John J Millichap

John J Millichap
Northwestern University | NU · Department of Pediatrics

MD

About

265
Publications
23,195
Reads
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2,867
Citations
Citations since 2016
86 Research Items
1956 Citations
20162017201820192020202120220100200300400
20162017201820192020202120220100200300400
20162017201820192020202120220100200300400
20162017201820192020202120220100200300400
Additional affiliations
July 2011 - present
Ann & Robert H. Lurie Children's Hospital of Chicago
Position
  • Pediatric Epileptologist

Publications

Publications (265)
Article
Biallelic pathogenic variants in SZT2 result in a neurodevelopmental disorder with shared features, including early-onset epilepsy, developmental delay, macrocephaly, and corpus callosum abnormalities. SZT2 is as a critical scaffolding protein in the amino acid sensing arm of the mTORC1 signalling pathway. Due to its large size (3432 amino acids),...
Article
We identified six novel de novo human KCNQ5 variants in children with motor/language delay, intellectual disability (ID) and/or epilepsy by whole-exome sequencing. These variants comprised of two nonsense and four missense alterations, were functionally characterized by electrophysiology in HEK293/CHO cells, together with four previously reported K...
Article
Full-text available
This study assessed the effectiveness of genetic testing in shortening the time to diagnosis of late‐infantile neuronal ceroid lipofuscinosis (NCL) type 2 (CLN2) disease. Individuals who received epilepsy gene panel testing through Behind the Seizure® (BTS), a sponsored genetic testing program (Cohort A), were compared to children outside of the sp...
Article
Objective In a randomized trial, we aimed to evaluate the efficacy of cosyntropin injectable suspension, 1 mg/mL, compared to vigabatrin for infantile spasms syndrome. An additional arm was included to assess the efficacy of combination therapy (cosyntropin and vigabatrin) compared with cosyntropin monotherapy. Methods: Children (2 months to 2 year...
Article
Objective The MAST family of microtubule-associated serine–threonine kinases (STK) have distinct expression patterns in the developing and mature human and mouse brain. To date, only MAST1 has been conclusively associated with neurological disease, with de novo variants in individuals with a neurodevelopmental disorder, including a mega corpus call...
Preprint
Objective The MAST family of microtubule-associated serine-threonine kinases (STK) have distinct expression patterns in the developing and mature human and mouse brain. To date, only MAST1 has been associated with neurological disease, with de novo variants in individuals with a neurodevelopmental disorder, including a mega corpus callosum. Method...
Article
Full-text available
Mutations in KCNQ2, which encodes a pore-forming K+ channel subunit responsible for neuronal M-current, cause neonatal epileptic encephalopathy, a complex disorder presenting with severe early-onset seizures and impaired neurodevelopment. The condition is exceptionally difficult to treat, partially because the effects of KCNQ2 mutations on the deve...
Preprint
Biallelic pathogenic variants in SZT2 result in a neurodevelopmental disorder with shared features, including early-onset epilepsy, developmental delay, macrocephaly, and corpus callosum abnormalities. SZT2 is as a critical scaffolding protein in the amino acid sensing arm of the mTOR signaling pathway. Due to its large size (3432 amino acids), lac...
Article
Full-text available
Infantile Spasms (IS) is a devastating epilepsy syndrome that typically begins in the first year of life. Symptoms consist of stereotypical spasms, developmental delay, and electroencephalogram (EEG) that may demonstrate hypsarhythmia. Current therapeutic approaches are not always effective and there is no reliable way to predict which patient will...
Article
Full-text available
Objective We identified a novel de novo SCN2A variant (M1879T) associated with infantile‐onset epilepsy that responded dramatically to sodium channel blocker antiepileptic drugs. We analyzed the functional and pharmacological consequences of this variant to establish pathogenicity, and to correlate genotype with phenotype and clinical drug response...
Article
Somatic variants in tumor necrosis factor receptor–associated factor 7 (TRAF7) cause meningioma, while germline variants have recently been identified in seven patients with developmental delay and cardiac, facial, and digital anomalies. We aimed to define the clinical and mutational spectrum associated with TRAF7 germline variants in a large serie...
Article
Congenital disorders of glycosylation (CDG) are metabolic disorders that affect the glycosylation of proteins and lipids. Since glycosylation affects all organs, CDG show a wide spectrum of phenotypes. We present a patient with microcephaly, dysmorphic facies, congenital heart defect, focal epilepsy, infantile spasms, skeletal dysplasia, and a type...
Preprint
Objective We identified a novel de novo SCN2A variant (M1879T) associated with infantile-onset epilepsy that responded dramatically to sodium channel blocker antiepileptic drugs. We analyzed the functional and pharmacological consequences of this variant to establish pathogenicity, and to correlate genotype with phenotype and clinical drug response...
Article
Full-text available
In 2019, the mission of Pediatric Neurology Briefs (PNB) remains the same: "PNB is a continuing education service designed to expedite and facilitate the review of current scientific research and advances in child neurology and related subjects."
Article
Full-text available
Objective: Pathogenic variants in KCNB1, encoding the voltage-gated potassium channel KV 2.1, are associated with developmental and epileptic encephalopathy (DEE). Previous functional studies on a limited number of KCNB1 variants indicated a range of molecular mechanisms by which variants affect channel function, including loss of voltage sensitiv...
Article
Rationale: Early-life epilepsies (ELEs) include some of the most challenging forms of epilepsy to manage. Given recent diagnostic and therapeutic advances, a contemporary assessment of the immediate short-term outcomes can provide a valuable framework for identifying priorities and benchmarks for evaluating quality improvement efforts. Methods:...
Article
The wobble position in the anticodon loop of tRNA is subject to numerous post‐transcriptional modifications. In particular, thiolation of the wobble uridine has been shown to play an important role in codon‐anticodon interactions. This modification is catalyzed by a highly conserved CTU1/CTU2 complex, disruption of which has been shown to cause abn...
Article
Full-text available
Objective: We identified a novel de novo KCNT1 variant in a patient with early-infantile epileptic encephalopathy (EIEE) and status dystonicus, a life-threatening movement disorder. We determined the functional consequences of this variant on the encoded KNa 1.1 channel to investigate the molecular mechanisms responsible for this disorder. Method...
Article
Full-text available
The ketogenic diet (KD) is an effective treatment option for intractable epilepsy. Here, we reviewed the last 10 years of our experience with the KD and characterized its use in patients under 3 years of age. Medical records of all patients under the age of 3 years who were treated with the ketogenic diet from April 2004 to June 2014 were retrospec...
Article
Full-text available
Objective: Molecular genetic etiologies in epilepsy have become better understood in recent years, creating important opportunities for precision medicine. Building on these advances, detailed studies of the complexities and outcomes of genetic testing for epilepsy can provide useful insights that inform and refine diagnostic approaches and illumi...
Preprint
Full-text available
Pathogenic variants in KCNB1 , encoding the voltage-gated potassium channel Kv2.1, are associated with developmental and epileptic encephalopathies (DEE). Previous functional studies on a limited number of KCNB1 variants indicated a range of molecular mechanisms by which variants affect channel function, including loss of voltage sensitivity, loss...
Book
Full-text available
A Representative Collection of Previously Published Articles
Article
The occurrence of non-epileptic hyperkinetic movements in the context of developmental epileptic encephalopathies is an increasingly recognized phenomenon. Identification of causative mutations provides an important insight into common pathogenic mechanisms that cause both seizures and abnormal motor control. We report bi-allelic loss-of-function C...
Preprint
Mutations in KCNQ2, which encodes a pore-forming K+ channel subunit responsible for neuronal M-current, cause neonatal epileptic encephalopathy, a complex disorder presenting with severe early-onset seizures and impaired neurodevelopment. The condition is exceptionally difficult to treat, partially because the effects of KCNQ2 mutations on the deve...
Article
Full-text available
In 2018, the mission of Pediatric Neurology Briefs (PNB) remains the same: “PNB is a continuing education service designed to expedite and facilitate the review of current scientific research and advances in child neurology and related subjects.”
Article
Advances in gene discovery for neurodevelopmental disorders have identified SCN2A dysfunction as a leading cause of infantile seizures, autism spectrum disorder, and intellectual disability. SCN2A encodes the neuronal sodium channel NaV1.2. Functional assays demonstrate strong correlation between genotype and phenotype. This insight can help guide...
Article
Full-text available
Infantile spasms are the defining seizures of West syndrome, a severe form of early life epilepsy with poorly-understood pathophysiology. We present a novel comparative analysis of infants with spasms versus other seizure-types and identify clinical, etiological, and molecular-genetic factors preferentially predisposing to spasms. We compared ages,...
Data
Evaluations performed in infants with and without spasms. (DOCX)
Data
epiSEEK® comprehensive sequence analysis of epilepsy and seizure disorders (471 genes). (DOCX)
Data
List of genes with pathogenic variants and their association with spasms. (DOCX)
Data
Significant enriched gene sets of pathways, cellular compartments and molecular functions and corresponding descriptions, analyses statistical values, and compiled categories, from the mSigDB gene ontology-pathway (GO-pathway) analysis. (DOCX)
Article
Importance More than half of infants with new-onset epilepsy have electroencephalographic and clinical features that do not conform to known electroclinical syndromes (ie, nonsyndromic epilepsy). Levetiracetam and phenobarbital are the most commonly prescribed medications for epilepsy in infants, but their comparative effectiveness is unknown. Obj...
Article
Objective: The aim of this study was to investigate periictal central apnea as a seizure semiological feature, its localizing value, and possible relationship with sudden unexpected death in epilepsy (SUDEP) pathomechanisms. Methods: We prospectively studied polygraphic physiological responses, including inductance plethysmography, peripheral ca...
Article
Full-text available
Objective: Pathogenic SLC6A1 variants were recently described in patients with myoclonic atonic epilepsy (MAE) and intellectual disability (ID). We set out to define the phenotypic spectrum in a larger cohort of SCL6A1-mutated patients. Methods: We collected 24 SLC6A1 probands and 6 affected family members. Four previously published cases were i...
Article
Objective There are no evidence-based guidelines on the preferred approach to treating early-life epilepsy. We examined initial therapy selection in a contemporary US cohort of children with newly diagnosed, non-syndromic, early-life epilepsy (onset <3 years). Methods Seventeen pediatric epilepsy centers participated in a prospective cohort study...
Article
Full-text available
Background: We aimed for a comprehensive delineation of genetic, functional and phenotypic aspects of GRIN2B encephalopathy and explored potential prospects of personalised medicine. Methods: Data of 48 individuals with de novo GRIN2B variants were collected from several diagnostic and research cohorts, as well as from 43 patients from the liter...
Article
Objectives: To determine whether certain characteristic electroencephalography (EEG) features are indicative of a genetic cause in early-life epilepsy. Study design: We enrolled a total of 100 patients with infantile-onset (<3 years) epilepsy due to known genetic cause (n?=?50) and nongenetic cause (acquired, structural, or unknown, n?=?50). The...
Article
Background: In children with abnormal imaging, single-stage epilepsy surgery is an attractive alternative to the two-stage approach that relies on invasive recording of seizures. Implanted electrodes carry risks of their own and extend hospitalization, but the efficacy of one-stage resections in a variety of pathologies and cerebral locations is n...
Article
Between April 1, 2016, and September 30, 2016, Neurology® received 2,565 new and 650 revised manuscripts (compared to 2,366 new and 646 revised manuscripts during this same period in 2015). We received 4,461 peer reviews (compared to 4,645 during the same period in 2015) for these papers. We can accept only a minority of submitted manuscripts and m...
Article
Full-text available
Pediatric Neurology Briefs (PNB) has been published monthly since 1987 as a continuing education service designed to expedite and facilitate review of current medical literature concerning pediatric neurology.
Article
Epilepsy and intellectual disability are associated with rare variants in the GluN2A and GluN2B (encoded by GRIN2A and GRIN2B) subunits of the N-methyl-D-aspartate receptor (NMDAR), a ligand-gated ion channel with essential roles in brain development and function. By assessing genetic variation across GluN2 domains, we determined that the agonist b...
Article
Variants in KCNQ2 encoding for Kv7.2 neuronal K+ channel subunits lead to a spectrum of neonatal-onset epilepsies, ranging from self-limiting forms to severe epileptic encephalopathy. Most KCNQ2 pathogenic variants cause loss-of-function, whereas few increase channel activity (gain-of-function). We herein provide evidence for a new phenotypic and f...
Article
The Neurology® Resident & Fellow page was launched in 2004 by Berch Griggs, then the Editor-in-Chief of Neurology, and Karen Johnston, Associate Editor. The Editors envisioned a forum for trainees and educators to publish articles on topics relevant to residency and fellowship. Articles in this experimental page included clinical reviews and educat...
Article
Objective: Infantile spasms (IS) represent a severe epileptic encephalopathy presenting in the first 2 years of life. Recommended first-line therapies (hormonal therapy or vigabatrin) often fail. We evaluated response to second treatment for IS in children in whom the initial therapy failed to produce both clinical remission and electrographic res...
Article
Full-text available
Objective: To advance the understanding of KCNQ2 encephalopathy genotype-phenotype relationships and to begin to assess the potential of selective KCNQ channel openers as targeted treatments. Methods: We retrospectively studied 23 patients with KCNQ2 encephalopathy, including 11 treated with ezogabine (EZO). We analyzed the genotype-phenotype re...
Article
Submissions to the journal are increasing steadily. During the 6-month interval from October 1, 2015, through March 31, 2016, Neurology® received 2,608 new and 608 revised manuscripts (compared to 2,476 new and 600 revised manuscripts during this same period in 2014-2015). We received 4,344 peer reviews (compared to 4,264 during the same period in...
Article
Advances in genetic testing have led to the identification of increasing numbers of novel gene mutations that underlie infantile-onset epileptic encephalopathies. Recently, a mutagenesis screen identified a novel gene, SZT2, with no known protein function that has been linked to epileptogenesis in mice. Thus far, two clinical reports have identifie...