102.2°F), rash, distal arthralgia of the small joints, and dry conjunctivitis. After 3 days with symptoms and signs of Zika infection, the patient remained asymptomatic for 7 days, and only then developed the AIWS symptoms.

According to the literature, 65% of AIWS cases occur in children under 18 years. Among adults, it is more common that the syndrome is caused by migraine, while in children, the most common cause is an infection. AIWS has already been linked to several infections, including H1N1 influenza.

"In this case, we studied extensively all viruses that can manifest in the central nervous system (CNS). The results were negative for Epstein-Barr virus, herpes, varicella-zoster virus, enteroviruses, parasites, and all arboviruses, except Zika. The serologic test was positive, as well as the molecular confirmation in urine," replied Dr Mondolfi, who is also an assistant professor of microbiology at Icahn School of Medicine at Mount Sinai, in the United States.

As reported in the  Journal of NeuroVirology , this patient had neither relevant past medical history, nor history of migraine, epilepsy, neurological disorders, use of medication or recreational drugs. During the periods of symptom remission, neurological, neuro-ophthalmic, electroencephalogram (EEG), computed tomography (CT), toxicological, and metabolic profile panel tests were performed.

"Everything was normal. This is the first case of Zika virus-associated metamorphopsia. It is a clinical manifestation of the Zika virus that had not been described before," said Dr Mondolfi.

Fearing it was an undetected herpes virus infection, doctors prescribed aciclovir for the patient. And, even without evidence in this regard, but fearing that the adolescent might develop Guillain-Barré Syndrome, she also received intravenous immunoglobulin.

"Zika is a neurotropic virus, but the patient had already passed the acute period, and there was no evidence of further inflammation. As she was a teenager, I remembered a very rare disease, N-methyl-D-aspartate anti-receptor (NMDA) encephalitis, which is more common in women and has a combination of neurological symptoms caused by a benign ovarian tumour. But the antibody panel also turned out negative. That left us with no possibilities," said Dr Mondolfi. "The only thing left to think was that it could share the substrate with the NMDA encephalitis and that we were facing a case of molecular mimicry."

The team hypothesised that the Zika virus caused an injury, exposing the antigens, and that the antibodies, by molecular mimicry, joined the neurons of the somatosensory areas.

"We were the first to suggest the hypothesis of molecular mimicry," said Dr Mondolfi.

It was then that the team decided to treat the event as an NMDA anti-receptor encephalitis. "What we do in these cases is give steroids or filter the blood by plasmapheresis," he explained.

"The patient was treated with steroids and in the first week had a partial response, with a reduction in the number of episodes. This gave impetus to the idea of a possible explanation of autoantibodies and molecular mimicry. So, we decided to do plasmapheresis. In the second week, the patient had a complete recovery."

Dr Mondolfi acknowledges that he has no way of knowing what would have happened had he not given this treatment, "but anti-NMDA encephalitis rarely resolves spontaneously".

More Hidden Alices?

Dr Fragoso believes that the Alice in Wonderland syndrome may be much more frequent than imagined.

People may not mention these occurrences to their doctors, she said, "because they think it is spiritual". She continued: "So, when the results of the tests show nothing unusual, they leave the clinic without any explanation."

She tells how she experienced episodes herself, as a child: "My hand grew and grew, and I looked at people, but no one found it strange. So, I'd put them in my pocket so no one could see, but I thought that my hand did not fit inside," she said.

The important thing here, argues Dr Fragoso, is for doctors to be alert: "When a patient with such a complaint turns up, think that it may be a case of Alice in Wonderland Syndrome. So you need to be very thorough in history taking and evaluation, so that the patient knows (s)he can talk to the doctor, that (s)he will be given due attention."

https://www.medscape.com/viewarticle/920937

SMARCC2 mutations

Inspired by a colleague's patient

Machol K, Rousseau J, Ehresmann S, Garcia T, Nguyen TTM, Spillmann RC, Sullivan JA, Shashi V, Jiang YH, Stong N, Fiala E, Willing M, Pfundt R, Kleefstra T, Cho MT, McLaughlin H, Rosello Piera M, Orellana C, Martínez F, Caro-Llopis A, Monfort S, Roscioli T, Nixon CY, Buckley MF, Turner A, Jones WD, van Hasselt PM, Hofstede FC, van Gassen KLI, Brooks AS, van Slegtenhorst MA, Lachlan K, Sebastian J, Madan-Khetarpal S, Sonal D, Sakkubai N, Thevenon J, Faivre L, Maurel A, Petrovski S, Krantz ID, Tarpinian JM, Rosenfeld JA, Lee BH; Undiagnosed Diseases Network, Campeau PM. Expanding the Spectrum of BAF-Related Disorders: De Novo Variants in SMARCC2 Cause a Syndrome with Intellectual Disability and Developmental Delay. Am J Hum Genet. 2019 Jan 3;104(1):164-178.

Abstract

SMARCC2 (BAF170) is one of the invariable core subunits of the ATP-dependent chromatin remodeling BAF (BRG1-associated factor) complex and plays a crucial role in embryogenesis and corticogenesis. Pathogenic variants in genes encoding other components of the BAF complex have been associated with intellectual disability syndromes. Despite its significant biological role, variants in SMARCC2 have not been directly associated with human disease previously. Using whole-exome sequencing and a web-based gene-matching program, we identified 15 individuals with variable degrees of neurodevelopmental delay and growth retardation harboring one of 13 heterozygous variants in SMARCC2, most of them novel and proven de novo. The clinical presentation overlaps with intellectual disability syndromes associated with other BAF subunits, such as Coffin-Siris and Nicolaides-Baraitser syndromes and includes prominent speech impairment, hypotonia, feeding difficulties, behavioral abnormalities, and dysmorphic features such as hypertrichosis, thick eyebrows, thin upper lip vermilion, and upturned nose. Nine out of the fifteen individuals harbor variants in the highly conserved SMARCC2 DNA-interacting domains (SANT and SWIRM) and present with a more severe phenotype. Two of these individuals present cardiac abnormalities. Transcriptomic analysis of fibroblasts from affected individuals highlights a group of differentially expressed genes with possible roles in regulation of neuronal development and function, namely H19, SCRG1, RELN, and CACNB4. Our findings suggest a novel SMARCC2-related syndrome that overlaps with neurodevelopmental disorders associated with variants in BAF-complex subunits.

Martínez F, Caro-Llopis A, Roselló M, Oltra S, Mayo S, Monfort S, Orellana C. High diagnostic yield of syndromic intellectual disability by targeted next-generation sequencing. J Med Genet. 2017 Feb;54(2):87-92.

Abstract

BACKGROUND:

Intellectual disability is a very complex condition where more than 600 genes have been reported. Due to this extraordinary heterogeneity, a large proportion of patients remain without a specific diagnosis and genetic counselling. The need for new methodological strategies in order to detect a greater number of mutations in multiple genes is therefore crucial.

METHODS:

In this work, we screened a large panel of 1256 genes (646 pathogenic, 610 candidate) by next-generation sequencing to determine the molecular aetiology of syndromic intellectual disability. A total of 92 patients, negative for previous genetic analyses, were studied together with their parents. Clinically relevant variants were validated by conventional sequencing.

RESULTS:

A definitive diagnosis was achieved in 29 families by testing the 646 known pathogenic genes. Mutations were found in 25 different genes, where only the genes KMT2D, KMT2A and MED13L were found mutated in more than one patient. A preponderance of de novo mutations was noted even among the X linked conditions. Additionally, seven de novo probably pathogenic mutations were found in the candidate genes AGO1, JARID2, SIN3B, FBXO11, MAP3K7, HDAC2 and SMARCC2. Altogether, this means a diagnostic yield of 39% of the cases (95% CI 30% to 49%).

CONCLUSIONS:

The developed panel proved to be efficient and suitable for the genetic diagnosis of syndromic intellectual disability in a clinical setting. Next-generation sequencing has the potential for high-throughput identification of genetic variations, although the challenges of an adequate clinical interpretation of these variants and the knowledge on further unknown genes causing intellectual disability remain to be solved.

Immune evasion strategies used by Zika virus to Infect the fetal eye and brain

Nelson BR, Roby JA, Dobyns WB, Rajagopal L, Gale M Jr, Adams Waldorf KM. Immune Evasion Strategies Used by Zika Virus to Infect the Fetal Eye and Brain. Viral Immunol. 2019 Nov 5. doi: 10.1089/vim.2019.0082. [Epub ahead of print]

Abstract

Zika virus (ZIKV) is a mosquito-transmitted flavivirus that caused a public health emergency in the Americas when an outbreak in Brazil became linked to congenital microcephaly. Understanding how ZIKV could evade the innate immune defenses of the mother, placenta, and fetus has become central to determining how the virus can traffic into the fetal brain. ZIKV, like other flaviviruses, evades host innate immune responses by leveraging viral proteins and other processes that occur during viral replication to allow spread to the placenta. Within the placenta, there are diverse cell types with coreceptors for ZIKV entry, creating an opportunity for the virus to establish a reservoir for replication and infect the fetus. The fetal brain is vulnerable to ZIKV, particularly during the first trimester, when it is beginning a dynamic process, to form highly complex and specialized regions orchestrated by neuroprogenitor cells. In this review, we provide a conceptual framework to understand the different routes for viral trafficking into the fetal brain and the eye, which are most likely to occur early and later in pregnancy. Based on the injury profile in human and nonhuman primates, ZIKV entry into the fetal brain likely occurs across both the blood/cerebrospinal fluid barrier in the choroid plexus and the blood/brain barrier. ZIKV can also enter the eye by trafficking across the blood/retinal barrier. Ultimately, the efficient escape of innate immune defenses by ZIKV is a key factor leading to viral infection. However, the host immune response against ZIKV can lead to injury and perturbations in developmental programs that drive cellular division, migration, and brain growth. The combined effect of innate immune evasion to facilitate viral propagation and the maternal/placental/fetal immune response to control the infection will determine the extent to which ZIKV can injure the fetal brain.

Courtesy of ResearchGate